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Neuroendocrine prostate cancer (NEPC) is thought to arise as prostate adenocarcinoma cells transdifferentiate into neuroendocrine (NE) cells to escape potent anti-androgen therapies however, the exact molecular events accompanying NE transdifferentiation and their plasticity remain poorly defined. Cell fate regulator ASCL1/hASH1’s expression was markedly induced in androgen deprived (AD) LNCaP cells and prominent nuclear localisation accompanied acquisition of the NE-like morphology and expression of NE markers (NSE). By contrast, androgen-insensitive PC3 and DU145 cells displayed clear nuclear hASH1 localisation under control conditions that was unchanged by AD, suggesting AR signalling negatively regulated hASH1 expression and localisation. Synthetic androgen (R1881) prevented NE transdifferentiation of AD LNCaP cells and markedly suppressed expression of key regulators of lineage commitment and neurogenesis (REST and ASCL1/hASH1). Post-AD, NE LNCaP cells rapidly lost NE-like morphology following R1881 treatment, yet ASCL1/hASH1 expression was resistant to R1881 treatment and hASH1 nuclear localisation remained evident in apparently dedifferentiated LNCaP cells. Consequently, NE cells may not fully revert to an epithelial state and retain key NE-like features, suggesting a “hybrid” phenotype. This could fuel greater NE transdifferentiation, therapeutic resistance and NEPC evolution upon subsequent androgen deprivation. Such knowledge could facilitate CRPC tumour stratification and identify targets for more effective NEPC management.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health 1 and the medical countermeasures available so far are limited 2 , 3 . Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-2 4 . Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein 5 , and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (S RBD ) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the S RBD , as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the S RBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents. An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans.

Scholarly efforts to understand conspiracy theories have grown significantly in recent years, and there is now a broad and interdisciplinary literature. In reviewing this body of work, we ask three specific questions. First, what factors are associated with conspiracy beliefs? Our review of the literature shows that conspiracy beliefs result from a range of psychological, political, and social factors. Next, how are conspiracy theories communicated? Here, we explain how conspiracy theories are shared among individuals and spread through traditional and social media platforms. Next, what are the societal risks and rewards associated with conspiracy theories? By focusing on politics and science, we argue that conspiracy theories do more harm than good. We conclude by suggesting several promising avenues for future research.

Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date 1 , 2 . In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes on the basis of their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of advanced antibody discovery platforms. A platform for rapid antibody discovery enabled the isolation of hundreds of human monoclonal antibodies against SARS-CoV-2 and the prioritization of potent antibody candidates for clinical trials in patients with COVID-19.

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir–lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir–lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352. Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI −5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [−4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related. The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated. ViiV Healthcare and Janssen R&D.

Purpose A primary barrier to improving exome sequencing diagnostic rates is the interpretation of variants of uncertain clinical significance. We aimed to determine the contribution of integrated untargeted metabolomics in the analysis of exome sequencing data by retrospective analysis of patients evaluated by both exome sequencing and untargeted metabolomics within the same clinical laboratory. Methods Exome sequencing and untargeted metabolomic data were collected and analyzed for 170 patients. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance in genes associated with a biochemical phenotype were extracted. Metabolomic data were evaluated to determine if these variants resulted in biochemical abnormalities that could be used to support their interpretation using current American College of Genetics and Genomics (ACMG) guidelines. Results Metabolomic data contributed to the interpretation of variants in 74 individuals (43.5%) over 73 different genes. The data allowed for the reclassification of 9 variants as likely benign, 15 variants as likely pathogenic, and 3 variants as pathogenic. Metabolomic data confirmed a clinical diagnosis in 21 cases, for a diagnostic rate of 12.3% in this population. Conclusion Untargeted metabolomics can serve as a useful adjunct to exome sequencing by providing valuable functional data that may not otherwise be clinically available, resulting in improved variant classification.

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1–reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493–0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.

The transcription factor BMAL1 is a core component of the molecular clock, regulating biological pathways that drive 24 h (circadian) rhythms in behaviour and physiology. The molecular clock has a profound influence on innate immune function, and circadian disruption is linked with increased incidence of multiple sclerosis (MS). However, the mechanisms underlying this association are unknown. Here we show that BMAL1 and time-of-day regulate the accumulation and activation of various immune cells in a CNS autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). In myeloid cells, BMAL1 maintains anti-inflammatory responses and reduces T cell polarization. Loss of myeloid BMAL1 or midday immunizations to induce EAE create an inflammatory environment in the CNS through expansion and infiltration of IL-1β-secreting CD11b + Ly6C hi monocytes, resulting in increased pathogenic IL-17 + /IFN-γ + T cells. These findings demonstrate the importance of the molecular clock in modulating innate and adaptive immune crosstalk under autoimmune conditions. Circadian controls of immune responses by the molecular clock have been reported, but the underlying mechanisms are unclear. Here the authors show that the master circadian gene, Bmal1 , is essential for modulating the homeostasis of myeloid cells to control pro-inflammatory IL-17 + /IFN-γ + T cells in autoimmunity.

Syntheses of carbonate chemistry spatial patterns are important for predicting ocean acidification impacts, but are lacking in coastal oceans. Here, we show that along the North American Atlantic and Gulf coasts the meridional distributions of dissolved inorganic carbon (DIC) and carbonate mineral saturation state (Ω) are controlled by partial equilibrium with the atmosphere resulting in relatively low DIC and high Ω in warm southern waters and the opposite in cold northern waters. However, pH and the partial pressure of CO 2 ( p CO 2 ) do not exhibit a simple spatial pattern and are controlled by local physical and net biological processes which impede equilibrium with the atmosphere. Along the Pacific coast, upwelling brings subsurface waters with low Ω and pH to the surface where net biological production works to raise their values. Different temperature sensitivities of carbonate properties and different timescales of influencing processes lead to contrasting property distributions within and among margins. Anthropogenic CO 2 is acidifying the ocean, but knowledge of the carbonate properties underlying these dynamics in coastal oceans is lacking. Here, the authors reveal spatial distribution patterns and variability in carbonate chemistry along North America’s coasts.