Conformational Flexibility in the Enterovirus RNA Replication Platform

A presumed RNA cloverleaf (5′CL), located at the 5′-most end of the noncoding region of the enterovirus genome, is the primary established site for initiation of genomic replication. Stem–loop B (SLB) and stem–loop D (SLD), the two largest stem–loops within the 5′CL, serve as recognition sites for protein interactions that are essential for replication. Here we present the solution structure of rhinovirus serotype 14 5′CL using a combination of nuclear magnetic resonance spectroscopy and small-angle X-ray scattering. In the absence of magnesium, the structure adopts an open, somewhat extended conformation. In the presence of magnesium, the structure compacts, bringing SLB and SLD into close contact, a geometry that creates an extensive accessible major groove surface, and permits interaction between the proteins that target each stem–loop

Latarjet Surgery Leads to Decreased Rates of Subjective Instability Compared to Bankart Repair with Concomitant Remplissage

Background: Predictive factors for performing remplissage concomitantly with arthroscopic Bankart repair include the presence of humeral or glenoid defects \u3e11% and/or revision surgery. International and societal consensus statements support these findings, as surgeons recommend the Latarjet procedure for patients with significant glenoid bone loss (\u3e15-20%) while remplissage is recommended for patients with off-track or engaging Hill-Sachs lesions without significant glenoid bone loss. While several studies have compared outcomes between Latarjet surgery and remplissage, these studies have only evaluated patients with engaging Hill-Sachs lesions, not consecutive patient cohorts indicated for each surgery. Purpose: To compare rates of recurrent instability, re-operation, revision, and return to play (RTP), as well as patient-reported outcomes including the American Shoulder and Elbow Surgeon Score (ASES), Single Assessment Numeric Evaluation (SANE), and Oxford Shoulder Instability Score (OSI) between Latarjet surgery and arthroscopic labral repair plus remplissage surgery (Remplissage) patients

Ethical considerations for integrating multimodal computer perception and neurotechnology

BackgroundArtificial intelligence (AI)-based computer perception technologies (e.g., digital phenotyping and affective computing) promise to transform clinical approaches to personalized care in psychiatry and beyond by offering more objective measures of emotional states and behavior, enabling precision treatment, diagnosis, and symptom monitoring. At the same time, passive and continuous nature by which they often collect data from patients in non-clinical settings raises ethical issues related to privacy and self-determination. Little is known about how such concerns may be exacerbated by the integration of neural data, as parallel advances in computer perception, AI, and neurotechnology enable new insights into subjective states. Here, we present findings from a multi-site NCATS-funded study of ethical considerations for translating computer perception into clinical care and contextualize them within the neuroethics and neurorights literatures.MethodsWe conducted qualitative interviews with patients (n = 20), caregivers (n = 20), clinicians (n = 12), developers (n = 12), and clinician developers (n = 2) regarding their perspective toward using PC in clinical care. Transcripts were analyzed in MAXQDA using Thematic Content Analysis.ResultsStakeholder groups voiced concerns related to (1) perceived invasiveness of passive and continuous data collection in private settings; (2) data protection and security and the potential for negative downstream/future impacts on patients of unintended disclosure; and (3) ethical issues related to patients’ limited versus hyper awareness of passive and continuous data collection and monitoring. Clinicians and developers highlighted that these concerns may be exacerbated by the integration of neural data with other computer perception data.DiscussionOur findings suggest that the integration of neurotechnologies with existing computer perception technologies raises novel concerns around dignity-related and other harms (e.g., stigma, discrimination) that stem from data security threats and the growing potential for reidentification of sensitive data. Further, our findings suggest that patients’ awareness and preoccupation with feeling monitored via computer sensors ranges from hypo- to hyper-awareness, with either extreme accompanied by ethical concerns (consent vs. anxiety and preoccupation). These results highlight the need for systematic research into how best to implement these technologies into clinical care in ways that reduce disruption, maximize patient benefits, and mitigate long-term risks associated with the passive collection of sensitive emotional, behavioral and neural data

Structural and Functional MRI Differences in Master Sommeliers: A Pilot Study on Expertise in the Brain

Our experiences, even as adults, shape our brains. Regional differences have been found in experts, with the regions associated with their particular skill-set. Functional differences have also been noted in brain activation patterns in some experts. This study uses multimodal techniques to assess structural and functional patterns that differ between experts and nonexperts. Sommeliers are experts in wine and thus in olfaction. We assessed differences in Master Sommeliers’ brains, compared with controls, in structure and also in functional response to olfactory and visual judgment tasks. MRI data were analyzed using voxel-based morphometry as well as automated parcellation to assess structural properties, and group differences between tasks were calculated. Results indicate enhanced volume in the right insula and entorhinal cortex, with the cortical thickness of the entorhinal correlating with experience. There were regional activation differences in a large area involving the right olfactory and memory regions, with heightened activation specifically for sommeliers during an olfactory task. Our results indicate that sommeliers’ brains show specialization in the expected regions of the olfactory and memory networks, and also in regions important in integration of internal sensory stimuli and external cues. Overall, these differences suggest that specialized expertise and training might result in enhancements in the brain well into adulthood. This is particularly important given the regions involved, which are the first to be impacted by many neurodegenerative diseases

Forest disturbance and vector transmitted diseases in thelowland tropical rainforest of central Panama

objective To explore possible changes in the community attributes of haematophagous insects as afunction of forest disturbance. We compare the patterns of diversity and abundance, plus thebehavioural responses of three epidemiologically distinct vector assemblages across sites depictingvarious levels of forest cover.methods Over a 3-year period, we sampled mosquitoes, sandflies and biting-midges in forestedhabitats of central Panama. We placed CDC light traps in the forest canopy and in the understorey togather blood-seeking females.results We collected 168 405 adult haematophagous dipterans in total, including 26 genera and 86species. Pristine forest settings were always more taxonomically diverse than the disturbed forest sites,confirming that disturbance has a negative impact on species richness. Species of Phlebotominae andCulicoides were mainly classified as climax (i.e. forest specialist) or disturbance-generalist, which tendto decrease in abundance along with rising levels of disturbance. In contrast, a significant portion ofmosquito species, including primary and secondary disease vectors, was classified as colonists (i.e.disturbed-areas specialists), which tend to increase in numbers towards more disturbed forest habitats.At pristine forest, the most prevalent species of Phlebotominae and Culicoides partitioned the verticalniche by being active at the forest canopy or in the understorey; yet this pattern was less clear indisturbed habitats. Most mosquito species were not vertically stratified in their habitat preference.conclusion We posit that entomological risk and related pathogen exposure to humans is higher inpristine forest scenarios for Culicoides and Phlebotominae transmitted diseases, whereas forestdisturbance poses a higher entomological risk for mosquito-borne infections. This suggests that theDilution Effect Hypothesis (DEH) does not apply in tropical rainforests where highly abundant, yetunrecognised insect vectors and neglected zoonotic diseases occur. Comprehensive, community levelentomological surveillance is, therefore, the key for predicting potential disease spill over in scenariosof pristine forest intermixed with anthropogenic habitats. We suggest that changes in forest qualityshould also be considered when assessing arthropod-borne disease transmission risk.objective To explore possible changes in the community attributes of haematophagous insects as afunction of forest disturbance. We compare the patterns of diversity and abundance, plus thebehavioural responses of three epidemiologically distinct vector assemblages across sites depictingvarious levels of forest cover.methods Over a 3-year period, we sampled mosquitoes, sandflies and biting-midges in forestedhabitats of central Panama. We placed CDC light traps in the forest canopy and in the understorey togather blood-seeking females.results We collected 168 405 adult haematophagous dipterans in total, including 26 genera and 86species. Pristine forest settings were always more taxonomically diverse than the disturbed forest sites,confirming that disturbance has a negative impact on species richness. Species of Phlebotominae andCulicoides were mainly classified as climax (i.e. forest specialist) or disturbance-generalist, which tendto decrease in abundance along with rising levels of disturbance. In contrast, a significant portion ofmosquito species, including primary and secondary disease vectors, was classified as colonists (i.e.disturbed-areas specialists), which tend to increase in numbers towards more disturbed forest habitats.At pristine forest, the most prevalent species of Phlebotominae and Culicoides partitioned the verticalniche by being active at the forest canopy or in the understorey; yet this pattern was less clear indisturbed habitats. Most mosquito species were not vertically stratified in their habitat preference.conclusion We posit that entomological risk and related pathogen exposure to humans is higher inpristine forest scenarios for Culicoides and Phlebotominae transmitted diseases, whereas forestdisturbance poses a higher entomological risk for mosquito-borne infections. This suggests that theDilution Effect Hypothesis (DEH) does not apply in tropical rainforests where highly abundant, yetunrecognised insect vectors and neglected zoonotic diseases occur. Comprehensive, community levelentomological surveillance is, therefore, the key for predicting potential disease spill over in scenariosof pristine forest intermixed with anthropogenic habitats. We suggest that changes in forest qualityshould also be considered when assessing arthropod-borne disease transmission risk

Root microbiota drive direct integration of phosphate stress and immunity

Plants live in biogeochemically diverse soils that harbor extraordinarily diverse microbiota. Plant organs associate intimately with a subset of these microbes; this community’s structure can be altered by soil nutrient content. Plant-associated microbes can compete with the plant and with each other for nutrients; they can also provide traits that increase plant productivity. It is unknown how the plant immune system coordinates microbial recognition with nutritional cues during microbiome assembly. We establish that a genetic network controlling phosphate stress response influences root microbiome community structure, even under non-stress phosphate conditions. We define a molecular mechanism regulating coordination between nutrition and defense in the presence of a synthetic bacterial community. We demonstrate that the master transcriptional regulators of phosphate stress response in Arabidopsis also directly repress defense, consistent with plant prioritization of nutritional stress over defense. Our work will impact efforts to define and deploy useful microbes to enhance plant performance

Design of synthetic bacterial communities for predictable plant phenotypes

Specific members of complex microbiota can influence host phenotypes, depending on both the abiotic environment and the presence of other microorganisms. Therefore, it is challenging to define bacterial combinations that have predictable host phenotypic outputs. We demonstrate that plant-bacterium binary-association assays inform the design of small synthetic communities with predictable phenotypes in the host. Specifically, we constructed synthetic communities that modified phosphate accumulation in the shoot and induced phosphate starvation-responsive genes in a predictable fashion. We found that bacterial colonization of the plant is not a predictor of the plant phenotypes we analyzed. Finally, we demonstrated that characterizing a subset of all possible bacterial synthetic communities is sufficient to predict the outcome of untested bacterial consortia. Our results demonstrate that it is possible to infer causal relationships between microbiota membership and host phenotypes and to use these inferences to rationally design novel communitie

How animal agriculture stakeholders define, perceive, and are impacted by antimicrobial resistance: challenging the Wellcome Trust’s Reframing Resistance principles

Humans, animals, and the environment face a universal crisis: antimicrobial resistance (AR). Addressing AR and its multidisciplinary causes across many sectors including in human and veterinary medicine remains underdeveloped. One barrier to AR efforts is an inconsistent process to incorporate the plenitude of stakeholders about what AR is and how to stifle its development and spread—especially stakeholders from the animal agriculture sector, one of the largest purchasers of antimicrobial drugs. In 2019, The Wellcome Trust released Reframing Resistance: How to communicate about antimicrobial resistance effectively (Reframing Resistance), which proposed the need to establish a consistent and harmonized messaging effort that describes the AR crisis and its global implications for health and wellbeing across all stakeholders. Yet, Reframing Resistance does not specifically engage the animal agriculture community. This study investigates the gap between two principles recommended by Reframing Resistance and animal agriculture stakeholders. For this analysis, the research group conducted 31 semi-structured interviews with a diverse group of United States animal agriculture stakeholders. Participants reported attitudes, beliefs, and practices about a variety of issues, including how they defined AR and what entities the AR crisis impacts most. Exploration of Reframing Resistance’s Principle 2, “explain the fundamentals succinctly” and Principle 3, “emphasis that this is universal issue; it can affect anyone, including you” reveals disagreement in both the fundamentals of AR and consensus of “who” the AR crisis impacts. Principle 2 may do better to acknowledge that animal agriculture stakeholders espouse a complex array of perspectives that cannot be summed up in a single perspective or principle. As a primary tool to combat AR, behavior change must be accomplished first through outreach to stakeholder groups and understanding their perspectives

Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni