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Many research questions in visual perception involve determining whether stimulus properties are represented and processed independently. In visual neuroscience, there is great interest in determining whether important object dimensions are represented independently in the brain. For example, theories of face recognition have proposed either completely or partially independent processing of identity and emotional expression. Unfortunately, most previous research has only vaguely defined what is meant by "independence," which hinders its precise quantification and testing. This article develops a new quantitative framework that links signal detection theory from psychophysics and encoding models from computational neuroscience, focusing on a special form of independence defined in the psychophysics literature: perceptual separability. The new theory allowed us, for the first time, to precisely define separability of neural representations and to theoretically link behavioral and brain measures of separability. The framework formally specifies the relation between these different levels of perceptual and brain representation, providing the tools for a truly integrative research approach. In particular, the theory identifies exactly what valid inferences can be made about independent encoding of stimulus dimensions from the results of multivariate analyses of neuroimaging data and psychophysical studies. In addition, commonly used operational tests of independence are re-interpreted within this new theoretical framework, providing insights on their correct use and interpretation. Finally, we apply this new framework to the study of separability of brain representations of face identity and emotional expression (neutral/sad) in a human fMRI study with male and female participants.

Abstract This statement from the Pediatric Academic Societies Maternal Child Health: First 1,000 Days Special Interest Group provides an overview of the rationale, evidence, and key action steps needed to engage Community Health Workers (CHWs) into team-based well-child care (WCC) for families in low-income communities. CHWs have been defined as public health workers who have a trusted and valued connection to a community. Integrating CHWs into early childhood WCC can allow for greater cultural relevancy for families, reduce the burden on clinicians to provide the wide range of WCC services, many of which do not require the expertise of a high-level clinician, and improve preventive care services to families during the vulnerable but critical period of early childhood. There are evidence-based approaches to integrating CHWs into early childhood WCC, as well as payment models that can support them. Implementation and spread of these models will require collaboration and engagement across health systems, clinics, payors, and CHWs; flexibility for local adaptation of these models to meet the needs of clinics, practices, CHWs, and communities; publicly available training resources for CHW education; and research findings to guide effective implementation that incorporates parent and caregiver engagement as well as sustainable payment models.

Summary: Background: Sweetened beverage taxes are associated with large decreases in sugar-sweetened beverage sales, but their effects on weight outcomes are unclear. We examined associations of the 2017 Philadelphia beverage tax with changes in adult weight outcomes. Methods: We obtained electronic health record data on adults 18–65 years old in Philadelphia (intervention) and other areas of Pennsylvania and New Jersey (control) from 2014 to 2019. Controlled interrupted time series models compared post-tax changes in trends of body mass index (BMI, primary outcome) and obesity prevalence (secondary outcome). A panel sample comprised 175,675 adults with at least one BMI measure in both the pre-tax (2014–2016) and post-tax (2017–2019) periods. A cross-sectional sample comprised 587,121 adults with at least one BMI measure from 2014 to 2019. Findings: Before tax implementation, Philadelphia panel patients had a mean BMI of 30.4 kg/m2 and an obesity prevalence of 44.5%. After implementation, in the panel sample, there was a −0.03 kg/m2 (95% CI: −0.07, 0.02) per quarter decrease in BMI vs. control, implying a −0.32 kg/m2 (−0.85, 0.20) change at the end of the 3-year study period. In the cross-sectional sample, there was a −0.05 kg/m2 (95% CI: −0.09, −0.01) per quarter decrease in BMI vs. control, implying a −0.60 kg/m2 (−1.04, −0.16) change at the end of the study period. Results for obesity prevalence were consistent with the BMI results. Interpretation: There was some limited evidence of a decrease in BMI and obesity prevalence in Philadelphia 3 years after beverage tax implementation. Replication of these results is needed. Funding: National Institutes of Health.

The Cape Bounty Arctic Watershed Observatory (CBAWO), Melville Island, Nunavut (74°55′N, 109°34′W) was established in 2003 to examine Arctic ecosystem processes that would be impacted by climate warming and permafrost degradation. This paper provides a synthesis of how remote sensing has contributed to biogeophysical modelling and monitoring at the CBAWO from 2003 to 2023. Given the location and isolated nature of the CBAWO in the Canadian High Arctic, remote sensing data and derivatives have been instrumental for studies examining ecosystem structure and function at local and landscape scales. In combination with field measurements, remote sensing data facilitated mapping and modelling of vegetation types, % vegetation cover and aboveground phytomass, soil moisture, carbon exchange rates, and permafrost degradation and disturbance. It has been demonstrated that even in an environment with limited vegetation cover and phytomass, spectral vegetation indices (e.g., the normalized difference vegetation index) are able to model various biogeophysical variables. These applications are feasible for research sites such as the CBAWO using high spatial resolution remote sensing data across the visible, infrared, and microwave regions of the electromagnetic spectrum. Furthermore, as the satellite record continues to expand, we will gain a greater understanding of the impacts arising from the expected continued warming at northern latitudes. Although the logistics for research in the Arctic remain challenging, today's technologies (e.g., high spatial resolution satellite remote sensing, automated in situ sensors and data loggers, and wireless communication systems) can support a host of scientific endeavours in the Arctic (and other remote sites) through modelling and monitoring of biogeophysical variables and Earth surface processes with limited but critical field campaigns. The research synthesized here for the CBAWO highlights the essential role of remote sensing of terrestrial ecosystems in the Canadian Arctic.

Lin41/Trim71 is a heterochronic gene encoding a member of the Trim-NHL protein family, and is the original, genetically defined target of the microRNA let-7 in C. elegans. Both the LIN41 protein and multiple regulatory microRNA binding sites in the 3’ UTR of the messenger RNA (mRNA) are highly conserved from nematodes to humans. Functional studies have described essential roles for mouse LIN41 in embryonic stem cells, cellular reprogramming and the timing of embryonic neurogenesis. We have used a new gene trap mouse line deficient in Lin41 to characterize Lin41 expression during embryonic development and in the postnatal central nervous system (CNS). In the embryo, Lin41 is required for embryonic viability and neural tube closure. Nevertheless, neurosphere assays suggest that Lin41 is not required for adult neurogenesis. Instead, we show that Lin41 promoter activity and protein expression in the postnatal CNS is restricted to ependymal cells lining the walls of the four ventricles. We use ependymal cell culture to confirm reestablishment of Lin41 expression during differentiation of ependymal progenitors to post-mitotic cells possessing motile cilia. Our results reveal that terminally differentiated ependymal cells express Lin41, a gene to date associated with self-renewing stem cells.

miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability.

Abstract The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21–bound transcriptome reveals strong interactions with the Rag1 3′-UTR. Arpp21–deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3′-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

Toll-like receptors (TLR) are key players of the innate and adaptive immune response in vertebrates. The original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis during development. Making use of real-time PCR, in situ hybridization, and immunohistochemistry we systematically examined the expression of TLR1-9 and the intracellular adaptor molecules MyD88 and TRIF during development of the mouse brain. Expression of TLR7 and TLR9 in the brain was strongly regulated during different embryonic, postnatal, and adult stages. In contrast, expression of TLR1-6, TLR8, MyD88, and TRIF mRNA displayed no significant changes in the different phases of brain development. Neurons of various brain regions including the neocortex and the hippocampus were identified as the main cell type expressing both TLR7 and TLR9 in the developing brain. Taken together, our data reveal specific expression patterns of distinct TLRs in the developing mouse brain and lay the foundation for further investigation of the pathophysiological significance of these receptors for developmental processes in the central nervous system of vertebrates.

Objective: There are gaps in receipt of maternal preventive services in the interconception period. Yet mother?infant dyads have frequent health care visits. Health systems have opportunities to better capitalize on existing visits to address dyad needs, but this possibility has not been fully explored. Methods: In this qualitative study we conducted semistructured interviews with clinical team members involved with birthing parents or infants after preterm birth. We conducted snowball sampling from teams in pediatrics, obstetrics, and family medicine at two geographically adjacent health systems. Interviews explored perspectives on existing barriers and facilitators to integrating dyad care across adult and infant teams. Interviews were audio-recorded, professionally transcribed, and coded using an integrated approach. Results: We interviewed 24 physicians, nurses, midwives, and social workers (March?November 2021). Participants identified barriers to integrated care including infrequent communication between clinical teams, which was generalizable to care of the birthing parent or infant as individuals, and additional barriers related to privacy, credentialing, and visit design that were specific to dyad care. To improve integration of dyad care, clinicians proposed adapting a variety tools and procedures currently used in their practices, including electronic health record tools for communication, dedicated roles to support communication or navigation, centralized information on resources for dyad care, referral protocols, identifying dyads for proactive outreach, and opportunities for clinicians to connect face-to-face about shared patients or families. Conclusions: Clinicians believe existing health care structures and processes can be adapted to address current substantial barriers to integrated dyad care.

In rule-based (RB) category-learning tasks, the optimal strategy is a simple explicit rule, whereas in information-integration (II) tasks, the optimal strategy is impossible to describe verbally. This study investigates the effects of two different category properties on learning difficulty in category learning tasks--namely, linear separability and variability on stimulus dimensions that are irrelevant to the categorization decision. Previous research had reported that linearly separable II categories are easier to learn than nonlinearly separable categories, but Experiment 1, which compared performance on linearly and nonlinearly separable categories that were equated as closely as possible on all other factors that might affect difficulty, found that linear separability had no effect on learning. Experiments 1 and 2 together also established a novel dissociation between RB and II category learning: increasing variability on irrelevant stimulus dimensions impaired II learning but not RB learning. These results are all predicted by the best available measures of difficulty in RB and II tasks.

Purpose: Motivational interviewing (MI) is an evidence-based strategy to modify health behaviors, including some risk factors for adverse birth outcomes. Black women, who have disproportionately high rates of adverse birth outcomes, have reported mixed preferences on MI. This study explored the acceptability of MI among Black women who are at high risk for adverse birth outcomes. Methods: We conducted qualitative interviews with women with a history of preterm birth. Participants were English-language proficient and had Medicaid-insured infants. We purposively oversampled women whose infants had medical complexity. Interviews explored experiences with health care and health behaviors after birth. The interview guide was iteratively developed to obtain specific reactions to MI by including videos demonstrating MI-consistent and MI-inconsistent counseling. Interviews were audio recorded, transcribed, and coded following an integrated approach in which we applied a priori codes related to MI and allowed themes to emerge from the data. Results: We interviewed 30 non-Hispanic Black women from October 2018 to July 2021. Eleven viewed the videos. Participants emphasized the importance of autonomy in decision-making and health behavior. Participants expressed a preference for MI-consistent clinical approaches, including autonomy support and building rapport, considering them respectful, nonjudgmental, and likely to support change. Conclusions: In this sample of Black women with a history of preterm birth, participants valued an MI-consistent clinical approach. Incorporating MI into clinical care may improve the experience of health care among Black women, thus serving as one strategy to promote equity in birth outcomes.

Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lag behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development.

Despite much research, the role of the medial temporal lobes (MTL) in category learning is unclear. Two unstructured categorization experiments explored conditions that might recruit MTL category learning and memory systems--namely, whether the stimulus display includes one or two stimuli, and whether category membership depends on configural properties of the stimulus features. The results supported three conclusions. First, in agreement with prior research, learning with single stimulus displays depended on striatal-mediated procedural learning. Second, and most important, learning with pair displays was mediated by MTL declarative memory systems. Third, the use of stimuli in which category membership depends on configural properties of the stimulus features made MTL learning slightly more likely. Overall, the results suggested that the MTL are most likely to mediate learning when the participant must decide which of two configural stimuli belongs to a selected category.

Abstract Background During March of 2020 the Centers for Disease Control and Prevention (CDC) announced non-pharmaceutical intervention (NPI) guidance as the primary mitigation strategy against growing COVID-19 community spread due to the absence of a vaccine or effective treatment at that time. CDC guidance states that NPIs are most effective when instituted in an early, targeted, and layered fashion. NPIs are effective in slowing spread, and measures should be custom-tailored to each population. This study examines factors associated with implementation and timing of NPI interventions across large public and private U.S. universities at the onset of the COVID-19 pandemic. Methods NPI decisions of interest include when U.S. universities canceled international travel, shifted to online learning, moved faculty/staff to remote work, limited campus housing, and closed campus for all non-essential personnel. Cox proportional hazard analyses of retrospective data were conducted to assess the time to NPI events. Hazard ratios were calculated for university governance, campus setting, religious affiliation, health infrastructure, faculty diversity, and student demographics. The methods control for variance inflation factors, COVID case prevalence, and time varying covariates of spring break and states’ state of emergency (SOE) orders. This study captures NPI decisions at 575 U.S. universities during spring of 2020 which affected the movement of seven million students and two million employees. Results Universities located in districts represented by Democratic party congressional members reported earlier NPI implementation than Republican (Cox proportional hazard ratio (HR) range 0.61–0.80). University religious affiliation was not associated with the timing any of the NPI decisions. Universities with more diverse faculty showed an association with earlier NPI implementation (HR range 0.65–0.76). The existence of university-affiliated health infrastructure was not associated with NPI timing. Conclusion University NPI implementation was largely driven by local COVID-19 epidemiology, culture and political concerns. The timing of university NPI decisions varied by regional politics, faculty demographics, university governance, campus setting, and foreign student prevalence adjusting for COVID-19 state case prevalence and spring break timing. Religious affiliation and presence of university health infrastructure were not associated with timing.

The field of computational cognitive neuroscience (CCN) builds and tests neurobiologically detailed computational models that account for both behavioral and neuroscience data. This article leverages a key advantage of CCN-namely, that it should be possible to interface different CCN models in a plug-and-play fashion-to produce a new and biologically detailed model of perceptual category learning. The new model was created from two existing CCN models: the HMAX model of visual object processing and the COVIS model of category learning. Using bitmap images as inputs and by adjusting only a couple of learning-rate parameters, the new HMAX/COVIS model provides impressively good fits to human category-learning data from two qualitatively different experiments that used different types of category structures and different types of visual stimuli. Overall, the model provides a comprehensive neural and behavioral account of basal ganglia-mediated learning.

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of Plasmodium falciparum that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy. The genes encoding P. falciparum circumsporozoite protein (PfCSP) and the ookinete protein P25 (Pfs25) are expressed as a Pfs25–PfCSP fusion protein, and the heterologous m8Δ-prime/AAV-boost immunization regimen in mice provided both 100% protection against PfCSP-transgenic P. berghei sporozoites and up to 100% transmission blocking efficacy, as determined by a direct membrane feeding assay using parasites from P. falciparum-positive, naturally-infected donors from endemic settings. Remarkably, the persistence of vaccine-induced immune responses were over 7 months and additionally provided complete protection against repeated parasite challenge in a murine model. We propose that application of the m8Δ/AAV malaria multistage vaccine platform has the potential to contribute to the landmark goals of the malaria vaccine technology roadmap, to achieve life-long sterile protection and high-level transmission blocking efficacy.

Nuclear positioning is important for the functionality of many cell types and is mediated by interactions of cytoskeletal elements and nucleoskeleton proteins. Nesprin proteins, part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, have been shown to participate in nuclear positioning in multiple cell types. Outer hair cells (OHCs) in the inner ear are specialized sensory epithelial cells that utilize somatic electromotility to amplify auditory signals in the cochlea. Recently, Nesprin-4 (encoded by Syne4) was shown to play a crucial role in nuclear positioning in OHCs. Syne4 deficiency in humans and mice leads to mislocalization of the OHC nuclei and cell death resulting in deafness. However, it is unknown how Nesprin-4 mediates the position of the nucleus, and which other molecular components are involved in this process. Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. Using in vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. Nuclear mislocalization and cell death of OHCs coincide with the onset of hearing and electromotility and are solely restricted to outer, but not inner, hair cells. Likewise, the C. elegans functional homolog of Nesprin-4, UNC-83, uses a similar motif to mediate interactions between migrating nuclei and kinesin-1. Overall, our results suggest that OHCs require unique cellular machinery for proper nuclear positioning at the onset of electromotility. This machinery relies on the interaction between Nesprin-4 and kinesin-1 motors supporting a microtubule cargo model for nuclear positioning.

Procedural learning of skills depends on dopamine-mediated striatal plasticity. Most prior work investigated single stimulus-response procedural learning followed by feedback. However, many skills include several actions that must be performed before feedback is available. A new procedural-learning task is developed in which three independent and successive unsupervised categorization responses receive aggregate feedback indicating either that all three responses were correct, or at least one response was incorrect. Experiment 1 showed superior learning of stimuli in position 3, and that learning in the first two positions was initially compromised, and then recovered. An extensive theoretical analysis that used parameter space partitioning found that a large class of procedural-learning models, which predict propagation of dopamine release from feedback to stimuli, and/or an eligibility trace, fail to fully account for these data. The analysis also suggested that any dopamine released to the second or third stimulus impaired categorization learning in the first and second positions. A second experiment tested and confirmed a novel prediction of this large class of procedural-learning models that if the to-be-learned actions are introduced one-by-one in succession then learning is much better if training begins with the first action (and works forwards) than if it begins with the last action (and works backwards).