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Affecting basic tenets of human existence such as health, economic as well as personal security and, of course, reproduction, the COVID-19 pandemic transcended medical specialties and professional disciplines. Yet, six months into the pandemic, there still exists no consensus on how to combat the virus in absence of a vaccine. Facing unprecedented circumstances, and in absence of real evidence on how to proceed, our organization early in the pandemic decided to act independently from often seemingly irrational guidance and, instead, to carefully follow a quickly evolving COVID-19 literature. Here described is the, likely, unique journey of a fertility center that maintained services during peaks of COVID-19 and political unrest that followed. Closely following publicly available data, we recognized relatively early that New York City and other East Coast regions, which during the initial COVID-19 wave between March and May represented the hardest-hit areas in the country, during the second wave, beginning in June and still in progress, remained almost completely unaffected. In contrast, south western regions, almost completely unaffected by the initial wave, were severely affected in the second wave. These two distinctively different infectious phenotypes suggested two likely explanations: The country was witnessing infections with two different SARS-CoV-2 viruses and NYC (along with the East Coast) acquired during the first wave much better immunity to the virus than south western regions. Both hypotheses since have been confirmed: East and West Coasts, indeed, were initially infected by two distinctively different lineages of the virus, with the East Coast lineage being 10-times more infectious. In addition, immunologists discovered an up to this point unknown long-term anti-viral innate (cellular) immune response which offers additional and much broader anti-viral immunity than the classical adaptive immunity via immobilizing antibodies that has been known for decades. Consequently, we predict that in the U.S., even in absence of an available vaccine, COVID-19, by September-October, will be at similarly low levels as are currently seen in NYC and other East Coast regions (generally < 1% test-positivity). We, furthermore, predict that, if current mitigation measures are maintained and no newly aggressive mutation of the virus enters the country, a significant fall-wave of COVID-19, in combination with the usual fall wave of influenza, appears unlikely. To continue serving patients uninterrupted throughout the pandemic, turned for all of our center's staff into a highly rewarding experience, garnered respect and appreciation from patients, and turned into an absolutely unique learning experience.

McrBC complexes are motor-driven nucleases functioning in bacterial self-defense by cleaving foreign DNA. The GTP-specific AAA+protein McrB powers translocation along DNA and its hydrolysis activity is stimulated by its partner nuclease McrC. Here, we report cryo-EM structures of Thermococcus gammatolerans McrB and McrBC, and E. coli McrBC. The McrB hexamers, containing the necessary catalytic machinery for basal GTP hydrolysis, are intrinsically asymmetric. This asymmetry directs McrC binding so that it engages a single active site, where it then uses an arginine/lysine-mediated hydrogen-bonding network to reposition the asparagine in the McrB signature motif for optimal catalytic function. While the two McrBC complexes use different DNA-binding domains, these contribute to the same general GTP-recognition mechanism employed by all G proteins. Asymmetry also induces distinct inter-subunit interactions around the ring, suggesting a coordinated and directional GTP-hydrolysis cycle. Our data provide insights into the conserved molecular mechanisms governing McrB family AAA+motors. The bacterial defense system McrBC is a two-component motor-driven nuclease complex that cleaves foreign DNA. Here, the authors present the structures of the GTP-specific AAA+motor protein McrB and two McrBC complexes and discuss the molecular mechanism of how McrC binding stimulates McrB GTP hydrolysis.

We each developed from a single cell—a fertilized egg—that divided and divided and eventually gave rise to the trillions of cells, of hundreds of types, that constitute the tissues and organs of our adult bodies. Advancing our understanding of the molecular programs underlying the emergence and differentiation of these diverse cell types is of fundamental interest and will affect almost every aspect of biology and medicine.

Human immunodeficiency virus type 1 (HIV-1) Vif recruits a cellular ubiquitin ligase complex to degrade antiviral APOBEC3 enzymes (APOBEC3C-H) and PP2A phosphatase regulators (PPP2R5A to PPP2R5E). While APOBEC3 antagonism is the canonical function of HIV-1 Vif, this viral accessory protein is also known to trigger G(2)/M cell cycle arrest. Vif initiates G(2)/M arrest by degrading multiple PPP2R5 family members, an activity prevalent among diverse HIV-1 and simian immunodeficiency virus (SIV) isolates. Here, computational protein-protein docking was used to delineate a Vif/CBF-beta/PPP2R5 complex in which Vif is predicted to bind the same PPP2R5 surface as physiologic phosphatase targets. This model was tested using targeted mutagenesis of amino acid residues within or adjacent to the putative interface to show loss or retention, respectively, of Vif-induced PPP2R5 degradation activity. Additionally, expression of a peptide that mimics cellular targets of PPP2R5s robustly inhibited Vif-mediated degradation of PPP2R5A but not APOBEC3G. Moreover, live-cell imaging studies examining Vif-mediated degradation of PPP2R5A and APOBEC3G within the same cell revealed that PPP2R5A degradation kinetics are comparable to those of APOBEC3G with a half-life of roughly 6 h postinfection, demonstrating that Vif can concurrently mediate the degradation of distinct cellular substrates. Finally, experiments with a panel of patient-derived Vif isolates indicated that PPP2R5A degradation activity is common in patient-derived isolates. Taken together, these results support a model in which PPP2R5 degradation and global changes in the cellular phosphoproteome are likely to be advantageous for viral pathogenesis. IMPORTANCE A critical function of HIV-1 Vif is to counteract the family of APOBEC3 innate immune proteins. It is also widely accepted that Vif induces G(2)/M cell cycle arrest in several different cell types. Recently, it has been shown that Vif degrades multiple PPP2R5 phosphoregulators to induce the G(2)/M arrest phenotype. Here, computational approaches are used to test a structural model of the Vif/PPP2R5 complex. In addition, imaging studies are used to show that Vif degrades these PPP2R5 substrates in roughly the same time frame as APOBEC3 degradation and that this activity is prevalent in patient-derived Vif isolates. These studies are important by further defining PPP2R5 proteins as a bona fide substrate of HIV-1 Vif.

COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the pro teases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Based on the human tissue specific distribution of SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 and other supportive evidence from the literature, we hypothesize that SARS-CoV-2 host cell entry receptor-ACE2 based mechanism in GI tissue may be involved in COVID-19 (i) in the pathogenesis of digestive symptoms, (ii) in increased diabetic complications, (iii) in disease recurrence.

Many photosynthetic organisms employ a CO2 concentrating mechanism (CCM) to increase the rate of CO2 fixation via the Calvin cycle. CCMs catalyze approximate to 50% of global photosynthesis, yet it remains unclear which genes and proteins are required to produce this complex adaptation. We describe the construction of a functional CCM in a non-native host, achieved by expressing genes from an autotrophic bacterium in an Escherichia coli strain engineered to depend on rubisco carboxylation for growth. Expression of 20 CCM genes enabled E. coli to grow by fixing CO2 from ambient air into biomass, with growth in ambient air depending on the components of the CCM. Bacterial CCMs are therefore genetically compact and readily transplanted, rationalizing their presence in diverse bacteria. Reconstitution enabled genetic experiments refining our understanding of the CCM, thereby laying the groundwork for deeper study and engineering of the cell biology supporting CO2 assimilation in diverse organisms.

The IFITM3 innate immunity protein directly binds presenilin near the active site and upregulates gamma-secretase activity and the production of amyloid-beta, and IFITM3 is upregulated in patients with late-onset Alzheimer's disease. Innate immunity is associated with Alzheimer's disease(1), but the influence of immune activation on the production of amyloid-beta is unknown(2,3). Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a gamma-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-beta. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to gamma-secretase and upregulates its activity, thereby increasing the production of amyloid-beta. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces gamma-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher gamma-secretase activity. The amount of IFITM3 in the gamma-secretase complex has a strong and positive correlation with gamma-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which gamma-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

Leading COVID-19 vaccine candidates have progressed through laboratory tests at record speed. Two early clinical trials suggest that immunization delivers a favourable immune response and safety profile, but questions remain.

The growth of the global terrestrial sink of carbon dioxide has puzzled scientists for decades. We propose that the role of land management practices-from intensive forestry to allowing passive afforestation of abandoned lands-have played a major role in the growth of the terrestrial carbon sink in the decades since the mid twentieth century. The Forest Transition, a historic transition from shrinking to expanding forests, and from sparser to denser forests, has seen an increase of biomass and carbon across large regions of the globe. We propose that the contribution of Forest Transitions to the terrestrial carbon sink has been underestimated. Because forest growth is slow and incremental, changes in the carbon density in forest biomass and soils often elude detection. Measurement technologies that rely on changes in two-dimensional ground cover can miss changes in forest density. In contrast, changes from abrupt and total losses of biomass in land clearing, forest fires and clear cuts are easy to measure. Land management improves over time providing important present contributions and future potential to climate change mitigation. Appreciating the contributions of Forest Transitions to the sequestering of atmospheric carbon will enable its potential to aid in climate change mitigation.