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Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (ACE2) binding site on viral spike receptor-binding domains (RBDs). Potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but moreconserved, cryptic epitope could recognize newly emergent zoonotic sarbecoviruses and variants, but they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (COVID-19) donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding and CDRH3-RBD main-chain H-bond interactions that extend an RBD beta sheet, thus reducing sensitivity to RBD side-chain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.

Background: Persons with severe opioid or cocaine use disorders are particularly vulnerable to morbidity and mortality. Heaviest use of mu-opioid receptor agonists and cocaine typically commences in early adulthood and is preceded by substantial adolescent exposure to cannabis and/or alcohol. Little information exists on the age trajectories of exposure to cannabis or alcohol in persons diagnosed with severe opioid or cocaine use disorders, compared to persons diagnosed with other substance use disorders (unrelated to opioids or cocaine). Method: This observational study had n = 854 volunteers (male = 581, female = 273; >= 18 years of age at the time of interview) and examined the ages of onset of heaviest use of cannabis and alcohol in persons diagnosed by DSM-IV criteria with opioid dependence (OD), both opioid and cocaine dependence (OD + CD) and cocaine dependence (CD). These age trajectory measures were compared to persons with other substance use disorders (primarily cannabis and alcohol use disorders, termed "Any Other Diagnoses"). Results: Unadjusted survival analyses showed persons diagnosed with either OD + CD or CD had earlier onset of heaviest use of cannabis (mean ages of 16.2 and 17.8, respectively) compared to the "Any Other Diagnoses" reference group (mean age = 19.5). A multivariate logistic regression showed that later onset of heaviest use of cannabis was associated with lower odds of being in the OD + CD or CD groups, when compared to the reference group. Conclusions: Persons diagnosed with severe cocaine use disorders or dual opioid and cocaine use disorders exhibit a pattern of heavy and especially early adolescent exposure to cannabis, compared to persons with other substance use disorders.

Background Ant colonies are plagued by a diversity of arthropod guests, which adopt various strategies to avoid or to withstand host attacks. Chemical mimicry of host recognition cues is, for example, a common integration strategy of ant guests. The morphological gestalt and body size of ant guests have long been argued to also affect host hostility, but quantitative studies testing these predictions are largely missing. We here evaluated three guest traits as triggers of host aggression-body size, morphological gestalt, and accuracy in chemical mimicry-in a community of six Eciton army ant species and 29 guest species. We quantified ant aggression towards 314 guests in behavioral assays and, for the same individuals, determined their body size and their accuracy in mimicking ant cuticular hydrocarbon (CHC) profiles. We classified guests into the following gestalts: protective, myrmecoid, staphylinid-like, phorid-like, and larval-shaped. We expected that (1) guests with lower CHC mimicry accuracy are more frequently attacked; (2) larger guests are more frequently attacked; (3) guests of different morphological gestalt receive differing host aggression levels. Results Army ant species had distinct CHC profiles and accuracy of mimicking these profiles was variable among guests, with many species showing high mimicry accuracy. Unexpectedly, we did not find a clear relationship between chemical host similarity and host aggression, suggesting that other symbiont traits need to be considered. We detected a relationship between the guests' body size and the received host aggression, in that diminutive forms were rarely attacked. Our data also indicated that morphological gestalt might be a valuable predictor of host aggression. While most ant-guest encounters remained peaceful, host behavior still differed towards guests in that ant aggression was primarily directed towards those guests possessing a protective or a staphylinid-like gestalt. Conclusion We demonstrate that CHC mimicry accuracy does not necessarily predict host aggression towards ant symbionts. Exploitation mechanisms are diverse, and we conclude that, besides chemical mimicry, other factors such as the guests' morphological gestalt and especially their body size might be important, yet underrated traits shaping the level of host hostility against social insect symbionts.

Embryonic development leads to the reproducible and ordered appearance of complexity from egg to adult. The successive differentiation of different cell types that elaborate this complexity results from the activity of gene networks and was likened by Waddington to a flow through a landscape in which valleys represent alternative fates. Geometric methods allow the formal representation of such landscapes and codify the types of behaviors that result from systems of differential equations. Results from Smale and coworkers imply that systems encompassing gene network models can be represented as potential gradients with a Riemann metric, justifying the Waddington metaphor. Here, we extend this representation to include parameter dependence and enumerate all three-way cellular decisions realizable by tuning at most two parameters, which can be generalized to include spatial coordinates in a tissue. All diagrams of cell states vs. model parameters are thereby enumerated. We unify a number of standard models for spatial pattern formation by expressing them in potential form (i.e., as topographic elevation). Turing systems appear nonpotential, yet in suitable variables the dynamics are low dimensional and potential. A time-independent embedding recovers the original variables. Lateral inhibition is described by a saddle point with many unstable directions. A model for the patterning of the Drosophila eye appears as relaxation in a bistable potential. Geometric reasoning provides intuitive dynamic models for development that are well adapted to fit time-lapse data.

Salmonella is one of the most common foodborne pathogens around the world. Phages are envisioned as a new strategy to control foodborne pathogenic bacteria and food safety. A Salmonella specific lytic phage vB_SalSLPSTLL (LPSTLL) was selected for food applications on the basis of lytic range, lytic efficiency, functional stability and characteristics. Phage LPSTLL was able to lyse 11 Salmonella serotypes, which represents the broadest range reported Salmonella phages, and was able to suppress the growth of Salmonella enterica in liquid culture over nine hours. LPSTLL exhibited rapid reproductive activity with a short latent period and a large burst size in one-step growth experiment. LPSTLL remained active over a pH range of 3.0 to 12.0, and at incubation temperatures up to 60 degrees C for 60 min, indicating wide applicability for food processing and storage. Significant reductions of viable Salmonella were observed in diverse foods (milk, apple juice, chicken and lettuce) with reductions up to 2.8 log CFU/mL recorded for milk. Sensory evaluation indicated that treatment with phage LPSTLL did not alter the visual or tactile quality of food matrices. Genome analysis of LPSTLL indicated the absence of any virulence or antimicrobial resistance genes. Genomic comparisons suggest phage LPSTLL constitutes a novel member of a new genus, the LPSTLLvirus with the potential for Salmonella biocontrol in the food industry.

Background: Atopic dermatitis (AD) is a common disease, with particularly high prevalence found in Africa. It is increasingly recognized that patients with AD of different ethnic backgrounds have unique molecular signatures in the skin, potentially accounting for treatment response variations. Nevertheless, the skin profile of patients with AD from Africa is unknown, hindering development of new treatments targeted to this patient population. Objective: To characterize the skin profile of patients with AD from Africa. Methods: Gene expression studies, including RNA sequencing (using threshold of fold change of >2 and false discovery rate of <0.05) and real-time polymerase chain reaction, were performed on skin biopsies of Tanzanian patients with moderate-to-severe AD and controls. Results: Tanzanian AD skin presented robust up-regulations of multiple key mediators of both T helper 2 (TH2) (interleukin 13 [IL-13], IL-10, IL-4R, CCL13,CCL17,CCL18,CCL26) and T(H)22 (IL22, S100As) pathways. Markers related to T(H)17 and IL-23 (IL-17A, IL-23A, IL-12, PI3, DEFB4B) and T(H)1 (interferon gamma, CXCL9,CXCL10, CXCL11) were also significantly overexpressed in AD tissues (FDR<.05), albeit to a lesser extent. IL-36 isoforms revealed substantial up-regulations in African skin. The barrier fingerprint of Tanzanian AD revealed no suppression of hallmark epidermal barrier differentiation genes, such as filaggrin, loricrin, and periplakin, with robust attenuation of lipid metabolism genes (ie, AWAT1). Conclusion: The skin phenotype of Tanzanian patientswith AD is consistentwith that of African Americans, exhibiting dominant T(H)2 and T(H)22 skewing, minimal dysregulation of terminal differentiation, and even broader attenuation of lipid metabolism-related products. These data highlight the unique characteristic of AD in Black individuals and the need to develop unique treatments targeting patients with AD fromthese underrepresented populations. (C) 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Objectives: Surveillance studies for Staphylococcus aureus carriage are a primary tool to survey the preva-lence of methicillin-resistant S. aureus (MRSA) in the general population, patients and healthcare workers. We have previously reported S. aureus carriage in various African countries, including Cape Verde. Methods: Whole-genome sequences of 106 S. aureus isolates from Cape Verde were determined. Results: Staphylococcus aureus carriage isolates in Cape Verde show high genetic variability, with the de-tection of 27 sequence types (STs) and three primary genetic clusters associated with ST152, ST15 and ST5. One transmission event with less than eight core-genome single nucleotide polymorphisms (cgSNP) differences was detected among the ST5-VI MRSA lineage. Genetic analysis confirmed the phenotypic resistance and allowed the identification of six independent events of plasmid or transposon loss asso-ciated with the deletion of blaZ in nine isolates. In the four ST5 MRSA isolates, loss of the blaZ plasmid coincided with the acquisition of SCCmec type VI and an unusual penicillin phenotype with a minimum inhibitory concentration (MIC) at the breakpoint, indicating an adaptation trend in this endemic lineage. Similar events of blaZ plasmid loss, with concomitant acquisition SCCmec elements, were detected among ST5 isolates from different geographical origins. Conclusion: Overall, the genome data allowed to place isolates in a phylogenetic context and to iden-tify different blaZ gene deletions associated with plasmid or transposon loss. Genomic analysis unveiled adaptation and evolution trends, namely among emerging MRSA lineages in the country, which deserve additional consideration in the design of future infection control protocols. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

The evolution of mass raiding has allowed army ants to become dominant arthropod predators in the tropics. Although a century of research has led to many discoveries about behavioural, morphological and physiological adaptations in army ants, almost nothing is known about the molecular basis of army ant biology. Here we report the genome of the iconic New World army ant Eciton burchellii, and show that it is unusually compact, with a reduced gene complement relative to other ants. In contrast to this overall reduction, a particular gene subfamily (9-exon ORs) expressed predominantly in female antennae is expanded. This subfamily has previously been linked to the recognition of hydrocarbons, key olfactory cues used in insect communication and prey discrimination. Confocal microscopy of the brain showed a corresponding expansion in a putative hydrocarbon response centre within the antennal lobe, while scanning electron microscopy of the antenna revealed a particularly high density of hydrocarbon-sensitive sensory hairs. E. burchellii shares these features with its predatory and more cryptic relative, the clonal raider ant. By integrating genomic, transcriptomic and anatomical analyses in a comparative context, our work thus provides evidence that army ants and their relatives possess a suite of modifications in the chemosensory system that may be involved in behavioural coordination and prey selection during social predation. It also lays the groundwork for future studies of army ant biology at the molecular level.

The bacterial mechanosensitive channel of small conductance (MscS) has been extensively studied to understand how mechanical forces are converted into the conformational changes that underlie mechanosensitive (MS) channel gating. We showed that lipid removal by p-cyclodextrin can mimic membrane tension. Here, we show that all cyclodextrins (CDs) can activate reconstituted Escherichia coli MscS, that MscS activation by CDs depends on CD-mediated lipid removal, and that the CD amount required to gate MscS scales with the channel's sensitivity to membrane tension. Importantly, cholesterol-loaded CDs do not activate MscS. CD-mediated lipid removal ultimately causes MscS desensitization, which we show is affected by the lipid environment. While many MS channels respond to membrane forces, generalized by the "force-from-lipids" principle, their different molecular architectures suggest that they use unique ways to convert mechanical forces into conformational changes. To test whether CDs can also be used to activate other MS channels, we chose to investigate the mechanosensitive channel of large conductance (MscL) and demonstrate that CDs can also activate this structurally unrelated channel. Since CDs can open the least tension-sensitive MS channel, MscL, they should be able to open any MS channel that responds to membrane tension. Thus, CDs emerge as a universal tool for the structural and functional characterization of unrelated MS channels.

Patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) generally have poor overall survival (OS). Interventions that result in improved OS after relapse are not well established. The efficacy of second cellular therapy and specific indications are matters of debate. This study was conducted to evaluate factors associated with postrelapse survival and the efficacy of a second course of cellular therapy. We retrospectively analyzed consecutive patients with AML and MDS who underwent a first allo-HCT between 2010 and 2017 at our center but subsequently relapsed. One hundred and four patients with AML and 44 patients with MDS were included (total n = 148). Bone marrow (BM) and peripheral blood stem cell grafts were either unmodified or T cell-depleted (TCD) by CD34(+) selection ex vivo. Forty-five patients (30.4%) received a second cellular therapy after relapse, either a second allo-HCT (n = 28; 18.9%) or donor leukocyte infusion (DLI) (n = 17; 11.5%). The median age at transplantation was 60 years (range, 24 to 78 years). The median time to relapse (TTR) after transplantation was 6.5 months (range, 1 to 60.9 months), and the ensuing median OS was 6 months (95% confidence interval [CI], 4.8 to 8.9 months). In univariable analysis, longer TTR, relapse type (measurable residual disease versus morphologic), relapse occurring in the most recent years, and receipt of cellular therapy after relapse were associated with better outcomes, whereas adverse cytogenetics and/or abnormality of TP53, as well as NPM1 mutation in patients with AML, were associated with adverse outcomes. Relapse type, year of relapse, and a variable resulting from the combination of TTR and receipt of second cellular therapy remained significantly associated with postrelapse survival in multivariable analysis. In a separate multivariable model, adjusted only for TTR, relapse type, and receipt of second cellular therapy, an adverse effect of NPM1 mutation on survival was confirmed. We could not show an effect of post-transplantation maintenance on survival after relapse. In both univariable and multivariable analysis, we found a positive association for second cellular therapy with survival after relapse in patients who relapsed early (<6 months) after allo-HCT and a similar trend in patients who relapsed late (>12 months) after transplantation. Two-year OS after a second cellular therapy was 44.9% (95% CI, 28.5% to 61.4%), and it was significantly better in patients with <5% BM blasts before cell infusion. We could not show different effects on survival after second cellular therapy for DLI versus second allo-HCT in univariable analysis. Survival after relapse is improving over time, but this remains a challenging event, especially for patients who relapse early after transplantation. We found that a second cellular therapy could offer a benefit even in these cases. Nonetheless, more research is needed to clarify the most appropriate treatment choices after relapse. These are probably driven by underlying genetic and immunologic conditions, which should be the focus of future studies. (c) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)