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The Anopheles stephensi mosquito is a major vector of malaria in south Asia, the Middle East, and southern China, where it is endemic and is known to transmit both Plasmodium [...]

Until recently, little or no endemic transmission of Plasmodium vivax has been reported in sub-Saharan Africa outside of the Horn of Africa (1). P. vivax was presumed to be largely [...]

The [sigma].sub.2 receptor has attracted intense interest in cancer imaging.sup.1, psychiatric disease.sup.2, neuropathic pain.sup.3-5 and other areas of biology.sup.6,7. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone.sup.2 and the tool compound PB28.sup.8. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 [mu]M, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the [sigma].sub.1 receptor. Crystal structures of two ligands bound to the [sigma].sub.2 receptor confirmed the docked poses. To investigate the contribution of the [sigma].sub.2 receptor in pain, two potent [sigma].sub.2-selective ligands and one potent [sigma].sub.1/[sigma].sub.2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model.sup.9, suggesting that the [sigma].sub.2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology. Crystal structures of the [sigma].sub.2 receptor are determined and used to perform a docking screen of nearly 500 million molecules, identifying [sigma].sub.2-selective ligands and providing insight into the role of [sigma].sub.2 in neuropathic pain., Author(s): Assaf Alon [sup.1] , Jiankun Lyu [sup.2] , Joao M. Braz [sup.3] , Tia A. Tummino [sup.2] [sup.4] , Veronica Craik [sup.3] , Matthew J. O'Meara [sup.5] , Chase [...]

I. INTRODUCTION 418 II. WORKPLACE DISCRIMINATION BASED ON GENDER IDENTITY 420 A. FEDERAL LAW ON EMPLOYMENT DISCRIMINATION AND THE UNITED 420 STATES MILITARY 1. Federal Laws on Employment Discrimination Against [...]

Background Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. Methods and findings We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. Conclusions In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. Trial registration clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165., Author(s): Steve M. Taylor 1,2,3,*, Sarah Korwa 4, Angie Wu 2, Cynthia L. Green 2,5, Betsy Freedman 1, Sheila Clapp 2, Joseph Kipkoech Kirui 4, Wendy P. O'Meara 1,3, Festus [...]

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption.sup.1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human-SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors., Author(s): David E. Gordon [sup.1] [sup.2] [sup.3] [sup.4] , Gwendolyn M. Jang [sup.1] [sup.2] [sup.3] [sup.4] , Mehdi Bouhaddou [sup.1] [sup.2] [sup.3] [sup.4] , Jiewei Xu [sup.1] [sup.2] [sup.3] [sup.4] [...]

Ecologists are keen to build on metropolitan China's increased awareness of the threats posed by environmental neglect. Ecologists are keen to build on metropolitan China's increased awareness of the threats posed by environmental neglect., Author(s): Sarah O'Meara Author Affiliations: Biodiversity's importance is growing in China's urban agenda Many cities in China, such as Xi'an (pictured), have experienced rapid growth in the past few decades. [...]