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Funding: Open access funded by Max Planck Society. The authors acknowledge the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy-EXC-2123 Quantum Frontiers - 390837967; Core program PC2-PN23080202 and the PN-III-P2-2.1-PED-2021-0378 (contract no. 575PED/2022) granted projects, financed by the Romanian Ministry of Research, Innovation and Digitalization/UEFISCDI; and the generous allocation of computer time at the computing center of Donostia International Physics Center and at the Red Española de Supercomputación (project QHS-2021-2-0019). A.A. acknowledges support from Project No. PID2019-103910GB-I00, funded by MCIN/AEI/10.13039/501100011033/ and FEDER Una manera de hacer Europa, and Project No. IT-1527-22 funded by the Basque Government. The changes of properties and preferential interactions based on subtle energetic differences are important characteristics of organic molecules, particularly for their functionalities in biological systems. Only slightly energetically favored interactions are important for the molecular adsorption and bonding to surfaces, which define their properties for further technological applications. Here, prochiral tetracenothiophene molecules are adsorbed on the Cu(111) surface. The chiral adsorption configurations are determined by Scanning Tunneling Microscopy studies and confirmed by first-principles calculations. Remarkably, the selection of the adsorption sites by chemically different moieties of the molecules is dictated by the arrangement of the atoms in the first and second surface layers. Furthermore, we have investigated the thermal effects on the direct desulfurization reaction that occurs under the catalytic activity of the Cu substrate. This reaction leads to a product that is covalently bound to the surface in chiral configurations. Publisher PDF

Monoclonal antibodies can provide important pre- or post-exposure protection against infectious disease for those not yet vaccinated or in individuals that fail to mount a protective immune response after vaccination. Inmazeb (REGN-EB3), a three-antibody cocktail against Ebola virus, lessened disease and improved survival in a controlled trial. Here, we present the cryo-EM structure at 3.1 Å of the Ebola virus glycoprotein, determined without symmetry averaging, in a simultaneous complex with the antibodies in the Inmazeb cocktail. This structure allows the modeling of previously disordered portions of the glycoprotein glycan cap, maps the non-overlapping epitopes of Inmazeb, and illuminates the basis for complementary activities and residues critical for resistance to escape by these and other clinically relevant antibodies. We further provide direct evidence that Inmazeb protects against the rapid emergence of escape mutants, whereas monotherapies even against conserved epitopes do not, supporting the benefit of a cocktail versus a monotherapy approach.

The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%-50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike. ispartof: CELL REPORTS vol:42 issue:1 ispartof: location:United States status: published

Om mogelijke risico’s van chemische stoffen in consumentenproducten te kunnen beoordelen, is een goede schatting nodig van de mate waarin mensen eraan blootstaan als zij het product gebruiken. Voor deze schatting heeft het RIVM het computerprogramma ConsExpo ontwikkeld, waarvoor recentelijk een webapplicatie is gemaakt (ConsExpo Web). Hiermee kan bijvoorbeeld de blootstelling van een bepaalde chemische stof binnenshuis tijdens het gebruik van bijvoorbeeld verf, schoonmaakmiddelen of cosmetica worden berekend. Voor de gebruikers van ConsExpo Web zijn Factsheets geschreven waarin standaardmodellen en standaardwaarden (defaults) staan voorgeschreven. Door deze modellen en waarden te gebruiken, wordt de blootstellingsschatting op een transparante en gestandaardiseerde manier uitgevoerd. Er zijn meerdere Factsheets, waarvan nu de Factsheet over doe-het-zelfproducten is herzien. In de Factsheet over doe-het-zelfproducten staan standaardwaarden die bruikbaar zijn om de blootstelling aan een stof in een doe-het-zelfproduct te schatten. Voorbeelden van die waarden zijn de frequentie van het gebruik en hoeveelheden van het gebruikte product. In de herziene versie staan de nieuwste beschikbare databronnen beschreven, is de nieuwe informatie beoordeeld en waar nodig zijn de standaardwaarden aangepast. Parallel aan de publicatie van de herziene doe-het-zelfproducten Factsheet zullen ook de gepubliceerde standaardwaarden in de ConsExpo-database van onder meer lijmen, kitten, vullers, en coatings worden vernieuwd.

Background Eusociality is widely considered to evolve through kin selection, where the reproductive success of an individual’s close relative is favored at the expense of its own. High genetic relatedness is thus considered a prerequisite for eusociality. While ants are textbook examples of eusocial animals, not all ants form colonies of closely related individuals. One such example is the ectatommine ant Rhytidoponera metallica, which predominantly forms queen-less colonies that have such a low intra-colony relatedness that they have been proposed to represent a transient, unstable form of eusociality. However, R. metallica is among the most abundant and widespread ants on the Australian continent. This apparent contradiction provides an example of how inclusive fitness may not by itself explain the maintenance of eusociality and raises the question of what other selective advantages maintain the eusocial lifestyle of this species. Results We provide a comprehensive portrait of the venom of R. metallica and show that the colony-wide venom consists of an exceptionally high diversity of functionally distinct toxins for an ant. These toxins have evolved under strong positive selection, which is normally expected to reduce genetic variance. Yet, R. metallica exhibits remarkable intra-colony variation, with workers sharing only a relatively small proportion of toxins in their venoms. This variation is not due to the presence of chemical castes, but has a genetic foundation that is at least in part explained by toxin allelic diversity. Conclusions Taken together, our results suggest that the toxin diversity contained in R. metallica colonies may be maintained by a form of group selection that selects for colonies that can exploit more resources and defend against a wider range of predators. We propose that increased intra-colony genetic variance resulting from low kinship may itself provide a selective advantage in the form of an expanded pharmacological venom repertoire. These findings provide an example of how group selection on adaptive phenotypes may contribute to maintaining eusociality where a prerequisite for kin selection is diminished.

Additional file 4: Figure S1. Activity of Rm1a and Rm4a. Figure S2. Cytotoxicity of R. metallica aculeatoxin peptides. Figure S3. Gene structures of some ant aculeatoxins. Figure S4. Presence of aculeatoxin alleles among workers from the same R. metallica colony. Figure S5. Phylogeny of R. metallica aculeatoxins estimated from full-length or only signal- and propeptide domains. Table S4. Recombination analysis of R. metallica clades 1–3.Table S5. Primers used to amplify aculeatoxins from R. metallica genomic DNA.

Additional file 2: Table S1. Peptides and proteins identified in the pooled venom of R. metallica. Peptide and protein names and corresponding encoding contig id are provided for each, along with the best BLAST hit against UniProtKB, evidence supporting their presence in the venom, mature molecular weight, expression level (TPM), and the sequence of the mature domain and full prepropeptide. Complete (1) evidence includes identification of the complete mature peptide sequence from either the bottom-up or top-down proteomic experiments, while “partial” includes only partial identification from the bottom-up experiment.

Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons. This work was supported by the University of Queensland Protein Production Facility and the Australian Cancer Research Foundation (ACRF) Cancer Biology Imaging Facility. Financial support was provided by the Australian Research Council (ARC; DP200102377, CE200100012) and the Australian National Health and Medical Research Council (NHMRC) fellowship to I.V. (APP1162503), Project grant (APP1162597) to M.M. and L.D.R., and Medical Research Council grant to J.J.C. and A.L.O. (MR/R011737/1). B.C.A. received funding from an NHMRC CJ Martin Fellowship (APP1162427). J.R.D. received funding through an ARC DECRA fellowship (DE210100422). S.D.H. and S.G.W. were supported by Merit Review Award B9253-C from the U.S. Dept. of Veterans Affairs Rehabilitation Service; The Center for Neuroscience & Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. M.R.I. and D.A.A. received grants from the UK Medical Research Council (MR/S003428/1, MR/W002426/1). J.J.C., S.L., A.M.H., J.Zhao. and J.N.W. were supported by the Wellcome Trust (200183). A.M.H. receives funding from Qatar University (QUSD-CMED-2018/9-3; QUCG-CMED-19/20-4). We thank Dr. Patrick Walsh and Vincent Truong from Anatomic Inc. for helpful discussions on the gene expression profile of Anatomic Inc. iPSC-derived sensory neurons; Virginia Nink (Queensland Brain Institute, University of Queensland) for expert assistance with flow cytometry; and Prof Jenny Stow and Dr Lin Luo (Institute for Molecular Bioscience, University of Queensland) for provision of FANTOM Riken cDNA plasmids. Scopus

Gene editing through repair of CRISPR-Cas9-induced chromosomal breaks offers a means to correct a wide range of genetic defects. Directing repair to produce desirable outcomes by modulating DNA repair pathways holds considerable promise to increase the efficiency of genome engineering. Here, we show that inhibition of non-homologous end joining (NHEJ) or polymerase theta-mediated end joining (TMEJ) can be exploited to alter the mutational outcomes of CRISPR-Cas9. We show robust inhibition of TMEJ activity at CRISPR-Cas9-induced double-strand breaks (DSBs) using ART558, a potent polymerase theta (Polϴ) inhibitor. Using targeted sequencing, we show that ART558 suppresses the formation of microhomology-driven deletions in favor of NHEJ-specific outcomes. Conversely, NHEJ deficiency triggers the formation of large kb-sized deletions, which we show are the products of mutagenic TMEJ. Finally, we show that combined chemical inhibition of TMEJ and NHEJ increases the efficiency of homology-driven repair (HDR)-mediated precise gene editing. Our work reports a robust strategy to improve the fidelity and safety of genome engineering.

This entry looks at the commons (land and other resources that are subject to common use) and wildlife conservation (protecting plant and animal species and their habitats). Historically, the societies of Northeast India had developed sophisticated ideas about shared resources. These were challenged by colonial and postcolonial concepts, an encounter that has many dimensions. Here, this entry focuses on just one: the emergence of zones that the state set aside for the protection of wildlife. ‘Vertical’ conservation spread throughout Northeast India, and this led to tensions between humans over who actually own the local habitat and has the right to fashion it. It also created new confrontations between humans and protected ‘flagship species’. Social scientists suggest that we can mitigate these complications by imagining ‘interspecies communities’ that embrace humans, animals, and plants.

DNA double-strand breaks are a major threat to cellular survival and genetic integrity. In addition to high fidelity repair, three intrinsically mutagenic DNA break repair routes have been described, i.e. single-strand annealing (SSA), polymerase theta-mediated end-joining (TMEJ) and residual ill-defined microhomology-mediated end-joining (MMEJ) activity. Here, we identify C. elegans Helicase Q (HELQ-1) as being essential for MMEJ as well as for SSA. We also find HELQ-1 to be crucial for the synthesis-dependent strand annealing (SDSA) mode of homologous recombination (HR). Loss of HELQ-1 leads to increased genome instability: patchwork insertions arise at deletion junctions due to abortive rounds of polymerase theta activity, and tandem duplications spontaneously accumulate in genomes of helq-1 mutant animals as a result of TMEJ of abrogated HR intermediates. Our work thus implicates HELQ activity for all DSB repair modes guided by complementary base pairs and provides mechanistic insight into mutational signatures common in HR-defective cancers., Microhomology-mediated end-joining (MMEJ) is a poorly defined mutagenic DNA break repair pathway. Here the authors show that the helicase HELQ is essential for polymerase theta-independent MMEJ, single-strand annealing and homologous recombination through synthesis dependent strand annealing in C. elegans.

The COVID-19 pandemic has limited in-lab cognitive testing. While at-home alternatives exist (testing over the phone), differences in test design and delivery complicate direct comparison of most in-lab and at-home tests. Here we describe the design, infrastructure, and implementation of the California Cognitive Assessment Battery (CCAB), a cognitive test battery and administration system. Using automated remote administration over cellular networks, identical computerized cognitive tests can be administered at-home or in the lab.The CCAB comprises 30+ computerized cognitive tests. Test delivery is automated through text, text-to-speech, and graphical instructions; test scoring is also automated, using automatic speech recognition for verbal responses. The test delivery infrastructure consists of two components: the test kit (MS Surface Pro tablet computer with mouse, headset, and cellular dongle) , and a web-browser application "CCAB Examiner," used by the test administrator to control test delivery, view real-time progress and scores, and monitor/chat with the participant via AV feeds. The system is coordinated by a cloud-based server which also delivers the CCAB Examiner application to any browser. Once connected, the "CCAB Test Station" application and CCAB Examiner communicate over a commercial Communication as a Service (CAAS) provider, which transmits AV streams and a text messaging protocol. CCAB Test Station is designed to isolate control, communications, and testing functions for maximal fault tolerance. For example, test administration continues automatically even if Examiner and Test Station lose connection. Test data is uploaded to the server during sessions and re-synced when the test kit returns.442 participants underwent three 90-minute CCAB test sessions on successive days (72 total tests per participant). More than 98% of participants finished all three sessions, and99% of tests were completed. Cellular connection failures occurred occasionally, but98% resulted only in the loss of A/V feeds for the examiner, while tests continued automatically and examiners were able to monitor real-time performance data.The CCAB permits identical tests to be administered at home or in the laboratory, while cellular-network based remote administration allows for nationwide access for all socioeconomic groups, even for people in remote areas without Wi-Fi, or those with limited technical expertise.

BackgroundMany studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring.MethodsThis exploratory case–cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period).ResultsThe analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92–3.90), p = 2.43 × 10−8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38–2.57), p = 7.06 × 10−5] and psychiatric [depressive disorder; HR = 2.11 (1.32–3.35), p = 1.70 × 10−3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54–0.71), p = 1.80 × 10−11].ConclusionsSixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.