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Abstract Background Loss of communication with loved ones and carers is one of the most isolating and debilitating effects of many neurological disorders. Assistive technology (AT) supports individuals with communication, but the acceptability of AT solutions is highly variable. In this paper a novel ear based control method of AT, the concept of ’EarSwitch’, is presented. This new approach is based on detecting ear rumbling, which is the voluntary contraction of the tensor tympani muscle (TTM), resulting in observable movement of the eardrum and a dull rumbling sound. ’EarSwitch’ has the potential to be a discreet method that can complement existing AT control methods. However, only a subset of the population can ear rumble and little is known about the ability of rumbling in populations with neurological disorders. Methods To explore the viability of the ’EarSwitch’ concept as an AT control method we conducted in-depth online surveys with (N=1853) respondents from the general population and (N=170) respondents with self-declared neurological disorders including Motor Neurone Disease (MND) and Multiple Sclerosis (MS).This is the largest ever study to explore ear rumbling and the first to explore whether rumbling is preserved among individuals with neurological disorders. In addition, we validated rumbling, and investigated usability of the ’EarSwitch’ concept as a control input, using in-person otoscopic examination with a subset of participants. Results A significant proportion of the population with neurological disorders could benefit from ’EarSwitch’ controllable AT. The upper bound prevalence of the ability to rumble without accompanying movements was 55% in the general population, 38% in the neurological population, and 20% of participants with MND (N=95) reported this ability. During the validation procedure, participants achieved high accuracy in self-reporting the ability to rumble (80%) and proved concept of using the ’EarSwitch’ method to control a basic interface. Discussion ’EarSwitch’ is a potential new AT control method control, either by itself or as a supplement to other existing methods. Results demonstrate self-reported ear rumbling is present among patients with different neurological disorders, including MND. Further research should explore how well the ability to rumble is preserved in different types and stages of neurological disorders.

Abstract New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC50 of 0.3 – 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv.

Abstract Older adults struggle with tasks requiring selective attention amidst distractions. Experimental observations about age-related decline have relied on visual search designs using static displays. However, natural environments often embed dynamic structures that afford proactive anticipation of task-relevant information. We investigate the capacity to benefit from spatiotemporal predictions across the adult lifespan. Participants (N = 300, aged 20–80) searched for multiple targets that faded in and out of displays among distractors. Half of the targets appeared at a fixed time and approximate location, whereas others appeared unpredictably. Overall search performance was reduced with age. Nevertheless, prediction-led behaviour, reflected in a higher detection of predictable targets, remained resistant to aging. Predictions were most pronounced when targets appeared in quick succession. When evaluating response speed, predictions were also significant but reduced with progressing age. While our findings confirm an age-related decline, we identified clear indications for proactive attentional guidance throughout adulthood.

Abstract Enzymatic nanomotors harvest kinetic energy through the catalysis of chemical fuels. When a drop containing nanomotors is placed in a fuel-rich environment, they assemble into ordered groups and exhibit intriguing collective behaviour akin to the bioconvection of aerobic microorganismal suspensions. This collective behaviour presents numerous advantages compared to individual nanomotors, including expanded coverage and prolonged propulsion duration. However, the physical mechanisms underlying the collective motion have yet to be fully elucidated. Our study investigates the formation of enzymatic swarms using experimental analysis and computational modelling. We show that the directional movement of enzymatic nanomotor swarms is due to their solutal buoyancy. We investigate various factors that impact the movement of nanomotor swarms, such as particle concentration, fuel concentration, fuel viscosity, and vertical confinement. We examine the effects of these factors on swarm self-organization to gain a deeper understanding. In addition, the urease catalysis reaction produces ammonia and carbon dioxide, accelerating the directional movement of active swarms in urea compared with passive ones in the same conditions. The numerical analysis agrees with the experimental findings. Our findings are crucial for the potential biomedical applications of enzymatic nanomotor swarms, ranging from enhanced diffusion in bio-fluids and targeted delivery to cancer therapy.

Abstract CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.

Abstract Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age.

Abstract As synthetic biology expands, creating “drag-and-drop” regulatory tools that can achieve diverse regulatory outcomes are paramount. Herein, we develop a approach for engineering complex post-transcriptional control by rewiring the Carbon Storage Regulatory (Csr) Network of Escherichia coli. We co-opt native interactions of the Csr Network to establish post-transcriptional logic gates and achieve complex bacterial regulation. First, we rationally engineer RNA-protein interactions to create a genetic toolbox of 12 BUFFER Gates that achieves a 15-fold range of expression. Subsequently, we develop a Csr-regulated NOT Gate by integrating a cognate 5’ UTR that is natively Csr-activated into our platform. We then deploy the BUFFER and NOT gates to build a bi-directional regulator, two input Boolean Logic gates OR, NOR, AND and NAND and a pulse-generating circuit. Last, we port our Csr-regulated BUFFER Gate into three industrially relevant bacteria simply by leveraging the conserved Csr Network in each species.

Abstract In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet treatable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edit human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplant them into rodent models of chronic lesions. Edited hOPCs display enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. We show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.

Abstract Background The extreme environment of the International Space Station (ISS) puts selective pressure on microorganisms unintentionally introduced during its 20+ years of service as a low-orbit science platform and human habitat. Such pressure leads to the development of new features not found in the Earth-bound relatives, which enable them to adapt to unfavorable conditions. Results In this study, we generated the functional annotation of the genomes of five newly identified species of Gram-positive bacteria, four of which are non-spore-forming and one spore-forming, all isolated from the ISS. Using a deep-learning based tool—deepFRI—we were able to functionally annotate close to 100% of protein-coding genes in all studied species, overcoming other annotation tools. Our comparative genomic analysis highlights common characteristics across all five species and specific genetic traits that appear unique to these ISS microorganisms. Proteome analysis mirrored these genomic patterns, revealing similar traits. The collective annotations suggest adaptations to life in space, including the management of hypoosmotic stress related to microgravity via mechanosensitive channel proteins, increased DNA repair activity to counteract heightened radiation exposure, and the presence of mobile genetic elements enhancing metabolism. In addition, our findings suggest the evolution of certain genetic traits indicative of potential pathogenic capabilities, such as small molecule and peptide synthesis and ATP-dependent transporters. These traits, exclusive to the ISS microorganisms, further substantiate previous reports explaining why microbes exposed to space conditions demonstrate enhanced antibiotic resistance and pathogenicity. Conclusion Our findings indicate that the microorganisms isolated from ISS we studied have adapted to life in space. Evidence such as mechanosensitive channel proteins, increased DNA repair activity, as well as metallopeptidases and novel S-layer oxidoreductases suggest a convergent adaptation among these diverse microorganisms, potentially complementing one another within the context of the microbiome. The common genes that facilitate adaptation to the ISS environment may enable bioproduction of essential biomolecules need during future space missions, or serve as potential drug targets, if these microorganisms pose health risks. Video Abstract

Abstract Background Simulation assessment can result in anxiety for students. These assessments involve being observed by assessors, so there is a significant socio-evaluative stress component which may cause greater anxiety if assessors are visible to students during assessments. The aim of this study was to determine the effect of assessor visibility on biological and physiological markers of stress and levels of anxiety experienced by pre-hospital emergency care students in a simulation assessment environment. Methods A paired comparison, pre-post test research design was used with two conditions; an assessor visible condition with simulation assessors visible to students in the room and an assessor not visible condition with assessors not in the room but connected via video link. With a sample of 29 emergency care students anxiety was measured with the State-Trait Anxiety Inventory and stress was measured with salivary cortisol and heart rate variability (HRV). Results Differences in state anxiety scores, HRV variables and salivary cortisol suggested lower stress and anxiety in the assessor visible group. Only heart rate was significantly different between the groups (p = 0.016), with a higher heart rate in the assessor not visible group. Conclusions Greater stress and anxiety may be experienced by students during emergency care simulation assessments when assessors are not visible to students.

Abstract Background Conflict in Syria since 2011 led to over one million Syrians fleeing to Lebanon, predominantly from economically disadvantaged areas with low literacy and high child marriage rates. Over 90% live in extreme poverty, in informal tented settlements with minimal access to education, healthcare or employment. Displacement and poverty have further increased early marriages and unplanned pregnancies, and curtailed access to sexual and reproductive healthcare (SRH) in the Bekaa valley. This is exacerbated by increasing rates of sexual and gender-based violence (SGBV), intimate partner violence and domestic violence. Study design We aimed to explore SRH beliefs and practices and teach on key SRH topics through focus group discussions (FGD) and questionnaires, co-designed with Syrian practitioners, conducted with Syrian men and women. FGD were recorded, transcribed and thematically analysed. Questionnaires collected demographics and explored SRH beliefs and practices. Findings 24 FGD with 203 participants, 72.4% female and 27.6% men. 90.1% participants were married with an average age-gap of 6.3 years between partners. Teenage marriage rates were 55.6% for women, and 47.4% delivered their first child before the age of 20. 43.6% participants were not using any contraception. Findings demonstrate the impacts of SRH cultural norms and changes due to displacement, financial crisis, and increased exposure to technology and NGOs. Conclusions SRH is multifaceted and contested, requiring systemic improvements in access to care, employment and education. This small but important proof-of-concept study demonstrates the possibility of engaging men and women in SRH discussion; paramount to empowering communities and challenging intergenerational SGBV.

Abstract Background A predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated. Methods Prostate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR

Abstract Background Low physical activity among older adults is related to adverse health outcomes such as depression and loneliness, poor physical function and increased risk of falls. This study was designed to increase physical activity through a digital, group-based, physical activity and music intervention and to examine its effectiveness on social, mental and physical health outcomes. Methods Participants were 34 older adults (65 years +) recruited across four care homes in Scotland to a pilot study. Surveys were administered at baseline and post-intervention, comprising measures of fear of falling, depression and anxiety, loneliness, sleep satisfaction and quality of life. A battery of physical function tests and saliva sampling for cortisol and dehydroepiandrosterone hormone analysis were also conducted at each time point. Additionally, process evaluation measures (recruitment, intervention fidelity, attendance, retention rates and safety) were monitored. The intervention comprised 12 weeks of three prescribed digital sessions per week: movement and music (n = 2) and music-only (n = 1), delivered by an activity coordinator in the care home. Post-intervention interviews with staff and participants were conducted to gain qualitative data on the acceptability of the intervention. Results An average of 88% of prescribed sessions were delivered. Pre- to post-intervention intention-to-treat analysis across all participants revealed significant improvements in anxiety, salivary DHEA, fear of falling and loneliness. There were no significant improvements in health-related quality of life, perceived stress, sleep satisfaction or physical function tests, including handgrip strength. Qualitative analysis highlighted benefits of and barriers to the programme. Conclusions The digital movement and music intervention was deemed acceptable and delivered with moderate fidelity, justifying progression to a full-scale trial. Although a proper control group would have yielded more confident causal relationships, preliminary psychosocial and biological effects were evident from this trial. To show significant improvements in physical function, it is likely that a bigger sample size providing sufficient power to detect significant changes, greater adherence, longer intervention and/or higher exercise volume may be necessary. Trial registration The trial is registered at ClinicalTrials.gov, number NCT05601102 on 01/11/2022.

Abstract Background Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. Methods Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. Discussion This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. Trial registration ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1

Abstract Background In recent years, covalent modifications on RNA nucleotides have emerged as pivotal moieties influencing the structure, function, and regulatory processes of RNA Polymerase II transcripts such as mRNAs and lncRNAs. However, our understanding of their biological roles and whether these roles are conserved across eukaryotes remains limited. Results In this study, we leveraged standard polyadenylation-enriched RNA-sequencing data to identify and characterize RNA modifications that introduce base-pairing errors into cDNA reads. Our investigation incorporated data from three Poaceae (Zea mays, Sorghum bicolor, and Setaria italica), as well as publicly available data from a range of stress and genetic contexts in Sorghum and Arabidopsis thaliana. We uncovered a strong enrichment of RNA covalent modifications (RCMs) deposited on a conserved core set of nuclear mRNAs involved in photosynthesis and translation across these species. However, the cohort of modified transcripts changed based on environmental context and developmental program, a pattern that was also conserved across flowering plants. We determined that RCMs can partly explain accession-level differences in drought tolerance in Sorghum, with stress-associated genes receiving a higher level of RCMs in a drought tolerant accession. To address function, we determined that RCMs are significantly enriched near exon junctions within coding regions, suggesting an association with splicing. Intriguingly, we found that these base-pair disrupting RCMs are associated with stable mRNAs, are highly correlated with protein abundance, and thus likely associated with facilitating translation. Conclusions Our data point to a conserved role for RCMs in mRNA stability and translation across the flowering plant lineage.

Abstract One of the greatest strengths of Drosophila genetics is its easily observable and selectable phenotypic markers. The mini-white marker has been widely used as a transgenic marker for Drosophila transgenesis. Flies carrying a mini-white construct can exhibit various eye colors ranging from pale orange to intense red, depending on the insertion site and gene dosage. Because the two copies of the mini-white marker show a stronger orange color, this is often used for selecting progenies carrying two transgenes together in a single chromosome after chromosomal recombination. However, some GAL4 lines available in the fly community originally have very strong red eyes. Without employing another marker, such as GFP, generating a recombinant chromosome with the strong red-eyed GAL4 and a desired UAS-transgene construct may be difficult. Therefore, we decided to change the red eyes of GAL4 lines to orange color. To change the eye color of the fly, we tested the CRISPR/Cas9 method with a guide RNA targeting the white gene with OK371-GAL4 and elav-GAL4. After a simple screening, we have successfully obtained multiple lines of orange-eyed OK371-GAL4 and elav-GAL4 that still maintain their original expression patterns. All of these simple experiments were performed by undergraduate students, allowing them to learn about a variety of different genetic experiments and genome editing while contributing to the fly research community by creating fruit fly lines that will be used in real-world research.

Abstract Background Social network analysis of animal societies allows scientists to test hypotheses about social evolution, behaviour, and dynamic processes. However, the accuracy of estimated metrics depends on data characteristics like sample proportion, sample size, and frequency. A protocol is needed to assess for bias and robustness of social network metrics estimated for the animal populations especially when a limited number of individuals are monitored. Methods We used GPS telemetry datasets of five ungulate species to combine known social network approaches with novel ones into a comprehensive five-step protocol. To quantify the bias and uncertainty in the network metrics obtained from a partial population, we presented novel statistical methods which are particularly suited for autocorrelated data, such as telemetry relocations. The protocol was validated using a sixth species, the fallow deer, with a known population size where $$\sim 85\%$$ ∼ 85 % of the individuals have been directly monitored. Results Through the protocol, we demonstrated how pre-network data permutations allow researchers to assess non-random aspects of interactions within a population. The protocol assesses bias in global network metrics, obtains confidence intervals, and quantifies uncertainty of global and node-level network metrics based on the number of nodes in the network. We found that global network metrics like density remained robust even with a lowered sample size, while local network metrics like eigenvector centrality were unreliable for four of the species. The fallow deer network showed low uncertainty and bias even at lower sampling proportions, indicating the importance of a thoroughly sampled population while demonstrating the accuracy of our evaluation methods for smaller samples. Conclusions The protocol allows researchers to analyse GPS-based radio-telemetry or other data to determine the reliability of social network metrics. The estimates enable the statistical comparison of networks under different conditions, such as analysing daily and seasonal changes in the density of a network. The methods can also guide methodological decisions in animal social network research, such as sampling design and allow more accurate ecological inferences from the available data. The R package aniSNA enables researchers to implement this workflow on their dataset, generating reliable inferences and guiding methodological decisions.

Abstract Background Endovascular treatment (ET) options for acute stroke due to distal middle cerebral artery occlusions are rapidly evolving, but data on outcome and safety are sparse. We therefore performed an analysis of patients undergoing ET for primary M3 occlusions in routine clinical practice in a nationwide registry. Methods Patients enrolled between 01/20 and 12/21 in the prospective, multicenter German Stroke Registry-Endovascular Treatment (GSR-ET) were screened for mechanical thrombectomy performed for primary M3 occlusion. We analyzed neurological deficit as measured by the National Institute of Health Stroke Scale (NIHSS), symptomatic intracranial hemorrhage (sICH), thrombectomy technique, successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3) and functional outcome as measured by the modified Rankin Scale (mRS) at discharge and 90 days. Results Out of 5574 patients, 11 patients (0.2%, median age 80 years, 54.5% female) underwent ET for primary M3 occlusion. All patients had pre-admission mRS ≤ 1, median NIHSS on admission was 8, and successful reperfusion was achieved in 6/11 patients (54.5%). While no vasospasm, dissection or perforation was reported, symptomatic intracranial hemorrhage occurred in 2 patients (18.2%). Favorable outcome (mRS ≤ 2) was achieved in 6/11 patients (54.5%) at 90-day follow-up. Conclusions ET for primary M3 occlusions is rarely performed. While technically feasible, the procedure’s potential benefits must be carefully weighed against its associated risks, including clinically relevant complications. Caution and further research is needed to optimize patient selection for this intervention. Trial Registration GSR-ET; ClinicalTrials.gov Identifier: NCT03356392; Trial Registration Date: 11/29/2017.

IntroductionLoneliness is a critical public health issue affecting older adults, with significant impacts on their mental and physical health, including increased risks of depression, cognitive decline, and higher mortality rates, necessitating distinct approaches for each condition given their unique implications and the exacerbation of these issues during the COVID-19 pandemic. We examine the implementation and outcomes of a Friendly Visitor Program (FVP) designed to mitigate loneliness among older adults. The program involved social work student interns providing virtual visits to older adults using computers and tablets, with the goal of enhancing social interaction and support.MethodsThe study utilized a qualitative narrative design for process evaluation and a longitudinal non-experimental, prospective research design for outcome evaluation, employing a three-level cross-classified longitudinal growth model to assess changes in loneliness among VFVP participants while also testing potential predictors of these changes.ResultsFindings indicated that the program was associated with reduced loneliness over time. Younger and White participants performed better in the program than older participants from other races and ethnicity. Satisfaction with visits and willingness to recommend the program were significant predictors of reduced loneliness. Unexpectedly, greater comfort with technology correlated with increased loneliness, suggesting overreliance on digital interactions may not substitute for in-person contact. Furthermore, improved social networks was associated with reduced loneliness, highlighting the importance of strong social networks.DiscussionThe study underscores the potential of friendly visitor interventions in addressing the challenges of lonely older adults and provides insights for optimizing such programs in the future.

Study region: The country of Senegal Study focus: One consequence of climate change is shifting precipitation patterns towards shorter rainfall regimes, posing challenges to societies relying on agricultural activities. A possible avenue to alleviate the impact of climate change is the construction small-scale reservoirs to locally supply irrigation water for small-holder farmers. Here, we assess the ability of small-scale reservoirs to close the agricultural water gap in Senegal. To this end we introduce a method to find locations and capacities of small-scale reservoirs in a 1 km hyper-resolution global hydrological model that are most effective in minimizing the water gap. New hydrologic insights for the region: We find that the effect of small-scale reservoirs varies regionally, and that the optimum design does not close the water gap. More locally, the water gap can be reduced during the growing season, indicating that small-holder farmers in vicinity to such reservoirs can benefit. To close the remaining water gap, we assessed the feasibility of groundwater pumping. With pumping, the water gap can be closed, yet often only at the expense of sustainable groundwater use. Due to the novelty of the methods presented, this study should not provide any input to actual decisions. It shows, however, the potential of using hyper-resolution hydrological models for small-scale analyses. More practically, it highlights the immense challenges for societies affected by the climate crisis to meet their water demand in a sustainable way.

Food and agricultural waste contribute to resource depletion, waste accumulation and climate change. Chicken egg and almond hull waste streams have favourable nutritional profiles but are underexplored for environmentally friendly livestock feed applications. We report extrusion processing and nutritional analysis of blends containing liquid egg and almond hulls. Compositions showed favourable processing, protein content comparable to grain silages and relatively low neutral detergent fibre. No differences in crude protein or fat were observed between Hard-variety and Nonpareil almond hull compositions. Hard-variety compositions contained nearly twice the crude fibre as Nonpareil mixtures. Crude protein increased from 9.3 to 13.8% with 30–50% egg content. Bacterial proliferation in extrudates was minimal due to the low water activity (aw = 0.80–0.82 in 30% egg formulations). No Salmonella or mycotoxins (aflatoxin, vomitoxin, zearalenone) were detected. This work provides a method for repurposing high moisture, high protein food waste into animal feed using abundant, low-cost almond crop residues and demonstrates the feasibility of creating an animal feed from liquid egg waste and almond hulls.

An emerging sector of the nootropic market is tea-based nutraceutical products, but there are limited data assessing the dose-dependent effects of these products.Purpose We conducted a randomized, double-blind, placebo-controlled crossover trial in young adults to examine the dose-dependent (600 mg versus 1200 mg), acute effects of consumption of an Ilex guayusa tea extract (GLE) on mood, cognitive and motor-cognitive performance, as well as its acute cardiovascular effects.Methods Twenty-five adults (mean ± SD, age = 28 ± 7 y; 9 M/16 F) completed familiarization and then three randomly ordered experimental visits where they consumed either 600 mg (GLE600) or 1200 mg (GLE1200) GLE or placebo (PLA). Following supplement consumption, participants completed a mood state survey, assessments of perceived jitteriness, energy, and focus, and neurocognitive and motor-cognitive testing. Blood pressure (BP), heart rate, and QT interval length were determined before and after supplementation.Results GLE600 significantly improved total mood disturbance (mean ± SE difference = -6.9 ± 2.6 au, p = 0.034), fatigue-inertia (−2.84 ± 0.89 au, p = 0.008), perceived energy (+13.00 ± 4.49 au; p = 0.02), motor speed (+4.52 ± 1.42 au, p = 0.008), and psychomotor speed (+7.20 ± 2.16 au, p = 0.005) relative to PLA. GLE1200 also improved psychomotor speed (+5.08 ± 2.16 ms, p = 0.045) and uniquely increased motor-cognitive performance as reflected by a decrease in reaction time (−0.106 ± 0.04 ms, p = 0.026) during a neurocognitive hop test. The effect of GLE on jitteriness was both dose- and sex-dependent. Jitteriness increased with increasing GLE dose in women only (p

ABSTRACTSynchrotron X-ray imaging has been utilised to detect the dynamic behaviour of molten pools during the metal additive manufacturing (AM) process, where a substantial amount of imaging data is generated. Here, we develop an efficient and robust deep learning model, AM-SegNet, for segmenting and quantifying high-resolution X-ray images and prepare a large-scale database consisting of over 10,000 pixel-labelled images for model training and testing. AM-SegNet incorporates a lightweight convolution block and a customised attention mechanism, capable of performing semantic segmentation with high accuracy (∼96%) and processing speed (< 4 ms per frame). The segmentation results can be used for quantification and multi-modal correlation analysis of critical features (e.g. keyholes and pores). Additionally, the application of AM-SegNet to other advanced manufacturing processes is demonstrated. The proposed method will enable end-users in the manufacturing and imaging domains to accelerate data processing from collection to analytics, and provide insights into the processes’ governing physics.

As queer and trans scientists, we face varied and systemic barriers to our professional success, resulting in our relative absence from faculty ranks at many institutions. In this Perspective, we call for a change in faculty hiring practices and present concrete guidance to make it a more inclusive process.

BackgroundCannabis use can have unintended, harmful consequences for adolescents, a developmental group that struggles with heightened pressure to align with peer attitudes and behaviors. The role of social-cognitive factors in shifting cannabis use dynamics remains under explored, particularly in states where recreational cannabis use is legal.ObjectivesThe present study examined multilevel longitudinal associations between resistance to peer influence, peer norms, and adolescent cannabis use over the course of 12 months.MethodParticipants were N=204 adolescents ages 15-19 (Mage = 18.68; 67% female) recruited via community outreach after the legalization of adult (age 21+) recreational cannabis use in the Portland, Oregon metropolitan region. Eligible participants endorsed 1+ heavy episodic drinking (HED) episode in the prior two months. Data were collected across four timepoints over 12 months. Multilevel latent growth curve modeling investigated associations between time-varying cognitive factors (resistance to peer influence, peer norms) and two cannabis outcomes (hazardous use, past-month use).ResultsFindings showed individual increases in hazardous cannabis use over time were significantly associated with adolescents reporting higher peer norms (i.e., higher perceived prevalence and frequency of peer cannabis use) and lower resistance to peer influence. When assessing between-adolescent differences, hazardous cannabis use was only associated with peer norms. Individual variation over time and between-adolescent differences on past-month cannabis use was associated with peer norms, but not resistance to peer influence.ConclusionsEvolving cognitive factors like resistance to peer influence and peer norms may enhance understanding of longitudinal changes in hazardous cannabis use among adolescents and implicate helpful targets for prevention and intervention. It is a public health priority to identify factors that contribute to adolescent use trajectories in this period of growing cannabis legislation in order to guide the development of impactful prevention and intervention strategies.

Background Individuals with a loss-of-function single-nucleotide polymorphism in the gene encoding PTPN22 have an increased risk for autoimmune diseases, and patients with cancer with such alleles may respond better to checkpoint blockade immunotherapy. Studies in PTPN22 knockout (KO) mice have established it as a negative regulator of T cell responses in cancer models. However, the role of PTPN22 in distinct immune cell compartments, such as dendritic cells (DCs), remains undefined.Methods We developed a novel PTPN22 conditional KO (cKO) mouse model that enables specific deletion in CD11c+ DCs by crossing to CD11c-Cre transgenic mice. Antitumor immunity was characterized using the B16.SIY and MC38.SIY cancer models and immune profiles of relevant tissues were evaluated by spectral flow cytometry. Antigen uptake, processing, and presentation, as well as DC proliferation to Flt3L, were characterized ex vivo.Results Deletion of PTPN22 in DCs resulted in augmented antitumor immunity in multiple syngeneic tumor models. Tumor antigen-specific CD8+ T cells were increased in the tumor microenvironment (TME) of PTPN22 cKO mice and improved tumor control was CD8+ T cell-dependent. Augmented T cell priming was also detected at early time points in the draining lymph nodes, and these effects were correlated with an increased number of proliferating CD103+ DCs, also seen in the TME. In vitro studies revealed increased DC proliferation in response to Flt3L, as well as increased antigen processing and presentation. PTPN22 cKO mice bearing MC38 parental tumors showed combinatorial benefit with anti-PD-L1 therapy.Conclusions Deletion of PTPN22 in DCs is sufficient to drive an augmented tumor antigen-specific T cell response, resulting in enhanced tumor control. PTPN22 negatively regulates DC proliferation and antigen processing and presentation. Our work argues that PTPN22 is an attractive therapeutic target for cancer immunotherapy and highlights the potential to modulate antitumor immunity through the manipulation of DC signaling.

Enzyme-catalyzed proximity labeling is a potent technique for the discernment of subtle molecular interactions and subcellular localization, furnishing contextual insights into the protein of interest within cells. Although ascorbate peroxidase2 (APEX2) has proven effective in this approach when overexpressed, its compatibility with endogenous proteins remains untested. We improved this technique for studying native protein–protein interactions in live Drosophila ovary tissue. Through CRISPR/Cas9 genome editing, APEX2 was fused with the endogenous dysfusion gene. By pre-treating the tissue with Triton X-100 to enhance biotin-phenol penetration, we successfully identified multiple proteins interacting with the native Dysfusion proteins that reside on the inner nuclear membrane. Our protocol offers a comprehensive workflow for delineating the interactome networks of ovarian components in Drosophila, aiding future studies on endogenous protein–protein interactions in various tissues of other animals.

Introduction: COVID-19 hospitalization rates among unvaccinated children are double of that of vaccinated children, and this difference is greater among racial and ethnic minority children. Vaccination rates among children remain suboptimal. Few studies have characterized barriers to COVID-19 vaccination among historically marginalized communities. Methods: From January 2022 to May 2022, parents and guardians of children aged 12 months to 18 years presenting for pediatric care at a hospital-based primary care clinic were surveyed about perceptions of COVID-19 vaccines, intentions to vaccinate their child, and trusted sources of information. Results: A total of 113 parents/guardians participated, with 92% self-identifying with a historically marginalized racial/ethnic group. A total of 54% of respondents either did not plan to vaccinate their child against COVID-19 or were unsure. The obstacles to vaccination most frequently cited were related to (1) unknown side effects, (2) the rapid development of the vaccine, and (3) unsafe ingredients. Worries about being used as experimental subjects and potential impacts on fertility were also reported. Parents who planned to vaccinate their child reported higher rates of trust in doctors, local clinics, hospitals, and health departments. Conclusions: High rates of COVID-19 vaccination hesitancy exist among parents/guardians from historically marginalized groups. Barriers to vaccination were frequently related to side effects, whereas a high level of trust in healthcare providers as sources of information may be a facilitator. Strategies to improve health outcomes and boost vaccination rates should focus on equipping pediatric healthcare providers with the knowledge and skills necessary to address these known barriers to COVID-19 vaccination.

Abstract Background Diabetes affects 75% of people in low-income countries, where conventional drugs like metformin are available, but newer drugs like alpha-glucosidase inhibitors are not accessible to most Southern African patients. Aim To evaluate the α-glucosidase and α-amylase inhibitory activities of fractionated aqueous extracts of Kigelia africana fruit (KAFE) and their phytochemical fingerprints using gas chromatography-mass spectrometry (GC–MS). Materials and methods We studied K. africana fruit fractions' inhibitory effects on alpha-glucosidase and alpha-amylase using bioassay-guided fractionation, and analyzed their phytochemical profiles with GC–MS. Key findings Both the aqueous extract and ethyl acetate fraction of the aqueous extract exhibited a low dose-dependent inhibition of alpha-amylase activity (p

Abstract People who inject drugs are frequently colonized with Staphylococcus aureus and have an increased risk for skin and soft tissue infections. This longitudinal study aims to describe S. aureus carriage in this group and the risk for infections during a 1-year follow-up. We included 61 participants from the Malmö Needle Exchange Program. Mapping of S. aureus carriage was conducted by screening cultures every third month and S. aureus growth was semi-quantified. Data regarding infections and living conditions were collected from structured interviews. Statistics included univariate analysis with the Fischer’s exact test, univariate logistic regression and multivariate logistic regression. S. aureus carriage was detected in 46–63% of participants, and 75% reported one or more infections during the study period. Self-reported infections were associated with carriage in perineum (OR 5.08 [95% CI 1.45–17.73]), in skin lesions (OR 1.48 [95% CI 1.21–1.81]), and unstable housing situation (OR 12.83 [95% CI 1.56–105.81]). Thus, people who inject drugs are frequent carriers of S. aureus and report a surprisingly high prevalence of skin and soft tissue infections. Homeless people and those with skin carriage seem to be at highest risk. Effective clinical interventions are needed, aiming at preventing infections in this vulnerable group.

Abstract Visual distraction is a ubiquitous aspect of everyday life. Studying the consequences of distraction during temporally extended tasks, however, is not tractable with traditional methods. Here we developed a virtual reality approach that segments complex behaviour into cognitive subcomponents, including encoding, visual search, working memory usage, and decision-making. Participants copied a model display by selecting objects from a resource pool and placing them into a workspace. By manipulating the distractibility of objects in the resource pool, we discovered interfering effects of distraction across the different cognitive subcomponents. We successfully traced the consequences of distraction all the way from overall task performance to the decision-making processes that gate memory usage. Distraction slowed down behaviour and increased costly body movements. Critically, distraction increased encoding demands, slowed visual search, and decreased reliance on working memory. Our findings illustrate that the effects of visual distraction during natural behaviour can be rather focal but nevertheless have cascading consequences.

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model. Methods Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months. Results CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions. Conclusions Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.

Silicon photonics is one of the most dynamic fields within photonics, and it has seen huge progress in the last 20 years, addressing applications in data centers, autonomous cars, and sensing. It is mostly focused on the telecommunications wavelength range (1.3 and 1.55 µm), where silicon becomes transparent. In this range, there are excellent light sources and photodetectors, as well as optical fibers operating with extremely low losses and dispersion. It is a technology that hugely benefits from the availability of complementary metal–oxide–semiconductor (CMOS) fabrication infrastructure and techniques used for microelectronics. Silicon and germanium, as another CMOS compatible group IV material, are transparent beyond the wavelength of 2 µm. The mid-IR wavelength range (2–20 µm) is of particular importance as it contains strong absorption signatures of many molecules. Therefore, Si- and Ge-based platforms open up the possibility of small and cost-effective sensing in the fingerprint region for medical and environmental monitoring. In this paper, we discuss the current mid-IR silicon photonics landscape, future directions, and potential applications of the field.

ABSTRACT The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others.

BackgroundThreonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).MethodsMechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).ResultsBAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.ConclusionsDual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.

Background and purpose: Parenting concerns can be a major source of distress for patients with cancer who are parents of dependent children; however, these are often not addressed in health care. The Parenting Concerns Questionnaire (PCQ) is an instrument designed to assess parents’ worries about the impact of cancer on their children and their ability to parent during this time. The Swedish version of the PCQ has, however, not been evaluated. This study therefore aimed to examine the psychometric properties of the PCQ in a sample of Swedish parents with cancer. Material and methods: A sample of 336 patients with cancer having dependent children (≤18 years) were included in a cross-sectional web-based survey. Participants completed questionnaires assessing parenting concerns, depression, anxiety, and stress symptoms (DASS); self-efficacy, family functioning (FAD-GF); and sociodemographic and clinical characteristics. Descriptive analyses, as well as reliability and validity analyses, were conducted followed by a confirmatory factor analysis of the factor structure proposed by the authors of the original version of the PCQ. Results: The majority were mothers (94.9%) with breast cancer (66.4%) aged 40–50 years (59.5%). The results showed evidence for convergent, criterion, and known group’s validity, but the original three-factor structure of the PCQ was not fully supported by confirmatory factor analysis. Interpretation: Evaluating parenting concerns may be an important step towards identifying patients who could benefit from targeted psychosocial interventions. However, the PCQ may require some further refinement to fully capture the breadth of parenting concerns in parents with cancer in different settings.

ABSTRACT The gut microbiome has the potential to buffer temporal variations in resource availability and consumption, which may play a key role in the ability of animals to adapt to a broad range of habitats. We investigated the temporal composition and function of the gut microbiomes of wild common marmosets (Callithrix jacchus) exploiting a hot, dry environment—Caatinga—in northeastern Brazil. We collected fecal samples during two time periods (July–August and February–March) for 2 years from marmosets belonging to eight social groups. We used 16S rRNA gene amplicon sequencing, metagenomic sequencing, and butyrate RT-qPCR to assess changes in the composition and potential function of their gut microbiomes. Additionally, we identified the plant, invertebrate, and vertebrate components of the marmosets’ diet via DNA metabarcoding. Invertebrate, but not plant or vertebrate, consumption varied across the year. However, gut microbiome composition and potential function did not markedly vary across study periods or as a function of diet composition. Instead, the gut microbiome differed markedly in both composition and potential function across marmosets residing in different social groups. We highlight the likely role of factors, such as behavior, residence, and environmental heterogeneity, in modulating the structure of the gut microbiome.IMPORTANCEIn a highly socially cohesive and cooperative primate, group membership more strongly predicts gut microbiome composition and function than diet.

Introduction: Rare cancers, in aggregate, represent a significant burden of disease in oncology and remain therapeutically challenging to manage due to a lack of clinical trials. Eccrine porocarcinoma is a rare cutaneous sweat-gland malignancy for which there remains no standard approach to metastatic disease. Case Presentation: We describe a patient diagnosed with metastatic disease, confirmed on bone biopsy; pathological analysis further revealed this was oestrogen receptor positive. She was commenced on the aromatase inhibitor letrozole, and denosumab, and showed a significant clinical and radiological response on bone scan within 7 months. At the time of report, over 2 years since commencing letrozole, she remains well with no evidence of progression. Conclusion: Our experience adds to the literature suggesting anti-oestrogen therapy can have significant benefit in patients with ER-positive non-breast cancer and is in keeping with increasing interest in therapies agnostic to site of origin but guided by expression/mutation of oncogenic drivers.

Abstract NF2-related schwannomatosis (NF2-SWN) is a rare genetic disorder and is associated with progressive morbidities. This study aimed to investigate the relationship between NF2-SWN disease severity, health-related Quality of Life (QoL), and mental health aspects of patients. Standardised questionnaires assessing mental health problems (symptoms of depression, anxiety, and somatic burden), psychological factors (resilience, loneliness, and personality functioning), and health-related QoL were administered to 97 patients with NF2-SWN. The results of these questionnaires were compared with physician-rated disease severity. Questionnaires were completed by 77 patients. Physician-rated disease severity scores were available for 55 patients. NF2-SWN patients showed a high prevalence of clinically relevant symptoms of depression (30%), anxiety (16%), and somatic burden (32%). Almost all variables showed moderate to high correlations with NF2-SWN-related QoL. NF2-SWN-related QoL was associated with physician-reported disease severity (r = 0.614). In the stepwise hierarchical linear regression analysis, a significant model with four predictors (disease severity type, depression symptoms, personality functioning, and gender) explained 64% of the variance in NF2-SWN-related QoL. Our results showed a strong association between NF2-SWN-related QoL and depression symptoms. Moreover, personality functioning is an important influencing factor, representing a modifiable construct that can be targeted by prevention programs or psychotherapy.

Abstract Observational learning is essential for the acquisition of new behavior in educational practices and daily life and serves as an important mechanism for human cognitive and social-emotional development. However, we know little about its underlying neurocomputational mechanisms from a developmental perspective. In this study we used model-based fMRI to investigate differences in observational learning and individual learning between children and younger adults. Prediction errors (PE), the difference between experienced and predicted outcomes, related positively to striatal and ventral medial prefrontal cortex activation during individual learning and showed no age-related differences. PE-related activation during observational learning was more pronounced when outcomes were worse than predicted. Particularly, negative PE-coding in the dorsal medial prefrontal cortex was stronger in adults compared to children and was associated with improved observational learning in children and adults. The current findings pave the way to better understand observational learning challenges across development and educational settings.

Abstract Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.

Abstract In this work we study in-depth the antireflection and filtering properties of ultrathin-metal-film-based transparent electrodes (MTEs) integrated in thin-film solar cells. Based on numerical optimization of the MTE design and the experimental characterization of thin-film perovskite solar cell (PSC) samples, we show that reflection in the visible spectrum can be strongly suppressed, in contrast to common belief (due to the compact metal layer). The optical loss of the optimized electrode (~ 2.9%), composed of a low-resistivity metal and an insulator, is significantly lower than that of a conventional transparent conductive oxide (TCO ~ 6.3%), thanks to the very high transmission of visible light within the cell (> 91%) and low thickness ( 370%. To assess the application potentials, integrated current density > 25 mA/cm2, power conversion efficiency > 20%, combined with vastly reduced device heat load by 177.1 W/m2 was achieved in state-of-the-art PSCs. Our study aims to set the basis for a novel interpretation of composite electrodes/structures, such as TCO–metal–TCO, dielectric–metal–dielectric or insulator–metal–insulator, and hyperbolic metamaterials, in high-efficiency optoelectronic devices, such as solar cells, semi-transparent, and concentrated systems, and other electro-optical components including smart windows, light-emitting diodes, and displays.

Abstract The aims of this qualitative research were (1) to gain more insight in the diagnostic and treatment history of patients with chronic temporomandibular disorder (TMD) pain; (2) to get a deeper understanding of possible factors that are involved in the possible delay in setting a TMD-pain diagnosis and receiving appropriate treatment; and (3) to get a deeper understanding of the perspectives and experiences of chronic TMD-pain patients on the possible improvement of various aspects of their diagnostic and treatment journey. Methods In this narrative research, semi-structured interviews took place with patients who experienced chronic orofacial pain (OFP) for at least three years before getting diagnosed with, and treated for, TMD pain by an OFP specialist in an interprofessional setting. Results In total, ten patients were interviewed in-depth. Patients experienced their chronic OFP in different ways, but all reported a significant impact of their pain on their quality of life. All patients visited numerous health care professionals before their TMD diagnosis was set. Among others, they underwent anti-neuropathic pain medication therapies and invasive surgeries, which did not significantly reduce their chronic OFP. The interprofessional TMD-pain treatment reduced the suffering of the chronic OFP substantially, also 6 months after the start of therapy, and improved the quality of life for all patients. In most of them, the OFP intensity was also decreased. Conclusion Chronic TMD-pain patients with a history of neuropathic pain treatment may experience a long journey until receiving the appropriate diagnosis and treatment. This stresses the need to improve the implementation of chronic TMD-pain guidelines.

Objective, sensitive, and meaningful disease assessments are critical to support clinical trials and clinical care. Speech changes are one of the earliest and most evident manifestations of cerebellar ataxias. This work aims to develop models that can accurately identify and quantify clinical signs of ataxic speech. We use convolutional neural networks to capture the motor speech phenotype of cerebellar ataxia based on time and frequency partial derivatives of log-mel spectrogram representations of speech. We train classification models to distinguish patients with ataxia from healthy controls as well as regression models to estimate disease severity. Classification models were able to accurately distinguish healthy controls from individuals with ataxia, including ataxia participants who clinicians rated as having no detectable clinical deficits in speech. Regression models produced accurate estimates of disease severity, were able to measure subclinical signs of ataxia, and captured disease progression over time. Convolutional networks trained on time and frequency partial derivatives of the speech signal can detect sub-clinical speech changes in ataxias and sensitively measure disease change over time. Learned speech analysis models have the potential to aid early detection of disease signs in ataxias and provide sensitive, low-burden assessment tools in support of clinical trials and neurological care.

Background: Central nervous system (CNS) tumors are the second most frequent type of neoplasm in childhood and adolescence, after leukemia. Despite the incorporation of molecular classification and improvement of protocols combining chemotherapy, surgery, and radiotherapy, CNS tumors are still the most lethal neoplasm in this age group. Mass spectrometry imaging (MSI) is a powerful tool to map the distribution of molecular species in tissue sections. Among MSI techniques, desorption electrospray ionization (DESI-MSI) has been demonstrated to enable reliable agreement with the pathological evaluation of different adult cancer types, along with an acceptable time scale for intraoperative use. Methods: In the present work, we aimed to investigate the chemical profile obtained by DESI-MSI as an intraoperative surgical management tool by profiling 162 pediatric brain biopsies and reporting the results according to the histopathology and molecular profile of the tumors. Results: The 2D chemical images obtained by DESI-MSI allowed us to distinguish tumor-transformed tissue from non-tumor tissue with an accuracy of 96.8% in the training set and 94.3% in the validation set after statistical modeling of our data using Lasso. In addition, high-grade and low-grade tumors also displayed a distinct chemical profile when analyzed by DESI-MSI. We also provided evidence that the chemical profile of brain tumors obtained by DESI-MSI correlates with methylation-based molecular classes and specific immunophenotypes found in brain biopsies. Conclusions: The results presented herein support the incorporation of DESI-MSI analysis as an intraoperative assistive tool in prospective clinical trials for pediatric brain tumors management in the near future.

Background How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.Methods CD4+ T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.Results We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.Conclusions Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4+ based T-cell therapies are now emerging in the clinic.

Movements for progressive social change (e.g., Black Lives Matter, #MeToo) are commonly met with reactionary counter-movements that seek to protect the rights and interests of structurally advantaged groups (e.g., All Lives Matter, #MenToo). Drawing on the insights of the social identity approach and the needs-based model of reconciliation, the current research explores whether men's support for progressive and reactionary action (i.e., their intentions to promote women's rights and men's rights, respectively) are shaped by their need to defend their group's moral identity. Combined analyses of three samples (N = 733) showed that men's social identification was associated with their reduced intentions to act for women's rights and positively related to their intentions to promote men's rights—effects mediated by their need for positive moral identity and defensiveness regarding the issue of gendered violence. Overall, the findings suggest that defensive construals regarding group-based inequalities may not only present a barrier to men's engagement in collective action for gender equality, but might also underlie their participation in reactionary actions designed to advance the rights of their own (advantaged) group.

The residential sector accounts for 33% of energy-related Greenhouse Gas (GHG) emissions globally and must undergo rapid emissions reductions in order to support broader society-wide sustainability and net-zero transitions. Additionally, urban areas account for approximately 70% of global GHG emissions. To provide a baseline for urban climate action plans and mitigation strategies, sub-national municipalities must quantify their sectoral baseline emissions in detail and develop strategies for reducing emissions relative to these baselines. Therefore, it is important to establish clear methodologies for computing these baselines in accordance with the best available science. This paper establishes a novel methodology for developing a residential sector emissions model using a data-driven and spatial mapping approach. This would form an important component of future multi-sectoral baseline emissions inventories. • The residential sector emissions model combines publicly available census and building energy performance datasets in order to model and visualize the distribution of energy demand and resultant emissions across an urban study domain in Ireland. • The methodology presented was developed in line with the approaches and requirements of the Global Covenant of Mayors and the Intergovernmental Panel on Climate Change. • It is envisioned that this residential sector emissions model methodology could be applied in any urban area worldwide.

The objective was to characterize the effects of increasing carcass weight on pork carcass characteristics and yields from traditional and alternative fabrication methods, as well as evaluate the size of novel retail cuts. Pigs (n = 85) were slaughtered and divided into 3 hot carcass weight (HCW) categories: Average (99 to 109 kg), Heavy (116 to 126 kg), and Very Heavy (134 to 144 kg). Loin muscle area (LMA) and back fat depth were measured on all carcasses. Paired right and left sides were fabricated traditionally and alternatively (shoulder separation at the 4th/5th rib), respectively. From the alternative side, the serratus ventralis (SV) was removed from the cellar-trimmed butt, and the triceps brachii (TB) was removed from the picnic shoulder. All individual primals and subprimals were weighed for yield calculations. Data were analyzed using the MIXED procedure in SAS including the main effect of weight class, with sex and sire line as fixed blocking effects. Differences were considered significant at P ≤ 0.05. Regardless of fabrication method, whole primal and subprimal weights increased (P < 0.01) in heavier carcass weight classes compared with lighter classes, but when expressed as a percentage of chilled side weight, these increases did not often translate into meaningful differences in distribution of carcass weight. While the alternative shoulder-loin separation reduced loin and belly length, loins and bellies from heavier carcasses weighed more than those from carcasses typically produced in the U.S. pork industry today. Serratus ventralis weight was increased (P < 0.01) approximately 0.28 kg from Average to Very Heavy, while the TB weight was increased (P < 0.01) approximately 0.24 kg from Average to Very Heavy. At heavier weights, alternative fabrication of carcasses yielded novel cuts from the shoulder including the SV and TB that were of size to warrant further exploration as retail offerings.