Abstract

In the modern world, the oral and transdermal routes are by far the most common means to administer exogenous estradiol and are widely used as a component of gender-affirming hormone therapy. Current clinical evidence shows no difference in feminising efficacy between these formulations at equivalent doses. Although both are well tolerated in general, the oral route is unphysiological in its metabolism and is associated with a significantly greater incidence of cardiovascular and thromboembolic complications. At low adult replacement doses, transdermal forms do not have these disadvantages and may be superior to their oral counterparts in feminisng hormone therapy.

Introduction

Estrogen replacement is both an important and necessary intervention for many transgender people (Hembree et al, 2017; Cheung et al, 2019). In the past, feminising therapy in this group was done using high dose estrogen monotherapy with parenteral esters of estradiol such as estradiol valerate or estradiol undecylate (Benjamin, 1967; Hamburger, 1969). Non-bioidentical oral estrogens such as conjugated equine estrogens and ethinylestradiol were also widely used (Meyer et al, 1986; Meyer, Walker and Suplee, 1989). However, with the significant progress made in drug development, bioidentical estradiol became widely available as oral and transdermal formulations for gender-affirming hormone therapy.
Today, some transgender individuals prefer to use injectable formulations of estradiol (Geffen et al, 2018). Nonetheless, the oral and transdermal routes of administration are used almost without exception for therapy in Europe and some other parts of the world and are probably most commonplace (Fisher and Maggi, 2015; Hamidi and Davidge-Pitts, 201930006-4/abstract); Seal, 2019). Many people receiving or eager to start hormone therapy may be interested to know what data exists regarding differences between oral and transdermal estradiol. As we require long-term therapy with these formulations, a discussion regarding adverse effects between these routes of administration may also be of importance. Although the focus of this review is largely on oral estradiol as compared with transdermal estradiol, a good amount of the discussion specific to transdermal estradiol can likely be extrapolated to other non-oral routes of administration when the doses have similar potency. For instance, estradiol administered by intramuscular or subcutaneous injection is a non-oral route of administration.

Pharmacology

Oral estradiol includes pill or tablet formulations, while transdermal estradiol is most commonly available as patches or gels (Kuhl, 2005). Oral estradiol and transdermal gel is usually administered once per day (Rohr, Volko and Schindler 2014). However, doses may be split and taken twice-daily. Theoretically, this would result in more stable estradiol levels, although is obviously less convenient. Estradiol pills may also be administered by the sublingual or buccal routes (Casper and Yen, 1981; Wren et al, 2003). Although some literature exists regarding their use for therapy in feminising hormone therapy, usage of these routes is probably still relatively rare in clinical practice (Jain, Kwan and Forcier 2019). In this review, I have used the term "oral estradiol" to refer only to the swallowing of estradiol tablets. Estradiol patches are applied and worn continuously. Different brands exist and transdermal patches are available for twice-weekly or weekly administration. A 50 μg/day dosage delivered by transdermal patch is considered to have similar potency to a 1 to 2 mg/day dosage of oral estradiol and to a 1.5 mg/day dosage of transdermal gel (Kuhl, 2005; Järvinen, Nykänen and Paasiniemi, 199900021-3)). However, as there is massive interindividual variability, these doses likely will not correspond to one another on an individual basis.
Estradiol is secreted by the ovaries into systematic circulation. As a result, the liver is not disproportionately exposed to the effects of the hormone (Gravholt et al, 2017). Transdermal estradiol is effective in mimicking this behaviour. However, orally administered estradiol, owing to passage through the gastrointestinal tract, is associated with disproportionate estrogenic exposure in the liver (Bińkowska, 2014). This behaviour gives rise to a number of differences between oral and transdermal estradiol. One such difference is that about 95% of oral estradiol is metabolised, as a consequence of the first pass effect, into estrone and other clinically weak/insignificant estrogens (Kuhz, Blode and Zimmermann, 1993). The ratio of estrone to estradiol is close to 1:1 in adult women and pubertal girls and with transdermal formulations (Kuhl, 2005; Frederiksen et al, 2020). However, with a dose of oral estradiol, postmenopausal women have been found to have about 5 times the concentration of estrone as estradiol (Kuhl, 2005). In some patients, the concentration of estrone may be 20 times higher than that of estradiol (Kuhnz, Gansau and Mahler, 1993). For this reason, the metabolism of oral estradiol has been described as unphysiologic (Gravholt et al, 2017; Mauras et al, 2019).

Efficacy

A subject of great interest to many transgender people taking feminising hormone therapy seems to be concerning which regimens might be most "effective". In particular, satisfactory breast development is often sought after. However, to date, no randomised controlled trials assessing the efficacy of different gender-affirming hormone regimens have been conducted (Reisman, Goldstein and Safer, 2019; Iwamoto et al, 2019). Moreover, there are no measures of breast development or other effects of transition that are universally agreed upon by the scientific community. For this reason, it is difficult to directly compare the findings of many studies.
Nonetheless, a number of observational studies have studied and quantified feminisation experienced with hormone therapy. In one prospective study, transgender women (n = 53) were treated with cyproterone acetate plus either oral or transdermal estradiol (Wierckx et al, 2014). It was noted that after 1 year, there was no apparent difference in physical measures such as breast circumference between the oral and transdermal groups. Another longitudinal and multicentre study of transgender women (n = 229) attending clinics in the Netherlands, Belgium and Italy also reported that the increase in breast-chest difference following 1 year of therapy did not differ between those using oral and transdermal formulations (de Blok et al, 2018). As a result of unsatisfactory development, many transgender women seek breast augmentation (Seal, 2016; de Blok et al, 2020). Although breast development itself was not measured, it is interesting to note that one retrospective study found no statistical difference in the rate of augmentation requests between users of different estrogen types (Seal et al, 2012). This suggests that oral estradiol valerate might be no more or less effective than the other estrogens in the study (oral conjugated estrogens and oral ethinylestradiol) in attaining a satisfying amount of breast development. Finally, it has been reported in a large cohort study of transgender women (n = 179) that percent changes in gynoid and android fat, total body fat and total lean body mass were not statistically different between the oral and transdermal estradiol groups if BMI and age were controlled for (Klaver et al, 2018).
Estrogen replacement, being a necessary therapy for the vast majority of individuals with Turner syndrome, has also been studied in adolescent girls (Gravholt et al, 2017; Klein and Phillips, 201930183-4/fulltext)). Girls treated with low dose oral estradiol (n = 56) were described in one study as having "similar" breast development to the normal Dutch population (Bannink et al, 2009). Other studies of puberty induction therapy have found that patients using low doses of transdermal estradiol gel (n = 21) and low dose intramuscular estradiol cypionate (n = 14) also all achieved breast Tanner stage 4 or 5 at final follow-up (Piippo et al, 2004; Rosenfield et al, 2005). A small randomised controlled trial of hypogonadal girls (n = 12) demonstrated that the response to oral and transdermal estradiol at comparable doses was near identical (Shah et al, 2014). All the girls receiving bioidentical estrogens achieved Tanner stage 3 or greater after 18 months of treatment, irrespective of route of administration. Interestingly, a cross sectional study of breast development in women with differences of sex development (DSD), including those with Turner syndrome, reported that breast satisfaction in the sample group was much lower than in women without a DSD (van de Grift and Kreukels, 2019). Some studies have found that breast development, in addition to breast satisfaction, seems to be poorer in Turner syndrome girls than in normal cisgender girls (Guo et al, 2019). Nevertheless, a recent review concluded that all these different regimens seemed to result in similar feminising outcomes (Klein et al, 2018).
In summary, current clinical evidence appears to show no difference in objectively measured outcomes between therapy with different routes of administration when the doses have comparable potency. Rather, when taken together, these findings indicate that the extent of breast development and other feminisation is independent of what route of administration is used (excerpts).

Safety and tolerability

In the past, estrogens in general have been associated with a greater overall incidence of adverse cardiovascular and thromboembolic events (Kuhl, 2005). These events can include deep vein thrombosis and myocardial infarction. Such complications of therapy have been attributed to estrogenic activity in the liver which, at sufficient exposure, causes an increased synthesis of liver proteins such as as sex-hormone binding globulin (von Schoultz et al, 1989; Ockrim, Lalani and Abel , 2006). Synthesis rates of lipids and coagulation factors have also been found to change. However, the type and route of administration of estrogen has been shown to modify risk (Olié, Canonico and Scarabin, 2011; Oliver-Williams et al, 2018).
Synthetic and non-bioidentical estrogens are more resistant to enzymatic metabolism by the liver and have disproportionate estrogenic effects relative to bioidentical estrogens such as estradiol (Kuhl, 2005). Because of this behaviour, they contribute to a much greater synthesis of liver proteins and are associated with a significantly higher risk of venous thromboembolism and other cardiovascular complications (Henriksson and Edhag, 1986; Kuhl, 2005; Lycette et al, 2006). A 2015 retrospective case-control study found that venous thromboembolism was 2 to 5 times more common in young women using combined oral contraceptives containing ethinylestradiol and other synthetic progestins than in non users (Vinogradova, Coupland and Hippisley-Cox, 2015). In 2019, the same authors published another case-control study; this time investigating women receiving hormone therapy at the menopause (Vinogradova, Coupland and Hippisley-Cox, 2019). A key finding was that low doses of oral estradiol (2 mg/day or less) were associated with a slight but significant increase in the incidence of venous thromboembolism, while low transdermal doses (100 μg/day or less) were not. This has also been reported by the ESTHER case-control and E3N cohort studies (Scarabin, 2014). Therefore, a strong advantage of transdermal estradiol over oral estradiol is that the incidence of venous thromboembolism is lower (Files and Kling, 2020). As with the synthetic estrogens, this difference is thought to be attributable to the disproportionate amount of estrogenic exposure in the liver that occurs with oral administration (Olié, Canonico and Scarabin, 2011). Nevertheless, high dose polyestradiol phosphate (160 to 240 mg/month) administered by intramuscular injection has been associated with significantly increased cardiovascular and thromboembolic morbidity and mortality in at least one large study of prostate cancer patients (Mikkola et al, 2005; Mikkola et al, 2007). While the increased incidence of these adverse events is clearly much lower than with oral estradiol, it is much less clear if it may be entirely eliminated by non-oral routes of administration at higher doses (further reading).
It is difficult to accurately determine the incidence of venous thromboembolism in transgender people receiving hormone therapy because of the diverse range of regimens employed in different geographical regions; which may confer different risks (Goldstein et al, 2019). Moreover, although a number of observational and retrospective studies have reported risk as low or relatively insignificant in our community, most are not adequately powered to accurately report risk (Khan et al, 2019). Based on the available evidence, we can probably safely assume that the incidence is low overall with modern regimens (Getahun et al, 2018; Ott et al, 201004661-X/fulltext); Pyra et al, 2020). It is particularly of note that these complications are, thankfully, mostly confined to people at higher baseline risk such as elderly individuals or those with inherited mutations that predispose to such toxicity (Silverstein et al, 1998; Bezgin et al, 2016). The absolute risk is likely low for most people. Nonetheless, the association between estrogens and adverse cardiovascular and thromboembolic events is of obvious importance. In the future, I intend on posting a more comprehensive evaluation of these complications with different doses and formulations of estrogens.

Summary and conclusions

In conclusion, oral and transdermal estradiol is metabolised differently. Perhaps most significantly, a dose of oral estadiol is predominantly converted by the liver into estrone and other estrogen metabolites before it enters circulation. By contrast, transdermal estradiol bypasses the liver and the conversion of the medication into these weak estrogens is mostly avoided. On average, a transdermal patch that delivers a 50 μg/day dose is thought to have similar estrogenic potency to a 1 to 2 mg/day dose of oral estradiol and to a 1.5 mg/day dose of transdermal gel.
In spite of these difference, there appears to be no evidence that oral estradiol provides more effective feminisation than transdermal estradiol or vice versa if the doses are similar. Instead, the existing clinical evidence seems to show that the extent of feminising changes such as breast development and fat distribution is independent of the route that estradiol is administered by. Contrariwise, there is a good amount of epidemiological evidence that oral estradiol is associated with a higher incidence of venous thrombosis than is transdermal estradiol at a comparable dose. For this reason, transdermal estradiol at physiological doses is likely safer than oral estradiol in long term gender affirming hormone therapy. I intend to discuss, in more detail, the subject of cardiovascular and thromboembolic toxicity with different doses and types of estrogens in a future review.

I made an evidence-based anti-vegan copypasta. Is there anything important missing?

Pastebin link with footnotes: https://pastebin.com/uXSCjwZK

Nutrition

Vegans lie to claim that health organizations agree on their diet:
1. There are many health authorities that explicitly advise against vegan diets, especially for children.
2. The Academy of Nutrition and Dietetics was founded by Seventh-day Adventists, an evangelistic vegan religion that owns meat replacement companies. Every author of their position paper is a career vegan, one of them is selling diet books that are cited in the paper. One author and one reviewer are Adventists who work for universities that publicly state to have a religious agenda. Another author went vegan for ethical reasons. They explicitly report "no potential conflict of interest". Their claims about infants and athletes are based on complete speculation (they cite no study following vegan infants from birth to childhood) and they don't even mention potentially problematic nutrients like Vitamin K or Carnitine.
3. Many, if not all, of the institutions that agree with the AND either just echo their position, don't cite any sources at all, or have heavy conflicts of interest. E.g. the Dietitians of Canada wrote their statement with the AND, the USDA has the Adventist reviewer in their guidelines committee, the British Dietetic Association works with the Vegan Society, the Australian Guidelines cite the AND paper as their source and Kaiser Permanente has an author that works for an Adventist university.
4. In the EU, all nutritional supplements, including B12, are by law required to state that they should not be used as a substitute for a balanced and varied diet.
5. In Belgium, parents can get imprisoned for imposing a vegan diet on children.
The supposed science around veganism is highly exaggerated. Nutrition science is in its infancy and the "best" studies on vegans rely on indisputably and fatally flawed food questionnaires that ask them what they eat once and then just assume they do it for several years:
1. Vegans aren't even vegan. They frequently cheat on their diet and lie about it.
2. Self-imposed dieting is linked to binge eating disorder, which makes people forget and misreport about eating the food they crave.
3. The vast majority of studies favoring vegan diets were conducted on people who reported to consume animal products and by scientists trained at Seventh-day Adventist universities. They have contrasting results when compared other studies. The publications of researchers like Joan Sabate and Winston Craig (reviewers and authors of the AND position paper, btw) show that they have a strong bias towards confirming their religious beliefs. They brag about their global influence on diet, yet generally don't disclose this conflict of interest. They have pursued people for promoting low-carbohydrate diets.
4. 80-100% of observational studies are proven wrong in controlled trials.
A vegan diet is not sustainable for the average person. Ex-vegans vastly outnumber current vegans, of which the majority have only been vegan for a short time. Common reasons for quitting are: concerns about health (23%), cravings (37%), social problems (63%), not seeing veganism as part of their identity (58%). 29% had health problems such as nutrient deficiencies, depression or thyroid issues, of which 82% improved after reintroducing meat. There are likely more people that quit veganism with health problems than there are vegans. Note that this is a major limitation of cohort studies on vegans as they only analyze the people who did not quit. (survivorship bias)
Vegans use appeals to authority or observational (non-causal) studies with tiny risk factors to vilify animal products. Respectable epidemiologists outside of nutrition typically reject these because they don't even reach the minimum threshold to justify a hypothesis and might compromise public health. The study findings are usually accompanied by countless paradoxes such as meat being associated with positive health outcomes in Asian cohorts:
1. Vegans like to say that meat causes cancer by citing the WHO's IARC. But the report actually says there's no evaluation on poultry/fish and that red meat has not been established as a cause of cancer. More importantly, Gordon Guyatt (founder of evidence-based medicine, pescetarian) criticized them for misleading the public and drawing conclusions from cherry-picked epidemiology (they chose only 56 studies out of the supposed 800+). A third of the committee voting against meat were vegetarians. Before the report was released, 23 cancer experts from eight countries looked at the same data and concluded that the evidence is inconsistent and unclear.
2. The idea that dietary raised cholesterol causes heart disease has never been proven.
3. Here's a compilation of large, government-funded clinical trials to oppose the claims made to blame meat and saturated fat for diabetes, cancer or CVD. Note that these have been ignored WHO and guidelines.
4. Much of the anti-meat push is coming from biased institutions like Adventist universities or Harvard School of Public Health who typically don't disclose their conflicts of interest. The latter conducted bribed studies for the sugar industry and was chaired by a highly influential supporter of vegetarianism for 26 years. He published hundreds of epidemiological anti-meat papers (e.g. the Nurses' Health Studies), tried to censor publications that oppose his views and wants to deemphasize the importance of experimental science. He has financial ties to seed oil, nut, fruit, vegetable and pharmaceutical industries and is part many plant-based movements like Blue Zones, True Health Initiative (Frank Hu, David Katz, Dean Ornish), EAT-Lancet and Lifestyle Medicine (Adventists, Michael Greger).
Popular sources that promote "plant-based diets" are actually just vegan propaganda in disguise:
1. Blue zones are bullshit. The longest living populations paradoxically consume the highest amount of meat. Buettner cherry-picks and ignores areas that have both high consumption of animal products and high life expectancies (Hong Kong, Switzerland, Spain, France, ... ). He praises Adventists for their health, but doesn't do the same for Mormons. Among others, he misrepresents the Okinawa diet by using data from a post WWII famine. The number of centenarians in blue zones is likely based on birth certificate fraud. The franchise also belongs to the SDA church now.
2. The website "nutritionfacts.org" is run by a vegan doctor who is known to misinterpret and cherry-pick his data. He and many other plant-based advocates like Klaper, Kahn and Davis all happen to be ethical vegans.
3. EAT-Lancet is pushing a nutrient deficient "planetary health diet" because it's essentially a global convention of vegans. Their founder and president is the Norwegian billionaire, hypocrite and animal rights activist Gunhild Stordalen. In 2017, they co-launched FReSH - a partnership of fertilizer, pesticide, processed food and flavouring companies.
4. The China Study, aka the Vegan Bible, has been debunked by hundreds of people including Campbell himself in his actual peer-reviewed publications on the study.
5. The Guardian, a pro-vegan newspaper that frequently depicts meat as bad for health and the environment, has received two grants totaling $1.78m from an investor of Impossible Foods.
A widespread lie is that the vegan diet is "clinically proven to reverse heart disease". The studies by Ornish and Esselstyn are made to sell their diet, but rely on confounding factors like exercise, medication or previous bypass surgeries (Esselstyn had nearly all of them exercise while pretending it was optional). All of them have tiny sample size, extremely poor design and have never been replicated in much larger clinical trials, which made Ornish suggest that we should discard the scientific method. Both diets included dairy.
Vegan diets are devoid of many nutrients and generally require more supplements than just B12. Some of them (Vitamin K2, EPA/DHA, Vitamin A) can only be obtained because they are converted from other sources, which is inefficient, limited or poor for a large part of the population. EPA+DHA from animal products have an anti-inflammatory effect, but converting it from ALA (plant sourced) does not seem to work the same. Taurine is essential for many people with special needs, while Creatine supplementation improves memory only in those who don't eat meat.
The US supplement industry is poorly regulated and has a history of spiking their products with drugs. Vitamin B complexes were tainted with anabolic steroids in the past, while algae supplements have been found to contain aldehydes. Supplements and fortified foods can cause poisoning, while natural products generally don't. Even vegan doctors caution and can't agree on what to supplement.
Restrictive dieting has psychological consequences including aggressive behavior, negative emotionality, loss of libido, concentration difficulties, higher anxiety measures and reduced self-esteem. There is an extremely strong link between meat abstention and mental disorders. While it's unknown what causes what, the vegan diet is low in or devoid of several important brain nutrients.
A vegan diet alone fulfills the diagnostic criteria of an eating disorder.
Patrik Baboumian, the strongest vegan on earth, lied about holding a world record that actually belongs to Brian Shaw. Patrik has never even been invited to World's Strongest Man. He dropped the weight during his "world record", which was done at a vegetarian food festival where he was the only competitor. His unofficial deadlift PR is 360kg, but the 2016 world record was 500kg. We can compare his height-relative strength with the Wilks Score and see that he is being completely dwarfed by Eddie Hall (208 vs 273). Patrik also lives on supplements. He pops about 25 pills a day to fix common vegan nutrient deficiencies and gets over 60% of his protein intake from drinking shakes.
Here's a summary on almost every pro athlete that either stopped being vegan, got injured, has only been vegan a couple of years, retired or was falsely promoted as vegan.
Historically, humans have always needed animal products and are highly adapted to meat consumption. There has never been a recorded civilization of humans that was able to survive without animal foods. Isotopic evidence shows that the first modern humans ate lots of meat and were the only natural predator of adult mammoths. Most of their historic technology and cave paintings revolved around hunting animals. Our abilities to throw and sweat likely developed for this reason. Our stomach's acidity is in the same range as obligate carnivores and its shape has changed so much from other hominids that we can't even digest cellulose anymore. The vegan diet is born out of ideology, species-inappropriate and could negatively affect future generations.
1. The cooked starch hypothesis that vegans use is inconsistent with many observations.
Compilations of nutrition studies:
1. Veganism slaughter house (80+ papers).
2. 70+ papers comparing vegans to non-vegans.
3. Scrolls and tomes against the Indoctrinated.
4. Zotero folder of 120+ papers.

Environment

Cow farts do not cause climate change. The EPA estimates that all agriculture produces about 10% of US greenhouse emissions, while animal agriculture is less than half of that. Other developed countries, like Germany, UK and Australia all have similarly low emissions. Vegans use global estimations that are skewed by developing countries with inefficient subsistence agriculture. Their main figure is an outdated and retracted source that compared lifecycle to direct emissions.
Many environmental studies that vegans use are heavily flawed because they were made by people who have no clue about agriculture, e.g. by the SDA church. A common mistake is that they use irrational theoretical models that assume we grow crops for animals because most of the plant weight is used as feed, The reality is that 86% of livestock feed is inedible by humans. They consume forage, food-waste and crop residues that could otherwise become an environmental burden. 13% of animal feed consists of potentially edible low-quality grains, which make up a third of global cereal (not total crop) production. All US beef cattle spend the majority of their life on pasture and upcycle protein even when grain-finished (0.6 to 1). Hence, UN FAO considers livestock crucial for food security and does not endorse veganism at all.
Plant-to-animal food comparisons are deceiving because animals provide many actually useful by-products that are needed for medicine, crop fertilization, clothing, pet food and public water safety. Vegans are in general very dishonest when comparing foods, as seen here where they compare 1kg of beef (2600 kcal, 260g protein) to 1kg of tomatoes (180 kcal, 9g protein). The claim that we could feed more people just with more calories is also wrong because the leading causes of malnutrition are deficiencies of Iron, Zinc, Folate, Iodine and Vitamin A - which are common and most bioavailable in animal products.
Vegan land use comparisons are half-truths that equate pastures with plantations. 57% of land used for feed is not even suitable for crops, while the rest is often much less productive. Grassland can sequester more carbon and has a four times lower rate of soil loss per unit area than cropland. Regenerative agriculture restores topsoil, is scalable, efficient and has high animal welfare. Big names like Kellogg are investing in it for long-term profit. On the other hand, removing livestock would create a food supply incapable of supporting the US population’s nutritional requirements due to lack of vitamin A, vitamin B12, vitamin D, calcium and fatty acids - while removing most animal by-products.
Water usage is possibly the most ridiculous way vegans deceive. The water footprint is divided into green (sourced from precipitation) and blue (sourced from the surface). Water scarcity is largely dependent on blue water use, which is why experts use lifecycle models. Vegan infographics always portray beef as a massive water hog by counting the rain that falls on the pasture. 96% of beef's water usage is green and it can even be produced without any blue water at all. The crops leading to the most depletion are wheat (22%), rice (17%), sugar (7%) and cotton (7%).
Going vegan won't do shit for the Amazon rainforest because the majority of Brazil's beef exports go to China and Hong Kong. The US or European countries each account for 2% or less. Soybean demand is driven by oil; the rest of the plant (80%) is a by-product that is exported as Chinese pig feed. Brazil is also a misrepresentative and atypical industry. Globally, cattle ranching accounts for 12%, commercial crops for 20% and subsistence farming for 48% of deforestation. The US use about half as much forest land for grazing than 70 years ago.
Livestock is not routinely supplemented with vitamin B12. Cows that consume cobalt (found in grass, which is free of B12) produce it with gut bacteria in the rumen. Gastrointestinal animals (including humans) initially can't absorb it, but instead excrete it and can then eat their own shit. B12 is in the soil because of excretions - ground bacteria exist but have never been shown to be the main source. Plants are devoid of B12 because competing bacteria consume it, not because of soil depletion. The "90% of B12 supplements go to livestock"-figure...
1. is bullshit that vegans keep on parroting. It originates from an article that calls humans herbivores, with no source.
2. ignores the fact that you can get B12 from seafood and venison. A can of sardines provides 3x the RDA.
3. is illogical because animals on unnatural diets can simply be given cobalt instead of the synthetic supplement that vegans rely on. Cows also destroy most of B12 in their gut before it can be absorbed.

Socioeconomics

Voluntary veganism is a privilege that is enabled by globalization and concentrated in first-world societies. Less than 1% of Indians are vegan. Jains, who are similar to vegans, are the wealthiest Indian community and even they still drink milk. In fact, India is a great example of why veganism doesn't work because they've religiously pursued it for thousands of years and still couldn't do it. Even Gandhi was an ex-vegan that had to warn them how dangerous the diet is.

Ethics

Veganism is a harmful ideology that promotes the abstinence from any "optional" animal suffering inflicted to support human health. For example, vaccines are not vegan. And just like meat, some people have already considered them unnecessary. Likewise, popular vegan communities also encourage people to put their carnivorous pets on a vegan diet to "avoid" cruelty. Hence, promoting animal rights is fundamentally anti-human because it will restrict or remove access to even the most basic needs, such as food or clothes. The only reason vegans are able to deny this is because they are pretending that the people who had to suffer for their ideology don't exist.
Vegans are not raising enough awareness about deficiencies and as a result harm innocent children. B12 deficiency can cause irreversible nerve damage, psychosis and is hard to notice. 10-50% of vegans say they don't even take any supplements.
Vegan diets are more dependent on slavery because they rely on global food supply. Many crops, especially cotton, nuts, oils and seeds that they have to include in higher quantities to make up for animal products are to a large extent child labor products from developing countries. 108 million children work in agriculture. Cheese replacements (guess who's responsible for that) are usually made with cashews, which burn the fingers of the women who have to remove the shells. A larger list of examples can be found here.
Vegans have never been able to define or measure that their diet causes less deaths/suffering than an omnivorous one. They are ignorantly contributing to an absolute bloodbath of trillions of zooplankton, mites, worms, crickets, grasshoppers, snails, frogs, turtles, rats, squirrels, possum, raccoons, moles, rabbits, boars, deer, 75% of insect biomass, half of all bird species and 20,000 humans per year. Two grass-fed cows are enough to feed someone for a year and, if managed properly, can restore biodiversity. The textbook vegan excuse where they try to blame plant agriculture on animals and use only mice deaths, fabricated feed conversion ratios of 20:1 and a coincidentally favourable per-calorie metric is nonsense because:
1. The majority of animal feed is either low-maintenance forage or a by-product that only exists because of human food harvest.
2. It literally shows that grass-fed beef kills fewer animals.
Vegans likely exploit more animals than the average person. The Vegan Society officially rejects beekeeping, but many commercial crops require to be pollinated by domestic bees that are forced to breed, shipped around and then worked to death. It's principally impossible to have a nutritionally complete vegan diet without forced pollination, but fodder crops do not exploit bees. As a result, human food crops kill five times as many bees as all livestock slaughter combined and directly support honey production (taking excess honey is necessary for colony health). Vegans should also call around and make sure that their seasonally changing food exporters don't rely on insects, terriers, sheep, ducks, organic fertilizers or anything from developing countries where animal labor is still common.
The ethical framework around veganism (negative utilitarianism) is so insane that its logical conclusion is to prevent as much life and biodiversity as possible in order to reduce suffering, which means it also favors Brazilian rainforest beef over crop cultivation. This line of thought is already followed by organizations like PETA who proudly state it to be their goal and will steal and euthanize other people's pets. Vegans reject appeals to nature when they are used to defend omnivorism, yet falsely assume that animals are more happy under the stress of natural selection. In contrast to livestock, wild animals are never guaranteed to receive shelter, protection, food, medical care, low stress or a quick death. Animal rights conflict with welfare because their goal is not to increase happiness, but just to oppose animal husbandry. Put differently, vegans pretend to support the wellbeing of animals, but can hardly even do so with their consumer power. What they are doing is more likely to kill off local ranchers and ensure a monopoly for Tyson/JBS, who are spearheading fake meat btw.
The average vegan is, based on their demographic, a New York hipster that has never seen a farm in their live. Animals are not being abused (This is one of the "factory farms" where 99% of animals come from). Undercover videos have often been staged by agenda-driven activists who get paid to apply for farm jobs and encourage animal abuse. The real industry has government-inspected welfare regulations. (Dominion straight up lies about pigs in slaugherhouses getting no water - it's required by law). Here's some actual industrial slaughterhouse footage of Beef, Turkey and Pork. For comparison, rodenticides are intentionally made to drain the life out of rats over three days so that they can't figure out what killed them.
Vegans love to misportray farm practises and anthropomorphize animals by giving them concepts that they don't care about, or even enjoy. Sexual coercion ("rape") is normal procreation and cows don't see a problem with it. They will even milk themselves when given the possibility. Pigs don't mind eating their own babies or getting shot. Even the myth that they are as intelligent as dogs comes from a questionable study made by animal rights advocates.
The reputation of vegans is based exactly on how they present themselves in public. Humans evolved to have predatory behaviour and as a result many people enjoy homesteading, hunting or fishing. Vegan activists frequently bother society and disrespect human biology - with thousands of years of history - for their arbitrarily chosen set of morals. There are actual animal rights terrorist groups that have sent bombs and stalked children, which they justify with it being done "in the name of veganism". Therefore, a very good reason to stay away from veganism is simply because someone doesn't want to be associated with a cult-like ideology.

Philosophy

The definition that vegans pride themselves with is a laughing stock because not only is it so loosely defined that it can be used to call everyone vegan, but it also shamelessly co-opts all the belief systems that have existed for much longer. According to this definition, Hindu, Buddhists, the Inuit and carnivores can all be called vegan, but are not following the diet and therefore considered impure (apparently caring about animals was invented by some British guy in 1944). Vegans are nothing more than people who abstain from animal products, in fact veganism was originally defined as a diet.
The misanthropic idea of "speciecism" was popularized by a nutjob philosopher who argues in favour of bestiality and belittles disabled people, but makes exceptions when it affects himself. Ironically, he eats animal products and calls consistent veganism fanatical. When it comes to the misanthropic aspect, animal rights activists themselves are the best example because they frequently insult minorities and crime victims by equating them to livestock with analogies to rape, murder, slavery or holocaust. The best part is that vegans are speciecists themselves because they justify their killing as "necessary for human survival" and still won't equate a cow to an insect.
Since vegans somehow manage to justify systematically poisoning and torturing insects by arbitrarily declaring that they can't suffer ("sentience"), they might aswell consider eating them. The same goes for bivalves, since there's about as much evidence that they feel pain as there is for plants.
A vegan diet itself is not even vegan under its own premises because it's not "practicable" to follow. It demands an opportunity cost of time, research and money that could be utilized in a better way and even then is not guaranteed to be efficient because it emphasizes purity. The entire following around veganism represents a Nirvana Fallacy and is the reason why the majority of people quit: Perfect is the enemy of good. A vegan diet makes it harder, and for many people impossible, to follow productive consumer approaches such as buying local, seasonal or supporting regenerative agriculture.

List of known nutrients that vegan diets either can't get at all or are typically low in, especially when uninformed and for people with special needs. Vegans will always say that "you can get X nutrient from Y specific source", but a full meal plan with sufficient quantities will essentially highlight how absurd a "well-planned" vegan diet is.

Vitamin B12
Vitamin B6 (Pyridoxal, Pyridoxamine)
Choline
Niacin (bio availability)
Vitamin B2
Vitamin A (Retinol, variable Carotene conversion)
Vitamin D3 (winter, northern latitudes, synthesis requires cholesterol)
Vitamin K2 MK-4 (variable K1 conversion)
Omega-3 (EPA/DHA; conversion from ALA is inefficient, limited, variable, inhibited by LA and insufficient for pregnancy)
Iron (bio availability)
Zinc (bio availability)
Calcium
Selenium
Iodine
Protein (per calorie, digestibility, Lysine, Leucine, elderly people, athletes)
Creatine (conditionally essential)
Carnitine (conditionally essential)
Carnosine
Taurine (conditionally essential)
CoQ10
Conjugated linoleic acid
Cholesterol
Arachidonic Acid (conditionally essential)
Glycine (conditionally essential)

Common vegan debate tactics/fallacies:

Nirvana fallacy: "There's no point in eating animal products because everything can be solved with a perfect vegan diet, supplements and genetic predisposition."
Proof by example: "Some people say they are vegan. Therefore, animal products are unnecessary."
Appeal to authority: Pointing to opinion papers written by vegan shills as proof that their diet is adequate.
No true Scotsman: "Everyone who failed veganism didn't do enough research. Properly planned vegan diets are healthy!" (aka not real Socialism)
Narcissist's prayer: "Everything bad that came out of veganism is fault of the world, not veganism itself."
No true Scotsman: "Veganism is not a diet, it's an ethical philosophy. No true vegan eats almonds, avocados or bananas ..."
Definist fallacy: "... as far as is possible and practicable." (Can be used to defend any case of hypocrisy)
Special pleading: "It's never ethical to harm animals for food, except when we 'accidentally' hire planes to rain poison from the sky." (You can trigger their cognitive dissonance by pointing that out.)
Special pleading: "Anyone who doesn't agree with my ideology has cognitive dissonance."
Appeal to emotion: Usage of words exclusive to humans (rape, murder, slavery, ... ) in the context of animals.
Fallacy fallacy: "Evolution is a fallacy because it's natural."
Texas sharpshooter fallacy: "A third of grains are fed to livestock. Therefore, a third of all crops are grown as animal feed."
False dilemma: "Producing only livestock is less sustainable than producing only crops, so we should only produce crops."
False cause: Asserting that association infers causation because it's the best data they have. ("Let's get rid of firefighters because they correlate to forest fires")
Faulty generalization: Highlighting mediocre athletes to refute the fact that vegans are underrepresented in elite sports.
JAQing off: This is how vegans convert other people. They always want them to justify eating meat by asking tons of loaded questions, presumably because nobody would care about their logically inconsistent arguments otherwise. Cults often employ this tactic to recruit new members. (They mistakenly call it the Socratic method)
Argument from ignorance: NameTheTrait aka "vegans are right unless you prove their nonsensical premises wrong". (It's essentially asking "When is a human not a human?")
Moving the goalposts: Whenever a vegan is cornered, they will dodge and change the subject to one of their other pillars (Ethics, Health, Environment or Sustainability) as seen here.
Ad hominem: Nit-picking statements out of context, attacking them in an arrogant manner, and then proclaiming everything someone says is wrong while not being able to refute the actual point. (see Kresser vs Wilks debate)

A Very detailed DD on $SESN (SESEN Biology)

What is Sesen Bio & what do they do?

They are a late-stage company developing fusion protein medicines. Their fusion protein approach tethers a tumor-targeting antibody fragment to a protein cytotoxic payload to form a single protein molecule designed to selectively and broadly kill cancer cells while minimizing toxicity to healthy cells and to activate the body’s innate immune response system.
In other words, they work to make a better treatment, one that kills cancer effectively in a way that does not harm normal healthy cells the same way traditional chemotherapy does.
Their key product is Vicinium for both:
- Head and neck cancer
- Cancer of the bladder

What is Vicinium?

Vicinium, also known as VB4-845, is an antibody-drug conjugate (ADC), developed for the treatment of high-grade non-muscle invasive bladder cancer (NMIBC). Vicinium is comprised of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of tumor cells to deliver a potent protein payload, Pseudomonas Exotoxin A (ETA). EpCAM has been shown to be overexpressed in NMIBC cells with minimal to no EpCAM expression observed on normal bladder cells.
The current standard/traditional form of treatment for bladder cancer at the moment is bacillus Calmette-Guérin (BCG) During phase 1 & 2 of clinical trials, Vicinium is proving to be more successful than the current standard form of treatment for Bladder Cancer. I will provide evidence for said statement soon.

** How successful is the current standard form of treatment(BCG) and how successful is Vicinium proving to be so far compared to BCG?**

According to this medical publication found on the government US National Library of Medicine website, it states that the current standard form of treatment which is "BCG", has upto 40% of people fail the treatment.
According to another medical publication posted on the same gov website, [the article states that Nearly three-fourths of patients](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773281) diagnosed with high-risk bladder cancer will recur, progress, or die within ten years of their diagnosis.
according to the preliminary findings of phase 3 of Vicinium trials, it goes to show that at the end of the 12month study:
- 40% of participants showed complete response rate to Vicinium
- 71% were recurrence free
- Overall survival rate at 12 months for those participating in the study is 98% (this just shows that currently on Vicinium, at the 12month mark, survival rate is at 98%. At the two year mark it could be the same or much lower, that statistic is unknown as of right now)
Here are links on what i have mentioned regarding phase 3 preliminary results
- Link 1
- Link 2
- Link 3
- Link 4

Significant Vicinium Press releases

In August 2018, SESN received Fast Track designation from the FDA for Vicinium for the treatment of high-risk NMIBC
In May 2019, SESN met with the FDA for a Type C meeting for CMC and reached agreement with the FDA on the analytical comparability plan to be used to assess comparability between the drug supply used in clinical trials and the potential commercial drug supply to be produced by Fujifilm.
In June 2019, SESN met with the FDA for a Type B Pre-BLA meeting regarding the approval pathway for Vicinium for the treatment of patients with high-risk, BCG-unresponsive NMIBC. At the meeting, we reached alignment with the FDA on an accelerated approval pathway for Vicinium along with Rolling Review
In November 2019, SESN met with the FDA for a Type C meeting to discuss the details of a post-marketing confirmatory trial for Vicinium for the treatment of high-risk NMIBC.
On December 4, 2019, SESN met with the FDA for a Type B pre-BLA meeting for CMC. At that meeting, we reached agreement with the FDA on the final content for Module 3 of the BLA.
On December 6, 2019, SESN initiated their BLA submission for Vicinium to the FDA under Rolling Review The submission consisted of Modules 1, 2, 4 and 5, with information amendments to be submitted to these modules throughout 2020. They anticipate completing Module 3 to finalize the BLA submission in the second half of 2020 (Q2).

Recent Financials (Q1 of 2020)

Their estimated EPS for the quarter according to the NASDAQ website was at -0.1 but they beat expectations and reported an EPS of 0.31
Net income was $41.6 million, or $0.31 per basic share and $0.31 per diluted share, for the three months ended March 31, 2020, compared to a net loss of $6.5 million, or $0.08 per basic and diluted share, for the same period in 2019
As stated in their most recent SEC Filings: "Based on our current operating plan, we anticipate having sufficient cash to fund our operations into 2021".

Manufacturing of Vicinium

In October 2018, SESN entered into a Master Bioprocessing Services Agreement with Fujifilm for the manufacturing process and technology transfer of Vicinium drug substance production.
In April 2019, the first full, commercial-scale cGMP run was completed at Fujifilm and all quality acceptance criteria were met. This supports Fujifilm’s ability to produce the bulk drug substance form of Vicinium for commercial purposes if we receive regulatory approval to market Vicinium for the treatment of high-risk NMIBC. Link
In February 2020, manufacturing of the pre-process performance qualification batch was completed at Fujifilm Full quality release testing of the drug substance has been completed and all quality acceptance criteria were met. In addition, the bulk drug substance from the Fujifilm pre-PPQ batch has been used to manufacture the first drug product PPQ batch by Baxter Oncology GmbH. Full quality release testing of the first drug product process performance qualification batch is currently underway.

Target Price & Forecasts

CNN money sets a median target price of $3, a low of $2.25 and a high estimate of $5
TipRanks sets a median target price at $3.63, a low of $2.25 and a high of $5
NASDAQ website sets a median target price of $3 and a high of $5

Risks involved

as requested, I will be providing a risks portion to my DDs
As stated in their recent SEC FIlings:
- "On March 2, 2020, we received written notice (the “Notice”) from The Nasdaq Stock Market, LLC (“Nasdaq”) indicating that we are not in compliance with the $1.00 minimum bid price requirement for continued listing on The Nasdaq Global Market, as set forth in Nasdaq Listing Rule 5450(a)(1). In accordance with Nasdaq Listing Rule 5810(c)(3)(A), we had a period of 180 calendar days, or until August 31, 2020, to regain compliance with the minimum bid price requirement. To regain compliance, the closing bid price of our common stock must meet or exceed $1.00 per share for a minimum of ten consecutive business days during this 180-day period." Link for this
Sesen Bio Received an extension and they have until November 12 2020 to reach compliance, if they do not they run the risk of delisting and would have to reapply to be listed on the Nasdaq market. If they do not come to compliance by then, they will "consider implementing available options to regain compliance with the minimum bid price requirement under the Nasdaq Listing Rules, including effecting a reverse stock split."

** Final thoughts and comments**

I believe that they will be approved by the FDA in the foreseeable future. Especially with the fact that they have been granted a fast track designation to approval of vicinium.
Not only that, but during their first quarter market research, data shows that Uruologists prefer Vicinium over Keytruda and traditional treatments. As stated by SESEN bio on their website: " The research revealed that, when prescribing a branded agent, Urologists would prescribe Vicinium to 83% of their patients compared to 17% for Keytruda" Link
I have personally invested 100 shares of SESN at the price of .78
I firmly believe they will reach to their low estimated price target due to all the science behind their work and the fact that they are currently debt free and have enough funds to last them through 2021.
As i always tell everyone, dont blindly buy stocks without doing your own research. I highly recommend that you do your own DD alongside reading all the material and links i have provided.
I do this so you, the reader, can have the best knowledge/information on a stock so you can , make a well informed decision before purchasing a stock.
Always remember, do not go all in on any stock, if you do, thats on you. Always purchase any stocks youre interested in with what you are comfortable spending
I hope this DD can help you make a well informed decision to either purchase or stay away from.
EDIT: I FORGOT TO MENTION THIS: Another reason why I believe in this stock & their flagship product is because there currently is a shortage of BCG. This shortage, alongside the fact Vicinium is expected to be approved sooner due to their fast track designation & successful manufacturing with partner Fujifilm, is why I truly do believe in this stock.
- Here are links regarding the shortage: Link 1 Link 2 Link 3 Link 4

Hope you guys enjoyed this DD and i hope it has helped you guys with making any decisions/answered questions regarding SESN.
Take care guys! :)

Photosynthesis boosted in plants, a musician makes music with artificial cells, and other things that happened This Week in Synthetic Biology

Every week, I compile the latest peer-reviewed research, preprints, and other news on genetic engineering and synthetic biology. This is the third week, and the response has been positive so far, so I will keep going!
***

Good morning. This week…

The New Yorker’s Raffi Khatchadourian wrote about Jackson Laboratory’s rapid shipments of “designer mice” for SARS-CoV-2 research, NewScientist covered a “radical new theory” on how life began on Earth, and CNN’s Milly Chan wrote a feature on Colorifix’s dyeing of fabrics with synthetic biology.
Meanwhile, the San Francisco Chronicle wrote about how proteins engineered to neutralize SARS-CoV-2 could soon show up in nose sprays, OneZero and Science Friday covered the first genetic edit in a squid, and Sarah Katz wrote a brilliant piece for Discover Magazine explaining why some deaf people oppose a CRISPR cure.
In industry news, Sherlock Biosciences announced a collaboration to launch CRISPR-based tests for SARS-CoV-2 and Mammoth Biosciences inked a deal for Doudna lab’s “miniature” Cas enzyme, CasΦ.

This week in research…

Listening to the Music of a Cell
Eduardo Reck Miranda is a professor of computer music at the University of Plymouth. In his latest paper, he introduces “a system for music composition informed by synthetic biology”, in which music is generated via simulations of various cellular processes, including transcription and protein folding. The study was published in Artificial Life.
E. coli 30875-8#articleInformation)Engineered to Grow Solely on Methanol30875-8#articleInformation) (They must be starving!)
At UCLA, the Liao lab has engineered E. coli to utilize methanol as its sole carbon source. With a paltry doubling time of 8.5 hours, the team began by using “metabolic robustness criteria” to engineer the strain, followed by laboratory evolution, and found that the final organism carefully balanced metabolic flux by tuning gene copy numbers and mutating key enzymes. The work was published in Cell.
Going Deeeep on the SARS-CoV-2 Receptor Binding Domain31003-5) (Open Access)
Researchers at the University of Washington and the Fred Hutchinson Cancer Research Center, in Seattle, have performed a deep-mutational scan on the SARS-CoV-2 receptor binding domain (RBD), the bit that binds to ACE2 on human cells. They created every single amino-acid substitution in the RBD, and show that, while most mutations are deleterious, some mutations enhance affinity for ACE2. The work was published in Cell.
Boosting Photosynthesis in Plants
At the University of Essex, the Raines lab inserted multiple genes, from red algae and cyanobacteria, into Nicotiana tabacum (tobacco) to stimulate both electron transport and Ribulose 1,5-bisphosphate turnover, increasing photosynthesis. The engineered plants also had an increase in above-ground biomass of up to 52% compared to controls. The study was published in Nature Plants. Read the press release.
E. Coli30363-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2451929420303636%3Fshowall%3Dtrue) Gets a 21st Amino Acid30363-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2451929420303636%3Fshowall%3Dtrue) (Open Access)
The Xiao lab at Rice University has engineered E. coli to both synthesize a 21st amino acid (5-hydroxyl-tryptophan, or 5HTP) and then site-specifically incorporate it into proteins. The team then used the engineered cell to “serve as a living indicator for reactive oxygen species”, as stated by Xiao in a Rice press release. The work was published in Chem.

More research…

A three-way combinatorial CRISPR screen for analyzing interactions among druggable targets31005-6) by Zhou, P. et al. in Cell Reports. (Open Access)
Application of CRISPR-Cas12a enhanced fluorescence assay coupled with nucleic acid amplification for the sensitive detection of African swine fever virus by Tao, G. et al. in ACS Synthetic Biology.
A versatile genetic control system in mammalian cells and mice responsive to clinically licensed sodium ferulate by Wang, Y. et al. in Science Advances. (Open Access)
Bacterial mock communities as standards for reproducible cytometric microbiome analysis by Cichocki, N. et al. in Nature Protocols.
Bacterial synthesis of C3-C5 diols via extending amino acid catabolism by Wang, J., et al. in PNAS.
Comprehensive study on Escherichia coli genomic expression: Does position really matter? by Goormans, A.R. et al. in Metabolic Engineering.
CRISPR-Cas13d Induces Efficient mRNA Knockdown in Animal Embryos by Kushawah, G. et al. in Developmental Cell. Read the press release.
De novo rational design of a freestanding, supercharged polypeptide, proton-conducting membrane by Ma, C. et al. in Science Advances. (Open Access)

Read the press release.

Read the press release.

Regulatory control circuits for stabilizing long-term anabolic product formation in yeast by D’Ambrosio, V. et al. in Metabolic Engineering. (Open Access)
Synthetic cross-phyla gene replacement and evolutionary assimilation of major enzymes by Sandberg, T.E. et al. in Nature Ecology & Evolution.

Read the press release, written by first author Troy Sandberg.

Synthetic protease-activated class B GPCRs by Willard, F.S. et al. in Biochemical and Biophysical Research Communications.
Unveiling of swainsonine biosynthesis via a multi-branched pathway in fungi by Luo, F. et al. in ACS Chemical Biology.

This week in reviews and commentary…

Cell-free approach for noncanonical amino acids incorporation into polypeptides by Cui, Z., Johnston, W. and Alexandrox, K. in Frontiers in Bioengineering and Biotechnology.
Computer-aided whole-cell design: Taking a holistic approach by integrating synthetic with systems biology by Marucci, L. et al. in Frontiers in Bioengineering and Biotechnology. (Open Access)
Engineering microbial diagnostics and therapeutics with smart control by Amrofell, M.B., Rottinghaus, A.G. and Moon, T.S. in Current Opinion in Biotechnology.
Heterologous biosynthesis as a platform for producing new generation natural products by Park, D., Swayambhu, G. and Pfeifer, B.A. in Current Opinion in Biotechnology.
Synthetic virus-derived nanosystems (SVNs) for delivery and precision docking of large multifunctional DNA circuitry in mammalian cells by Aulicino, F., Capin, J. and Berger, I. in Pharmaceutics. (Open Access)
Use of cell and genome modification technologies to generate improved “off-the-shelf” CAR T and CAR NK cells by Morgan, M.A. et al. in Frontiers in Immunology (Open Access)

This week in preprints…

An ultra-high affinity synthetic nanobody blocks SARS-CoV-2 infection by locking Spike into an inactive conformation by Schoof, M. et al. bioRxiv.

This preprint was also featured in a STAT News article.

Characterizing and controlling nanoscale self-assembly of suckerin-12 by Hershewe, J.M. et al. bioRxiv.
Coronacept - a potent immunoadhesin against SARS-CoV-2 by Cohen-Dvashi, H. et al. bioRxiv.
dCas9 regulator to neutralize competition in CRISPRi circuits by Huang, H. et al. bioRxiv.
DNA-based nanocarriers to enhance the optoacoustic contrast of tumors in vivo by Joseph, J. et al. bioRxiv.
Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions by Rombouts, J. and Gelens, L. bioRxiv.
Efficacy of Targeting SARS-CoV-2 by CAR-NK Cells by Ma, M.T. et al. bioRxiv.
Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2 by Walls, A.C. et al. bioRxiv.
Engineered sex distortion in the global agricultural pest Ceratitis capitata by Meccariello, A. et al. bioRxiv.
Rational engineering of Kluyveromyces marxianus to create a chassis for the production of aromatic products by Rajkumar, A.S. and Morrissey, J.P. bioRxiv.
Reproducibility in systems biology modelling by Tiwari, K. et al. bioRxiv.
Single-cell lineage and transcriptome reconstruction of metastatic cancer reveals selection of aggressive hybrid EMT states by Simeonov, K.P. et al. bioRxiv.
Systematic engineering of artificial metalloenzymes for new-to-nature reactions by Vornholt T, et al. bioRxiv.
Thanks for all of the positive feedback so far :D Happy reading.

The Next Pandemic: Confronting Emerging Disease and Antibiotic Resistance

Two problems not commonly discussed prior to the novel Coronavirus outbreak are the emergence of infectious disease and the related increasing prevalence of antimicrobial resistance. Here, I will explain the science behind these problems and some solutions that can be driven by legislation. My background is more squarely rooted in the science, so I apologize if I lean too heavily in this area as opposed to the economics and policy focus of this subreddit. I frequent this sub and enjoy the discourse here, and in my area this is one topic that overlaps with public health policy that I am passionate about.
To understand emerging disease and antimicrobial resistance, it’s important to understand evolution
The novel coronavirus, SARS-CoV2, is an example of an emerging infectious disease. SARS-CoV2 is a disease that, prior to 2019, had not to the best of our knowledge infected a human being. The genetic makeup of the virus indicates that the virus is natural, originating likely as a bat or pangolin Coronavirus that acquired the ability to infect humans, and that it is not man-made (1). Why do new diseases come into existence? Why haven’t humans encountered all the diseases capable of infecting us? Furthermore, why do diseases that we had previously thought conquered have the newfound ability to harm us again, in spite of our advancements in antibiotic development?
The answer to these questions is partially answered by evolution. Several novel viruses, like SARS-CoV1, MERS, and SARS-CoV2, began as zoonosis: infection by a pathogen with an animal source. Viruses, though generally considered non-living, contain nucleic acid genomes (either RNA or DNA) similar to every other organism in the tree of life. This genome is subject to selective pressures, just as with every other nucleic-acid containing being, and mutates non-specifically (that is, an organism develops a mutation, then selective pressures have a positive, negative, or neutral effect on retaining or discarding the mutation). An animal coronavirus that recognizes surface molecules on animal cells that have some similarity to human cell surface molecules may only be a few small genome changes away from being capable of infecting humans. It is likely that SARS-CoV2 emerged in one of two ways: as either an animal virus that mutated within an animal that gained the ability to infect humans, or as an animal virus that jumped to humans, and within the human host was selected for the ability to infect humans (1). The advent of novel viruses is also facilitated by the horizontal transfer of genetic material between distinct viral lineages. In Influenza viruses, this can take the form of segments of genome being transferred wholesale between viruses. Influenza viruses contain a genome composed entirely of RNA in multiple segments of sequence. Segments “re-assort” when flu viruses of distinct lineage infect the same cell, and viral genomes are mixed during the process of producing new viruses. Alternatively, as would be the case in coronaviruses, recombination occurs through a mechanism not fully understood, where whole portions of genome are exchanged between viruses (2).
The problem of antimicrobial resistance is also best understood through evolution. To explain this phenomenon, I will describe mainly how resistance manifests in bacteria, but similar processes drive resistance to anti-virals, anti-fungals, and anti-parasitics. Antibiotics are largely derived from natural sources: as microbes compete for resources, there is a drive to reduce competitors numbers by killing them or inhibiting their growth. Antibiotics are typically small molecules that target essential processes for bacterial growth; commonly cell wall biosynthesis (preventing growth and division of the cell, an example being penicillin), protein synthesis (blocks the process of translation, an example being erythromycin), production of RNA (blocks the process of transcription, an example being rifampin) or production of DNA (blocks the process of replication, an example being fluoroquinolone). These antibiotics arose through selective pressures, and in response bacteria have developed systems to circumvent the deleterious effects of antibiotics. These include: rapidly excreting the antibiotic before it is capable of inhibiting growth (efflux pumps, a notable offender being Pseudomonas aeruginosa, a common pathogen in patients with cystic fibrosis), degrading the antibiotic (beta-lactamases are a class of enzyme that degrade beta-lactam family antibiotics, such as penicillin), modifying the antibiotic (the most common mechanism for aminoglycoside resistance is to chemically modify the antibiotic so it doesn’t work), or simply modifying the target (Streptococcus pneumoniae is a microbe that causes multiple diseases that is naturally resistant to beta-lactams by modification of the drug target, the aptly-named Penicilin-binding protein) (3). As humans, it has been beneficial to identify these natural compounds and use them medically to treat infection.
Bacteria have incredible genome plasticity, engaging in a process known as horizontal gene transfer (HGT; sometimes referred to as lateral gene transfer) that increases the prevalence of resistant microbes. Not all bacteria are capable of this set of processes, but importantly several medically important pathogens, such as E. coli, Salmonella, Yersinia pestis, Acinetobacter baumannii engage in processes that facilitate the transfer of genetic material between bacteria. There are several molecular mechanisms for HGT: bacteria-infecting viruses can transmit pieces of genetic material between similar bacteria (transduction), bacteria can form a bridge that transfers plasmids (conjugation; plasmids are typically circular pieces of DNA, and are typically maintained independently of the bacterial chromosome and commonly encode antibiotic resistance genes), or bacteria can simply pick up naked DNA in the environment and integrate that DNA into their chromosomes (natural transformation) (3). The effect of these processes is that, when a gene that imparts resistance to a particular antibiotic is introduced into a population, it may spread between members of the population, not just within the progeny of the cells that encode the resistance gene. This is especially true when a gene that imparts resistance is on a plasmid or is otherwise mobilizable (transposons, or jumping genes, are also common perpetrators of transmission in that they move somewhat readily and often encode drug resistance). The key point to understand here is that while genes are present in bacteria, either on a chromosome or on a mobilizable element, these genes are capable of moving to many other members of the same population.
To understand this in more practical terms, many people have undergone a course of antibiotics and experienced gastrointestinal distress or stomach pains. This can be attributed to disturbing your normal intestinal microbiome, as you kill off non-resistant bacteria. Now assume you have an infection of some sort, it could be anywhere in your body accessible to an orally administered antibiotic, and your doctor prescribes you an antibiotic. It is possible, and possibly probable, that within your gut are bacteria that harbor resistance genes. In the absence of the antibiotic, these are likely to have a neutral or possibly deleterious effect; think of this like a welder that is unable to remove his welding mask: it certainly helps when he is welding, but is cumbersome at other times of the day. Taking the antibiotic results in high selection for resistant microbes to grow and prosper. This allows the resistant bugs to soon outnumber the non-resistant bugs. Ultimately, this increases the concentration of the resistance genes in the population of microbes in your gut. Subsequent to this, you may encounter an infection of a gastrointestinal pathogen that, in infecting your gut, acquires the resistance genes that you selected for. In disseminating this pathogen, you are also disseminating this resistance gene. Additionally, and perhaps more importantly, in taking antibiotics you select for drug resistance in the opportunistic pathogens of your body, notably Clostridium dificile and Staphylococcus epidermidis. These microbes are capable of causing disease, but reside in you or on you and cause infection when conditions are optimal for their growth.
The problem of antimicrobial resistance is convergent with emerging pathogens, as many pathogens “re-emerge” as they develop resistance to antimicrobials. While TB cannot be said to be an emerging pathogen as the world has been experiencing a TB pandemic since at least the early 1800’s, TB is re-emerging in the since that increased drug resistance has led to strains of TB that are not treatable via the traditional course of antibiotics (4). Similarly, common pathogens such as E. coli, Klebsiella, and Clostridium dificile are bugs that have become increasingly resistant to the antibitoics used to treat them (5). Acinetobacter baumanii, a soil microbe with resistance to a spectrum of antibiotics, became a common Gulf and Iraq War wound infection. Many of these pathogens find a home in hospitals, where the use of antibiotics is prevalent and potential hosts are abundant. Furthermore, the recently emerged pathogen HIV, the causal agent of AIDS, is intersectional with that of antibiotic resistance, as infection with HIV increases susceptibility to bacterial infections due to reduced immune cell numbers; increased infection rates of Both issues, antibiotic resistance and emerging pathogens, pose a threat to human health the world over, and I will attempt to address both of these issues in this post.
The problem of emerging disease and antibiotic resistance is exacerbated by humans
To what extent do emerging diseases and antibiotic resistance affect humans? SARS-CoV2 has had an extensive impact on human health and living, and the response to shut down to stop the spread of the virus has had a large economic impact. It is impossible to accurately predict the threat posed by non-discovered viruses, so the next threat could be relatively benign, or truly horrific. This is not to fearmonger, there is no reason to suspect that such a virus is bound to steamroll us soon, but to say that the next plague may be brewing inside a pig in a Chinese farm or outside our homes in the bodies of ticks, and we would not know it. The US Center for Disease Control and Prevention (CDC) has published two Antibiotic Resistance Threat reports on the subject, in 2013 and 2019. In the 2013 edition, it was reported that 2 million people in the United States will acquire an antibiotic resistant infection, and that 23,000 will die as a direct result of that infection (5). While by 2019 this was realized to be an underestimation of the drug-resistant cases, new approaches had determined that the true value had lowered from 2013 to 2019, with an updated estimate of 2.8 million cases and 35,000 fatalities in 2019 (6). An excellent illustration of the problem can be found on page 28 of the 2013 report, which reports the introduction date (left) and the date at which resistance was observed on the right for crucial antibiotic groups. Commonly, within a decade of the introduction of an antibiotic, resistance emerges. This problem cannot be expected to go away on its own, and more than likely pathogens commonly thought vanquished will re-emerge with drug-resistant characteristics.
There are human processes that contribute to the emergence of disease and spread of antibiotic resistance. In China, Wet Markets bring together livestock from all over the country, creating an environment that is diverse in the microbial life that live commensally and parasitically in and on these animals. The proximity of these animals allows for the exchange of these microbes; these microbes are then capable of exchanging genetic material. As I described for Flu and Coronaviruses, viruses that come into contact within cells are capable of genetic recombination, a process that can result in viruses that are capable of infecting humans. This is not to say this is a common phenomenon, just that 1) the process is accelerated by live animal markets and 2) this practice and resulting genetic recombination of zoonotic viruses is thought to have contributed to both the original and novel SARS-CoV outbreaks.
In the United States, a textbook example of an emerging disease is Lyme Disease (7). Named for the town of Lyme, Connecticut, Lyme Disease is caused by the peculiar bacterium known as Borellia burgdorferi. Borellia is a corkscrew-shaped bacteria that is interesting for its ability to grow without iron (a key component of the immune response is the sequestration of iron away from pathogens). Lyme Disease is spread through ticks, and the number of infectious cases is exacerbated by reforestation and settlement close to wooded areas in suburban environments. As building projects move closer to forested areas, exposure to arthropod-borne illnesses will be expected to rise.
Beyond settlement and the wet market practice, the emergence of new infectious disease is complicated by global warming and healthcare practices. Global warming is hypothesized to drive heat resistance in fungi, potentially improving their capacity to grow within the human body (8). The pathogenic potential of fungi is hypothesized to be limited by the heat of the human body, and there is some speculation that global warming is a contributing factor to the emergence of the notorious fungal pathogen Candida auris (8). These claims should be taken with a grain of salt and evaluated critically, but it is possible that human-caused climate change will disturb the ecology of our planet with as of yet unforeseen consequences, among them the generation novel and resurgent diseases.
In healthcare, over-prescription of and a lack of regulation on antibiotics has caused the problem to worsen (5,6). When a patient receives an antibiotic, the drug has an effect on all microbes where the drug is bioavailable. This includes the intestines, which contain a resident population of microbes, and the skin, which contains Staphylococci resident species that prevent colonization by pathogenic strains of similar bacteria. These residents are then selected for their ability to resist the drug, causing an increase in resistance among the healthy microbiota. These resistance genes, as I have described, can then move between dissimilar bacteria in the same environment. If a harmful strain of E. coli is introduced into such an environment, for example, it has a higher likelihood of encountering and assimilating the genetic potential to resist antibiotics than in an environment that is naïve to the antibiotic. Patients are commonly prescribed antibiotics for infections that are more likely to be caused by a virus, or in instances where an infection is likely to run course without medical intervention. The increased exposure to antibiotics causes the microbiota to increase the concentration of resistance genes. Additionally, in places like India, the regulations on antibiotics are much more laxed than even the United States, where one is able to purchase over-the-counter antibiotics. This allows anyone to give themselves an incomplete course of antibiotics for any condition, even if the symptoms are not caused by an infection of any kind. Additionally, prescription antibiotics that have deteriorated with time, or are manufactured with subpar quality control resulting in lower concentrations, that remain in circulation exacerbate the problem by establishing sub-inhibitory concentrations of the antibiotic in the body and resulting in selection for resistance. Furthermore, environmental pollution of antibiotics into natural water sources and sewage results in increased environmental concentrations of resistance genes. These genes can spill into humans by exposure to microbes in these environments (9).
Agriculture provides another increase in the concentration of resistance genes (10). Livestock are fed antibiotics, which increase the weight of animals in an as-of-yet not understood mechanism. A deleterious consequence of this increase in yield with antibiotic usage is the increase in resistance in response to this widespread antibiotic usage. These resistance genes then find their way into humans, whether through ingestion of food contaminated with resistant microbes.
Science and technology can solve the problem, but face institutional and biological challenges
There are both institutional and scientific challenges to combating emerging disease and antibiotic resistance. Some of these problems are easily apparent as I have described above: countries with laxed restrictions on who can obtain antibiotics, countries where the drugs are used often over-prescribed, suburbanization, and global warming all contribute to the problem.
Scientifically, there are challenges in that novel diseases are difficult to combat. The novel Coronavirus had the precedent of other coronaviruses (i.e. SARS and MERS) that had been studied and their virology dissected, but that won’t necessarily be the case everytime a novel pathogen infects a human. A technological benefit to this problem is the use of meta-genomics, which allows for DNA/RNA sequencing without prior knowledge of the nucleic acid sequence of the genome. Within weeks of the first identification of the virus, its sequence was available to researchers. This was not the case during the outbreak of SARS-CoV1, when meta-genomics approaches such as Illumina Sequencing, NanoPore Sequencing, and Pacific Biosciences Sequencing were not available. In the event of a novel disease emergence, this information would be vital to combating the pathogen.
Despite not knowing necessarily what the next threat will be, expanding the human knowledge base on microbes is an essential component of any plan to fight emerging diseases. Any emerging disease is likely to be similar to other microbes that we have encountered, and knowledge of the physiology of these organisms helps to understand weaknesses, transmission, and potential therapeutic targets. The study of all microorganisms therefore benefits the effort to combat the next pandemic, as any one piece of information could be critical.
Surveillance is perhaps the most important tool to fight emerging infectious disease; knowing the problem exists is a crucial step to curbing spread. A recent example of successful surveillance can be seen in a recent PNAS publication regarding the presence of potential pandemic influenza in hogs, and the presence of antibodies against this particular class of flu viruses in swine workers (11). While at present it does not appear that the virus has acquired the ability to cause a pandemic, this knowledge allows for immunologists to potentially include viral antigens specific to this particular viral class in seasonal vaccines. Surveillance is critical in controlling both emerging diseases and antibiotic resistance: knowledge of what potential pathogens emerge where, and what microbes are exhibiting resistance to what drugs, can drive containment and treatment efforts.
To combat antibiotic resistance, new drugs must be developed, but there are hurdles in identification, validation, and production of new antibiotics. First, potential new antibiotics have to be either identified or designed. This often involves looking through filtered environmental samples to determine the presence of small molecules that inhibit bacterial growth, or chemically altering known drugs to circumvent drug resistance. This is not necessarily difficult, as there are microbes in the soil and water that produce potential therapeutics, but this does require both time and money, as well as the consideration that it is likely that resistance to that novel therapeutic exists in the environment from which it was pulled. New drugs must be safe, but due to the abundance of antibiotics presently in use and their historic efficacy, the standard for antibiotics to pass safety regulations is extremely high. As drug resistance becomes more common, it will become apparent that more and more side effects may have to be tolerated to prevent death due to bacterial infection. Finally, and the most important challenge to developing antibiotics is that the profit margin on antibiotics is low for drug companies in the present market, disincentivizing research and production of novel drugs.
In addition to stand-alone antibiotics, new inhibitors of resistance must be developed as well. Clavulanic acid is one such inhibitor, and is administered with the beta-lactam drug amoxicillin to improve its ability to kill bacteria. Bacteria that are resistant beta-lactams often encode enzymes called beta-lactamases. Beta-lactamases break open the active portion of the beta-lactam molecule, rendering it ineffective in attacking its target. Clavulanic acid is a beta-lactam itself, and is a target for the beta-lactamase enzyme; however, when the enzyme begins to degrade clavulanic acid, the enzyme becomes stuck at an intermediate step in the reaction, rendering the beta-lactamase enzyme useless. These drugs must also be explored and screened for in environmental samples, as well as developed. It is possible to take a rational approach to drug design, with increasing knowledge of how resistance mechanisms work. This means that scientists specifically look at, say, a beta-lactamase enzyme at the molecular level, and design a small molecule that will fit into the enzyme and block its function. Chemists then design the molecule to test its efficacy.
Ultimately, scientists either know how to solve the problem, or know how to get the tools they need to solve the problem. It is the institutional challenges that make the problem more difficult to solve.
How legislation can improve the ability of scientists to combat emerging disease and drug resistance
In discussing emerging diseases and antibiotic resistance, I try to draw parallels to the problem of global warming: a global problem with global solutions. I don’t have a novel solution to climate change to discuss here, other than to parrot this subreddit’s typical ideas, so I will omit that discussion here. That is to say, global warming is a driver for emerging infectious disease, and fighting global warming is important to combat the potential rise of fungal pathogens. I will, however, discuss some ideas for combating emerging disease and drug resistance. These ideas are mostly derived from scientists familiar with the problem,
Funding for research, basic and applied, is crucial. No bit of knowledge hurts in the fight against human disease. Learning how Alphaviruses replicate, determining the structure of E. coli outer membrane proteins, and examining the life cycle of the non-pathogen Caulobacter crescentus all contribute to the fight against the next disease. The more we know, the more powerful our vision is in understanding the inner machinations of disease. Every immune response, every molecular mechanism, and every aspect of microbial physiology is potentially a drug or vaccine target, a clue into pathogenesis, or an indication of how a bug is likely to spread. The Trump administration has not been kind to science funding (12). Science that does not appear to have benefit at first glance often does in the long run, and for this reason I will stress the importance of funding research of this sort, as well as funding applied research.
Knowing is half the battle. In combating emerging diseases, it is important to know they exist. As I have mentioned the example of recent viral surveillance with regard to the novel reassortment influenza viruses, I would like to stress the importance of funding surveillance programs in fighting emerging disease and drug resistance. There are currently US governmental surveillance programs that provide valuable information about the spread of drug resistance, such as NARMS in the United States (13).
In the United States, there is a need for greater accountability in using antibiotics. Resistance is unlikely to completely go away, even when the use of an antibiotic is discontinued, but the levels of resistant bacteria dwindle when the selective pressure is reduced. For this reason, several medical practitioners have proposed a rotating schedule of prescription antibiotics, that includes the retention of some new antibiotics from use. The reasoning for this is that, in the years following the halted use of a particular antibiotic, it is expected that the concentration of resistant bacteria will decrease. As I discussed with the example of always wearing a welding helmet, carrying resistance genes often imparts some form of growth defect on the resistant bacteria (for example, altering an essential gene targeted by an antibiotic may render the bacteria resistant, but there is a reason such a gene is essential, in that it’s required for growth; changing the gene in a substantive way may negatively impact its performance and by extension make these resistant bacteria less fit). A rotating cycle of what antibiotics are allowed to be prescribed, informed by surveillance data, would buy time for the development of new antibiotics as well. Additionally, higher standards should be required for the prescription of antibiotics, to increase accountability of physicians; these standards could involve clinically verifying the presence of susceptible bacteria prior to administering a drug in situations where the disease in not life-threatening.
There is a need to reduce the environmental pollution of drugs into sewage and natural bodies of water as well. This will require research into cost-effective methods for reducing the population of resistant bugs and drugs in these environments. In the case of natural bodies of water, a source of contamination is often factories where drugs are produced. Often, waters near these factories have high levels of antibiotics that select for resistance to develop and spread. This may require legislation to improve environmental outcomes, as well as surveillance of drug resistance gene levels and the levels of antibiotics in these waters to ensure compliance.
There is also a need to halt the use of antibiotics in treating livestock (14). Halting the use of antibiotics typically results in reductions of antibiotic resistant bug populations within a year or two (10). I don’t know of studies that estimate the economic cost of halting use of antibiotics in American meat, but in the case of Denmark, livestock production does not appear to have been significantly impacted.
I think that the most challenging problem will be for drug companies to develop new antibiotics when there is not presently a financial incentive to do so. Because antibiotics are still largely effective, and the financial benefit to adding an antibiotic to the market does not outweigh the cost to put a drug to market, there is not currently a large incentive to produce new drugs (15). To address this negative externality, it is necessary to generate financial incentives of some form for the production of new antibiotics. This may take the form of subsidizing antibiotic discovery efforts and drug safety trials; additionally, applied research with the goal of specifically finding new antibiotics should see increased funding.
To combat the problem overseas, it is obvious that obtaining an antibiotic course must occur through a doctor. This eliminates false self-diagnoses of bacterial infections. The problem of wet markets may be partially resolved by preventing animals that do not regularly contact each other from being traded and stored in the same vicinity as animals that are not typically encountered. This may involve limiting a particular wet market to the trade of animals that come from a particular geographic area, preventing geographically diverse microbes from encountering each other.
It's on all of us to stop the next pandemic:
If you made it this far, thank you reading this post and I hope that I have convinced you of the importance of this issue! There are simple steps that we can all take as consumers to reduce antimicrobial resistance: don’t take antibiotics unless prescribed by a doctor and buy meat that was produced without antibiotics. I welcome any and all criticism, and would love to hear people's ideas! Please let me know of any errors as well, or any missed concepts that I glossed over. I've been excited to give my two cents to this sub, and I don't want to mislead in any way.
Sources:
1: Andersen, KG, et al. 2020. The Proximal Origin of Sars-CoV-2. Nature Medicine 26: 450-452.
2: Su, Shou, et al. 2016. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Cell Trends in Microbiology 24(6): 490-502. https://doi.org/10.1016/j.tim.2016.03.003
3: Munita, JM; Arias, CA. 2016. Mechanisms of Antibiotic Resistance. Microbiology Spectrum VMBF-0016-2015. doi:10.1128 /microbiolspec.VMBF-0016-2015.
4: Shah, NS; et al. 2007. Worldwide Emergence of Extensively Drug-resistant Tuberculosis. Emerging Infectious Diseases 13(3): 380-387. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725916/
5: CDC Antibiotic Threats Report, 2013. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf
6: CDC Antibiotic Threats Report, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
7: Barbour, AG; Fish, D. 1993. The Biological and Social Phenomenon of Lyme Disease. Science 260(5114):1610-1616. https://pubmed.ncbi.nlm.nih.gov/8503006/
8: Casadevall, A; Kontoyiannis, DP; Robert, V. 2019. On the Emergence of Candida auris: Climate Change, Azoles, Swamps, and Birds. mBio 10.1128/mBio.01397-19. https://mbio.asm.org/content/10/4/e01397-19
9: Kraemer, SA; Ramachandran, A; Perron, GG. 2019. Antibiotic Pollution in the Environment: From Microbial Ecology to Public Policy. Microorgansims 7(6): 180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616856/
10: Levy, S. 2014. Reduced Antibiotic Use in Livestock: How Denmark Tackled Resistance. Environmental Health Perspectives 122(6): A160-A165. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050507/
11: Sun, H, et al. 2020. Prevalent Eurasian avian-like H1N1 swine influenza virus with 2009 pandemic viral genes facilitating human infection. Proceedings of the National Academy of Science https://doi.org/10.1073/pnas.1921186117.
12: Kaiser, J. 2020. National Institutes of Health would see 7% cut in 2021 under White House plan. Science Magazine. https://www.sciencemag.org/news/2020/02/national-institutes-health-would-see-7-cut-2021-under-white-house-plan
13: About NARMS: National Antimicrobial Resistance Monitoring System for Enteric Bacteria. https://www.cdc.gov/narms/about/index.html
14: Khachatourians, GG. 1998. Agricultural use of antibiotics and the evolution and transfer of antibiotic-resistant bacteria. CMAJ 159(9):1129-1136 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1229782/
15: Jacobs, Andrew. 2019. Crisis Looms in Antibiotics as Drug Makers Go Bankrupt. The New York Times. https://nyti.ms/366f7it

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CDC Admits 98 Million Americans Received Polio Vaccines Contaminated With Cancer Virus

conjugated protein pdf video

Section 5.1: The structure of the protein may be described as follows: < type of protein> is conjugated with <name of polymer contained in conjugate> at a degree of substitution of <n moles of polymer/mole of protein>. The average molecular mass is approximately <Y> of which the protein moiety constitutes approximately <X>. Acrolein is a ubiquitous environmental pollutant. Whey protein and conjugated linoleic acid are widely used weight-loss supplements. We aimed to evaluate blood lipid profiles, oxidative stress and mitochondrial bioenergetics function in hearts of rats treated with acrolein and/or the weight-loss supplements. ADVERTISEMENTS: Conjugated proteins are proteins that contain non-protein constituents or prosthetic groups. The prosthetic groups are permanently associated with the molecule, usually through covalent and/or non-covalent linkages with the side chains of certain amino acids. Conjugated proteins can be divided into three major classes: (1) Chromo proteins ADVERTISEMENTS: (2) Glycoproteins ... conjugated antibodies to their targets, the protein levels can be converted to oligonucleotide levels. In this report we describe a simple method for preparing oligonucleotide-conjugated antibodies and discuss this method’s application in oligonucleotide extension reaction (OER) for multiplex protein detection. Conjugation Polymeric Chains of SUMO-2 and SUMO-3 Are Conjugated to Protein Substrates by SAE1/SAE2 and Ubc9* Received for publication, May 9, 2001, and in revised form, July 9, 2001 Published, JBC Papers in Press, July 12, 2001, DOI 10.1074/jbc.M104214200 Michael H. Tatham‡, Ellis Jaffray, Owen A. Vaughan, Joana M. P. Desterro§, Antonio Blanco, Gustavo Blanco, in Medical Biochemistry, 2017. Hemoglobin. Hemoglobin is a conjugated protein whose prosthetic group, heme, gives it its typical intense red color.Among the heme proteins are the cytochromes, which are substances that act as electron carriers and enzymes, such as catalase and peroxidase; myoglobin, a molecule that carries and stores oxygen in muscle; and ... These are proteins conjugated with lipids such as neutral fat, phospholipids and cholesterol Metalloproteins These are metal-binding proteins. A ˜-globulin, termed transferrin is capable of combining with iron, copper and zinc. This protein constitutes 3% of the total plasma protein. PDF Proteins are made ... There are 20 different kinds of amino acids that are linked together by peptide bond to make a protein molecule. ... The non-amino acid moiety of the conjugated protein ...

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Proteins - YouTube

The four levels of protein structure are primary, secondary, tertiary, and quaternary. It is helpful to understand the nature and function of each level of p... About Press Copyright Contact us Creators Advertise Developers Terms Privacy Policy & Safety How YouTube works Test new features Press Copyright Contact us Creators ... About Press Copyright Contact us Creators Advertise Developers Terms Privacy Policy & Safety How YouTube works Test new features Press Copyright Contact us Creators ... The Amoeba Sisters explain enzymes and how they interact with their substrates. Vocabulary covered includes active site, induced fit, coenzyme, and cofactor.... Nick Gee, the CEO and CSO of Innova Biosciences, explains the benefits of using directly conjugated antibodies and the various approaches and techniques that... Developed and produced by http://www.MechanismsinMedicine.comAnimation Description: The DNA is shown as a circular double strand within the bacterial cell. ... Paul Andersen explains the structure and importance of proteins. He describes how proteins are created from amino acids connected by dehydration synthesis. ... Matt Wenning has a masters in biomechanics- and has broken multiple all time world records in powerlifting . He has had major contacts with armed forces units such as US Army rangers - 82nd ... After a polypeptide is produced in protein synthesis, it's not necessarily a functional protein yet! Explore protein folding that occurs within levels of pro... Do you remember tripping over as a kid and cutting your knee? And then like magic the bleeding suddenly stops? Have you ever wondered why this happens?Our bo...

(PDF) Protein Structure and Function - ResearchGate

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Nutritional Lipids Market Regional Data in Terms of Value and Volume by 2024

Effect of β-Hydroxybutyrate on Autophagy Dynamics During Severe Hypoglycemia and the Hypoglycemic Coma. (Pub Date: 2020)

Abstract

Oral versus transdermal estradiol in feminising hormone therapy for transgender individuals

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Introduction

Pharmacology

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Summary and conclusions

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A Very detailed DD on $SESN (SESEN Biology)

Photosynthesis boosted in plants, a musician makes music with artificial cells, and other things that happened This Week in Synthetic Biology

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The Next Pandemic: Confronting Emerging Disease and Antibiotic Resistance

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CDC Admits 98 Million Americans Received Polio Vaccines Contaminated With Cancer Virus

conjugated protein pdf video

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Proteins - YouTube