Not Beyond Reasonable Doubt: Howard Temin’s Provirus Hypothesis Revisited

During the 1960s, Howard M. Temin (1934–1994), dared to advocate a “heretical” hypothesis that appeared to be at variance with the central dogma of molecular biology, understood by many to imply that information transfer in nature occurred only from DNA to RNA. Temin’s provirus hypothesis offered a simple explanation of both virus replication and viral-induced cancer and stated that Rous sarcoma virus, an RNA virus, is replicated via a DNA intermediate. Popular accounts of this scientific episode, written after the discovery of an RNA-directed DNA polymerase in 1970, tend to describe the reaction to his proposition as ardent opposition. Typically these accounts use a ‹molecular biology’ standpoint emphasizing the central dogma’s part in its rejection. In this article, however, this episode will be examined from a joint perspective of virology and experimental cancer research. From this perspective it is clear that Temin’s work was well within the epistemological and methodological boundaries of virology and cancer research. Still, scientists did have␣reasons to doubt the provirus hypothesis, but these do not seem to be good enough to either justify an account that portrays Temin as a renegade or his ideas as heretical.     

An Endogenous Foamy-like Viral Element in the Coelacanth Genome

Little is known about the origin and long-term evolutionary mode of retroviruses. Retroviruses can integrate into their hosts'' genomes, providing a molecular fossil record for studying their deep history. Here we report the discovery of an endogenous foamy virus-like element, which we designate ‘coelacanth endogenous foamy-like virus’ (CoeEFV), within the genome of the coelacanth (Latimeria chalumnae). Phylogenetic analyses place CoeEFV basal to all known foamy viruses, strongly suggesting an ancient ocean origin of this major retroviral lineage, which had previously been known to infect only land mammals. The discovery of CoeEFV reveals the presence of foamy-like viruses in species outside the Mammalia. We show that foamy-like viruses have likely codiverged with their vertebrate hosts for more than 407 million years and underwent an evolutionary transition from water to land with their vertebrate hosts. These findings suggest an ancient marine origin of retroviruses and have important implications in understanding foamy virus biology.     

Enhancements to the Rosetta Energy Function Enable Improved Identification of Small Molecules that Inhibit Protein-Protein Interactions

Protein-protein interactions are among today’s most exciting and promising targets for therapeutic intervention. To date, identifying small-molecules that selectively disrupt these interactions has proven particularly challenging for virtual screening tools, since these have typically been optimized to perform well on more “traditional” drug discovery targets. Here, we test the performance of the Rosetta energy function for identifying compounds that inhibit protein interactions, when these active compounds have been hidden amongst pools of “decoys.” Through this virtual screening benchmark, we gauge the effect of two recent enhancements to the functional form of the Rosetta energy function: the new “Talaris” update and the “pwSHO” solvation model. Finally, we conclude by developing and validating a new weight set that maximizes Rosetta’s ability to pick out the active compounds in this test set. Looking collectively over the course of these enhancements, we find a marked improvement in Rosetta’s ability to identify small-molecule inhibitors of protein-protein interactions.     

Pedagogy of the Black academic

I am just starting my career as a cancer biologist, but I have always been a Black man in America. This means that I have always inhabited a world that generally disregarded my existence in some form or another. It is June 17th, 2020 and protests have been happening for weeks since the killing of George Floyd in Minneapolis. The current state of America may be uneasy for some, but for many Americans, the looming threat of exclusion and violence has been an unwelcome companion since birth. This letter is not about a single person, but the Black academic’s experience of race inside and outside of the academy during a time of social upheaval. I have trained in a variety of institutions, big and small, and all the while acutely aware of the impact of my Blackness on my science. The intent of the following is to provoke the reader to reflect on how we as a nation can move toward radically positive change and not incremental adjustments to the status quo. The views expressed are my own and are the result of years of personal experience observing the anti-Black standard in America.

About the AuthorI am currently a cancer biologist at the University of Minnesota Medical School. My lab works to eliminate cancer health disparities in African Heritage communities and investigates the roles of lipids in modifying the immune response in tumors. This is what I do, but not all of who I am. I am also the eldest child of a mother, who managed to convince me that she had eyes in the back of her head (thank you, Mom; it kept me honest). I am a big brother, a husband, and a father. I also consider myself a fortunate Black man in America. I grew up in places where many of my friends did not live to adulthood. If they managed to survive past adolescence, it was usually their dreams that died prematurely. I was lucky to have survived and to continue chasing my dream of becoming a scientist. I never considered myself the fastest, strongest, or even smartest kid growing up, but I was the most determined. Determined, despite the lack of access to role models in science that looked like me or shared my life experience. Now my mission is to increase the number of dreams achieved and impact as many young minds as my time on this planet permits.As a Black scientist, I sometimes have to remind myself that I have never been immune to racism. Because as you spend thousands of hours delving into the microscopic world, the macroworld starts to fade into the background like white noise. And if you get good at it, you almost forget about the strange looks, the excessive questioning, or even the obligatory “tailing” in stores, on campus, or at home. But it is strange to realize how much you have grown accustomed to discrimination and the fact that you unconsciously prepare for it daily, before it ever shows its ugly head, like a prize fighter training months before a fight.This past month, amid the Coronavirus Disease 2019 (COVID-19) pandemic, the rest of the world has decided to say police are bad, and oh, by the way, Black lives matter too—as if the oppression of Black bodies was new, or as though the recent string of names added to the ever-growing list of innocent Black Americans killed by authorities is an atypical occurrence. Well sadly it is not, and it never has been in this country or any other place with colonial origins. That is the truth, and there is no other way to state it. America is a country built on and driven by racist ideology.So, as a Black American in an “essential” worker role (I am now working on COVID–19-related research), I have physically been at work daily during the pandemic, as the spirit of solidarity sweeps the globe. As much as I want to say this is progress, I find myself asking “why now, and not then?” Why didn’t this happen when Trayvon Martin was murdered; why didn’t this happen when Rodney King was beaten (Alvarez and Buckley, 2013; Mullen and Skitka, 2006)? Is it a sign of the end times, or is it just that racism/White supremacy has finally run its course?I have a theory about why we are now seeing a mass movement against discrimination and police brutality (a.k.a. state-sanctioned murder). My theory states that had it not been for COVID-19 and the nationwide shutdown of normal life, none of this protesting would even be feasible. Why do you ask? The simple answer is that some people with the financial means can normally find ways to distract themselves with various activities, some noble and some … not so much, whereas other folks are less able to disconnect from the drudgery of hand-to-mouth living. Leave it to a global health crisis to reprioritize everyone’s entire life in one fell swoop. Suddenly, people who had vacation plans are stuck at home, whereas people who were just making ends meet are now unable to make those ends meet anymore. The haves and the have-nots are now both in an altered reality. Does this make them equal now? No, but it does allow people to see who their real friends, allies, and enemies are. I suspect that it’s the pulling back of the curtain that has made many people ready to fight, not to mention it is also very likely that many folks, after experiencing weeks of cabin fever, just needed some way to let off all that pent-up energy.Before COVID-19 became a full-time concern, tensions in the United States were already high as the recent killings of unarmed Black Americans (Breonna Taylor and Ahmaud Arbery) had gone viral and cries for justice echoed from coast to coast (Lovan, 2020). Once the reality of the pandemic set in and shelter-in-place orders were issued nationally, the situation became a powder keg waiting for just the right moment. That moment happened in North Minneapolis on May 25, 2020. With the release of the video showing the killing of George Floyd, the entire country and much of the world had a reason to go on a “righteous rampage” that has seemed to get the results some thought impossible to achieve. It cannot be overstated how critical social media has been in displaying the oppression of Black Americans at the hands of authorities to the entire world.Now, several months into the protests, the possibility of a “new’’ new normal has people dreaming of singing Kumbaya in technicolor. Yet, as one of the few Black faculty on my campus, I still feel like people are watching me, but for a different reason now. As various reforms are broadcast across the university, the random wellness “check-ins” start creeping in, and the requests for feedback on “new initiatives’’ seem to be like a new flavor of spam in my inbox.Now, I do appreciate the fact that people are starting to notice the oppressive nature of not being White in today’s world (in particular being Black in America), but I have been doing this for a while now, and I am not sure if hashtagged initiatives are healthy for anyone. Plus, it’s kind of creepy watching all of these people jump on the social justice bandwagon, when they weren’t here 4 mo ago or 4 years ago. For many Black academics, it is not about being involved with something when it’s trending; it’s about being “about that life” when it is inconvenient as hell. Again, I do appreciate the fact that more people are willing to fight oppression, racism, and White supremacy (even if only digitally), but you will have to forgive me if I do not trust you just yet. I mean, you are just checking in during what could be the last leg of a marathon, and we’ve been running this whole damn time!Here is a short answer to every wellness check-in email that many of the Black academics I know have received in the last 2 mo: “we were never okay in the first place, but thanks for FINALLY asking!” We don’t need any more bias training, hashtags, or email check-ins. It was a nice start, but it too has become a part of the status quo. The work now and always has been the eradication of underrepresentation, hurtful socialization, and ridiculously skewed power dynamics, not just the awareness of the fact. I don’t have all the answers, but if real change is desired, I think we can first start by teaching history accurately to EVERYONE, no more whitewashing the reality of America’s story and ignoring the contributions of Black academics (and Black Americans in general). Second, stop being silent when you see or hear racism at work or home. If you do nothing when racism shows up, you ARE a racist! Third, the privileged class must relinquish their “privilege” once and for all. That means the powers that were inherited based on historical (and present day) theft and oppression have to dissipate, with the ultimate goal of power sharing. The country club atmosphere of academia and the “fit culture” must erode in favor of true meritocracy. The best person for the job and not “the person who won’t make me uncomfortable by making me see my own deeply held prejudices and fears.”Honestly, Black academics SHOULD not be charged with the task of fixing broken systems, along with protecting themselves and mentees, while working toward tenure. But if we (Black academics) are not driving the car, progress will likely go the wrong way again (getting rid of Uncle Ben and Aunt Jemima does not correct the underlying pathology). Paulo Freire’s Pedagogy of the Oppressed speaks to this in saying, “the violence of the oppressors prevents the oppressed from being fully human, the response of the latter to this violence is grounded in the desire to pursue the right to be human … the oppressed, fighting to be human, take away the oppressors’ power to dominate and suppress, they restore to the oppressors the humanity they had lost in the exercise of oppression.” (Friere, 1972, p. 56). This means that if we (Black academics) want to be treated as humans and as scholars, we must show you what that humanity looks like FIRST. Now the question is, are you willing to learn or are you going to co-opt this moment, this movement to make it into something that fits your preconceived notion of the acceptable levels of Blackness in the academy?     

Elda Grabocka: Stress-buffering comes in granules

Elda Grabocka investigates the role of stress granules in obesity and cancer.

When one thinks of high school, sharing hallways with students from 80 different countries is not the usual image that springs to mind. This was indeed Elda Grabocka’s experience. She grew up in Pogradec, a remote town in Albania—her parents, both physicians, were assigned to this location by the state. Elda won one of the two spots available for Albanian students in a national competition to attend the United World College of the Adriatic in Trieste, Italy, a high school focused on social change that brings together students from around the globe to promote intercultural understanding. Elda still remembers, with a smile on her face, the first glimpse at the laboratories as the senior students were working on their thesis projects: “That was exactly what I wanted to do!” She barely spoke English at the time and had to catch up to the level of her peers, but her perseverance and passion prevailed, and she obtained the International Baccalaureate Diploma (IBD). For the independent study of the IBD program, she submitted a research project in chemistry, which ended up being an important learning and life lesson: “That helped me understand that I was more suited to biology! In hindsight, it was great to have that experience so early; I certainly had no awareness then how essential failing and then learning from your failures is to science, but having a level of comfort with it from the beginning was probably a bonus.”Elda Grabocka. Photo courtesy of Chris Hamilton Photography.But science was not the only professional option Elda contemplated—her volunteering experience with relief organizations in various refugee camps made her consider a career in public health and humanitarian relief efforts. She finally sought a PhD degree in molecular pharmacology and structural biology in the laboratory of Phil Wedegaertner at Thomas Jefferson University. After studying heterotrimeric G-proteins and how the subcellular localization of their exchange factors regulates function, Elda felt the need to seek greener pastures. She went on to do a postdoc on one of longest-studied oncogenes, RAS—her choice wasn’t motivated by the field, but by the mentor, Dafna Bar-Sagi. Elda’s admiration for Dafna is notable when she speaks about her time at the New York University Langone Medical Center: “It’s remarkable how many novel aspects of RAS biology that have shaped and then re-shaped our thinking about this oncogene have come out of her lab; I felt there was a depth and breadth to her approach to scientific research that if I could learn, I’d be able to see more of the angles, so to speak, ask better questions; she has really expanded my mind in all those aspects.” Elda’s work focused on the interplay between the mutated forms of RAS and the wild-type isoforms, which she and others have shown is context dependent, with the wild-type isoforms acting as both tumor suppressors and tumor promoters (1). While still in Dafna’s laboratory, Elda pursued a more independent scientific interest: the role of stress granules in mutant KRAS cells. In 2016, Elda returned to her alma mater, joining the Department of Cancer Biology at the Sidney Kimmel Cancer Center at Jefferson as an assistant professor, with stress granules in cancer as the focus of her laboratory. We contacted her to learn more about her research journey.What interested you about stress granules and their connection with obesity and cancer?I became interested in stress granules and their potential role in cancer early in my postdoc. I read a review by Stephen Elledge’s group where they described the “stress phenotype” of cancer as an important player in tumorigenesis. I realized that cancer cells exist mostly in a state of stress—for example, mutated genes, like oncogenic RAS, are potent inducers of many types of cellular stresses. I was working on a RAS ubiquitination project, and one of the candidates for a RAS de-ubiquitinating enzyme we were looking at was implicated in stress granule formation. Little was known about stress granules at the time—they are induced by types of stresses associated with tumors (hypoxia, oxidative stress, osmotic pressure, proteotoxic stress, metabolic stress, etc.), so the question I asked was whether stress granules could function as a stress coping/adaptation mechanism in cancer. Indeed, I found that stress granules are prevalent in tissues from patients with pancreatic cancer and mouse models of pancreatic cancer. Remarkably, not all cancer cells are the same in their capacity to form stress granules—all cells will make stress granules under stress, but KRAS mutant cancer cells have a heightened ability to do so because signaling from mutant KRAS enhances the levels of a critical molecule to stress granule formation, 15-deoxy-prostaglandin J2 (2). This enhanced capacity to make stress granules, in turn, renders KRAS mutant cells more resistant to stress and more dependent on stress granules; inhibition of stress granules leads to increased cell death in KRAS mutant versus KRAS wild-type cancer cells.Immunofluorescence staining of pancreatic ductal adenocarcinoma tissue showing cancer cells in red, stress granules in green, and nuclei in blue. Image courtesy of the Grabocka laboratory.The work establishing this dependence was in vitro, so the primary goal when I started my laboratory was to determine their relevance in tumorigenesis, which led me to explore their connection to obesity and cancer for several reasons. First, obesity is a major predisposing factor for several cancers, including pancreatic and colon, which are prevalent KRAS-driven cancers for which treatment options are limited. Second, obesity is a complex pathology which likely impacts the pathobiology, the therapy response, and even the evolution of cancers that arise in this setting. Given that cell stress and inflammation are key features in obesity, this would make the ideal background to study the contribution of stress granules in tumorigenesis. I think this pre-existing stress [obesity] might necessitate the engagement of stress adaptive mechanisms from the early stages of tumorigenesis and may also lead to a high dependence on these processes.What are you currently working on, and what is up next for you?It’s a very exciting time to be working on stress granules! The field has grown significantly over the past 10 yr or so, especially with the renewed interest in phase separation. As organelles that form via phase separation when a cell is under stress, stress granules are perhaps one of the best examples of phase separation in vivo and a great platform to understand its relevance. The recent advances in defining the composition, as well as key molecular drivers and their functional domains in stress granule assembly, have been of great benefit. We are now better positioned to define the stress granule–specific functions in health and disease. Because stress granules are induced by various types of stresses, they could function as a pan-stress adaptation mechanism in cancer. This is a very appealing angle, as if we can solve how stress granules enable stress adaptation, which is a major focus of my laboratory, we could have better anti-cancer therapies.The composition of stress granules, comprising hundreds of proteins and mRNAs involved in several aspects of cell biology, prompted me to ask whether cytoprotection under stress is their main and/or only function. What other cellular processes stress granules regulate, whether these vary with the type of stress, and how such processes are integrated into the stress response of cancer cells are burning questions we are currently working on, as the answers will advance our understanding of the role of stress granules in cancer. The “chronic stress” of cancer is heterogenous in both spatial and temporal terms, as well as in the type of stress and intensity. I am also very curious to see if and how heterogeneity in stress stimuli impact the composition of stress granules and the processes they regulate, and how this may affect tumor evolution. Also, cancer cells are not the only cells in the tumor that make stress granules. As a matter of fact, we reported that KRAS mutant cells can stimulate stress granule formation in a paracrine manner. An ongoing project in the laboratory that I’m very excited about is focused on understanding the contribution of stress granules to the pro-tumorigenic microenvironment.What kind of approach do you bring to your work?My approach is very hypothesis and observation driven; the latter in the sense that it can often be that initial spark that inspires an idea, draws connections, and looks for context and meaning. I also find that sometimes the answer to my next question or the question I don’t know to ask yet is hidden right in front of my eyes, so paying careful attention to the data is key. It is also where objective and critical evaluation of experimental results starts. There’s one line that’s firmly ingrained in my mind from my postdoctoral training, which is “Science is self-correcting.” It’s a note of caution that if you don’t pay attention and see only what you want to see, it will still eventually prove you wrong, and you’d have wasted a lot of time in the process. So I try to minimize that waste as much as possible—unavoidable entirely, having a favorite hypothesis is part of the scientific thinking process, but crucial to remember to follow the data and not just convince yourself.What has been the biggest accomplishment in your career so far?I’m still quite early in my career to start listing accomplishments. I feel privileged to do the work I do; I essentially get funded to pursue ideas that I find interesting. So I have a hard time with this question because it has a hint of pride, and when you start adding pride to privilege, as a junior principal investigator especially, it gets a bit too self-serving. I hope that the work we are doing stands the test of time and leads to or helps lead to a meaningful impact on patients’ lives—that would be a great accomplishment.What has been the biggest challenge in your career so far?The past two years of COVID have certainly been a different reality, and a constantly shifting one at that. From a career perspective, so much of a scientific career happens at the bench: experiments happen at the bench, we train at the bench, animal work is long and requires multiple dedicated essential personnel and facilities, so inevitably, remote work, or shift work, limited occupancy, and the shortages we are now seeing in the supply chain have been a major challenge for everyone. I do think junior laboratories like mine experience that a bit harder. The bandwidth to absorb these challenges is much smaller if you’re just starting out, or if you’ve had a laboratory for a couple of years and are just ramping up. I must say though that it has made for stronger teamwork in the laboratory, and we’ve had to be really focused and efficient—so there’s an upside!Out for a paddle. Photo courtesy of Elda Grabocka.Any tips for a successful research career?Hard to say, because certainly it means different things to different people. The only tip I would give perhaps is to define what that means, what that success looks like for oneself, and be true to that. I expect how each one defines it also changes with time and experience, but I do think it’s very important to identify what success means as early as possible and let that be what you measure your efforts against. It’s easy to get distracted, overwhelmed, or even disheartened otherwise. My own definition is quite simple: success is doing what I love to do, working toward answering a meaningful scientific question, and enabling/supporting my trainees to reach their potential—keeping that in mind has been very important and helpful.     

Fluctuations of Hi-Hat Timing and Dynamics in a Virtuoso Drum Track of a Popular Music Recording

Long-range correlated temporal fluctuations in the beats of musical rhythms are an inevitable consequence of human action. According to recent studies, such fluctuations also lead to a favored listening experience. The scaling laws of amplitude variations in rhythms, however, are widely unknown. Here we use highly sensitive onset detection and time series analysis to study the amplitude and temporal fluctuations of Jeff Porcaro’s one-handed hi-hat pattern in “I Keep Forgettin’”—one of the most renowned 16th note patterns in modern drumming. We show that fluctuations of hi-hat amplitudes and interbeat intervals (times between hits) have clear long-range correlations and short-range anticorrelations separated by a characteristic time scale. In addition, we detect subtle features in Porcaro’s drumming such as small drifts in the 16th note pulse and non-trivial periodic two-bar patterns in both hi-hat amplitudes and intervals. Through this investigation we introduce a step towards statistical studies of the 20th and 21st century music recordings in the framework of complex systems. Our analysis has direct applications to the development of drum machines and to drumming pedagogy.     

From Chattel to Consenter: Adolescents and Informed Consent: 2009 Grover Powers Lecture

Angela Holder was to give the Grover Powers Memorial Lecture at the weekly Grand Rounds conducted by the Yale Department of Pediatrics on Wednesday, May 27, 2009, but unfortunately, she died one month earlier, on April 22, leaving behind her prepared address, “From Chattel to Consenter: Adolescents and Informed Consent,” which she had regarded as the pinnacle of a remarkable career, much of it spent at Yale. As the Grover Powers honoree, the department’s highest honor, Ms. Holder was only the fourth woman of 46 recipients and the first who was not a physician. On the date scheduled for her address, tributes were presented by her son, John Holder, and her longtime colleague, Dr. Robert Levine, co-founder of Yale’s Interdisciplinary Bioethics Center. Their comments follow Angela Holder’s completed but undelivered Grover Powers address. — Myron Genel, MD, Professor Emeritus of PediatricsUnder the common law of England and in the early years of the United States, a minor (defined as anyone under 21) was a chattel or possession of his or her father [1-4]. A father had the right to sue a physician who treated his son or daughter perfectly properly but without the father’s permission because such an intervention contravened the father’s right to control the child. Beginning in the early years of the 20th century, by the end of World War II and into the 1950s, the notion that a 16-year-old was a legally different entity from a 6-year-old gradually became law in all states.¹ The first hospital unit for adolescents was created in 1951 at Boston Children’s Hospital, and the concept of “adolescent medicine” was born [5].As the law in this area currently defines “adolescent,” we are discussing someone 14 or older who may be (1) living at home with his or her parents; (2) Not living at home but still dependent on parents (i.e., a 16-year-old college freshman living in a dorm); (3) an “emancipated minor” who is married, emancipated by a court order, or a parent (other than in North Carolina), living away from home and self-supporting; or (4) a runaway or throwaway. At any time in this country, there are about 200,000 adolescents living on the streets with no adult supervision or involvement [6].Regardless of the age of the patient, informed consent consists of five elements: (1) An explanation of what will happen; (2) explanation of the risks; (3) explanation of the projected benefits; (4) alternatives (including doing nothing); and (5) why the physician thinks it should be done, which I interpret as a right to know one’s diagnosis. While the doctrine of “therapeutic privilege” means that in rare cases a physician may withhold some information from an adult patient if she or he believes the patient cannot “deal with the information,” there can never be any withholding of information from an adolescent. If the patient can’t deal with the information to be presented, then parents have to be involved and give permission to treat the adolescent.In some cases, when parents are involved, they do not want their adolescent to know his or her diagnosis. While this is usually not a good idea, it normally falls under the rubric of “professional judgment,” and the physician has every right to decide to follow the parents’ instruction if she agrees with it. In some situations, however, the adolescent must be told what his or her illness is, whether parents like it or not. For example, if a teenager is HIV positive, he or she must be told, must be instructed about safe sex, and must be asked to divulge the names of any sex partners. Parents who say, “Oh, no, don’t tell him, he would never do anything like that, so it doesn’t matter,” should be tactfully but firmly led to accept the fact that he may well have and if he hasn’t yet, he will certainly in the future. There has been at least one successful malpractice case in which the physician did not, at the request of the parents, tell his adolescent patient that he had HIV. The patient’s girlfriend caught it and sued the physician [7]. I feel sure there are many more cases like this that have been quietly settled and no one will ever hear about.Usually, questions about adolescents giving consent to treatments that their parents don’t know about involve outpatient treatment. In the first place, hospital administrators, who are much more interested in getting paid than they are in advancing the rights of autonomous adolescents, are not going to admit for a non-emergency problem a minor whose parent has not made some sort of financial arrangement to pay for it. Secondly, in most households, if Little Herman doesn’t show up for supper or throughout the evening, someone notices and a few telephone calls later discovers that Little Herman is in the hospital.     

NAR Breakthrough Article: Highlights of the DNA cutters: a short history of the restriction enzymes

In the early 1950’s, ‘host-controlled variation in bacterial viruses’ was reported as a non-hereditary phenomenon: one cycle of viral growth on certain bacterial hosts affected the ability of progeny virus to grow on other hosts by either restricting or enlarging their host range. Unlike mutation, this change was reversible, and one cycle of growth in the previous host returned the virus to its original form. These simple observations heralded the discovery of the endonuclease and methyltransferase activities of what are now termed Type I, II, III and IV DNA restriction-modification systems. The Type II restriction enzymes (e.g. EcoRI) gave rise to recombinant DNA technology that has transformed molecular biology and medicine. This review traces the discovery of restriction enzymes and their continuing impact on molecular biology and medicine.     

Socio-Demographic Predictors and Distribution of Pulmonary Tuberculosis (TB) in Xinjiang,China: A Spatial Analysis

Objectives

Xinjiang is one of the high TB burden provinces of China. A spatial analysis was conducted using geographical information system (GIS) technology to improve the understanding of geographic variation of the pulmonary TB occurrence in Xinjiang, its predictors, and to search for targeted interventions.

Methods

Numbers of reported pulmonary TB cases were collected at county/district level from TB surveillance system database. Population data were extracted from Xinjiang Statistical Yearbook (2006~2014). Spatial autocorrelation (or dependency) was assessed using global Moran’s I statistic. Anselin’s local Moran’s I and local Getis-Ord statistics were used to detect local spatial clusters. Ordinary least squares (OLS) regression, spatial lag model (SLM) and geographically-weighted regression (GWR) models were used to explore the socio-demographic predictors of pulmonary TB incidence from global and local perspectives. SPSS17.0, ArcGIS10.2.2, and GeoDA software were used for data analysis.

Results

Incidence of sputum smear positive (SS+) TB and new SS+TB showed a declining trend from 2005 to 2013. Pulmonary TB incidence showed a declining trend from 2005 to 2010 and a rising trend since 2011 mainly caused by the rising trend of sputum smear negative (SS-) TB incidence (p<0.0001). Spatial autocorrelation analysis showed the presence of positive spatial autocorrelation for pulmonary TB incidence, SS+TB incidence and SS-TB incidence from 2005 to 2013 (P <0.0001). The Anselin’s Local Moran’s I identified the “hotspots” which were consistently located in the southwest regions composed of 20 to 28 districts, and the “coldspots” which were consistently located in the north central regions consisting of 21 to 27 districts. Analysis with the Getis-Ord Gi* statistic expanded the scope of “hotspots” and “coldspots” with different intensity; 30 county/districts clustered as “hotspots”, while 47 county/districts clustered as “coldspots”. OLS regression model included the “proportion of minorities” and the “per capita GDP” as explanatory variables that explained 64% the variation in pulmonary TB incidence (adjR² = 0.64). The SLM model improved the fit of the OLS model with a decrease in AIC value from 883 to 864, suggesting “proportion of minorities” to be the only statistically significant predictor. GWR model also improved the fitness of regression (adj R² = 0.68, AIC = 871), which revealed that “proportion of minorities” was a strong predictor in the south central regions while “per capita GDP” was a strong predictor for the southwest regions.

Conclusion

The SS+TB incidence of Xinjiang had a decreasing trend during 2005–2013, but it still remained higher than the national average in China. Spatial analysis showed significant spatial autocorrelation in pulmonary TB incidence. Cluster analysis detected two clusters—the “hotspots”, which were consistently located in the southwest regions, and the “coldspots”, which were consistently located in the north central regions. The exploration of socio-demographic predictors identified the “proportion of minorities” and the “per capita GDP” as predictors and may help to guide TB control programs and targeting intervention.     

You are the most valuable reagent in the lab: mental health before and during the pandemic

No one maps out their tenure as a postdoc anticipating a life-altering tragedy. But mental health crises of all kinds affect academic trainees and staff at similar or higher levels than the general public. While the mental health resources available to trainees are often set by healthcare providers, all levels of university leadership can work to remove material and immaterial obstacles that render such resources out of reach. I describe how access to care via telemedicine helped me following a loss in my family.

Over the years, my siblings and close friends have sought mental health resources like therapy, psychoanalysis, or psychiatry, so I loosely understood their benefits. When I was a PhD student I went to therapy briefly, but my counselor and I decided I could do without it. Since I started my postdoc, stress manifested in some new ways but I managed it well with my usual coping strategies and support. That changed one bright December morning in 2019 while I was preparing for our weekly lab meeting. My phone rang indicating a call from my father, whom I had spoken to the night before to celebrate the news of my nephew’s birth. But the voice on the phone was that of a family friend, telling me that my father had died overnight of an undiagnosed heart condition. In the moment I couldn’t even understand what was happening, saying over and over, “but I talked to him last night.” Soon I was sitting at home, dazed, on a string of tearful calls with family and friends.I often read words like “lifted” or “buoyed” to describe the stabilizing support of a network of loved ones. In my case this network was tethering me to reality over the next few weeks, preventing me from spinning off the Earth’s surface in a storm of sorrow and anxiety. The trauma also took a strange physical form and convinced me that I was suffering from a cardiac condition of my own. I had a panic attack during which I went to urgent care convinced my own heart was about to give way. Night after night these physical symptoms prevented me from sleeping.Graced by many loving connections with my siblings, my boyfriend, and close friends, I was actually weathering the process as well as one can. My PI gave me a firm directive to take as much time off as I needed. These were two key elements early in my healing process: a supportive network and an understanding advisor. The third was getting professional help, which I soon realized I needed. Even if I felt OK one day, I didn’t trust that I’d be OK the next. My grief formed too thick and too broad a landscape for me to navigate without help.Deciding to seek mental health resources and realizing that one needs them are often the hardest parts. Connecting with those resources once the decision has been made should be as simple as possible. I called a mental health number, and a triage counselor noted my therapy needs and verified my insurance. She asked what times and locations I preferred and then searched for an open appointment with a therapist who accepted my insurance. She also informed me that my coverage allowed 12 sessions with no copay, which was a pleasant surprise. The therapist who agreed to see me had very few openings, in part because this all happened in December—the holidays are especially busy for therapists. I was aiming for a time after normal working hours, or in the morning before I would head to lab, but none of those times were available. I didn’t like interrupting my workday to trot off to therapy. Taking a long break once a week meant I couldn’t run experiments or mentor my student during that time. But I made the sacrifice because my highest priority was getting the help I needed. There was no shortcut. Prioritizing mental health over lab work is tough for researchers, and I would never have accepted that kind of weekly disruption before my dad’s passing. But as a wonderful mentor of mine used to say, “You are the most valuable reagent in the lab.” She wasn’t describing mental health at the time, but the phrase now provided a guiding principle for my recovery. My first few sessions were on Tuesdays at 2:00 pm.The afternoon break turned out to be less disruptive than I had feared, because I had recently come back to the lab and was working short days. Had she asked, I would have told my PI where I was on Tuesday afternoons, but she wasn’t normally abreast of my daily schedule, so I didn’t seek her approval beforehand. Coordinating experiments with lab members thankfully wasn’t an issue because my work was largely independent; I simply let lab members know that I’d would be out of the lab for a bit on those days.The weeks went by, and the benefits of therapy accrued, helping me in large and small ways as I grieved. In mid-March of 2020, my therapist followed public health guidelines and asked all her clients to transition to remote sessions. While this was easy and sensible, it was still a little disappointing. Therapists are professional empaths, among many other things, and doing away with the physical presence and exchange with her was a blow. Yet therapy via video felt less odd simply because most of my social interactions were now virtual. Thankfully I didn’t have to move out of state for the lockdown (as did many students living in campus housing), which meant I could stay with the same therapist without any insurance complications.A few weeks into lockdown, I asked my therapist whether we had reached the limit of my 12 sessions without a copay. She replied with the good news that my insurance provider had waived all copays for mental health costs due to the pandemic. By that time therapy had generated a platform and an outlet to explore areas of my grief beyond the trauma of my father’s passing. Without needing to weigh the costs and benefits of this resource, I saw my therapist for another 4 months. I slowly took stock of my upbringing in an unconventional family and the loss of my mother when I was 25 and waded through a series of difficult decisions regarding my father’s estate. My father’s death changed me at a depth that is untouched by any amount of therapy or treatment. I’m not “healed”: I feel aged, more brittle, and a little ground down compared with who I had been. But therapy guided me through the worst of my grief, past the acute trauma to help me grasp what I was going through.Since the pandemic began, the number of people reporting increased stress or mental health issues has steadily increased (information on the impact of COVID-19 measures on mental health: https://www.apa.org/workforce/publications/depression-anxiety-coronavirus.pdf) (also see Mental health resources for trainees). I am fortunate to have affordable health insurance and the support from my lab and my department. The ease of finding my institution’s phone number for mental health resources was itself an important benefit. I share these pieces of my story with humility and understanding that not everyone enjoys the privileges that I do and the knowledge that everyone weathers life’s tragedies in their own way. It is not lost on me that some benefits stemmed from a policy change made by a private insurance provider. The provider made the right decision to waive copays, freeing me from having to choose between cost and my mental health needs. Yet had I been a student who had to move out of state due to COVID-19, access to mental health resources might have been disrupted or cut off. The need for reduced out-of-pocket costs for healthcare is known and needs no repetition, but the benefits of telehealth should be a low-cost component of health plans offered to students and staff (information on telehealth recommendations: https://www.apaservices.org/advocacy/news/congress-patient-telehealth?_ga=2.231013471.1538013741.1619359426-1228006513.1619359425 and http://www.apaservices.org/practice/advocacy/state/leadership/telebehavioral-health-policies.pdf?_ga=2.3385904.1067518037.1620039082-1228006513.1619359425.I’m not a cloud of emotions attached to a pair of good pipetting hands, I’m a human who is choosing to spend my time doing research. This observation is easy to repeat, by trainees as much as by faculty and administrators, but much harder to act upon in the midst of conflicting priorities. Consider my story a success: Because I could access the resources I needed, I was able to prioritize my mental health in the midst of my ambitious research program even during the lockdown.MEET THE AUTHORI have been a postdoc in Stefani Spranger’s lab at MIT for 4 years. Supported by an Irvington Fellowship from the Cancer Research Institute, my work examines the behaviors of dendritic cells in tumors that contribute to productive or unproductive anti-tumor immune responses. My doctoral work examined modes of multicellular invasion controlled by the actin cytoskeleton with Margaret Gardel at the University of Chicago. Earlier I was a lab technician with Thea Tlsty at the University of California, San Francisco, which followed a bachelor’s degree in biology at the University of California, Santa Cruz. I serve on the Committee for Students and Postdocs at the American Society for Cell Biology, where I chair the Outreach Subcommittee.     

Detection of a Novel,Integrative Aging Process Suggests Complex Physiological Integration

Many studies of aging examine biomarkers one at a time, but complex systems theory and network theory suggest that interpretations of individual markers may be context-dependent. Here, we attempted to detect underlying processes governing the levels of many biomarkers simultaneously by applying principal components analysis to 43 common clinical biomarkers measured longitudinally in 3694 humans from three longitudinal cohort studies on two continents (Women’s Health and Aging I & II, InCHIANTI, and the Baltimore Longitudinal Study on Aging). The first axis was associated with anemia, inflammation, and low levels of calcium and albumin. The axis structure was precisely reproduced in all three populations and in all demographic sub-populations (by sex, race, etc.); we call the process represented by the axis “integrated albunemia.” Integrated albunemia increases and accelerates with age in all populations, and predicts mortality and frailty – but not chronic disease – even after controlling for age. This suggests a role in the aging process, though causality is not yet clear. Integrated albunemia behaves more stably across populations than its component biomarkers, and thus appears to represent a higher-order physiological process emerging from the structure of underlying regulatory networks. If this is correct, detection of this process has substantial implications for physiological organization more generally.     

It's a Wonderful Life: A Career as an Academic Scientist

Many years of training are required to obtain a job as an academic scientist. Is this investment of time and effort worthwhile? My answer is a resounding “yes.” Academic scientists enjoy tremendous freedom in choosing their research and career path, experience unusual camaraderie in their lab, school, and international community, and can contribute to and enjoy being part of this historical era of biological discovery. In this essay, I further elaborate by listing my top ten reasons why an academic job is a desirable career for young people who are interested in the life sciences.Students are attracted to careers in academic science because of their interest in the subject rather than for financial reward. But then they hear messages that make them think twice about this career choice. It is difficult to find a job: “Hear about Joe? Three publications as a postdoc and still no job offers.” The NIH pay line is low: “Poor Patricia, she is now on her third submission of her first NIH grant.” Publishing is painful: “Felix''s grad school thesis work has been rejected by three journals!” Academic jobs are demanding: “Cathy has spent her last three weekends writing grants rather than being with her family.”Such scenarios do take place, but if you think that this is what a career in academic science is about, then you need to hear the other side of the story. And this is the purpose of this article—a chance to reflect on the many good things about the academic profession. In the classic movie It''s a Wonderful Life, George Bailey is at the point of despair but regains his confidence through the wisdom and perspective of a guardian angel, Clarence. Doubt and setbacks also are bound to happen in science (as is true of other careers), but pessimism should not rule the day. It is a great profession and there are many happy endings. I would like to share my top ten reasons of why being an academic professor is a “wonderful life,” one that bright and motivated young people should continue to aspire to pursue.     

Is Beauty in the Face of the Beholder?

Opposing forces influence assortative mating so that one seeks a similar mate while at the same time avoiding inbreeding with close relatives. Thus, mate choice may be a balancing of phenotypic similarity and dissimilarity between partners. In the present study, we assessed the role of resemblance to Self’s facial traits in judgments of physical attractiveness. Participants chose the most attractive face image of their romantic partner among several variants, where the faces were morphed so as to include only 22% of another face. Participants distinctly preferred a “Self-based morph” (i.e., their partner’s face with a small amount of Self’s face blended into it) to other morphed images. The Self-based morph was also preferred to the morph of their partner’s face blended with the partner’s same-sex “prototype”, although the latter face was (“objectively”) judged more attractive by other individuals. When ranking morphs differing in level of amalgamation (i.e., 11% vs. 22% vs. 33%) of another face, the 22% was chosen consistently as the preferred morph and, in particular, when Self was blended in the partner’s face. A forced-choice signal-detection paradigm showed that the effect of self-resemblance operated at an unconscious level, since the same participants were unable to detect the presence of their own faces in the above morphs. We concluded that individuals, if given the opportunity, seek to promote “positive assortment” for Self’s phenotype, especially when the level of similarity approaches an optimal point that is similar to Self without causing a conscious acknowledgment of the similarity.