Sustained insulin treatment restoring metabolic status, body weight, and cognition in an anorexia nervosa-like animal model in mice.

INTRODUCTION: Anorexia Nervosa (AN) is a psycho-socio-biological disease characterized by severe weight loss as result of dieting and hyperactivity. Effective treatments are scarce, despite its significant prevalence and mortality. AN patients show lower basal insulin levels and increased metabolic clearance, leading to weight loss, cognitive deficits, and hormonal imbalances. Low-dose polymer insulin could potentially reverse these effects by restoring brain function, reducing fear of weight gain, encouraging food intake, and restoring fat depots. This study evaluates an insulin delivery system designed for sustained release and AN treatment. METHODS: AN-like model was established through dietary restriction (DR). On days 1-25, mice were on DR, and on days 26-31 they were on ad libitum regimen. An insulin-loaded delivery system was administered subcutaneously (1% w/w insulin). The impact of insulin treatment on gene expression in the hippocampus (cognition, regulation of stress, neurogenesis) and hypothalamus (eating behavior, mood) was assessed. Behavioral assays were conducted to evaluate motor activity and cognitive function. RESULTS: The delivery system demonstrated sustained insulin release, maintaining therapeutic plasma levels. Diet restriction mice treated with the insulin delivery system showed body weight restoration. Gene expression analysis revealed enhanced expression of CB1 and CB2 genes associated with improved eating behavior and cognition, while POMC expression was reduced. Insulin-polymer treatment restored cognitive function and decreased hyperactivity in the AN-like model. CONCLUSION: The PSA-RA-based insulin delivery system effectively restores metabolic balance, body weight, and cognitive function in the AN model. Its ability to steadily release insulin makes it a promising candidate for AN treatment."

Xyloglucan deficiency leads to a reduction in turgor pressure and changes in cell wall properties, affecting early seedling establishment.

Xyloglucan is believed to play a significant role in cell wall mechanics of dicot plants. Surprisingly, Arabidopsis plants defective in xyloglucan biosynthesis exhibit nearly normal growth and development. We investigated a mutant line, cslc-Δ5, lacking activity in all five Arabidopsis cellulose synthase like-C (CSLC) genes responsible for xyloglucan backbone biosynthesis. We observed that this xyloglucan-deficient line exhibited reduced cellulose crystallinity and increased pectin levels, suggesting the existence of feedback mechanisms that regulate wall composition to compensate for the absence of xyloglucan. These alterations in cell wall composition in the xyloglucan-absent plants were further linked to a decrease in cell wall elastic modulus and rupture stress, as observed through atomic force microscopy (AFM) and extensometer-based techniques. This raised questions about how plants with such modified cell wall properties can maintain normal growth. Our investigation revealed two key factors contributing to this phenomenon. First, measurements of turgor pressure, a primary driver of plant growth, revealed that cslc-Δ5 plants have reduced turgor, preventing the compromised walls from bursting while still allowing growth to occur. Second, we discovered the conservation of elastic asymmetry (ratio of axial to transverse wall elasticity) in the mutant, suggesting an additional mechanism contributing to the maintenance of normal growth. This novel feedback mechanism between cell wall composition and mechanical properties, coupled with turgor pressure regulation, plays a central role in the control of plant growth and is critical for seedling establishment in a mechanically challenging environment by affecting shoot emergence and root penetration.

A comprehensive hierarchical comparison of structural connectomes in Major Depressive Disorder cases v. controls in two large population samples.

BACKGROUND: The brain can be represented as a network, with nodes as brain regions and edges as region-to-region connections. Nodes with the most connections (hubs) are central to efficient brain function. Current findings on structural differences in Major Depressive Disorder (MDD) identified using network approaches remain inconsistent, potentially due to small sample sizes. It is still uncertain at what level of the connectome hierarchy differences may exist, and whether they are concentrated in hubs, disrupting fundamental brain connectivity. METHODS: We utilized two large cohorts, UK Biobank (UKB, N = 5104) and Generation Scotland (GS, N = 725), to investigate MDD case-control differences in brain network properties. Network analysis was done across four hierarchical levels: (1) global, (2) tier (nodes grouped into four tiers based on degree) and rich club (between-hub connections), (3) nodal, and (4) connection. RESULTS: In UKB, reductions in network efficiency were observed in MDD cases globally (d = -0.076, pFDR = 0.033), across all tiers (d = -0.069 to -0.079, pFDR = 0.020), and in hubs (d = -0.080 to -0.113, pFDR = 0.013-0.035). No differences in rich club organization and region-to-region connections were identified. The effect sizes and direction for these associations were generally consistent in GS, albeit not significant in our lower-N replication sample. CONCLUSION: Our results suggest that the brain's fundamental rich club structure is similar in MDD cases and controls, but subtle topological differences exist across the brain. Consistent with recent large-scale neuroimaging findings, our findings offer a connectomic perspective on a similar scale and support the idea that minimal differences exist between MDD cases and controls.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

The stability of cognitive abilities: A meta-analytic review of longitudinal studies.

Cognitive abilities, including general intelligence and domain-specific abilities such as fluid reasoning, comprehension knowledge, working memory capacity, and processing speed, are regarded as some of the most stable psychological traits, yet there exist no large-scale systematic efforts to document the specific patterns by which their rank-order stability changes over age and time interval, or how their stability differs across abilities, tests, and populations. Determining the conditions under which cognitive abilities exhibit high or low degrees of stability is critical not just to theory development but to applied contexts in which cognitive assessments guide decisions regarding treatment and intervention decisions with lasting consequences for individuals. In order to supplement this important area of research, we present a meta-analysis of longitudinal studies investigating the stability of cognitive abilities. The meta-analysis relied on data from 205 longitudinal studies that involved a total of 87,408 participants, resulting in 1,288 test-retest correlation coefficients among manifest variables. For an age of 20 years and a test-retest interval of 5 years, we found a mean rank-order stability of ρ = .76. The effect of mean sample age on stability was best described by a negative exponential function, with low stability in preschool children, rapid increases in stability in childhood, and consistently high stability from late adolescence to late adulthood. This same functional form continued to best describe age trends in stability after adjusting for test reliability. Stability declined with increasing test-retest interval. This decrease flattened out from an interval of approximately 5 years onward. According to the age and interval moderation models, minimum stability sufficient for individual-level diagnostic decisions (rtt = .80) can only be expected over the age of 7 and for short time intervals in children. In adults, stability levels meeting this criterion are obtained for over 5 years. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The expanding role of sonography for the diagnosis of deep infiltrating endometriosis: Results of a large case series.

OBJECTIVE: To investigate the value of the sonographic identification of deep infiltrating endometriosis (DIE) in women presenting with complaints suggestive of DIE. Sonography findings were correlated with subsequent surgical exploration, and histologic verification. METHODS: A retrospective observational case series was investigated to document the ability of the use of sonography to accurately detect the presence of deep infiltrating endometriosis. The clinical observations were performed consistent with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations for observational studies. Recognizing the real-world office setting for this may introduce the importance of the practical clinical aspects of diagnostic procedures in general. RESULTS: Three-dimensional transvaginal sonography was able to accurately identify deep invasive endometriosis in 92% of the 100 women subjectively complaining of the associated symptoms of endometriosis, who underwent sonography, surgical exploration, and pathologic analysis. Additional sonographic evidence of pelvic pathology was found during the course of this investigation, perhaps complementing other means for diagnosing endometriosis. CONCLUSION: Three-dimensional transvaginal sonography is a diagnostic tool that can effectively identify deep infiltrating endometriosis, which may otherwise go undetected and untreated. These findings should encourage the use of sonography for the detection of this subtype of endometriosis.

Expert opinion survey on Israel's food system: implications for food and health policies.

BACKGROUND: While there has been increasing global recognition and impetus for action to transform food systems towards greater food security, sustainability and better health outcomes, Israel has only recently begun to focus on the diverse challenges of its food system and its potential for transformation. METHODS: An expert opinion survey (n = 50) on Israel's food system was conducted as part of a larger study on the systemic features of Israel's food system transition to understand its policy gaps and find strategies towards a healthy and sustainable food system. The survey ranks the relevance and importance of food system challenges and policy preferences. Policy implications are then examined by identifying potential priorities, gaps and dissensus. RESULTS: The survey finds that there is a majority agreement (76%) that Israel's food policies are lacking or severely lacking. Respondents relate strongly to both concepts of nutritional security (90% think that access to nutritious food is relevant or highly relevant) and national food security (more than 80% perceive food security as part of national security). Respondents overwhelmingly recognize the benefits of Israeli agriculture with 60-90% agreeing or strongly agreeing that it benefits food security, economic value and national identity. Top-ranked problems include overall systemic problems such as the lack of national goals, strategic planning, and integrated policymaking across ministries, and specific ones such as food waste, costly farming inputs, and food affordability. The most preferred policy actions include establishing a national strategy for food and agriculture, making food affordable for vulnerable households, and incentivising sustainable farming methods. The key policy gaps include the lack of resilience in agriculture and the food system, insufficient data and knowledge for policy action, inadequate attention to the regulation of the food industry for better health and inadequate food policy attention for minority groups. CONCLUSIONS: Building on this study's findings, further policy research and implementation areas to be covered include government responsibility for universal food security, strategic systemic policies for food systems, prevention and preparedness for future crises, and promoting resilience. The way forward may best be through an inter-ministerial committee with the responsibility, budgets, mandate and executive authority to plan data-driven policies for a sustainable food system for Israel's future.

Beyond the factor indeterminacy problem using genome-wide association data.

Latent factors, such as general intelligence, depression and risk tolerance, are invoked in nearly all social science research where a construct is measured via aggregation of symptoms, question responses or other measurements. Because latent factors cannot be directly observed, they are inferred by fitting a specific model to empirical patterns of correlations among measured variables. A long-standing critique of latent factor theories is that the correlations used to infer latent factors can be produced by alternative data-generating mechanisms that do not include latent factors. This is referred to as the factor indeterminacy problem. Researchers have recently begun to overcome this problem by using information on the associations between individual genetic variants and measured variables. We review historical work on the factor indeterminacy problem and describe recent efforts in genomics to rigorously test the validity of latent factors, advancing the understanding of behavioural science constructs.

Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience.

INTRODUCTION: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy. METHODS: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions. RESULTS: Of the 25 patients with ASUC treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) of the 18 patients with available data and who did not undergo colectomy experienced steroid-free clinical remission (1 patient did not have complete data), 1 (4%) patient experienced a venous thromboembolic event, while 5 (20%) patients were readmitted. DISCUSSION: Upadacitinib along with intravenous corticosteroids may be an effective treatment for ASUC.

Deploying a national clinical text processing infrastructure.

OBJECTIVES: Clinical text processing offers a promising avenue for improving multiple aspects of healthcare, though operational deployment remains a substantial challenge. This case report details the implementation of a national clinical text processing infrastructure within the Department of Veterans Affairs (VA). METHODS: Two foundational use cases, cancer case management and suicide and overdose prevention, illustrate how text processing can be practically implemented at scale for diverse clinical applications using shared services. RESULTS: Insights from these use cases underline both commonalities and differences, providing a replicable model for future text processing applications. CONCLUSIONS: This project enables more efficient initiation, testing, and future deployment of text processing models, streamlining the integration of these use cases into healthcare operations. This project implementation is in a large integrated health delivery system in the United States, but we expect the lessons learned to be relevant to any health system, including smaller local and regional health systems in the United States.

A TaqMan-based RT-qPCR assay for serotyping of Southern African territories (SAT) 2 strains of Foot-and-Mouth disease virus (FMDV) in Southern Africa.

OBJECTIVE: Determining the serotype of circulating virus strains is important in implementing effective vaccination. In this study, Foot-and-Mouth Disease (FMD) Southern African territory 2 (SAT2) specific primers and TaqMan probe were designed towards rapid SAT2 detection and serotyping. The primers were tested by endpoint reverse transcription (RT) polymerase chain reaction (PCR) and quantitative PCR (RT-qPCR) using the vaccine strain SAT2035. The SAT2 serotype-specific RT-qPCR assay was compared with currently used ELISA and VP1 sequencing using Cohen's kappa statistics. RESULTS: The primers yielded amplicons of band size 190 bp during endpoint RT-PCR. When coupled with the probe, the primers reaction efficiency was determined to be 99% with an r2 value of 0.994. The results show that the SAT2 assay has comparable performance to VP1 sequencing (k = 1) and a moderate degree of agreement with ELISA (k = 0.571). The data shows that the newly designed assay could be considered for serotyping of SAT2 strains. However, for this assay to be complete there is a need to design effective SAT1 and SAT3 primers and probes that can be multiplexed to target other serotypes that co-circulate within relevant FMD endemic pools. For future implementation of the assay there is also a need to increase the number of field samples towards validation of the assay.

Stability of DNA-Methylation Profiles of Biological Aging in Children and Adolescents.

Background and Objectives: Methylation profile scores (MPSs) index biological aging and aging-related disease in adults and are cross-sectionally associated with social determinants of health in childhood. MPSs thus provide an opportunity to trace how aging-related biology responds to environmental changes in early life. Information regarding the stability of MPSs in early life is currently lacking. Method: We use longitudinal data from children and adolescents ages 8-18 (N = 428, M age = 12.15 years) from the Texas Twin Project. Participants contributed two waves of salivary DNA-methylation data (mean lag = 3.94 years), which were used to construct four MPSs reflecting multi-system physiological decline and mortality risk (PhenoAgeAccel and GrimAgeAccel), pace of biological aging (DunedinPACE), and cognitive function (Epigenetic-g). Furthermore, we exploit variation among participants in whether they were exposed to the COVID-19 pandemic during the course of study participation, in order to test how a historical period characterized by environmental disruption might affect children's aging-related MPSs. Results: All MPSs showed moderate longitudinal stability (test-retest rs = 0.42, 0.44, 0.46, 0.51 for PhenoAgeAccel, GrimAgeAccel, and Epigenetic-g, and DunedinPACE, respectively). No differences in the stability of MPSs were apparent between those whose second assessment took place after the onset of the COVID-19 pandemic vs. those for whom both assessments took place prior to the pandemic. Conclusions: Aging-related DNA-methylation patterns are less stable in childhood than has been previously observed in adulthood. Further developmental research on the methylome is necessary to understand which environmental perturbations in childhood impact trajectories of biological aging and when children are most sensitive to those impacts.

Genetic analysis of selection bias in a natural experiment: Investigating in-utero famine effects on elevated body mass index in the Dutch Hunger Winter Families Study.

Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen's d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.

Cohort profile: Genetic data in the German Socio-Economic Panel Innovation Sample (SOEP-G).

The German Socio-Economic Panel (SOEP) serves a global research community by providing representative annual longitudinal data of respondents living in private households in Germany. The dataset offers a valuable life course panorama, encompassing living conditions, socioeconomic status, familial connections, personality traits, values, preferences, health, and well-being. To amplify research opportunities further, we have extended the SOEP Innovation Sample (SOEP-IS) by collecting genetic data from 2,598 participants, yielding the first genotyped dataset for Germany based on a representative population sample (SOEP-G). The sample includes 107 full-sibling pairs, 501 parent-offspring pairs, and 152 triads, which overlap with the parent-offspring pairs. Leveraging the results from well-powered genome-wide association studies, we created a repository comprising 66 polygenic indices (PGIs) in the SOEP-G sample. We show that the PGIs for height, BMI, and educational attainment capture 22∼24%, 12∼13%, and 9% of the variance in the respective phenotypes. Using the PGIs for height and BMI, we demonstrate that the considerable increase in average height and the decrease in average BMI in more recent birth cohorts cannot be attributed to genetic shifts within the German population or to age effects alone. These findings suggest an important role of improved environmental conditions in driving these changes. Furthermore, we show that higher values in the PGIs for educational attainment and the highest math class are associated with better self-rated health, illustrating complex relationships between genetics, cognition, behavior, socio-economic status, and health. In summary, the SOEP-G data and the PGI repository we created provide a valuable resource for studying individual differences, inequalities, life-course development, health, and interactions between genetic predispositions and the environment.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.