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The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

IntroductionSome caregivers are hesitant about topical fluoride for their children despite evidence that fluoride prevents caries and is safe. Recent work described a five domain model of caregivers' topical fluoride hesitancy. We developed the Fluoride Hesitancy Identification Tool (FHIT) item pool based on the model. This study sought to evaluate the FHIT's psychometric properties in an effort to generate a short, simple to score, reliable, and valid tool that measures caregivers' topical fluoride hesitancy.MethodsIn 2021 and 2022, we conducted an observational, cross-sectional study of caregivers, collecting data from two independent caregiver samples (n1 = 523; n2 = 612). The FHIT item pool included 33 items. We used confirmatory factor analyses (CFA) to examine whether the FHIT items measured five separate domains as hypothesized and to reduce the number of items. We then fit item response theory (IRT) models and computed Cronbach's alpha for each domain. Last, we examined the construct validity of the FHIT and evaluated scoring approaches.ResultsAfter dropping 8 items, CFA supported a five factor model of topical fluoride hesitancy, with no cross-loadings (RMSEA = 0.079; SRMR = 0.057; CFI = 0.98; TLI = 0.98). We further reduced the items to four per domain (20 items total). Marginal alphas showed that the item sets provided reliability of ≥0.90 at hesitancy levels at and above average. The domains correlated more strongly with each other and topical fluoride refusal than with other questions on the survey.DiscussionOur results support the FHIT's ability to reliably and validly measure five domains of topical fluoride hesitancy using the average score of the four items in each domain.

Comparisons and linkage between multiple imaging scales are essential for neural circuit connectomics. Here, we report 20 new recombinant rabies virus (RV) vectors that we have developed for multi-scale and multi-modal neural circuit mapping tools. Our new RV tools for mesoscale imaging express a range of improved fluorescent proteins. Further refinements target specific neuronal subcellular locations of interest. We demonstrate the discovery power of these new tools including the detection of detailed microstructural changes of rabies-labeled neurons in aging and Alzheimer's disease mouse models, live imaging of neuronal activities using calcium indicators, and automated measurement of infected neurons. RVs that encode GFP and ferritin as electron microscopy (EM) and fluorescence microscopy reporters are used for dual EM and mesoscale imaging. These new viral variants significantly expand the scale and power of rabies virus-mediated neural labeling and circuit mapping across multiple imaging scales in health and disease.

ImportanceThe hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.

Gene functional descriptions offer a crucial line of evidence for candidate genes underlying trait variation. Conversely, plant responses to environmental cues represent important resources to decipher gene function and subsequently provide molecular targets for plant improvement through gene editing. However, biological roles of large proportions of genes across the plant phylogeny are poorly annotated. Here we describe the Joint Genome Institute (JGI) Plant Gene Atlas, an updateable data resource consisting of transcript abundance assays spanning 18 diverse species. To integrate across these diverse genotypes, we analyzed expression profiles, built gene clusters that exhibited tissue/condition specific expression, and tested for transcriptional response to environmental queues. We discovered extensive phylogenetically constrained and condition-specific expression profiles for genes without any previously documented functional annotation. Such conserved expression patterns and tightly co-expressed gene clusters let us assign expression derived additional biological information to 64 495 genes with otherwise unknown functions. The ever-expanding Gene Atlas resource is available at JGI Plant Gene Atlas (https://plantgeneatlas.jgi.doe.gov) and Phytozome (https://phytozome.jgi.doe.gov/), providing bulk access to data and user-specified queries of gene sets. Combined, these web interfaces let users access differentially expressed genes, track orthologs across the Gene Atlas plants, graphically represent co-expressed genes, and visualize gene ontology and pathway enrichments.

Quantitative fatty acid signature analysis (QFASA) is a common method of estimating the composition of prey species in the diets of consumers from polar and temperate ecosystems in which lipids are an important source of energy. A key characteristic of QFASA is that the large number of fatty acids that typically comprise lipids permits the dietary contributions of a correspondingly large number of prey types to be estimated. Several modifications to the original QFASA methods have been suggested in the literature and a significant extension of the original model published in 2017 allows simultaneous estimation of both diet proportions and calibration coefficients, which are metabolic constants in the model whose values must otherwise be estimated in independent feeding experiments. However, comparisons of diet estimates obtained using different estimation options have been limited. QFASA has been used to estimate the diet composition of several polar bear (Ursus maritimus) subpopulations, including the Southern Beaufort Sea (SBS) subpopulation. Prior QFASA estimates of SBS polar bear diet composition have most often been obtained using variations of the original QFASA model. We investigated the influence of variations in QFASA analytical methods on diet estimates by re-estimating the diet composition of polar bears from the Alaska portion of the SBS using three different methods and found that differences among the three sets of estimates were substantial. Our results illustrate how important the careful and deliberate selection of QFASA methods can be and we provide some guidance on techniques one might use to evaluate options.

ABSTRACT Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To address this gap, gain insights into vLRTI pathophysiology, and test a novel diagnostic approach, we assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 critically ill children using SomaScan. We performed differential expression (DE) and pathway analyses comparing vLRTI (n = 40) to controls with non-infectious acute respiratory failure (n = 22), developed a diagnostic classifier using LASSO regression, and analyzed matched TA and plasma samples. We further investigated the impact of viral load and bacterial coinfection on the proteome. The TA signature of vLRTI was characterized by 200 DE proteins (Padj

The Chilean degu (Octodon degus) is a medium sized, long-lived rodent with traits that make them a natural model for neuroscience research. Their social behaviors, diurnality, and extended developmental time course, when compared to other rodents, make them useful for social behavioral, chronobiology, and developmental research. Lab-kept degus have a long lifespan (5–8 years) and may naturally develop age-related diseases that resemble Alzheimer’s disease. While there is significant interest in using the Octodon degus for neuroscience research, including aging and Alzheimer’s disease studies, laboratory management and methods for degus research are currently not standardized. This lack of standardization potentially impacts study reproducibility and makes it difficult to compare results between different laboratories. Degus require species-specific housing and handling methods that reflect their ecology, life history, and group-living characteristics. Here we introduce major principles and ethological considerations of colony management and husbandry. We provide clear instructions on laboratory practices necessary for maintaining a healthy and robust colony of degus for Alzheimer’s disease neuroscience research towards conducting reproducible studies. We also report detailed procedures and methodical information for degu Apoe genotyping and ethologically relevant burrowing behavioral tasks in laboratory settings.

Our cognitive capacities like working memory and attention are known to systematically vary over time with our physical activity levels, dietary choices, and sleep patterns. However, whether our metacognitive capacities--such as our strategic use and optimization of cognitive resources--show a similar relationship with these key lifestyle factors remains unknown. Here we addressed this question in healthy young adults by examining if physical activity, diet, and sleep patterns were predictive of self-reported metacognitive status. Participants completed a set of validated surveys assessing these lifestyle factors over the past week to month, as well as three measures of metacognition. Using multiple regression and exploratory factor analyses we identified four clusters of metacognitive processes that are sensitive to lifestyle behaviours. Specifically, knowledge of and offline regulation of cognition is linked with physical activity, on-line cognitive regulation is related to diet, and metacognitive worry is associated with sleep behaviours. These findings suggest that lifestyle behaviours do not just affect objective cognitive functioning, but also the meta-level processes we use to monitor our cognitive performance and exert strategic control over our cognitive resources.

In neuro-oncology, MR imaging is crucial for obtaining detailed brain images to identify neoplasms, plan treatment, guide surgical intervention, and monitor the tumor's response. Recent AI advances in neuroimaging have promising applications in neuro-oncology, including guiding clinical decisions and improving patient management. However, the lack of clarity on how AI arrives at predictions has hindered its clinical translation. Explainable AI (XAI) methods aim to improve trustworthiness and informativeness, but their success depends on considering end-users’ (clinicians') specific context and preferences. User-Centered Design (UCD) prioritizes user needs in an iterative design process, involving users throughout, providing an opportunity to design XAI systems tailored to clinical neuro-oncology. This review focuses on the intersection of MR imaging interpretation for neuro-oncology patient management, explainable AI for clinical decision support, and user-centered design. We provide a resource that organizes the necessary concepts, including design and evaluation, clinical translation, user experience and efficiency enhancement, and AI for improved clinical outcomes in neuro-oncology patient management. We discuss the importance of multi-disciplinary skills and user-centered design in creating successful neuro-oncology AI systems. We also discuss how explainable AI tools, embedded in a human-centered decision-making process and different from fully automated solutions, can potentially enhance clinician performance. Following UCD principles to build trust, minimize errors and bias, and create adaptable software has the promise of meeting the needs and expectations of healthcare professionals.

ABSTRACT Climate change coupled with large‐scale surface disturbances necessitate active restoration strategies to promote resilient and genetically diverse native plant communities. However, scarcity of native plant materials hinders restoration efforts, leading practitioners to choose from potentially viable but nonlocal seed sources. Genome scans for genetic variation linked with selective environmental gradients have become a useful tool in such efforts, allowing rapid delineation of seed transfer zones along with predictions of genomic vulnerability to climate change. When properly applied, genome scans can reduce the risk of maladaptation due to mismatches between seed source and planting site. However, results are rarely replicated among complimentary data sources. Here, we compared RAD‐seq datasets with 819 and 2699 SNPs (in 625 and 356 individuals, respectively) from the Mojave Desert winter annual Chylismia brevipes. Overall, we found that the datasets consistently characterized both neutral population structure and genetic–environmental associations. Ancestry analyses indicated consistent spatial genetic structuring into four regional populations. We also detected a marked signal of isolation by resistance (IBR), wherein spatial genetic structure was better explained by habitat resistance than by geographic distance. Potentially adaptive loci identified from genome scans were associated with the same environmental gradients—fall precipitation, winter minimum temperature, and precipitation timing—regardless of dataset. Paired with our finding that habitat resistance best explained genetic divergence, our results suggest that isolation of populations within environmentally similar habitats—and subsequent local adaption along gradients parallel to these habitats—drive genome‐wide divergence in this species. Moreover, strong genetic associations with winter precipitation timing, along with forecasted shifts in precipitation regime due to midcentury climate change, could impact future population dynamics, habitat distribution, and genetic connectivity for C. brevipes populations within the Mojave Desert.

Background Patients on dialysis are commonly prescribed multiple medications (polypharmacy), many of which are potentially inappropriate medications (PIMs). PIMs are associated with an increased risk of falls, fractures, and hospitalization. Deprescribing is a promising intervention to reduce PIMs.Methods We previously conducted a prospective controlled trial whereby we provided deprescribing decision support to nephrologists in one of two tertiary care outpatient hemodialysis units in Montreal, Canada. We aimed to collect information on barriers and facilitators to implementing deprescribing decision support with an electronic tool (MedSafer) by conducting semi-structured interviews among the four nephrologists who participated in the intervention arm of the study, between February and April 2023, following completion of the study. The four nephrologists had conducted medication reviews for a total of 68 patients on the intervention unit during the study. Interviews with participating nephrologists were conducted and transcribed by the study lead. Afterwards, data was coded and analyzed thematically with a focus on their perspective on participating in a quality improvement project during their clinical practice. Two graduate students used a combination of deductive (Theoretical Domains Framework) and inductive coding to analyze each transcribed interview in duplicate. Each coder then created a mind map to visually interpret results and derive themes. A senior qualitative researcher oversaw the development of the final common themes from the interviews.Results Four themes were developed: 1) the importance of deprescribing for patients on hemodialysis, 2) barriers to the success of the deprescribing intervention (e.g., the lack of a clinical pharmacist on the unit), 3) resources that were needed during the intervention (e.g., multidisciplinary team members to facilitate medication reconciliation), and 4) resources that facilitated the intervention (e.g., the provision of deprescribing brochures to patients).Conclusions This was the first study to explore the perspectives of nephrologists participating in a quality improvement project on deprescribing for patients on hemodialysis. This study interviewed a limited number of prescribers, which could limit the contextualized understanding and transferability of the nephrologists’ experiences. As a next step, some of the facilitators identified by the nephrologists should be implemented and studied in a larger clinical trial.Trial registration: NCT05585268

BackgroundTobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome.MethodsSecondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g.ResultsPatients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality.ConclusionAmong critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities.ImpactTobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

We present a case of an 81-year-old woman who presented to the emergency department with bleeding from a right breast wound. The patient had prior imaging suggestive of bilateral silicone implant rupture and a history of low tolerance for MRI scans. Ultrasound imaging in the emergency setting showed findings in the right breast suggestive of a fistula with free silicone and hematoma. A subsequent photon-counting CT scan with custom silicone-specific segmentation allowed differentiation of silicone from hematoma, provided anatomic assessment and location of the fistula, and revealed bilateral silicone-induced lymphadenopathy.

Abstract Background Hypertension (HTN) involves genetic variability in the renin‐angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen (AGT) messenger RNA (mRNA) is endogenously bound by miR‐122‐5p and rs699 A > G decreases reporter mRNA in the microRNA functional‐assay PASSPORT‐seq. The AGT promoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases AGT transcription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C > T counterbalances AGT decreased by rs699 A > G, and when these variants occur independently, it translates to HTN‐related phenotypes. Methods We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis. Results In silico, rs699 A > G is predicted to increase miR‐122‐5p binding affinity by 3%. Mir‐eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA‐binding site in the AGT mRNA. Unexpectedly, rs699 A > G increases AGT mRNA in an AGT‐plasmid‐cDNA HepG2 expression model. Genotype‐Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell‐type‐specific effects on AGT mRNA abundance, and suggest paracrine renal renin‐angiotensin‐system perturbations could mediate the rs699 A > G associations with HTN. Conclusions We found that rs5051 C > T and rs699 A > G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a fourfold larger effect than in White participants. Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C > T or rs699 A > G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.

Hippocampal CA1 neuronal ensembles generate sequential patterns of firing activity that contribute to episodic memory formation and spatial cognition. Here we used in vivo calcium imaging to record neural ensemble activities in mouse hippocampal CA1 and identified CA1 excitatory neuron sub-populations whose members are active across the same second-long period of time. We identified groups of hippocampal neurons sharing temporally correlated neural calcium activity during behavioral exploration and found that they also organized as clusters in anatomical space. Such clusters vary in membership and activity dynamics with respect to movement in different environments, but also appear during immobility in the dark suggesting an internal dynamic. The strong covariance between dynamics and anatomical location within the CA1 sub-region reveals a previously unrecognized form of topographic representation in hippocampus that may guide generation of hippocampal sequences across time and therefore organize the content of episodic memory.