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'Cumulative cultural evolution' broadly describes the process by which cultural traits accumulate improvements to efficacy over generations of social learning and innovation. The term can arguably be applied without much controversy to the cultural evolution of tool use, for example. However, it has recently gained momentum in the aesthetic realm as well, where it has been used to describe changes to sexually selected cultural traits. These, the argument goes, can gain efficacy in the sense of evoking stronger emotional responses from receivers. Here, we use examples from birdsong literature to outline our objections to the application of cumulative cultural evolution to cultural traits that achieve popularity based on no standard other than social or sexual preference. Moreover, we distinguish between categories of cultural traits that are preferred for different functional reasons, presenting arguments for or against describing changes to each as improvements. We conclude by proposing that a detailed and nuanced understanding of the mechanisms and outcomes of cultural change is of more service to behavioural and cultural science than a fraught binary distinction between what we can and cannot label 'cumulative'. • We summarize current definitions of 'cumulative cultural evolution' (CCE). • We suggest areas where CCE may apply to socially learned vocal communication. • We use birdsong to explore the untenability of applying CCE in the aesthetic realm. • More nuanced distinctions are needed between cultural traits than CCE can provide. [ABSTRACT FROM AUTHOR]

Morphogenesis of the nervous system involves a highly complex spatio-temporal pattern of physical forces (mainly tension and pressure) acting on cells and tissues that are pliable but have an intricately organized cytoskeletal infrastructure. This review begins by covering basic principles of biomechanics and the core cytoskeletal toolkit used to regulate the shapes of cells and tissues during embryogenesis and neural development. It illustrates how the principle of 'tensegrity' provides a useful conceptual framework for understanding how cells dynamically respond to forces that are generated internally or applied externally. The latter part of the review builds on this foundation in considering the development of mammalian cerebral cortex. The main focus is on cortical expansion and folding – processes that take place over an extended period of prenatal and postnatal development. Cortical expansion and folding are likely to involve many complementary mechanisms, some related to regulating cell proliferation and migration and others related to specific types and patterns of mechanical tension and pressure. Three distinct multi-mechanism models are evaluated in relation to a set of 18 key experimental observations and findings. The Composite Tension Plus (CT+) model is introduced as an updated version of a previous multi-component Differential Expansion Sandwich Plus (DES+) model (Van Essen, 2020); the new CT+ model includes 10 distinct mechanisms and has the greatest explanatory power among published models to date. Much needs to be done in order to validate specific mechanistic components and to assess their relative importance in different species, and important directions for future research are suggested. • Mechanical tension mediated by the cytoskeleton plays a key role in many aspects of morphogenesis. • Expansion and folding of cerebral cortex are key to achieving a large cortical surface area while keeping wiring compact. • The Composite Tension Plus (CT+) model invokes 10 distinct mechanisms to account for cortical expansion and folding. [ABSTRACT FROM AUTHOR]

• Data support EEG as an important tool to measure delirium-relevant aspects in mice. • During critical illness mice showed slow-wave EEG dominance and sleep disruption. • Hypersensitivity to auditory stimuli during sepsis can be measured in sick mice. • Cognitive disruption was observed in some mice following recovery from systemic inflammation. • Deficits post sepsis associated with altered hippocampal long term potentiation. Sepsis and systemic inflammation are often accompanied by severe encephalopathy, sleep disruption and delirium that strongly correlate with poor clinical outcomes including long-term cognitive deficits. The cardinal manifestations of delirium are fluctuating altered mental status and inattention, identified in critically ill patients by interactive bedside assessment. The lack of analogous assessments in mouse models or clear biomarkers is a challenge to preclinical studies of delirium. In this study, we utilized concurrent measures of telemetric EEG recordings and neurobehavioral tasks in mice to characterize inattention and persistent cognitive deficits following polymicrobial sepsis. During the 24-hour critical illness period for the mice, slow-wave EEG dominance, sleep disruption, and hypersensitivity to auditory stimuli in neurobehavioral tasks resembled clinical observations in delirious patients in which alterations in similar outcome measurements, although measured differently in mice and humans, are reported. Mice were tested for nest building ability 7 days after sepsis induction, when sickness behaviors and spontaneous activity had returned to baseline. Animals that showed persistent deficits determined by poor nest building at 7 days also exhibited molecular changes in hippocampal long-term potentiation compared to mice that returned to baseline cognitive performance. Together, these behavioral and electrophysiological biomarkers offer a robust mouse model with which to further probe molecular pathways underlying brain and behavioral changes during and after acute illness such as sepsis. [ABSTRACT FROM AUTHOR]

Lead (Pb2+) ions, among heavy toxic metals, are extensively distributed and bioaccumulate in food chains, prompting researchers to monitor their levels in water and biosystems. Consequently, aiming to protect the environment and human health, this study synthesizes a straightforward naphthalene-naphthalene dyad-based "turn-on" fluorescent chemosensor (S) tailored for detecting Pb2+ ions. This selective response to Pb2+ ions over other competing metal ions is characterized by hypsochromic changes in fluorescence enhancement resulting from an intramolecular charge transfer (ICT) process from -OH group (donor) to the naphthyl ring (acceptor) following the complexation of S-Pb2+. Moreover, cross-contamination titration for probe S was conducted in the presence of various distinct competitive metal ions. By employing Job's plot and B-H plot, the complicated stoichiometry (1:2) and association constant (K a = 9.45×104 M−1) of S-Pb2+ were studied. The probe's interaction with Pb2+ is studied using spectroscopic measurements and DFT calculations. The probe demonstrated exceptional selectivity and sensitivity, achieving a limit of detection (LOD) value of 12.50×10−6 M for Pb2+ in a buffered THF:H 2 O (50:50, v:v) medium. The applicability of chemosensor S spans across various water, food, and E. coli samples, indicating its potential in monitoring and managing Pb2+ toxicity in wastewater and biosystems. [Display omitted] • The study reports sensor S, detecting toxic Pb2+ ions rapidly and applicable in food, water, and living cells. • The sensor demonstrated high selectivity and sensitivity via ICT mechanistic process. • The detection limit (LOD) of 12.50 µM for Pb2+ is lower than many previous reports. • The sensor's versatility is showcased by its applicability in both biological and environmental contexts. [ABSTRACT FROM AUTHOR]

Background: Phase I trial to determine the safety and efficacy of paclitaxel, sapanisertib, and serabelisib. Patients and methods : Patients with previously treated advanced solid tumors were eligible for this open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) with weekly paclitaxel. A traditional 3 + 3 dose escalation design with 5 dosing cohorts was used. Patient reported outcomes were also evaluated. Results: 19 heavily pretreated patients were enrolled (10 ovarian, 3 breast, and 6 endometrial cancers). All patients received comprehensive genomic profiling prior to enrollment. RP2D is sapanisertib 3 or 4 mg, serabelisib 200 mg on days 2–4, 9–11, 16–18 and 23–25 with paclitaxel 80 mg/m2 on days 1, 8 and 15 every 28 days. All patients in Cohort 5 required dose reductions and one patient experienced a DLT. The most frequent grade 3 or 4 adverse events were decreased WBCs (20%), nonfebrile neutropenia (12%), anemia (9%), elevated liver enzymes (4%), and hyperglycemia (11%). 3 patients had a CR, 4 had a PR, and 4 patients had SD > six months. ORR was 47% and CBR was 73% in 15 evaluable patients. Including all 19 enrolled patients, the PFS was 11 months and OS is still ongoing at 17 months. Conclusions: The combination of sapanisertib, serabelisib, and paclitaxel was safe and generally well tolerated. Preliminary efficacy was remarkable in an area of unmet need, especially for patient with PI3K/AKT/mTOR pathway aberrations. Positive effects and sustained clinical benefit were even seen in patients that were refractory to platinum and had failed taxane, everolimus, or temsirolimus. Clinical Trial number : ClinicalTrials.gov , NCT03154294 • Sapanisertib, serabelisib and paclitaxel was a safe and well tolerated combination in heavily pretreated patients • Antitumor activity was observed, especially with endometrioid endometrial cancer and those with PI3K aberrations • In this heavily pretreated population with advanced solid tumors, the ORR = 47%, the CBR = 73%, PFS = 11 months, and OS = 17 months, and is ongoing • The study was awarded a plenary session at this year's Society of Gynecologic Oncology meeting in March 2022 [ABSTRACT FROM AUTHOR]

Progress in understanding physiological mechanisms often consists of discrete discoveries made across different models and species. Accordingly, understanding the mechanistic bases for how altering nitric oxide (NO) bioavailability impacts exercise tolerance (or not) depends on integrating information from cellular energetics and contractile regulation through microvascular/vascular control of O 2 transport and pulmonary gas exchange. This review adopts state-of-the-art concepts including the intramyocyte power grid, the Wagner conflation of perfusive and diffusive O 2 conductances, and the Critical Power/Critical Speed model of exercise tolerance to address how altered NO bioavailability may, or may not, affect physical performance. This question is germane from the elite athlete to the recreational exerciser and particularly the burgeoning heart failure (and other clinical) populations for whom elevating O 2 transport and/or exercise capacity translates directly to improved life quality and reduced morbidity and mortality. The dearth of studies in females is also highlighted, and areas of uncertainty and questions for future research are identified. • We summarize the effects of nitrate(NO 3 −)/nitrite(NO 2 −) supplementation on exercise tolerance in healthy subjects and heart failure patients, starting with the impact of greater nitric oxide (NO) bioavailability on muscle perfusive and diffusive O 2 conductance up to the mechanisms by which nitrate supplementation enhances muscle contractile function • We also explore how the positive effects of elevated intramyocyte NO bioavailability combine with NO-induced cytochrome c oxidase inhibition to better distribute O 2 across the myocyte • Finally, we highlight what little is known regarding sex differences in response to NO 3 − supplementation and identify next-step questions in this vital arena. [ABSTRACT FROM AUTHOR]

The difference in infant health outcomes by maternal opioid use disorder (OUD) status is understudied. We measured the association between maternal OUD during pregnancy and infant mortality and investigated whether this association differs by infant neonatal opioid withdrawal syndrome (NOWS) or maternal receipt of medication for OUD (MOUD) during pregnancy. We sampled 204,543 Medicaid-paid births from Wisconsin, United States (2010–2018). The primary exposure was any maternal OUD during pregnancy. We also stratified this exposure on NOWS diagnosis (no OUD; OUD without NOWS; OUD with NOWS) and on maternal MOUD receipt (no OUD; OUD without MOUD; OUD with <90 consecutive days of MOUD; OUD with 90+ consecutive days of MOUD). Our outcome was infant mortality (death at age <365 days). Demographic-adjusted logistic regressions measured associations with odds ratios (OR) and 95% confidence intervals (CI). Maternal OUD was associated with increased odds of infant mortality (OR 1.43; 95% CI 1.02–2.02). After excluding infants who died <5 days post-birth (i.e., before the clinical presentation of NOWS), regression estimates of infant mortality did not significantly differ by NOWS diagnosis. Likewise, regression estimates did not significantly differ by maternal MOUD receipt in the full sample. Maternal OUD is associated with an elevated risk of infant mortality without evidence of modification by NOWS nor by maternal MOUD treatment. Future research should investigate potential mechanisms linking maternal OUD, NOWS, MOUD treatment, and infant mortality to better inform clinical intervention. • We examined opioid use disorder (OUD) and infant mortality in a large birth cohort. • Maternal OUD in pregnancy may increase the odds of infant mortality. • Association did not significantly vary by neonatal opioid withdrawal syndrome. • Association did not significantly vary by medication for OUD receipt in pregnancy. [ABSTRACT FROM AUTHOR]

We used three years of house finch, Haemorhous mexicanus , song recordings spanning four decades in the introduced eastern range to assess how individual level cultural transmission mechanisms drive population level changes in birdsong. First, we developed an agent-based model (available as a new R package called 'TransmissionBias') that simulates the cultural transmission of house finch song given different parameters related to transmission biases, or biases in social learning that modify the probability of adoption of particular cultural variants. Next, we used approximate Bayesian computation and machine learning to estimate what parameter values likely generated the temporal changes in diversity in our observed data. We found evidence that strong content bias, likely targeted towards syllable complexity, plays a central role in the cultural evolution of house finch song in the New York metropolitan area. Frequency and demonstrator biases appear to be neutral or absent. Additionally, we estimated that house finch song is transmitted with extremely high fidelity. Future studies can use our simulation framework to better understand how cultural transmission and population declines influence song diversity in wild populations. • We analysed house finch songs from three years spanning four decades in New York. • We compared real data against simulations to make inferences about cultural transmission. • Content bias, likely for syllable complexity, drives cultural evolutionary changes. • Frequency and demonstrator biases were absent and transmission fidelity was high. [ABSTRACT FROM AUTHOR]

• A significant proportion of private hospitals experience financial distress • For-profit status was associated with an increased risk of financial distress • A higher share of Medicaid revenue was associated with increased odds of distress Hospitals are closing after poor financial performance leaving many patients without access to medical care. Identifying the factors associated with financial distress offers hospitals avenues for potential intervention to avoid bankruptcy and closure. We performed a retrospective analysis of private U.S. hospitals' financial information from 2011 to 2018. A mixed effects logistic regression model was used with the primary outcome of hospital financial distress (based on the Altman Z-score). Our sample included 2,720 private hospitals contributing a total of 20,022 hospital-year observations. The proportion of hospitals experiencing financial distress each year ranged from 22.0% to 24.3%. For-profit status was associated with an increased odds of financial distress (adjusted odds ratio (aOR), 4.36 [95% Confidence Interval (CI) 3.05 - 6.24]) as compared to non-profit status. A higher share of hospital revenue from Medicaid was also associated with increased odds of financial distress (aOR for the highest quartile, 2.28 [95% CI 1.73 - 3.00]) as compared to the lowest quartile. A higher case mix index (aOR for the highest quartile, 0.32 [95% CI 0.23 - 0.46]) and an increased share of hospital revenue from outpatient services (aOR for the highest quartile, 0.34 [95% CI 0.23 - 0.49]) were associated with decreased odds of financial distress as compared to their respective lowest quartiles. A significant proportion of private U.S. hospitals experience financial distress. Increasing case complexity and the proportion of patient revenue from outpatient services may represent avenues to avoid financial distress. [ABSTRACT FROM AUTHOR]

α-herpesviruses have been very successful, principally because they establish lifelong latency in sensory ganglia. An essential piece of the lifecycle of α-herpesviruses involves the capacity to travel from sensory neurons to epithelial tissues following virus reactivation from latency, a process known as anterograde transport. Virus particles formed in neuron cell bodies hitchhike on kinesin motors that run along microtubules, the length of axons. Herpes simplex virus (HSV) and pseudorabies virus (PRV) have been intensely studied to elucidate anterograde axonal transport. Both viruses use similar strategies for anterograde transport, although there are significant differences in the form of virus particles transported in axons, the identity of the kinesins that transport viruses, and how certain viral membrane proteins, gE/gI and US9, participate in this process. This review compares the older models for HSV and PRV anterograde transport with recent results, which are casting a new light on several aspects of this process. • α−herpesvirus anterograde axonal transport can involve unenveloped or enveloped capsids or both. • α−herpesviruses use at least two families of kinesin motors for anterograde transport. • Membrane proteins US9 and gE/gI promote virus assembly in the cytoplasm and sorting of viruses into axons. [ABSTRACT FROM AUTHOR]

Commercial vegetable crop transplanters currently use several unsynchronised planting units mounted to a common transport frame. The objective of this work was to assess the performance of a new transplanting technology to improve the plant placement accuracy and spatiotemporal planting synchronization across adjacent rows, thus producing a grid-like planting pattern using adjacent vegetable crop transplanters. The feasibility of synchronisation of adjacent transplanting units for vegetable crops was demonstrated using tomato as the target crop. A colour, digital, high-speed computer vision analysis of the motion and dynamics of the plant trajectories of transplanted tomatoes was conducted. The high-speed video analysis led to the design and testing of an improved plant support mechanism to enhance the control and precision of the transplanting of vegetable crops. The absolute deviation values of the final location in the soil were reduced by approximately 25% for both the right planter and left planter compared to those in previous years. These results serve as the fundamental basis for a mechatronic system that can precisely transplant vegetable crops in a grid-like pattern across rows as a critical first step in a systematic approach to fully automated individual plant care. • Sustainable agricultural production remains a major challenge for agriculture. • New insights into plant dynamics during tomato transplanting obtained. • Synchronised plant placement in adjacent rows reduces plant-to-plant competition. • Synchronised plant placement facilitates the use of an automatic intra-row weeding. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, protein sorting is a highly regulated mechanism important for many physiological events. After synthesis in the endoplasmic reticulum and trafficking to the Golgi apparatus, proteins sort to many different cellular destinations including the endolysosomal system and the extracellular space. Secreted proteins need to be delivered directly to the cell surface. Sorting of secreted proteins from the Golgi apparatus has been a topic of interest for over thirty years, yet there is still no clear understanding of the machinery that forms the post-Golgi carriers. Most evidence points to these post-Golgi carriers being tubular pleomorphic structures that bud from the trans -face of the Golgi. In this review, we present the background studies and highlight the key components of this pathway, we then discuss the machinery implicated in the formation of these carriers, their translocation across the cytosol, and their fusion at the plasma membrane. [ABSTRACT FROM AUTHOR]

The use of social network analysis to quantify animal social relationships has increased exponentially over the last two decades. A popular aspect of social network analysis is the use of individually based network metrics. Despite the diversity of social network metrics that exist and the large number of studies that generate network metrics, little guidance exists on the number and type of metrics that should be analysed in a single study. Here, we comment on the 'hypothesize after results are known' (HARKing) phenomenon in the context of social network analysis, a practice that we term 'metric hacking' and define as the use of statistical criteria to select which metrics to use rather than a priori choice based on a research hypothesis. We identify three situations where metric hacking can occur in studies quantifying social network metrics: (1) covariance among network metrics as explanatory variables in the same model; (2) covariance among network metrics as response variables in multiple models; and (3) covariance between response and explanatory variables in the same model. We outline several quantitative and qualitative issues associated with metric hacking, provide alternative options and guidance on the appropriate use of multiple network metrics to avoid metric hacking. By increasing awareness of the use of multiple social network metrics, we hope to encourage better practice for the selection and use of social network metrics in animal social network analysis. • We outline quantitative and qualitative issues associated with metric hacking. • We provide guidance on the appropriate use of multiple network metrics. • We encourage diligent consideration of methods and reasoned justification of metrics. • Reasoned a priori choice of metrics will improve our understanding of social networks. [ABSTRACT FROM AUTHOR]

Tissue-specific extracellular matrix (ECM) proteins can play a key role in regulating the fate of stem cells and can potentially be utilized for therapeutic applications. Realising this potential requires further characterization of the diversity of biomolecules present in tissue-specific ECMs and an evaluation of their role as regulatory cues for regenerative medicine applications. The goal of this study was to identify specific soluble factors within the ECM of articular cartilage (AC) and growth plate (GP) that may impart chondro-inductivity or osteo-inductivity respectively. To this end, the significantly different proteins between both matrisomes were searched against the STRING database platform, from which C-type lectin domain family-11 member-A (CLEC11A) and S100 calcium-binding protein-A10 (S100A10) were identified as potential candidates for supporting osteogenesis, and Gremlin-1 (GREM1) and TGF-β induced gene human clone-3 (βIGH3) were identified as potential candidates for supporting stable chondrogenesis. Stimulation of chondrogenically-primed bone marrow-derived stem cells (BMSCs) with the AC-specific proteins GREM1 and βIGH3 had no noticeable effect on the deposition of collagen-II, a marker of chondrogenesis, but appeared to suppress the production of the hypertrophic marker collagen-X, particularly for higher concentrations of GREM1. Stimulation with GREM1 was also found to suppress the direct osteoblastic differentiation of BMSCs. In contrast, stimulation with the GP-specific factors CLEC11A and S100A10 was found to enhance osteogenesis of BMSCs, increasing the levels of mineralization, particularly for higher concentration of CLEC11A. Together these results demonstrate that AC- and GP-specific proteins may play a key role in developing novel strategies for engineering phenotypically stable articular cartilage or enhancing the regeneration of critically-sized bone defects. • Distinct regulatory proteins from the matrisomes of growth plate (GP) and articular cartilage (AC) were identified. • The AC-specific proteins, GREM1 and βIGH3, suppressed the synthesis of type X collagen during chondrogenesis of MSCs. • GREM1 was also found to suppress the direct osteoblastic differentiation of MSCs. • The GP-specific proteins, CLEC11A and S100A10, were found to enhance osteogenesis. [ABSTRACT FROM AUTHOR]

The Nucleosome Remodeling and Deacetylase (NuRD) complex uniquely combines both deacetylase and remodeling enzymatic activities in a single macromolecular complex. The methyl-CpG–binding domain 2 and 3 (MBD2 and MBD3) proteins provide a critical structural link between the deacetylase and remodeling components, while MBD2 endows the complex with the ability to selectively recognize methylated DNA. Hence, NuRD combines three major arms of epigenetic gene regulation. Research over the past few decades has revealed much of the structural basis driving formation of this complex and started to uncover the functional roles of NuRD in epigenetic gene regulation. However, we have yet to fully understand the molecular and biophysical basis for methylation-dependent chromatin remodeling and transcription regulation by NuRD. In this review, we discuss the structural information currently available for the complex, the role MBD2 and MBD3 play in forming and recruiting the complex to methylated DNA, and the biological functions of NuRD. Image 1 • In this review, we discuss the structure and function of the Nucleosome Remodeling and Deacetylase (NuRD) complex. • We focus on the role of MBD2 and MBD3 proteins in forming the complex and recognizing methylated DNA. • We describe the biological role of NuRD in gene regulation and highlight the limitations of our current knowledge. [ABSTRACT FROM AUTHOR]

Weed control is a significant cost for speciality crop producers, especially on organic farms. Agricultural operations are still largely dependent on hand weeding that is labour intensive and labour shortages and rising wages have led to a surge in food production costs. Thus, there is an inherent need to automate weed control and contain both labour costs and demands. Automatically distinguishing weeds from the crop plant is a complex problem since weeds come in a wide variety of colours, shapes, and sizes, and crop plant foliage is often overlapped with itself or occluded by the weeds. Current technology in commercial use, cannot reliably and effectively perform the differentiation task in such complex scenarios in real-time. As a solution to this problem, our team at the University of California, Davis has developed a novel concept called crop signalling, a technology to make crop plants machine readable and reliably distinguishable from weeds for automatic weed control. Four different techniques have been investigated and developed to make smart crop marking systems such as a) systemic markers, b) fluorescent proteins, c) plant labels and d) topical markers. Indoor experiments have been conducted for each method. Field experiments, using plant labels and the topical markers methods, have been successfully conducted for real-time weed control in tomato and lettuce. The results demonstrated that robots could automatically detect and distinguish 99.7% of the crop plants with no false positive errors in dense complex outdoor scenes with high weed densities. The crop/weed differentiation was thus effective, fast, reliable, and commercialisation of robotic weed control using the technique may be feasible. • A novel crop signalling technique is presented for robotic weed control. • The method automatically classifies crops from weeds using machine-vision method. • Crop and weed differentiation were effective, fast, and reliable. • Experiments conducted for real-time weed control in tomato and lettuce field. • Commercialisation of robotic weed control using the technique may be feasible. [ABSTRACT FROM AUTHOR]

• 75 adolescents read and heard time-locked narratives during an fMRI scan. • Inter-subject correlation (ISC) was used to analyze reading ability's impact. • ISC was more sensitive to individual differences in reading ability than GLMs. • Reading ability affects brain activity in more regions than previously thought. • Worse readers had more idiosyncratic responses than better readers across the brain. Recent work using fMRI inter-subject correlation analysis has provided new information about the brain's response to video and audio narratives, particularly in frontal regions not typically activated by single words. This approach is very well suited to the study of reading, where narrative is central to natural experience. But since past reading paradigms have primarily presented single words or phrases, the influence of narrative on semantic processing in the brain – and how that influence might change with reading ability – remains largely unexplored. In this study, we presented coherent stories to adolescents and young adults with a wide range of reading abilities. The stories were presented in alternating visual and auditory blocks. We used a dimensional inter-subject correlation analysis to identify regions in which better and worse readers had varying levels of consistency with other readers. This analysis identified a widespread set of brain regions in which activity timecourses were more similar among better readers than among worse readers. These differences were not detected with standard block activation analyses. Worse readers had higher correlation with better readers than with other worse readers, suggesting that the worse readers had "idiosyncratic" responses rather than using a single compensatory mechanism. Close inspection confirmed that these differences were not explained by differences in IQ or motion. These results suggest an expansion of the current view of where and how reading ability is reflected in the brain, and in doing so, they establish inter-subject correlation as a sensitive tool for future studies of reading disorders. [ABSTRACT FROM AUTHOR]

• Cortico-cerebellar functional connectivity predicts cerebellar task activation. • A single connectome measurement can predict across a multi-domain task battery. • Predictions are unique to the individual. • Findings indicate highly specific cerebellar contributions to cognition. The cerebellum is gaining scientific attention as a key neural substrate of cognitive function; however, individual differences in the cerebellar organization have not yet been well studied. Individual differences in functional brain organization can be closely tied to individual differences in brain connectivity. 'Connectome Fingerprinting' is a modeling approach that predicts an individual's brain activity from their connectome. Here, we extend 'Connectome Fingerprinting' (CF) to the cerebellum. We examined functional MRI data from 160 subjects (98 females) of the Human Connectome Project young adult dataset. For each of seven cognitive task paradigms, we constructed CF models from task activation maps and resting-state cortico-cerebellar functional connectomes, using a set of training subjects. For each model, we then predicted task activation in novel individual subjects, using their resting-state functional connectomes. In each cognitive paradigm, the CF models predicted individual subject cerebellar activity patterns with significantly greater precision than did predictions from the group average task activation. Examination of the CF models revealed that the cortico-cerebellar connections that carried the most information were those made with the non-motor portions of the cerebral cortex. These results demonstrate that the fine-scale functional connectivity between the cerebral cortex and cerebellum carries important information about individual differences in cerebellar functional organization. Additionally, CF modeling may be useful in the examination of patients with cerebellar dysfunction, since model predictions require only resting-state fMRI data which is more easily obtained than task fMRI. [ABSTRACT FROM AUTHOR]

The entropy conservative/stable staggered grid tensor-product algorithm of Parsani et al. [1] is extended to multidimensional SBP discretizations. The required SBP preserving interpolation operators are proven to exist under mild restrictions and the resulting algorithm is proven to be entropy conservative/stable as well as elementwise conservative. For 2-dimensional simplex elements, the staggered grid algorithm is shown to be more accurate and have a larger maximum time step restriction as compared to the collocated algorithm. The staggered algorithm significantly reduces the number of (computationally expensive) two-point flux evaluations, which is potentially important for both explicit and implicit time-marching schemes. Furthermore, the staggered algorithm requires fewer degrees of freedom for comparable accuracy, which has favorable implications for implicit time-marching schemes. • Develop an entropy conservative/stable scheme for multi-D SBP operators. • Prove that prolongation/restriction operator pairs exist under mild assumptions. • The staggered algorithm is more accurate and reduces the DOFs. • The staggered algorithm allows a larger stable time step. [ABSTRACT FROM AUTHOR]

• Maternal antenatal atopy is associated with ADHD-related behaviors among children. • Girls may be more sensitive to antenatal maternal atopy compared to boys. • Antenatal maternal atopy may contribute to the incidence of clinically significant ADHD. • Mechanisms may involve maternal immune activation during fetal neurodevelopment. Identifying modifiable risk factors for neuropsychological correlates of attention deficit hyperactivity disorder (ADHD) in early childhood can inform prevention strategies. Prenatal inflammatory states, such as maternal asthma and other atopic disorders, have been increasingly linked to enhanced risk for neurobehavioral disorders in children, with some studies suggesting sex-specific effects. To assess the association between maternal active asthma and/or atopy in the antenatal period and child symptoms of ADHD during mid-childhood and, given the male-bias in ADHD prevalence, to examine modifying effects of child sex. The study sample includes 250 maternal-child pairs enrolled in the Boston-based Asthma Coalition on Community, Environment and Social Stress (ACCESS) pregnancy cohort. We defined antenatal active atopy based on maternal report of current asthma, allergic rhinitis or atopic dermatitis during and/or in the year before pregnancy. When children were approximately 6 years old, mothers completed a battery of standardized child behavior rating scales designed for evaluating symptoms of ADHD. We used multivariable quantile regression to assess the relations between maternal antenatal atopy and symptoms of ADHD among children. In adjusted models, maternal atopy was significantly associated with greater risk for ADHD behaviors, as indicated by scores on the Conners' Parent Rating Scale-Revised ADHD index (β = 3.32, 95% CI: 0.33, 6.32). In sex-stratified models this association was stronger among girls (5.96, 95% CI = 0.95, 10.96) compared to boys (−2.14, 95% CI = −5.75, 1.45, p-interaction = 0.01). Among girls, we observed a similar finding for the Behavior Assessment System for Children 2nd Edition Parent Rating Scale Attention Problems subscale (β = 7.77, 95% CI = 1.57, 13.97). Results from other outcome subscales were similar in magnitude and direction, however, associations did not reach statistical significance at the p = 0.05 level. Maternal antenatal active atopy may be a risk factor for the development of ADHD-like symptoms, especially among girls. [ABSTRACT FROM AUTHOR]

The nearest neighbor graph is an important structure in many data mining methods for clustering, advertising, recommender systems, and outlier detection. Constructing the graph requires computing up to n 2 similarities for a set of n objects. This high complexity has led researchers to seek approximate methods, which find many but not all of the nearest neighbors. In contrast, we leverage shared memory parallelism and recent advances in similarity joins to solve the problem exactly. Our method considers all pairs of potential neighbors but quickly filters pairs that could not be a part of the nearest neighbor graph, based on similarity upper bound estimates. The filtering is data dependent and not easily predicted, which poses load balance challenges in parallel execution. We evaluated our methods on several real-world datasets and found they work up to two orders of magnitude faster than existing methods, display linear strong scaling characteristics, and incur less than 1% load imbalance during filtering. • Exact shared memory cosine similarity graph construction methods are proposed. • Work by filtering the search space, ignoring objects that will not be neighbors. • Threshold bounded graph construction works extremely well with high thresholds. • Fast approximate graph used to bootstrap k -nearest neighbor graph construction. [ABSTRACT FROM AUTHOR]

Highlights • Accurate quantitation of vitamin D 3 requires resolution of vitamin D and previtamin D • Columns that can resolve the four vitamin D forms identified • Equivalent thermal isomerisation of vitamin D 2 and vitamin D 3 to their previtamin forms confirms use of vitamin D 2 as an internal standard. Abstract Conventional methods using HPLC with UV detection have used vitamin D 2 as an internal standard with the expectation that this fully compensates for the heat-dependent equilibrium of vitamin D 3 with its previtamin. Previtamin D has a different spectral absorptivity from vitamin D and may be present in different proportions in samples and standards. Therefore, vitamin D 2 and vitamin D 3 and their previtamin forms must be chromatographically resolved to achieve accurate quantitation of total vitamin D. This study identified four chromatographic columns (ACE C 18 , ACE C 18 AR, Vydac 201 TP C 18 and Polaris C 18 -Ether) with adequate selectivity that should be applied for food testing and further confirmed that both parent vitamins isomerise at the same rate under thermal conditions. [ABSTRACT FROM AUTHOR]

While scholars and practitioners are increasingly aware of the positive effect of idiosyncratic deals (i-deals) on employee attitudes, little is known about how i-deals might affect work and career outcomes for employees with disabilities, a marginalized and understudied group. The present study builds on Conservation of Resources (COR) theory to explain how i-deals might influence perceived work ability for employees with disabilities, and in turn, their turnover intentions. Furthermore, this study is the first to compare the experiences of employees with physical, psychological and no disabilities regarding these relationships. Our hypotheses are tested using field data from 19,770 employees working for a German federal agency. In brief, the negative direct effect of i-deals on turnover intentions is found to be stronger for employees with physical disabilities than for those without disabilities. Further, the results indicate a significant negative indirect effect of i-deals on turnover intentions through perceived work ability for all employee groups. As expected, we find that this indirect effect increases in magnitude when going from the condition having a physical disability or no disability to the condition having a psychological disability. Implications for research, theory and practice are discussed. • I-deals serve as work accommodation for employees with and without disabilities. • I-deals contribute to lowered turnover partly through enhancement of work ability. • Persons with disabilities report lower turnover intention through i-deals. • I-deals are particularly beneficial for persons with psychological disabilities. • I-deals can foster job retention of vulnerable groups in the workforce. [ABSTRACT FROM AUTHOR]

Abstract We describe analyses to estimate the global burden of disease associated with methylmercury (MeHg). An intelligence quotient < 70, indicating intellectual disability (ID), was selected as the critical disease, maternal hair Hg concentration during pregnancy selected as the critical exposure biomarker, and a dose-effect relationship of an 0.18 point IQ reduction per µg/g increase in maternal hair Hg was assumed, based on a meta-analysis. A systematic review was conducted to obtain country-specific data on the distribution of maternal hair Hg concentrations. The country-specific incidence of MeHg-associated ID was calculated, and a random effects model was used to impute the incidence for countries for which no exposure data could be found. The global burden of MeHg-associated ID was quantified in terms of Disability-Adjusted Life Years (DALYs) using the World Health Organization (WHO) Global Health Estimates methodology, and presented by 14 subregions. In 2015, the global total for MeHg-associated cases of ID was 226,655; 210,074 of these cases (93%) were mild cases of ID. The highest rate of ID (6 cases per 100,000 population) was found in the Americas D subregion. The global DALY estimate was 1,963,869. The Western Pacific B subregion contributed the most to this total (696,417), although the Americas D subregion had the greatest rate (54 DALYs per 100,000 population). The burden of disease associated with MeHg is therefore highly subregion-dependent even in areas that are geographically related. The priority given to reducing this burden can therefore be expected to vary considerably by subregion depending on other health needs. Highlights • Diet is the primary pathway for exposure to methylmercury (MeHg). • Prenatal exposure to MeHg causes impaired cognitive development. • Globally, MeHg causes nearly 250,000 cases of intellectual disability per year. • MeHg associated intellectual disability represents nearly 2 million DALYs globally. • The Western Pacific B subregion accounts for more than one third of the DALY. [ABSTRACT FROM AUTHOR]

Abstract Neuropeptides play critical roles in cnidarian development. However, although they are known to play key roles in settlement and metamorphosis, their temporal and spatial developmental expression has not previously been characterized in any coral. We here describe Acropora millepora LWamide and RFamide and their developmental expression from the time of their first appearance, using in situ hybridization and FMRFamide immunohistochemistry. AmRFamide transcripts first appear in the ectoderm toward the oral end of the planula larva following blastopore closure. This oral bias becomes less apparent as the planula develops. The cell bodies of AmRFamide -expressing cells are centrally located in the ectoderm, with narrow projections to the mesoglea and to the cell surface. As the planula approaches settlement, AmRFamide expression disappears and is undetectable in the newly settled polyp. Expressing cells then gradually reappear as the polyp develops, becoming particularly abundant on the tentacles. AmLWamide transcripts first appear in ectodermal cells of the developing planula, with minimal expression at its two ends. The cell bodies of expressing cells lie just above the mesoglea, in a position distinct from those of AmRFamide -expressing cells, and have a narrow projection extending across the ectoderm to its surface. AmLWamide- expressing cells persist for most of the planula stage, disappearing shortly before settlement, but later than AmRFamide -expressing cells. As is the case with AmRFamide , expressing cells are absent from the polyp immediately after settlement, reappearing later on its oral side. AmLWamide expression lags that of AmRFamide in both its disappearance and reappearance. Antibodies to FMRFamide stain cells in a pattern similar to that of the transcripts, but also cells in areas where there is no expression revealed by in situ hybridization, most notably at the aboral end of the planula and in the adult polyp. Adult polyps have numerous staining cells on the tentacles and oral discs, as well as an immunoreactive nerve ring around the mouth. There are scattered staining cells in the coenosarc between polyps and staining cells are abundant in the mesenterial filaments. The above results are discussed in the context of our knowledge of the behavior of coral planulae at the time of their settlement and metamorphosis. Corals are facing multiple environmental threats, and these results both highlight the need for, and bring us a step closer to, a mechanistic understanding of a process that is critical to their survival. Highlights • Sequences of the Acropora neuropeptides RFamide and LWamide are presented. • Both transcripts disappear before metamorphosis, then reappear in the settled polyp. • The distribution of anti-FMRFamide positive cells in the adult polyp is described. • The Acropora nervous system differs significantly from that of Nematostella. • The roles of LWamide and RFamide in cnidarian metamorphosis are discussed. [ABSTRACT FROM AUTHOR]

Abstract The reducing environment in the eye lens diminishes with age, leading to significant oxidative stress. Oxidation of lens crystallin proteins is the major contributor to their destabilization and deleterious aggregation that scatters visible light, obscures vision, and ultimately leads to cataract. However, the molecular basis for oxidation-induced aggregation is unknown. Using X-ray crystallography and small-angle X-ray scattering, we describe the structure of a disulfide-linked dimer of human γS-crystallin that was obtained via oxidation of C24. The γS-crystallin dimer is stable at glutathione concentrations comparable to those in aged and cataractous lenses. Moreover, dimerization of γS-crystallin significantly increases the protein's propensity to form large insoluble aggregates owing to non-cooperative domain unfolding, as is observed in crystallin variants associated with early-onset cataract. These findings provide insight into how oxidative modification of crystallins contributes to cataract and imply that early-onset and age-related forms of the disease share comparable development pathways. Graphical abstract Unlabelled Image Highlights • Oxidized γS is dimeric with one inter- (C24) and two intramolecular disulfides (C22–C26). • The dimeric structure is extended and is not perturbed relative to the monomer. • γS dimer is stable at glutathione concentrations akin to aged and cataractous lenses. • γS dimer exhibits non-cooperative unfolding and increased aggregation propensity. • Oxidation of γS C22, C24, and C26 has been identified in age-related cataract lenses. [ABSTRACT FROM AUTHOR]

Abstract Background Circumcision is widely accepted for newborns in the United States. However, circumcision carries a risk of complications, the rates of which are not well described in the contemporary era. Methods We performed a longitudinal population analysis of the California Office of Statewide Health Planning and Development database between 2005 and 2010. Using International Classification of Procedures, Ninth Revision, Clinical Modification and Current Procedural Terminology codes, we calculated early and late complication rates by Kaplan–Meier survival estimates. Late complications were defined as those that occurred between 30 d and 5 y after circumcision. Descriptive analysis of complications was obtained by analysis of variance, chi-square test, or log-rank test. On adjusted analysis, a Cox proportional hazard model was performed to determine the risk of early and late complications, adjusting for patient demographics. Results A total of 24,432 circumcised children under age 5 y were analyzed. Overall, cumulative complication rates over 5 y were 1.5% in neonates, 0.5% of which were early, and 2.9% in non-neonates, 2.2% of which were early. On adjusted analysis, non-neonates had a higher risk of early complications (OR 18.5). In both neonates and non-neonates, the majority of patients with late complications underwent circumcision revision. Conclusions Circumcision has a complication rate higher than previously recognized. Most patients with late complications after circumcision received an operative circumcision revision. Clinicians should weigh the surgical risks against the reported medical benefits of circumcision when counseling parents about circumcision. [ABSTRACT FROM AUTHOR]

Abstract The human cerebral cortex is estimated to comprise 200–300 distinct functional regions per hemisphere. Identification of the precise anatomical location of an individual's unique set of functional regions is a challenge for neuroscience that has broad scientific and clinical utility. Recent studies have demonstrated the existence of four interleaved regions in lateral frontal cortex (LFC) that are part of broader visual attention and auditory attention networks (Michalka et al., 2015; Noyce et al., 2017; Tobyne et al., 2017). Due to a large degree of inter-subject anatomical variability, identification of these regions depends critically on within-subject analyses. Here, we demonstrate that, for both sexes, an individual's unique pattern of resting-state functional connectivity can accurately identify their specific pattern of visual- and auditory-selective working memory and attention task activation in lateral frontal cortex (LFC) using "connectome fingerprinting." Building on prior techniques (Saygin et al., 2011; Osher et al., 2016; Tavor et al., 2016; Smittenaar et al., 2017; Wang et al., 2017; Parker Jones et al., 2017), we demonstrate here that connectome fingerprint predictions are far more accurate than group-average predictions and match the accuracy of within-subject task-based functional localization, while requiring less data. These findings are robust across brain parcellations and are improved with penalized regression methods. Because resting-state data can be easily and rapidly collected, these results have broad implications for both clinical and research investigations of frontal lobe function. Our findings also provide a set of recommendations for future research. Graphical abstract Image 1 Highlights • Multiple visual- and auditory-biased regions exist in lateral frontal cortex (LFC). • 'Connectome Fingerprinting' (CF) attempts to identify brain regions in individuals. • CF uses resting-state functional connectivity to predict task activation patterns. • CF accurately predicts location of sensory modality-selective regions in LFC. • Our findings also present 'best practice' recommendations for performing CF. [ABSTRACT FROM AUTHOR]

Abstract In this article we develop an ab-initio formulation for the analysis of certain solutions to the macroscopic Maxwell equations in bulk homogeneous materials that are separated by a planar interface that may sustain field-dependent electric currents induced by a surface admittance tensor. Based on Clemmow's description of complex inhomogeneous plane time-harmonic waves, a systematic procedure is given that yields particular global solutions in terms of solutions to a system of bivariate polynomial and linear eigen-value equations for a set of six complex dimensionless scalars. This algebraic system is amenable to rapid numerical analysis using Maple or Matlab on a laptop. From the resulting solutions, analytic formulae for the electromagnetic fields can be expressed in terms of values for these six scalars and the electromagnetic phenomenological properties of the bulk media and their interface. We show explicitly how general properties of Surface Plasmon–Polariton (SPP) and Brewster modes follow from this unified viewpoint without appeal to any reflections in a Fresnel formulation. In particular we emphasise that endowing the material interface with (in general) anisotropic admittance properties can lead to new global electromagnetic field characteristics offering new possibilities for the control of surface characteristics by using recent advances in the fabrication of meta-materials. We illustrate our results by showing how a mono-layer of graphene in a normal magneto-static field can be used to construct a tunable meta-surface for SPP generation and how a simple conducting Ohmic interface can be used to excite both transverse electric and transverse magnetic Brewster modes as a function of the interface admittance. [ABSTRACT FROM AUTHOR]

It remains an elusive goal to simultaneously model the astrophysics of Solar System accretion while reproducing the mantle chemistry of more than one inner terrestrial planet. Here, we used a multistage core-mantle differentiation model based on Rubie et al. (2011, 2015) to track the formation and composition of Earth and Mars in various Grand Tack formation simulations. Prior studies showed that in order to recreate Earth's mantle composition, it must grow first from reduced (Fe-metal rich and O-poor) building blocks and then from increasingly oxidized (FeO rich) material. This accretion chemistry occurs when an oxidation gradient exists across the disk so that the innermost solids are reduced and increasingly oxidized material is found at greater heliocentric distances. For a suite of Grand Tack simulations, we investigated whether Earth and Mars can be simultaneously produced by the same oxidation gradient. Our model did not find an oxidation gradient that simultaneously reproduces the mantle compositions of Earth and Mars. Due to its small mass and rapid formation, the formation history of Mars-like planets is very stochastic which decreases the likelihood of compatibility with an Earth-producing oxidation gradient in any given realization. To reconcile the accretion history and ideal chemistry of the Mars-like planet with the oxidation gradient of an Earth-producing disk, we determined where in the Earth-producing disk Mars must have formed. We find that the FeO-rich composition of the Martian mantle requires that Mars' building blocks must originate exterior to 1.0 astronomical units (AU). • Earth's building blocks reflect an average of the entire inner disk, unlike Mars. • Mars' growth history varies greatly between simulations due to dynamical mixing. • Mars' building blocks must originate exterior to 1 AU to reproduce FeO rich mantle. [ABSTRACT FROM AUTHOR]

We advance a recent comprehensive model of climate change risk perceptions by investigating the role of media in shaping individuals' health risk perceptions. Results from a national survey in Australia (n = 1023) show that perceived health risks associated with climate change are related but distinct from perceived harm to self and society as measured in previous risk perception studies. Moreover, the full model explains 47% variance in health risks and 74% in perceived harm; While experiential processes (21%) account for about half of the variance in health risks, cognitive factors explain the largest share of variance in perceived harm (32%). Media processes explain a 10% variance in health risks and a 14% variance in perceived harm. News interest and media exposure to extreme weather events are significant to understand public health risks and harm perceptions, even after accounting for several other socio-demographic, cognitive, experiential, and socio-cultural factors. Findings support a conditional media effects model. Media can, directly and indirectly, affect public health risk perceptions by providing vicarious experience opportunities and information that Australians are looking for in the media about climate change. • Media processes explain significant variance in climate change related health risks. • Cognitive factors explain the largest share of variance in perceived harm. • Experiential processes account for about half of the variance in health risks. [ABSTRACT FROM AUTHOR]

[Display omitted] Electronic health records (EHR), containing detailed longitudinal clinical information on a large number of patients and covering broad patient populations, open opportunities for comprehensive predictive modeling of disease progression and treatment response. However, since EHRs were originally constructed for administrative purposes not for research, in the EHR-linked studies, it is often not feasible to capture reliable information for analytical variables, especially in the survival setting, when both accurate event status and event times are needed for model building. For example, progression-free survival (PFS), a commonly used survival outcome for cancer patients, often involves complex information embedded in free-text clinical notes and cannot be extracted reliably. Proxies of PFS time such as time to the first mention of progression in the notes are at best good approximations to the true event time. This leads to difficulty in efficiently estimating event rates for an EHR patient cohort. Estimating survival rates based on error-prone outcome definitions can lead to biased results and hamper the power in the downstream analysis. On the other hand, extracting accurate event time information via manual annotation is time and resource intensive. The objective of this study is to develop a calibrated survival rate estimator using noisy outcomes from EHR data. In this paper, we propose a two-stage semi-supervised calibration of noisy event rate (SCANER) estimator that can effectively overcome censoring induced dependency and attains more robust performance (i.e., not sensitive to misspecification of the imputation model) by fully utilizing both a small-labeled set of gold-standard survival outcomes annotated via manual chart review and a set of proxy features automatically captured via EHR in the unlabeled set. We validate the SCANER estimator by estimating the PFS rates for a virtual cohort of lung cancer patients from one large tertiary care center and the ICU-free survival rates for COVID patients from two large tertiary care centers. In terms of survival rate estimates, the SCANER had very similar point estimates compared to the complete-case Kaplan Meier estimator. On the other hand, other benchmark methods for comparison, which fail to account for the induced dependency between event time and the censoring time conditioning on surrogate outcomes, produced biased results across all three case studies. In terms of standard errors, the SCANER estimator was more efficient than the KM estimator, with up to 50% efficiency gain. The SCANER estimator achieves more efficient, robust, and accurate survival rate estimates compared to existing approaches. This promising new approach can also improve the resolution (i.e., granularity of event time) by using labels conditioning on multiple surrogates, particularly among less common or poorly coded conditions. [ABSTRACT FROM AUTHOR]

A critical issue in many neuroimaging studies is the comparison between brain maps. Nonetheless, it remains unclear how one should test hypotheses focused on the overlap or spatial correspondence between two or more brain maps. This “correspondence problem” affects, for example, the interpretation of comparisons between task-based patterns of functional activation, resting-state networks or modules, and neuroanatomical landmarks. To date, this problem has been addressed with remarkable variability in terms of methodological approaches and statistical rigor. In this paper, we address the correspondence problem using a spatial permutation framework to generate null models of overlap by applying random rotations to spherical representations of the cortical surface, an approach for which we also provide a theoretical statistical foundation. We use this method to derive clusters of cognitive functions that are correlated in terms of their functional neuroatomical substrates. In addition, using publicly available data, we formally demonstrate the correspondence between maps of task-based functional activity, resting-state fMRI networks and gyral-based anatomical landmarks. We provide open-access code to implement the methods presented for two commonly-used tools for surface based cortical analysis (https://www.github.com/spin-test). This spatial permutation approach constitutes a useful advance over widely-used methods for the comparison of cortical maps, thereby opening new possibilities for the integration of diverse neuroimaging data. [ABSTRACT FROM AUTHOR]

Functional mapping of cerebral blood volume (CBV) changes has the potential to reveal brain activity with high localization specificity at the level of cortical layers and columns. Non-invasive CBV imaging using Vascular Space Occupancy (VASO) at ultra-high magnetic field strengths promises high spatial specificity but poses unique challenges in human applications. As such, 9.4 T B 1 + and B 0 inhomogeneities limit efficient blood tagging, while the specific absorption rate (SAR) constraints limit the application of VASO-specific RF pulses. Moreover, short T 2 * values at 9.4 T require short readout duration, and long T 1 values at 9.4 T can cause blood-inflow contaminations. In this study, we investigated the applicability of layer-dependent CBV-fMRI at 9.4 T in humans. We addressed the aforementioned challenges by combining multiple technical advancements: temporally alternating pTx B 1 + shimming parameters, advanced adiabatic RF-pulses, 3D-EPI signal readout, optimized GRAPPA acquisition and reconstruction, and stability-optimized RF channel combination. We found that a combination of suitable advanced methodology alleviates the challenges and potential artifacts, and that VASO fMRI provides reliable measures of CBV change across cortical layers in humans at 9.4 T. The localization specificity of CBV-fMRI, combined with the high sensitivity of 9.4 T, makes this method an important tool for future studies investigating cortical micro-circuitry in humans. [ABSTRACT FROM AUTHOR]

Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety. In functional in vitro assays C2816 retained full agonism at GLP-1R and CCKR1 at lower potency compared to parent molecules, whereas a previously reported fusion peptide in the opposite orientation, (pGlu-Gln)-CCK-8/exendin-4, exhibited no activity at either receptor. Acutely, in vivo, C2816 increased cFos in key central nuclei relevant to feeding behavior, and reduced food intake in wildtype (WT), but less so in GLP-1R-deficient (GLP-1RKO), mice. In sub-chronic studies in diet-induced obese (DIO) mice, C2816 exerted superior reduction in body weight compared to co-administration of AC3174 and AC170222 albeit at a higher molar dose. These data suggest that the synergistic pharmacological effects of GLP-1 and CCK pathways can be harnessed in a single therapeutic peptide. [ABSTRACT FROM AUTHOR]

We examine how insertion of a delay in a system of ordinary differential equations can change the asymptotic dynamics and stabilize the structure of the system under further change. [ABSTRACT FROM AUTHOR]

The human mitochondrial genome has been extensively studied for its function and disease associations. Utilizing five types of high-throughput sequencing data on ten breast cancer patients (total N = 50), we examined several aspects of the mitochondrial genome that have not been thoroughly studied, including the occurrence of tri-allelic heteroplasmy, the difference between DNA and RNA, and the variants association with polynucleotide tracts. We validated four previously reported and identified 23 additional tri-allelic positions. Furthermore, we detected 18 single nucleotide and seven InDel differences between DNA and RNA. Previous studies have suggested that some of these differences are caused by post transcriptional methylation. The rest can be accredited to RNA editing, polyadenylation or sequencing errors. Most importantly, we found that the tri-allelic positions, and differences between DNA and RNA, are strongly associated with polynucleotide tracts in the mitochondrial genome, suggesting DNA instability or difficulty sequencing around the polynucleotide tract regions. [ABSTRACT FROM AUTHOR]

The secondary structure of an RNA is often implicit to its function. Recently, various high-throughput RNA structure probing techniques have been developed to elucidate important RNA structure–function relationships genome-wide. These techniques produce unwieldy experimental data sets that require evaluation with unique computational pipelines. Herein, we present StructureFold2, a user-friendly set of analysis tools that makes precise data processing and detailed downstream analyses of such data sets both available and practical. StructureFold2 processes high-throughput reads sequenced from libraries prepared after experimental probing for reverse transcription (RT) stops generated by chemical modification of RNA at solvent accessible residues. This pipeline is able to analyze reads generated from a variety of structure-probing chemicals (e.g. DMS, glyoxal, SHAPE). Notably, StructureFold2 offers a new fully featured suite of utilities and tools to guide a user through multiple types of analyses. A particular emphasis is placed on analyzing the reactivity patterns of transcripts, complementing their use as folding restraints for predicting RNA secondary structure. StructureFold2 is hosted as a Github repository and is available at ( https://github.com/StructureFold2/StructureFold2 ). [ABSTRACT FROM AUTHOR]

Uncontrolled burning of municipal solid waste (MSW) is an important source of air pollution and is wide spread in many developing countries, but only limited data quantify the extent of domestic open burning of household waste. Here, we present some of the first field data to be reported on the uncontrolled domestic burning of waste. A representative community of Mexico (Huejutla de Reyes Municipality) was investigated and household surveys, interviews with waste operators and a waste characterisation analysis were completed to assess the extent of, and factors controlling, the open burning of waste. Waste collection provision to rural communities was very limited and, consequently 92% of households in rural areas reported that they disposed of waste by uncontrolled burning in backyards or unofficial dumps. Overall, 24% of the total MSW generated in the Municipality was disposed by uncontrolled burning. Urban and periurban areas received twice-weekly collections and the rate of uncontrolled burning was considerably smaller compared to rural households, corresponding to approximately 2% of total waste generation. Carbon equivalency calculations showed that burning waste in backyards represented approximately 6% of the total and 8.5% of fuel related CO 2 Eq emissions by the municipality. Moreover, the equivalent carbon dioxide (CO 2 Eq) from black carbon (BC) emitted by uncontrolled burning in backyards was over fifteen times larger compared to methane (CH 4 ) potentially released from equivalent amounts of combustible biodegradable waste disposal at the official dumpsite. An assessment of local respiratory health data showed the incidence of disease was higher in rural than in urban areas, when the opposite trend is typically observed in the international literature; given the high rate of burning activity found in rural areas we suggest that open burning of waste could be a major reason for the apparent poorer respiratory health status of the rural population and requires further investigation. The results emphasise the importance of including BC from uncontrolled burning of waste in international emission inventories of greenhouse gases and in the assessment of the health status of local communities in developing countries where this practice is prevalent. [ABSTRACT FROM AUTHOR]

Central to Alzheimer's disease (AD) pathology is the assembly of monomeric amyloid-β peptide (Aβ) into oligomers and fibers. The most abundant protein in the blood plasma and cerebrospinal fluid is human serum albumin. Albumin can bind to Aβ and is capable of inhibiting the fibrillization of Aβ at physiological (μM) concentrations. The ability of albumin to bind Aβ has recently been exploited in a phase II clinical trial, which showed a reduction in cognitive decline in AD patients undergoing albumin–plasma exchange. Here we explore the equilibrium between Aβ monomer, oligomer and fiber in the presence of albumin. Using transmission electron microscopy and thioflavin-T fluorescent dye, we have shown that albumin traps Aβ as oligomers, 9 nm in diameter. We show that albumin-trapped Aβ oligomeric assemblies are not capable of forming ion channels, which suggests a mechanism by which albumin is protective in Aβ-exposed neuronal cells. In vivo albumin binds a variety of endogenous and therapeutic exogenous hydrophobic molecules , including cholesterol, fatty acids and warfarin. We show that these molecules bind to albumin and suppress its ability to inhibit Aβ fiber formation. The interplay between Aβ, albumin and endogenous hydrophobic molecules impacts Aβ assembly; thus, changes in cholesterol and fatty acid levels in vivo may impact Aβ fibrillization, by altering the capacity of albumin to bind Aβ. These observations are particularly intriguing given that high cholesterol or fatty acid diets are well-established risk factors for late-onset AD. [ABSTRACT FROM AUTHOR]

In epilepsy, individual seizures can be triggered by a variety of external and internal stimuli. One of the most common trigger factors reported by patients is stress. However prevalent, stress-related triggering of episodes seems underappreciated in epilepsy for various reasons, and its misinterpretation often leads to other diagnoses, e.g., psychogenic nonepileptic seizures (PNES) or normal reactions. This article illustrates the significant role of stress as a seizure-provoking factor by referring to nine patient narratives. From this perspective, it appears that there are characteristic patterns of stress triggering, e.g., stress-induced sleep disruption, forms of acute stress, or relaxation after stress. Sometimes seizures are mistaken as symptoms of stress. Patient narratives contain interesting clues relating reports about stress and seizure histories to different epilepsy syndromes as well as nonepileptic episodes in a way that can strongly support the diagnostic process. A narrative approach is particularly valuable in this context. Therefore, accounts of stress triggering in seizures and other episodes should not be neglected, but rather taken seriously, sought and actively explored as a crucial element when taking clinical histories in patients with episodic attacks. [ABSTRACT FROM AUTHOR]

Frogs in the genus Amnirana (family Ranidae) are widely distributed across sub-Saharan Africa and present a model system for exploring the relationship between diversification and geography across the continent. Using multiple loci from the mitochondrial ( 16S ) and nuclear genomes ( DISP2 , FICD , KIAA2013 , REV3L ), we generated a strongly supported species-level phylogeny that provides insights into the continental biogeography of African species of Amnirana , which form a monophyletic group within the genus. Species delimitation analyses suggest that there may be as many as seven additional species of Amnirana in Africa. The biogeographic history of Amnirana is marked by several dispersal and vicariance events, including dispersal from the Lower Guinean Forest into the Congo Basin. In addition, phylogeographic patterns within two widespread species, A. albolabris and A. galamensis, reveal undescribed cryptic diversity. Populations assigned to A. albolabris in western Africa are more closely related to A. fonensis and require recognition as a distinct species. Our analyses reveal that the Lower and Upper Guinean Forest regions served as important centers of interspecific and intraspecific diversifications for Amnirana . [ABSTRACT FROM AUTHOR]