CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it's co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.

The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI's ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.

Neural and psychological correlates of post-traumatic stress symptoms in a community adult sample.

A multitude of factors are associated with the symptoms of post-traumatic stress disorder. However, establishing which predictors are most strongly associated with post-traumatic stress disorder symptoms is complicated because few studies are able to consider multiple factors simultaneously across the biopsychosocial domains that are implicated by existing theoretical models. Further, post-traumatic stress disorder is heterogeneous, and studies using case-control designs may obscure which factors relate uniquely to symptom dimensions. Here we used Bayesian variable selection to identify the most important predictors for overall post-traumatic stress disorder symptoms and individual symptom dimensions in a community sample of 569 adults (18 to 85 yr of age). Candidate predictors were selected from previously established risk factors relevant for post-traumatic stress disorder and included psychological measures, behavioral measures, and resting state functional connectivity among brain regions. In a follow-up analysis, we compared results controlling for current depression symptoms in order to examine specificity. Poor sleep quality and dimensions of temperament and impulsivity were consistently associated with greater post-traumatic stress disorder symptom severity. In addition to self-report measures, brain functional connectivity among regions commonly ascribed to the default mode network, central executive network, and salience network explained the unique variability of post-traumatic stress disorder symptoms. This study demonstrates the unique contributions of psychological measures and neural substrates to post-traumatic stress disorder symptoms.

KG-Hub-building and exchanging biological knowledge graphs.

MOTIVATION: Knowledge graphs (KGs) are a powerful approach for integrating heterogeneous data and making inferences in biology and many other domains, but a coherent solution for constructing, exchanging, and facilitating the downstream use of KGs is lacking. RESULTS: Here we present KG-Hub, a platform that enables standardized construction, exchange, and reuse of KGs. Features include a simple, modular extract-transform-load pattern for producing graphs compliant with Biolink Model (a high-level data model for standardizing biological data), easy integration of any OBO (Open Biological and Biomedical Ontologies) ontology, cached downloads of upstream data sources, versioned and automatically updated builds with stable URLs, web-browsable storage of KG artifacts on cloud infrastructure, and easy reuse of transformed subgraphs across projects. Current KG-Hub projects span use cases including COVID-19 research, drug repurposing, microbial-environmental interactions, and rare disease research. KG-Hub is equipped with tooling to easily analyze and manipulate KGs. KG-Hub is also tightly integrated with graph machine learning (ML) tools which allow automated graph ML, including node embeddings and training of models for link prediction and node classification. AVAILABILITY AND IMPLEMENTATION: https://kghub.org.

Worldwide forest surveys reveal forty-three new species in Phytophthora major Clade 2 with fundamental implications for the evolution and biogeography of the genus and global plant biosecurity.

During 25 surveys of global Phytophthora diversity, conducted between 1998 and 2020, 43 new species were detected in natural ecosystems and, occasionally, in nurseries and outplantings in Europe, Southeast and East Asia and the Americas. Based on a multigene phylogeny of nine nuclear and four mitochondrial gene regions they were assigned to five of the six known subclades, 2a-c, e and f, of Phytophthora major Clade 2 and the new subclade 2g. The evolutionary history of the Clade appears to have involved the pre-Gondwanan divergence of three extant subclades, 2c, 2e and 2f, all having disjunct natural distributions on separate continents and comprising species with a soilborne and aquatic lifestyle and, in addition, a few partially aerial species in Clade 2c; and the post-Gondwanan evolution of subclades 2a and 2g in Southeast/East Asia and 2b in South America, respectively, from their common ancestor. Species in Clade 2g are soilborne whereas Clade 2b comprises both soil-inhabiting and aerial species. Clade 2a has evolved further towards an aerial lifestyle comprising only species which are predominantly or partially airborne. Based on high nuclear heterozygosity levels ca. 38 % of the taxa in Clades 2a and 2b could be some form of hybrid, and the hybridity may be favoured by an A1/A2 breeding system and an aerial life style. Circumstantial evidence suggests the now 93 described species and informally designated taxa in Clade 2 result from both allopatric non-adaptive and sympatric adaptive radiations. They represent most morphological and physiological characters, breeding systems, lifestyles and forms of host specialism found across the Phytophthora clades as a whole, demonstrating the strong biological cohesiveness of the genus. The finding of 43 previously unknown species from a single Phytophthora clade highlight a critical lack of information on the scale of the unknown pathogen threats to forests and natural ecosystems, underlining the risk of basing plant biosecurity protocols mainly on lists of named organisms. More surveys in natural ecosystems of yet unsurveyed regions in Africa, Asia, Central and South America are needed to unveil the full diversity of the clade and the factors driving diversity, speciation and adaptation in Phytophthora. Taxonomic novelties: New species: Phytophthora amamensis T. Jung, K. Kageyama, H. Masuya & S. Uematsu, Phytophthora angustata T. Jung, L. Garcia, B. Mendieta-Araica, & Y. Balci, Phytophthora balkanensis I. Milenkovic, Z. Tomic, T. Jung & M. Horta Jung, Phytophthora borneensis T. Jung, A. Durán, M. Tarigan & M. Horta Jung, Phytophthora calidophila T. Jung, Y. Balci, L. Garcia & B. Mendieta-Araica, Phytophthora catenulata T. Jung, T.-T. Chang, N.M. Chi & M. Horta Jung, Phytophthora celeris T. Jung, L. Oliveira, M. Tarigan & I. Milenkovic, Phytophthora curvata T. Jung, A. Hieno, H. Masuya & M. Horta Jung, Phytophthora distorta T. Jung, A. Durán, E. Sanfuentes von Stowasser & M. Horta Jung, Phytophthora excentrica T. Jung, S. Uematsu, K. Kageyama & C.M. Brasier, Phytophthora falcata T. Jung, K. Kageyama, S. Uematsu & M. Horta Jung, Phytophthora fansipanensis T. Jung, N.M. Chi, T. Corcobado & C.M. Brasier, Phytophthora frigidophila T. Jung, Y. Balci, K. Broders & I. Milenkovic, Phytophthora furcata T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora inclinata N.M. Chi, T. Jung, M. Horta Jung & I. Milenkovic, Phytophthora indonesiensis T. Jung, M. Tarigan, L. Oliveira & I. Milenkovic, Phytophthora japonensis T. Jung, A. Hieno, H. Masuya & J.F. Webber, Phytophthora limosa T. Corcobado, T. Majek, M. Ferreira & T. Jung, Phytophthora macroglobulosa H.-C. Zeng, H.-H. Ho, F.-C. Zheng & T. Jung, Phytophthora montana T. Jung, Y. Balci, K. Broders & M. Horta Jung, Phytophthora multipapillata T. Jung, M. Tarigan, I. Milenkovic & M. Horta Jung, Phytophthora multiplex T. Jung, Y. Balci, K. Broders & M. Horta Jung, Phytophthora nimia T. Jung, H. Masuya, A. Hieno & C.M. Brasier, Phytophthora oblonga T. Jung, S. Uematsu, K. Kageyama & C.M. Brasier, Phytophthora obovoidea T. Jung, Y. Balci, L. Garcia & B. Mendieta-Araica, Phytophthora obturata T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora penetrans T. Jung, Y. Balci, K. Broders & I. Milenkovic, Phytophthora platani T. Jung, A. Pérez-Sierra, S.O. Cacciola & M. Horta Jung, Phytophthora proliferata T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora pseudocapensis T. Jung, T.-T. Chang, I. Milenkovic & M. Horta Jung, Phytophthora pseudocitrophthora T. Jung, S.O. Cacciola, J. Bakonyi & M. Horta Jung, Phytophthora pseudofrigida T. Jung, A. Durán, M. Tarigan & M. Horta Jung, Phytophthora pseudoccultans T. Jung, T.-T. Chang, I. Milenkovic & M. Horta Jung, Phytophthora pyriformis T. Jung, Y. Balci, K.D. Boders & M. Horta Jung, Phytophthora sumatera T. Jung, M. Tarigan, M. Junaid & A. Durán, Phytophthora transposita T. Jung, K. Kageyama, C.M. Brasier & H. Masuya, Phytophthora vacuola T. Jung, H. Masuya, K. Kageyama & J.F. Webber, Phytophthora valdiviana T. Jung, E. Sanfuentes von Stowasser, A. Durán & M. Horta Jung, Phytophthora variepedicellata T. Jung, Y. Balci, K. Broders & I. Milenkovic, Phytophthora vietnamensis T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora ×australasiatica T. Jung, N.M. Chi, M. Tarigan & M. Horta Jung, Phytophthora ×lusitanica T. Jung, M. Horta Jung, C. Maia & I. Milenkovic, Phytophthora ×taiwanensis T. Jung, T.-T. Chang, H.-S. Fu & M. Horta Jung. Citation: Jung T, Milenkovic I, Balci Y, Janousek J, Kudlácek T, Nagy ZÁ, Baharuddin B, Bakonyi J, Broders KD, Cacciola SO, Chang T-T, Chi NM, Corcobado T, Cravador A, Dordevic B, Durán A, Ferreira M, Fu C-H, Garcia L, Hieno A, Ho H-H, Hong C, Junaid M, Kageyama K, Kuswinanti T, Maia C, Májek T, Masuya H, Magnano di San Lio G, Mendieta-Araica B, Nasri N, Oliveira LSS, Pane A, Pérez-Sierra A, Rosmana A, Sanfuentes von Stowasser E, Scanu B, Singh R, Stanivukovic Z, Tarigan M, Thu PQ, Tomic Z, Tomsovský M, Uematsu S, Webber JF, Zeng H-C, Zheng F-C, Brasier CM, Horta Jung M (2024). Worldwide forest surveys reveal forty-three new species in Phytophthora major Clade 2 with fundamental implications for the evolution and biogeography of the genus and global plant biosecurity. Studies in Mycology 107: 251-388. doi: 10.3114/sim.2024.107.04.

A systematic comparison of additive and interaction approaches to modeling the effects of syndemic problems on HIV outcomes in South Africa.

Much of the research on the effects of syndemics on HIV outcomes has utilized an additive approach. However, interaction effects may better account for syndemic synergy than an additive approach, but it remains difficult to specify interaction effects without empirical guidance. We sought to systematically compare additive and interaction effects approaches to modeling the effects of syndemic problems on antiretroviral therapy (ART) using empirically specified interaction terms. Participants were 194 people with HIV (PWH) who received HIV care in Khayelitsha, South Africa. In a series of linear regression models, we examined ten syndemic problems: depression, alcohol use, intimate partner violence (IPV), post-traumatic stress, social anxiety, substance use, food insecurity, poverty, housing instability, and structural barriers to care. Depression, substance use, and food insecurity were selected for interaction terms based on a prior network analysis, which found these problems to be most central. The additive models did not produce statistically significant findings. However, the interaction effects models yielded significant interaction terms in both the full model and a parsimonious model. There was a statistically significant effect of the interaction between depression and food insecurity on ART adherence (b = 0.04, Robust SE = 0.02, 95%CI [0.001-0.08], p = .012). This pattern of results was replicated in the parsimonious model. Findings suggest that when feasible, interaction effects approaches may be a helpful syndemic modeling technique. Results may inform future intervention targets, such as depression and food insecurity, and the importance of addressing both structural and psychosocial syndemic problems.

Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target.

Astrocyte dysfunctions have been consistently observed in patients affected with depression and other psychiatric illnesses. Although over the years our understanding of these changes, their origin, and their consequences on behavior and neuronal function has deepened, many aspects of the role of astroglial dysfunction in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) remain unknown. In this review, we summarize the known astroglial dysfunctions associated with MDD and PTSD, highlight the impact of chronic stress on specific astroglial functions, and how astroglial dysfunctions are implicated in the expression of depressive- and anxiety-like behaviors, focusing on behavioral consequences of astroglial manipulation on emotion-related and fear-learning behaviors. We also offer a glance at potential astroglial functions that can be targeted for potential antidepressant treatment.

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice.

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1ß), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

Intersecting Relationships of Psychosocial and Structural Syndemic Problems Among People with HIV in South Africa: Using Network Analysis to Identify Influential Problems.

In South Africa, little is known about interrelationships between syndemic problems among people with HIV (PWH). A better understanding of syndemic problems may yield important information regarding factors amenable to mitigation. We surveyed 194 PWH in Khayelitsha, outside of Cape Town, South Africa. We used network analysis to examine the frequency of 10 syndemic problems and their interrelationships. Syndemic problems among PWH in South Africa were common; 159 (82.8%) participants reported at least 2 co-occurring syndemic problems and 90 (46.9%) endorsed 4 or more. Network analysis revealed seven statistically significant associations. The most central problems were depression, substance use, and food insecurity. Three clusters of syndemics were identified: mood and violence; structural factors; and behavioral factors. Depression, substance use, and food insecurity commonly co-occur among PWH in sub-Saharan Africa and interfere with HIV outcomes. Network analysis can identify intervention targets to potentially improve HIV treatment outcomes.

RESUMEN: En Sudáfrica, poco se sabe sobre interrelaciones entre problemas sindémicos entre personas con VIH (PCV). Un major entendimiento de los problemas sindémicos puede arrojar información importante sobre los factores susceptibles de mitigación. Utilizamos el análisis de redes para examinar la frecuencia de 10 problemas sindémicos y sus interrelaciones. Problemas sindémicos entre PCV en Sudáfrica eran communes; 159 (82.8%) participantes presentaron al menos 2 problemas sindémicos concurrentes y 90 (46.9%) presentaron 4 o más. El análisis de red reveló siete asociaciones estadísticamente significativas. Los problemas más centrales fueron la depresión, el uso de sustancias y la inseguridad alimentaria. Se indetificaron tres grupos de sindemias: estado de ánimo y violencia; factores estructurales; y factores de comportamiento. La depresión, el uso de sustancias y la inseguridad alimentaria comúnmente ocurren simultáneamente entre las PCV en el África subsahariana e interfieren con los resultados del VIH. El análisis de redes puede identificar objetivos de intervención para potencialmente mejorar los resultados del tratamiento del VIH.

Global reward processing deficits predict negative symptoms transdiagnostically and transphasically in a severe mental illness-spectrum sample.

Reward processing impairments are a key factor associated with negative symptoms in those with severe mental illnesses. However, past findings are inconsistent regarding which reward processing components are impaired and most strongly linked to negative symptoms. The current study examined the hypothesis that these mixed findings may be the result of multiple reward processing pathways (i.e., equifinality) to negative symptoms that cut across diagnostic boundaries and phases of illness. Participants included healthy controls (n = 100) who served as a reference sample and a severe mental illness-spectrum sample (n = 92) that included psychotic-like experiences, clinical high-risk for psychosis, bipolar disorder, and schizophrenia participants. All participants completed tasks measuring four RDoC Positive Valence System constructs: value representation, reinforcement learning, effort-cost computation, and hedonic reactivity. A k-means cluster analysis of the severe mental illness-spectrum samples identified three clusters with differential reward processing profiles that were characterized by: (1) global reward processing deficits (22.8%), (2) selective impairments in hedonic reactivity alone (40.2%), and (3) preserved reward processing (37%). Elevated negative symptoms were only observed in the global reward processing cluster. All clusters contained participants from each clinical group, and the distribution of these groups did not significantly differ among the clusters. Findings identified one pathway contributing to negative symptoms that was transdiagnostic and transphasic. Future work further characterizing divergent pathways to negative symptoms may help to improve symptom trajectories and personalized treatments.

Developmental age and biological sex influence muscarinic receptor function and neuron morphology within layer VI of the medial prefrontal cortex.

Acetylcholine (ACh) neurotransmission within the medial prefrontal cortex (mPFC) plays an important modulatory role to support mPFC-dependent cognitive functions. This role is mediated by ACh activation of its nicotinic (nAChR) and muscarinic (mAChR) classes of receptors, which are both present on mPFC layer VI pyramidal neurons. While the expression and function of nAChRs have been characterized thoroughly for rodent mPFC layer VI neurons during postnatal development, mAChRs have not been characterized in detail. We employed whole-cell electrophysiology with biocytin filling to demonstrate that mAChR function is greater during the juvenile period of development than in adulthood for both sexes. Pharmacological experiments suggest that each of the M1, M2, and M3 mAChR subtypes contributes to ACh responses in these neurons in a sex-dependent manner. Analysis of dendrite morphology identified effects of age more often in males, as the amount of dendrite matter was greatest during the juvenile period. Interestingly, a number of positive correlations were identified between the magnitude of ACh/mAChR responses and dendrite morphology in juvenile mice that were not present in adulthood. To our knowledge, this work describes the first detailed characterization of mAChR function and its correlation with neuron morphology within layer VI of the mPFC.

Glycan Node Analysis Detects Varying Glycosaminoglycan Levels in Melanoma-Derived Extracellular Vesicles.

Extracellular vesicles (EVs) play important roles in (patho)physiological processes by mediating cell communication. Although EVs contain glycans and glycosaminoglycans (GAGs), these biomolecules have been overlooked due to technical challenges in comprehensive glycome analysis coupled with EV isolation. Conventional mass spectrometry (MS)-based methods are restricted to the assessment of N-linked glycans. Therefore, methods to comprehensively analyze all glyco-polymer classes on EVs are urgently needed. In this study, tangential flow filtration-based EV isolation was coupled with glycan node analysis (GNA) as an innovative and robust approach to characterize most major glyco-polymer features of EVs. GNA is a molecularly bottom-up gas chromatography-MS technique that provides unique information that is unobtainable with conventional methods. The results indicate that GNA can identify EV-associated glyco-polymers that would remain undetected with conventional MS methods. Specifically, predictions based on GNA identified a GAG (hyaluronan) with varying abundance on EVs from two different melanoma cell lines. Enzyme-linked immunosorbent assays and enzymatic stripping protocols confirmed the differential abundance of EV-associated hyaluronan. These results lay the framework to explore GNA as a tool to assess major glycan classes on EVs, unveiling the EV glycocode and its biological functions.

Systematically Modulating Aptamer Affinity and Specificity by Guanosine-to-Inosine Substitution.

Aptamers are widely used in small molecule detection applications due to their specificity, stability, and cost effectiveness. One key challenge in utilizing aptamers in sensors is matching the binding affinity of the aptamer to the desired concentration range for analyte detection. The most common methods for modulating affinity have inherent limitations, such as the likelihood of drastic changes in aptamer folding. Here, we propose that substituting guanosine for inosine at specific locations in the aptamer sequence provides a less perturbative approach to modulating affinity. Inosine is a naturally occurring nucleotide that results from hydrolytic deamination of adenosine, and like guanine, it base pairs with cytosine. Using the well-studied cocaine binding aptamer, we systematically replaced guanosine with inosine and were able to generate sequences having a range of binding affinities from 230 nM to 80 µM. Interestingly, we found that these substitutions could also modulate the specificity of the aptamers, leading to a range of binding affinities for structurally related analytes. Analysis of folding stability via melting temperature shows that, as expected, aptamer structure is impacted by guanosine-to-inosine substitutions. The ability to tune binding affinity and specificity through guanosine-to-inosine substitution provides a convenient and reliable approach for rapidly generating aptamers for diverse biosensing applications.

Perceived neighborhood factors, health behaviors, and related outcomes in the Hispanic Community Health Study/Study of Latinos.

Hispanic/Latino populations may experience significant neighborhood disadvantage, but limited research has explored whether these factors affect their health behaviors. Associations between perceived neighborhood factors at Visit 1 and health behaviors and related outcomes at Visit 2 in the Hispanic Community Health Study/Study of Latinos were evaluated. Multivariable logistic regression assessed cross-sectional and longitudinal relationships between perceived neighborhood social cohesion (NSC, 5 items), and neighborhood problems (NP, 7 items), with cancer screening, current smoking, excessive/binge drinking, hypertension, obesity, physical activity, and poor diet by gender and birthplace. NSC and NP scores were converted into quartiles. Mean age of participants was 42.5 years and 62.1% were women. Perceived NP, but not perceived NSC, differed by gender (p < 0.001). In unstratified models, no significant associations were observed between perceived NSC and any health behavior, whereas greater perceived NP was associated with less adherence to colon cancer screening (moderate level: aOR = 0.68, 95% CI = 0.51, 090) and more physical activity (very high level: aOR = 1.34, 95% CI = 1.06, 1.69) compared to low perceived NP. Women with moderate perceived NP, versus low NP, had a lower odds of colon cancer screening at Visit 1 (aOR = 0.62, 95% CI = 0.43, 0.91) and higher odds of mammogram adherence at Visit 2 (aOR = 2.86, 95% CI = 1.44, 5.68). Men with high perceived NP had a higher odds of excessive or binge drinking at Visit 2 (aOR = 1.99, 95% CI = 1.19, 3.31). We conclude that perceived NP were significantly related to health behaviors among HCHS/SOL individuals. Perceptions of neighborhood environment may be considered modifiable factors of structural neighborhood environment interventions.

Symptom-level networks of youth- and parent-reported depression and anxiety in a transdiagnostic clinical sample.

Depression and anxiety disorders confer a significant public health concern for youth and their co-occurrence places youth at a higher risk for poorer psychosocial outcomes. In the present study, we use network analysis to investigate the role of and interactions among individual depression and anxiety symptoms in a treatment-seeking clinical sample. METHODS: We estimate regularized partial correlation networks for youth- and parent reported symptoms in a transdiagnostic sample of youth (N = 417, ages 8-18). We examined features of the symptom-level networks such as network stability, centrality, bridge symptoms, and communities in both youth- and parent-reported networks. RESULTS: Results indicate stable networks with disorder-specific clustering, such that symptoms were more interconnected within compared to between disorders. Symptoms related to self-comparison to peers and negative views of the future were most central in both networks. Symptoms of depression and anxiety were connected by worries for the future and hopelessness in the youth-reported network, whereas self-comparison to peers and low self-efficacy were bridge symptoms in the parent network. Distinct symptom clusters emerged in the parent- and youth-reported networks. CONCLUSIONS: Our findings indicate that negative self-evaluation, negative views of the future, and repetitive negative thinking more generally are influential symptoms in the presentation and co-occurrence of depression and anxiety and as such may be promising targets in the treatment and prevention of depression and anxiety in youth.

Whole-Brain Functional Dynamics Track Depressive Symptom Severity.

Depressive symptoms are reported by 20% of the population and are related to altered functional integrity of large-scale brain networks. The link between moment-to-moment brain function and depressive symptomatology, and the implications of these relationships for clinical and community populations alike, remain understudied. The present study examined relationships between functional brain dynamics and subclinical-to-mild depressive symptomatology in a large community sample of adults with and without psychiatric diagnoses. This study used data made available through the Enhanced Nathan Kline Institute-Rockland Sample; 445 participants between 18 and 65 years of age completed a 10-min resting-state functional MRI scan. Coactivation pattern analysis was used to examine the dimensional relationship between depressive symptoms and whole-brain states. Elevated levels of depressive symptoms were associated with increased frequency and dwell time of the default mode network, a brain network associated with self-referential thought, evaluative judgment, and social cognition. Furthermore, increased depressive symptom severity was associated with less frequent occurrences of a hybrid brain network implicated in cognitive control and goal-directed behavior, which may impair the inhibition of negative thinking patterns in depressed individuals. These findings demonstrate how temporally dynamic techniques offer novel insights into time-varying neural processes underlying subclinical and clinically meaningful depressive symptomatology.

Extracellular vesicle glucose transporter-1 and glycan features in monocyte-endothelial inflammatory interactions.

Monocyte-induced endothelial cell inflammation is associated with multiple pathological conditions, and extracellular vesicles (EVs) are essential nanosized components of intercellular communication. EVs derived from endotoxin-stimulated monocytes were previously shown to carry pro-inflammatory proteins and RNAs. The role of glucose transporter-1 (GLUT-1) and glycan features in monocyte-derived EV-induced endothelial cell inflammation remains largely unexplored. This study demonstrates that EVs derived from endotoxin-stimulated monocytes activate inflammatory pathways in endothelial cells, which are partially attributed to GLUT-1. Alterations in glycan features and increased levels of GLUT-1 were observed in EVs derived from endotoxin-stimulated monocytes. Notably, inhibition of EV-associated GLUT-1, through the use of fasentin, suppressed EV-induced inflammatory cytokines in recipient endothelial cells.

Chronic Stress Alters Astrocyte Morphology in Mouse Prefrontal Cortex.

BACKGROUND: Neuromorphological changes are consistently reported in the prefrontal cortex of patients with stress-related disorders and in rodent stress models, but the effects of stress on astrocyte morphology and the potential link to behavioral deficits are relatively unknown. METHODS: To answer these questions, transgenic mice expressing green fluorescent protein (GFP) under the glial fibrillary acid protein (GFAP) promotor were subjected to 7, 21, or 35 days of chronic restraint stress (CRS). CRS-induced behavioral effects on anhedonia- and anxiety-like behaviors were measured using the sucrose intake and the PhenoTyper tests, respectively. Prefrontal cortex GFP+ or GFAP+ cell morphology was assessed using Sholl analysis, and associations with behavior were determined using correlation analysis. RESULTS: CRS-exposed male and female mice displayed anxiety-like behavior at 7, 21, and 35 days and anhedonia-like behavior at 35 days. Analysis of GFAP+ cell morphology revealed significant atrophy of distal processes following 21 and 35 days of CRS. CRS induced similar decreases in intersections at distal radii for GFP+ cells accompanied by increased proximal processes. In males, the number of intersections at the most distal radius step significantly correlated with anhedonia-like behavior (r = 0.622, P < .05) for GFP+ cells and with behavioral emotionality calculated by z-scoring all behavioral measured deficits (r = -0.667, P < .05). Similar but not significant correlations were observed in females. No correlation between GFP+ cell atrophy with anxiety-like behavior was found. CONCLUSION: Chronic stress exposure induces a progressive atrophy of cortical astroglial cells, potentially contributing to maladaptive neuroplastic and behavioral changes associated with stress-related disorders.

Elucidating mechanisms of quality-of-life disparities in Hispanic women with breast cancer: An examination of disease stage, coping, and affect.

OBJECTIVES: Compared to non-Hispanic white (NHW) women, Hispanic women with breast cancer (BCa) are more likely to be diagnosed at later stages of disease and experience reduced quality of life (QOL) following diagnosis. We hypothesized that the demands of later-stage disease results in a perceived inability to cope and greater distress for Hispanic women, resulting in decreased QOL. METHODS: Hispanic (51%) and NHW (49%) women (N = 198) with newly diagnosed stage 0-3 BCa in Miami were enrolled in two trials between 2006 and 2019. In this cross-sectional analysis, a multiple-group structural equation modeling approach was applied to baseline measures of coping confidence (Measure of Current Status Scale), negative and positive affect (Affect Balance Scale), QOL (Functional Assessment of Cancer Therapy - Breast), and disease stage. RESULTS: In our model, later-stage disease was not associated with worse QOL for Hispanic or NHW women. However, there were differences between Hispanic and NHW women on the path from disease stage to (1) coping confidence, (2) positive affect, and (3) negative affect, such that later disease stage was associated with lower coping confidence (b[SE] = -1.75[0.59], p = 0.002), less positive affect (b[SE] = -0.21[0.10], p = 0.026), and greater negative affect (b[SE] = 0.15[0.08], p = 0.052) among Hispanic, but not NHW, women. In addition, an indirect effect was found from greater stage to poorer QOL via less positive affect among Hispanic women only (b[SE] = -0.49[0.24], p = 0.041). CONCLUSIONS: This data supports our theory that Hispanic women experience worse emotional distress at later-stage disease than do NHW women, in turn impacting QOL.

The Aryne-Abramov Reaction as a 1,2-Benzdiyne Platform for the Generation and Solvent-Dependent Trapping of 3-Phosphonyl Benzynes.

Synthetic methodology utilizing two aryne intermediates (i.e., a formal benzdiyne) enables the rapid generation of structurally complex molecules with diverse functionality. This report describes the sequential generation of two ortho-benzyne intermediates for the synthesis of 2,3-disubstituted aryl phosphonates. Aryl phosphonates have proven useful in medicinal chemistry and materials science, and the reported methodology provides a two-step route to functionally dense variants by way of 3-phosphonyl benzyne intermediates. The process begins with regioselective trapping of a 3-trifloxybenzyne intermediate by an O-silyl phosphite in an Abramov-like reaction to bond the strained Csp carbons with phosphorus and silicon. Standard aryne-generating conditions follow to convert the resulting 2-silylphenyl triflate into a 3-phosphonyl benzyne, which readily reacts with numerous aryne trapping reactants to form a variety of 2,3-difunctionalized aryl phosphonate products. DFT computational studies shed light on important mechanistic details and revealed that 3-phosphonyl benzynes are highly polarizable. Specifically, the distortion in the internal bond angles at each of the Csp atoms was strongly influenced by both the electronegativity of the phosphonate ester groups as well as the dielectric of the computational solvation model. These effects were verified experimentally as the regioselectivity of benzyl azide trapping increased with more electronegative esters and/or increasingly polar solvents. Conversely, replacing the conventional solvent, acetonitrile, with nonpolar alternatives provided attenuated or even inverted selectivities. Overall, these studies showcase new reactivity of benzyne intermediates and extend the aryne relay methodology to include organophosphonates. Furthermore, this work demonstrates that the regioselectivity of aryne trapping reactions could be tuned by simply changing the solvent.