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Navigating the broad and rapidly evolving market landscape of software solutions is complex whether you are a sustainability leader, building owner, energy manager, or building engineer with energy and greenhouse gas (GHG) emissions reduction goals for aportfolio of buildings. The Department of Energy’s Better Buildings partners have noted this complexity and the associated lack of publicly available information. In response, this report reviews the ecosystem of environmental, social, and governance (ESG), energymanagement information systems (EMIS), and decarbonization software with the goal oforienting prospective users to current offerings. Organizations can utilize this guidance to determine the specific capabilities needed to support decarbonization efforts and procure appropriate software to streamline the GHG emissions reduction process. In this paper, we refer to “decarbonization software” as the category of software that meets an organization’s needs for decarbonization planning, implementation, and tracking. This software may have a heritage in ESG or EMIS, or it may be an entirely new product. This report offers a snapshot of today’s rapidly evolving decarbonization software capabilities, along with guidance for procuring and utilizing it that will remain relevant despite any future software changes.Exploratory research was conducted on over 100 software providers, and interviews were held with 28 of them. Note that inclusion in this report does not indicate an endorsement, nor does a product’s absence from this report indicate a lack of suitability

Abstract: Background: Physical activity (PA) is associated with increased release of brain derived neurotrophic factor (BDNF), a mechanism that may underlie protective effects of PA on cognitive and brain aging. The Met allele of the BDNF Val66Met single‐nucleotide polymorphism reduces activity‐dependent BDNF release and is associated with increased phosphorylated tau (p‐tau181) in dementia populations. We sought to determine whether BDNF Val66Met influences the effects of PA on plasma p‐tau181 and cognition in older adults without dementia. Method: 123 older adults from the UCSF Memory and Aging Center completed blood draw assayed for p‐tau181 (Quanterix Simoa), BDNF Val66Met (rs6265) genotyping (Sequenom), 30‐days of FitbitTM actigraphy monitoring, and comprehensive neuropsychological evaluation (Mage = 73.93; SDage = 8.88, 59% female, 42% Met‐allele carriers). Habitual PA levels were operationalized via average daily step count. Composite z‐scores were calculated for cognitive domains of memory and executive functioning. Linear regression was used to determine the moderating effect of BDNF genotype on the relationship between PA and plasma p‐tau181. Moderated mediation analyses subsequently examined the consequences of this moderation effect on cognitive outcomes. Result: Average PA, plasma p‐tau181, and cognitive z‐scores did not differ between Met‐allele carriers and Val/Val participants. BDNF genotype moderated the relationship between PA and plasma p‐tau181 (b = 0.18, p = 0.036), whereby higher PA was associated with lower plasma p‐tau181 concentrations in Val/Val participants only (Figure 1). In moderated mediation analyses examining cognitive outcomes, plasma p‐tau181 concentration mediated the relationship between PA and executive function for Val/Val participants only (index of mod‐med = ‐0.037, p = 0.031; Figure 2). Models examining memory did not reach statistical significance. Conclusion: Findings converge with prior studies highlighting BDNF release as a potential mechanism underlying the neuroprotective effects of physical activity, including lower AD pathological burden and better cognition. These results further elucidate sources of individual variation observed in the effects of PA on the brain in older adults. Future work should further examine the molecular pathways bridging the effects of the BDNF Val66Met polymorphism on PA‐related benefits for brain aging to guide personalized neurotrophic treatments in older adults.

BACKGROUND: Peak-width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD. METHODS: We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID-1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimers Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders. RESULTS: Higher PSMD was associated with lower general cognition in MarkVCID-1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], -0.8 [-1.2, -0.4], P

ObjectiveOur objective was to investigate the overall and sex-specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults.MethodsMale and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren-Lawrence grade (KLG) of KOA severity (0-1, 2, or 3-4). Outcome measures included whole-body muscle mass, thigh fat-free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics.ResultsOverall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex-specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti-inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%-0.011%) and lower leg power (mean -51.56 W, 95% CI -74.03 to -29.10 W) and specific power (mean -5.38 W/L, 95% CI -7.31 to -3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power.ConclusionMuscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients.

BackgroundAssociations between childhood trauma, neurodevelopment, alcohol use disorder (AUD), and posttraumatic stress disorder (PTSD) are understudied during adolescence.MethodsUsing 1652 participants (51.75% female, baseline Mage = 14.3) from the Collaborative Study of the Genetics of Alcoholism, we employed latent growth curve models to (1) examine associations of childhood physical, sexual, and non-assaultive trauma (CPAT, CSAT, and CNAT) with repeated measures of alpha band EEG coherence (EEGc), and (2) assess whether EEGc trajectories were associated with AUD and PTSD symptoms. Sex-specific models accommodated sex differences in trauma exposure, AUD prevalence, and neural development.ResultsIn females, CSAT was associated with higher mean levels of EEGc in left frontocentral (LFC, ß = 0.13, p = 0.01) and interhemispheric prefrontal (PFI, ß = 0.16, p < 0.01) regions, but diminished growth in LFC (ß = -0.07, p = 0.02) and PFI (ß = -0.07, p = 0.02). In males, CPAT was associated with lower mean levels (ß = -0.17, p = 0.01) and increased growth (ß = 0.11, p = 0.01) of LFC EEGc. Slope of LFC EEGc was inversely associated with AUD symptoms in females (ß = -1.81, p = 0.01). Intercept of right frontocentral and PFI EEGc were associated with AUD symptoms in males, but in opposite directions. Significant associations between EEGc and PTSD symptoms were also observed in trauma-exposed individuals.ConclusionsChildhood assaultive trauma is associated with changes in frontal alpha EEGc and subsequent AUD and PTSD symptoms, though patterns differ by sex and trauma type. EEGc findings may inform emerging treatments for PTSD and AUD.

Weight-centric health practices are based on the principle that excess weight predicts chronic disease, informing a growing sociopolitical movement to address an "obesity epidemic." This hyper-focus on preventing obesity may contribute to weight stigma (i.e., the devaluation and discrimination of individuals based on body size) and other iatrogenic outcomes for youth, including the development and maintenance of eating disorders (EDs). Current evidence-based treatments for EDs include language and practices that may reinforce fears of fatness, body shame, and unhealthy dietary restriction without guidance on addressing weight stigma. Here, we present case examples from three adolescent patients across ED presentations and body sizes to (1) elucidate the role of weight stigma in ED development, (2) highlight the ubiquity and harms of weight stigma within ED treatments, and (3) outline thoughtful protocol adaptations to avoid further harm and facilitate recovery. We conclude with a call for immediate action to advance research characterizing the harms of weight-centric approaches in existing ED interventions to reduce the risk of iatrogenic effects on youth with EDs and advance weight-inclusive approaches to ED treatment.

The human face plays a central role in emotions and social communication. The emotional and somatic motor networks generate facial behaviors, but whether facial behaviors have representations in the structural anatomy of the human brain is unknown. We coded 16 facial behaviors in 55 healthy older adults who viewed five videos that elicited emotions and examined whether individual differences in facial behavior were related to regional variation in gray matter volume. Voxel-based morphometry analyses revealed that greater emotional facial behavior during the disgust trial (i.e. greater brow furrowing and eye tightening as well as nose wrinkling and upper lip raising) and the amusement trial (i.e. greater smiling and eye tightening) was associated with larger gray matter volume in midcingulate cortex, supplementary motor area, and precentral gyrus, areas spanning both the emotional and somatic motor networks. When measured across trials, however, these facial behaviors (and others) only related to gray matter volume in the precentral gyrus, a somatic motor network hub. These findings suggest that the emotional and somatic motor networks store structural representations of facial behavior and that the midcingulate cortex is critical for generating the predictable movements in the face that arise during emotions.

IntroductionCardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsTwo hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.ResultsAmong variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.DiscussionBetter baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.HighlightsBetter cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4-7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

Many energy efficiency financing programs could achieve greater uptake and impact by more effectively recruiting participants.This report examines some of the primary factors that have contributed to high participant uptake among successful financing programs. We review best practices in partnerships (Chapter 2), direct marketing (Chapter 3), and program design (Chapter 4) that facilitate robust participation.This report is primarily designed for state and local governments that have established energy efficiency financing programs or are considering doing so and are seeking insight into how they can ramp up program participation. In disseminating lessons learned from well-established programs that have experienced success in their target markets, the objective is to help scale up the large number of energy efficiency financing programs that seek to replicate these successes. This report can inform states, local governments, and other entities that will establish or expand clean energy financing programs with funding made available under the Infrastructure Investment and Jobs Act and the Inflation Reduction Act.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

BackgroundCognitive impairment and dementia are frequently under-recognized. Health system strategies anchored in primary care are essential to address gaps in timely, comprehensive diagnosis. The goal of this paper is to describe the adaptation of a tablet-based brain health assessment (TabCAT-BHA) intervention and the study protocol to test its effectiveness in improving the detection of cognitive impairment, including dementia.MethodsThis mixed-methods, pragmatic, cluster randomized, hybrid effectiveness-implementation trial is being conducted in two 18-month waves with 26 Kaiser Permanente Southern California primary care clinics, with 13 serving as intervention clinics and 13 as usual care clinics. Patients 65 years and older with memory concerns (n ~ 180,000) receiving care at the 26 clinics will be included in the analyses. Primary care clinics are provided the following practice supports as part of the TabCAT-BHA intervention: brief education and training on neurocognitive disorders and study workflows; digital tools to assess cognitive function and support clinician decision making and documentation; and registered nurse support during the work-up and post-diagnosis periods for primary care providers, patients, and families. The intervention was adapted based on engagement with multiple levels of clinical and operational leaders in the healthcare system. Effectiveness outcomes include rates of cognitive impairment diagnosis in primary care and rates of completed standardized cognitive assessments and specialist referrals with incident diagnoses. Implementation outcomes include acceptability-appropriateness-feasibility, adoption, and fidelity.ResultsWe identified seven themes organized by system-, provider-, and patient-level domains that were used to adapt the TabCAT-BHA intervention. Accordingly, changes were made to the provider education, diagnostic work-up, and post-diagnostic support. Results will be reported in fall of 2027.ConclusionsOur engagement with multiple primary and specialty care clinical and operational leaders to adapt the TabCAT-BHA intervention to these primary care clinics has informed the protocol to evaluate the interventions effectiveness for improving the detection of cognitive impairment, including dementia, in an integrated healthcare system.Trial registationClinicaltrials.gov: NCT06090578 (registered 10/24/23).

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

IntroductionAlzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated.MethodsWe examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD.ResultsWe examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini-Mental Status Examination (MMSE) decline over time (p = 0.033).DiscussionComorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort.HighlightsAutopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).

Liquefaction triggering is typically predicted using fully-empirical and/or semi-empirical models. Hence, such models are heavily reliant upon available liquefaction (and/or lack thereof) case history data. These predictive models are based on a variety of factors, describing the demand (i.e., the cyclic stress ratio, CSR in existing legacy models) and the capacity (i.e., the cyclic resistance ratio, CRR). However, the degree to which these factors truly affect models’ performance is unknown. To explore this aspect and quantitatively rank the importance of liquefaction input model parameters, we leverage a Random Forest Machine Learning (ML) approach using two methods: (1) a feature importance metric based on the Gini impurity index, and (2) a SHapley Additive exPlanations (SHAP)-based approach. Both approaches were employed using typical input factors used in legacy liquefaction triggering models based on cone penetration test (CPT) data. Such analyses were performed using all reviewed (i.e., fully vetted) data in the Next Generation Liquefaction (NGL) database. Our analysis then separately explores the impact on resulting models of seven input parameters. We show that the most important input parameters are: (1) the peak ground acceleration, (2) the soil behavior type index, and (3) the earthquake magnitude (which serves as a proxy for duration in such models). The input parameters with the lowest importance are the total and the effective vertical stresses. A limitation of this analysis is that the ML model used does not allow for extrapolation beyond the range of the data. As a result, for input parameters with narrow distributions of the data (i.e., somewhat limited parameter space), a lower ranking could be associated with such limited availability of a wide range of values, rather than being related to actual low importance. This limitation likely accounts for the low importance attached to stress-related input parameters since legacy case histories are generally related to shallower (

Ensuring safety in physical human–robot interaction is challenging due to hardware and control architecture differences across robots, and is often implemented as system-dependent ad hoc approaches. To offer a holistic solution, we present a hardware-independent safety-focused admittance control approach, which promotes safety at the reference-generation level. This safety framework can restrict virtual dynamics through soft virtual bounds. Hard bounds are also introduced as a way to impose infinitely stiff soft bounds. As part of the overall approach, we also present a method for serial manipulator and multisegment entity collision avoidance by using partial Jacobians. In order to demonstrate the methodology's versatility across hardware platforms, we experimentally validate on two robotic systems: first, the Virtual Reality Exoskeleton (V-Rex), a nonanthropomorphic full-body haptic device composed of five robotic arms interacting with the body at the hands, feet, and pelvis; and second, the EXO-UL8, an anthropomorphic bimanual upper limb exoskeleton; which exist on opposite ends of the task/joint space control, nonredundant/redundant, off-the-shelf (industrial)/custom, nonanthropomorphic/anthropomorphic spectra. Experimental results validate virtual dynamics, soft bounds, hard bounds, and multi-arm collision avoidance on both systems. In all cases, both systems respect bound and collision constraints, supporting the approach as a safety-focused admittance control design.

Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development.

The ability to study chemical dynamics on ultrafast timescales has greatly advanced with the introduction of X-ray free electron lasers (XFELs) providing short pulses of intense X-rays tailored to probe atomic structure and electronic configuration. Fully exploiting the full potential of XFELs requires specialized experimental endstations along with the development of techniques and methods to successfully carry out experiments. The liquid jet endstation (LJE) at the Linac Coherent Light Source (LCLS) has been developed to study photochemistry and biochemistry in solution systems using a combination of X-ray solution scattering (XSS), X-ray absorption spectroscopy (XAS), and X-ray emission spectroscopy (XES). The pump-probe setup utilizes an optical laser to excite the sample, which is subsequently probed by a hard X-ray pulse to resolve structural and electronic dynamics at their intrinsic femtosecond timescales. The LJE ensures reliable sample delivery to the X-ray interaction point via various liquid jets, enabling rapid replenishment of thin samples with millimolar concentrations and low sample volumes at the 120 Hz repetition rate of the LCLS beam. This paper provides a detailed description of the LJE design and of the techniques it enables, with an emphasis on the diagnostics required for real-time monitoring of the liquid jet and on the spatiotemporal overlap methods used to optimize the signal. Additionally, various scientific examples are discussed, highlighting the versatility of the LJE.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.

BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders. RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components. CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events get under the skin to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging (n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATPmax) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

While animal models of Alzheimer's disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain precludes its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4-12 Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology-entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients (n = 50; age, 60 ± 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls (n = 35; age, 63 ± 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI-, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI- in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology.

IntroductionWith emergence of disease-modifying therapies, efficient diagnostic pathways are critically needed to identify treatment candidates, evaluate disease severity, and support prognosis. A combination of plasma biomarkers and brief digital cognitive assessments could provide a scalable alternative to current diagnostic work-up.MethodsWe examined the accuracy of plasma biomarkers and a 10-minute supervised tablet-based cognitive assessment (Tablet-based Cognitive Assessment Tool Brain Health Assessment [TabCAT-BHA]) in predicting amyloid β positive (Aβ+) status on positron emission tomography (PET), concurrent disease severity, and functional decline in 309 older adults with subjective cognitive impairment (n = 49), mild cognitive impairment (n = 159), and dementia (n = 101).ResultsCombination of plasma pTau181, Aβ42/40, neurofilament light (NfL), and TabCAT-BHA was optimal for predicting Aβ-PET positivity (AUC = 0.962). Whereas NfL and TabCAT-BHA optimally predicted concurrent disease severity, combining these with pTau181 and glial fibrillary acidic protein was most accurate in predicting functional decline.DiscussionCombinations of plasma and digital cognitive markers show promise for scalable diagnosis and prognosis of ADRD.HighlightsThe need for cost-efficient diagnostic and prognostic markers of AD is urgent. Plasma and digital cognitive markers provide complementary diagnostic contributions. Combination of these markers holds promise for scalable diagnosis and prognosis. Future validation in community cohorts is needed to inform clinical implementation.

IntroductionAssociations of cerebellar atrophy with specific neuropathologies in Alzheimer's disease and related dementias (ADRD) have not been systematically analyzed. This study examined cerebellar gray matter volume across major pathological subtypes of ADRD.MethodsCerebellar gray matter volume was examined using voxel-based morphometry in 309 autopsy-proven ADRD cases and 80 healthy controls. ADRD subtypes included AD, mixed Lewy body disease and AD (LBD-AD), and frontotemporal lobar degeneration (FTLD). Clinical function was assessed using the Clinical Dementia Rating (CDR) scale.ResultsDistinct patterns of cerebellar atrophy were observed in all ADRD subtypes. Significant cerebellar gray matter changes appeared in the early stages of most subtypes and the very early stages of AD, LBD-AD, FTLD-TDP type A, and progressive supranuclear palsy. Cortical atrophy positively predicted cerebellar atrophy across all subtypes.DiscussionOur findings establish pathology-specific profiles of cerebellar atrophy in ADRD and propose cerebellar neuroimaging as a non-invasive biomarker for differential diagnosis and disease monitoring.HighlightsCerebellar atrophy was examined in 309 patients with autopsy-proven neurodegeneration. Distinct patterns of cerebellar atrophy are found in all pathological subtypes of Alzheimer's disease and related dementias (ADRD). Cerebellar atrophy is seen in early-stage (Clinical Dementia Rating [CDR] ≤1) AD, Lewy body dementia (LBD), frontotemporal lobar degeneration with tau-positive inclusion (FTLD-tau), and FTLD-transactive response DNA binding protein (FTLD-TDP). Cortical atrophy positively predicts cerebellar atrophy across all neuropathologies.

As part of the next generation liquefaction (NGL) project, we are developing probabilistic triggering and manifestation models using laboratory data and cone penetration test (CPT) case histories in the NGL database. The case histories are used to develop probabilistic models for surface manifestation conditional on susceptibility, liquefaction triggering, soil properties, stratigraphic details, and other features. Susceptibility is interpreted as a sole function of soilcomposition and is expressed as a probabilistic function of soil behavior type index, Ic, obtained from CPT. A triggering model is derived based on laboratory tests on high-quality specimens from literature; this model captures mean responses and uncertainty reflective of data dispersionand is considered as a Bayesian prior that will subsequently be updated by field observation data. A manifestation model is then regressed from field case histories where surface manifestation was or was not observed, information on soil conditions that enables identification of layers likely to liquefy, and ground shaking conditions. We describe the approach applied to develop our manifestation model; for a given layer this model considers layer depth, thickness, CPT tip resistance, and Ic. The result of this process is a logistic function in which manifestation probability decreases with increasing depth, decreasing thickness, increasing tip resistance, and increasing Ic. Profile manifestation is then derived by aggregating individual layer manifestationprobabilities.

ObjectiveMany factors contribute to inadequate diversity in Alzheimer disease (AD) clinical trials. We evaluated eligibility rates among racial and ethnic groups at US sites in large global multisite trials in early AD.MethodsUsing screening data from 4 randomized, double-blind, placebo-controlled clinical trials in early AD, we assessed rates of eligibility among racial and ethnic groups controlling for other demographic covariates. Each trial incorporated positron emission tomography and/or cerebrospinal fluid to evaluate brain amyloid pathology, as well as typical eligibility criteria used in early AD trials.ResultsAcross the trials, 10,804 US participants were screened: 193 (2%) were of Hispanic ethnicity and Black race, 2,624 (25%) were of Hispanic ethnicity and White race, 118 (1%) were of non-Hispanic ethnicity (NH) and Asian race, 696 (7%) were of NH ethnicity and Black race, and 7,017 (65%) were of NH ethnicity and White race. Data from 156 participants who did not fit into these categories were excluded. Accounting for age, sex, and trial and using NH White participants as a reference group, we observed higher probabilities of ineligibility for amyloid biomarker criteria among Hispanic Black (odds ratio [OR] = 3.20, 95% confidence interval [CI] = 2.11-4.88), Hispanic White (OR = 4.15, 95% CI = 3.58-4.83), NH Asian (OR = 2.35, 95% CI = 1.23-4.55), and NH Black (OR = 3.75, 95% CI = 2.80-5.06) participants.InterpretationDifferential eligibility may contribute to underrepresentation of some minoritized racial and ethnic groups in early AD trials. Amyloid biomarker eligibility is a requirement to confirm the diagnosis of AD and for treatment with amyloid-lowering drugs and differed among racial and ethnic groups. ANN NEUROL 2024;95:288-298.

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.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

BackgroundFalls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated.MethodsIn this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy (MRS) after an acute bout of exercise (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS).ResultsAt least one fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400m walk gait speed (1.0 ± 0.2 vs. 1.1 ± 0.2, p

BackgroundLiver fibrosis is caused by chronic toxic or cholestatic liver injury. Fibrosis results from the recruitment of myeloid cells into the injured liver, the release of inflammatory and fibrogenic cytokines, and the activation of myofibroblasts, which secrete extracellular matrix, mostly collagen type I. Hepatic myofibroblasts originate from liver-resident mesenchymal cells, including HSCs and bone marrow-derived CD45+ collagen type I+ expressing fibrocytes. Recombinant human serum amyloid P (hSAP), a natural inhibitor of fibrocyte activation into myofibroblasts, was shown to ameliorate experimental renal, lung, skin, and cardiac fibrosis. We investigated if hSAP can ameliorate the development of liver fibrosis of different etiologies.MethodsReporter Collagen-α(1)I-GFP mice were subjected to cholestatic liver injury (by ligation of the common bile duct) or toxic liver injury (by carbon tetrachloride administration) and treated prophylactically or therapeutically with hSAP (12.5 μg/g). Primary cultures of mouse fibrocytes and HSCs were stimulated to activate with or without incubation with hSAP.ResultsWe demonstrate that treatment with hSAP suppressed hepatic fibrosis by ≈50% through dual mechanisms. hSAP prevented the recruitment of fibrocytes into the injured liver and their differentiation into myofibroblasts. Remarkably, hSAP also inhibited the activation of HSCs into myofibroblasts.ConclusionsSince HSCs serve as a major source of collagen type I-producing myofibroblasts and fibrocytes stimulate fibrosis, hSAP may become part of the therapy of liver fibrosis of different etiologies.

Reward processing involves evaluation of stimuli to inform what an individual works to pursue or avoid. Patients with behavioral variant frontotemporal dementia (bvFTD) often display reward processing changes, including insensitivity to aversive stimuli. It is unknown how early in the disease course reward changes are detectable. We recruited mutation positive (symptomatic and asymptomatic) and negative members of families with known mutations in progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72). The sample included 4 groups: asymptomatic non-carriers (n = 34), asymptomatic carriers [Clinical Dementia Rating (CDR) 0, n = 16], mildly symptomatic carriers (CDR 0.5, n = 10) and bvFTD (sporadic and genetic, n = 45). A series of tasks utilized pleasant, unpleasant, and neutral olfactants to probe reward consumption and effort to obtain reward. A group by valence interaction showed unpleasant scent ratings were more positive in groups with greater disease severity [χ2(6) = 87.983, p

Achieving thermal comfort in buildings while maintaining energy efficiency is a critical challenge in architecture and engineering design and operation. Traditional thermal comfort metrics used in the early stages of design tend to neglect two key aspects: spatial variability of thermal conditions within buildings and the promotion of passive design strategies over active conditioning systems. This oversight leads to localized discomfort, excessive energy use, and increased vulnerability to overheating. To address these issues, we propose a novel metric called spatial Thermal Autonomy (sTA). The primary advantage of sTA is its ability to capture spatial variability in thermal conditions, offering a more comprehensive view of comfort across different building zones. Additionally, sTA supports passive design by quantifying a building's capacity to maintain comfort without active energy use. We performed a simulation case study evaluating sTA for different thermal zone sizes, passive design levels, and climate scenarios. Our findings suggest that buildings with high spatial thermal autonomy tend to use less energy, demonstrate greater thermal resilience during extreme weather or power outages, and experience fewer local discomfort problems. Optimizing building designs for spatial Thermal Autonomy encourages passive design solutions in key decisions related to building form, envelope, conditioning strategies, and HVAC system design. In buildings with reduced heating and cooling loads, this approach supports the increased adoption of local low-energy personal comfort systems, such as fans or local heating solutions, and can lead to more adaptive, resilient, and comfortable indoor environments in a changing climate.

BackgroundTraumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications.MethodsWe studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education).ResultsYears of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1).ConclusionsLifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

The modification of fertile stamens into sterile staminodes has occurred independently many times in the flowering plant lineage. In the genus Aquilegia (columbine) and its closest relatives, the two stamen whorls closest to the carpels have been converted to staminodes. In Aquilegia, the only genetic analyses of staminode development have been reverse genetic approaches revealing that B-class floral identity genes are involved. A. jonesii, the only species of columbine where staminodes have reverted to fertile stamens, allows us to explore the genetic architecture of staminode development using a forward genetic approach. We performed QTL analysis using an outcrossed F2 population between A. jonesii and a horticultural variety that makes fully developed staminodes, A. coerulea 'Origami'. Our results reveal a polygenic basis for staminode loss where the two staminode whorls are under some level of independent control. We also discovered that staminode loss in A. jonesii is not complete, in which staminode-like traits sometimes occur in the inner fertile stamens, potentially representing a fading boundary of gene expression. The QTLs identified in this study provide a map to guide future reverse genetic and functional studies examining the genetic basis and evolutionary significance of this trait.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

OBJECTIVE: For the majority of patients with lupus nephritis-related end-stage kidney disease (LN-ESKD), kidney transplant is associated with better outcomes than dialysis. Access to kidney transplant requires an initial referral to a transplant center and medical evaluation prior to waitlisting. The studys objective was to examine access to these early steps in the kidney transplant process among patients with LN-ESKD. METHODS: Adults who began treatment for ESKD in the Southeast, Northeast, New York, or Ohio River Valley U.S. regions from 1/1/2012 to 12/31/2019, followed through 6/30/2021, were identified from the United States Renal Data System. Referral and evaluation start data were collected from 28 of 48 transplant centers across these regions. The exposure was primary cause of ESKD (LN-ESKD vs other-ESKD). The outcomes were referral and evaluation start at a transplant center. Cox models quantified the association between LN-ESKD (vs other-ESKD) and referral and evaluation start. RESULTS: Among 192,318 patients initiating treatment for ESKD, 0.4% had LN-ESKD. Over half (58%) of LN-ESKD patients were referred before study end, and among those referred, 66% started the evaluation. In adjusted analyses, patients with LN-ESKD were referred (HR: 1.09, 95% CI: 0.99, 1.19) and started the transplant evaluation (HR: 1.13, 95% CI: 1.00, 1.28) at a higher rate than patients with other-ESKD. Among referred patients with LN-ESKD, the median time from ESKD start to referral was 2.9 months (IQR:

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.