Monitoring water harvesting in metal-organic frameworks, one water molecule at a time.

Metal-organic frameworks (MOFs) have gained prominence as potential materials for atmospheric water harvesting, a vital solution for arid regions and areas experiencing severe water shortages. However, the molecular factors influencing the performance of MOFs in capturing water from the air remain elusive. Among all MOFs, Ni2X2BTDD (X = F, Cl, Br) stands out as a promising water harvester due to its ability to adsorb substantial amounts of water at low relative humidity (RH). Here, we use advanced molecular dynamics simulations carried out with the state-of-the-art MB-pol data-driven many-body potential to monitor water adsorption in the three Ni2X2BTDD variants as a function of RH. Our simulations reveal that the type of halide atom in the three Ni2X2BTDD frameworks significantly influences the corresponding molecular mechanisms of water adsorption: while water molecules form strong hydrogen bonds with the fluoride atoms in Ni2F2BTDD, they tend to form hydrogen bonds with the nitrogen atoms of the triazolate linkers in Ni2Cl2BTDD and Ni2Br2BTDD. Importantly, the large size of the bromide atoms reduces the void volume in the Ni2Br2BTDD pores, which enable water molecules to initiate an extended hydrogen-bond network at lower RH. These findings not only underscore the prospect for precisely tuning structural and chemical modifications of the frameworks to optimize their interaction with water, but also highlight the predictive power of simulations with the MB-pol data-driven many-body potential. By providing a realistic description of water under different thermodynamic conditions and environments, these simulations yield unique, molecular-level insights that can guide the design and optimization of energy-efficient water harvesting materials.

Contraceptive Provision to Women With Intellectual and Developmental Disabilities Enrolled in Medicaid.

OBJECTIVE: To compare contraceptive provision to women with and without intellectual and developmental disabilities enrolled in North Carolina Medicaid. METHODS: Our retrospective cohort study used 2019 North Carolina Medicaid claims to identify women aged 15-44 years with and without intellectual and developmental disabilities at risk for pregnancy who were continuously enrolled during 2019 or had Family Planning Medicaid with at least one claim. We calculated the proportion in each cohort who received 1) most or moderately effective contraception, 2) long-acting reversible contraception, 3) short-acting contraception, and 4) individual methods. We classified contraceptive receipt by procedure type and disaggregated across sociodemographic characteristics. Adjusting for age, race, ethnicity, and urban or rural setting, we constructed logistic regression models to estimate most or moderately effective contraceptive provision odds by intellectual and developmental disability status and by level or type of intellectual and developmental disability. We performed subanalyses to estimate co-occurrence of provision and menstrual disorders. RESULTS: Among 9,508 women with intellectual and developmental disabilities and 299,978 without, a significantly smaller proportion with intellectual and developmental disabilities received most or moderately effective contraception (30.1% vs 36.3%, P <.001). With the exception of injectable contraception, this trend was consistent across all measures and remained statistically significant after controlling for race, ethnicity, age, and urban or rural status (adjusted odds ratio 0.75, 95% CI 0.72-0.79; P <.001). Among those who received most or moderately effective contraception, a significantly greater proportion of women with intellectual and developmental disabilities had co-occurring menstrual disorders (31.3% vs 24.3%, P <.001). CONCLUSION: These findings suggest disparities in contraceptive provision and potential differences in clinical indication by intellectual and developmental disability status. Future studies should investigate reasons for and barriers to contraceptive use among women with intellectual and developmental disabilities.

Activated tissue resident memory T-cells (CD8+CD103+CD39+) uniquely predict survival in left sided "immune-hot" colorectal cancers.

Introduction: Characterization of the tumour immune infiltrate (notably CD8+ T-cells) has strong predictive survival value for cancer patients. Quantification of CD8 T-cells alone cannot determine antigenic experience, as not all infiltrating T-cells recognize tumour antigens. Activated tumour-specific tissue resident memory CD8 T-cells (TRM) can be defined by the co-express of CD103, CD39 and CD8. We investigated the hypothesis that the abundance and localization of TRM provides a higher-resolution route to patient stratification. Methods: A comprehensive series of 1000 colorectal cancer (CRC) were arrayed on a tissue microarray, with representative cores from three tumour locations and the adjacent normal mucosa. Using multiplex immunohistochemistry we quantified and determined the localization of TRM. Results: Across all patients, activated TRM were an independent predictor of survival, and superior to CD8 alone. Patients with the best survival had immune-hot tumours heavily infiltrated throughout with activated TRM. Interestingly, differences between right- and left-sided tumours were apparent. In left-sided CRC, only the presence of activated TRM (and not CD8 alone) was prognostically significant. Patients with low numbers of activated TRM cells had a poor prognosis even with high CD8 T-cell infiltration. In contrast, in right-sided CRC, high CD8 T-cell infiltration with low numbers of activated TRM was a good prognosis. Conclusion: The presence of high intra-tumoural CD8 T-cells alone is not a predictor of survival in left-sided CRC and potentially risks under treatment of patients. Measuring both high tumour-associated TRM and total CD8 T-cells in left-sided disease has the potential to minimize current under-treatment of patients. The challenge will be to design immunotherapies, for left-sided CRC patients with high CD8 T-cells and low activate TRM,that result in effective immune responses and thereby improve patient survival.

Characterization of the Immune Microenvironment in Inflammatory Breast Cancer Using Multiplex Immunofluorescence.

INTRODUCTION: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poorly characterized immune microenvironment. METHODS: We used a five-colour multiplex immunofluorescence panel, including CD68, CD4, CD8, CD20, and FOXP3 for immune microenvironment profiling in 93 treatment-naïve IBC samples. RESULTS: Lower grade tumours were characterized by decreased CD4+ cells but increased accumulation of FOXP3+ cells. Increased CD20+ cells correlated with better response to neoadjuvant chemotherapy and increased CD4+ cells infiltration correlated with better overall survival. Pairwise analysis revealed that both ER+ and triple-negative breast cancer were characterized by co-infiltration of CD20 + cells with CD68+ and CD4+ cells, whereas co-infiltration of CD8+ and CD68+ cells was only observed in HER2+ IBC. Co-infiltration of CD20+, CD8+, CD4+, and FOXP3+ cells, and co-existence of CD68+ with FOXP3+ cells correlated with better therapeutic responses, while resistant tumours were characterized by co-accumulation of CD4+, CD8+, FOXP3+, and CD68+ cells and co-expression of CD68+ and CD20+ cells. In a Cox regression model, response to therapy was the most significant factor associated with improved patient survival. CONCLUSION: Those results reveal a complex unique pattern of distribution of immune cell subtypes in IBC and provide an important basis for detailed characterization of molecular pathways that govern the formation of IBC immune landscape and potential for immunotherapy.

The impact of trauma-informed design on psychological well-being in homeless shelters.

Trauma-informed design is an emerging concept that combines elements of interior design, environmental psychology, and clinical psychology. Previous reports describe the potential impact of the physical space and design of homeless shelters on positive psychological outcomes (Pable, 2012). However, there is little known research on these outcomes. This article provides preliminary support for positive outcomes through a program evaluation of a trauma-informed design of resident bedrooms at two homeless shelters in North Carolina. Residents (n = 61) were asked to take a presurvey (before room design) and postsurvey (after design) that assessed their experiences of preparedness, hopefulness, and safety. Among those who completed both pre and postsurveys (n = 43), there was a statistically significant improvement in all three factors following the design, with the largest effect sizes for safety and total score average. Additionally, qualitative findings indicate participants felt the design updates increased their experiences of dignity (n = 17) and safety (n = 13), with some indicating increased feelings of hope (n = 4). We discuss implications for other homeless shelters, as well as similar institutions that support people in transitional housing. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Exploring Theater Neuroscience: Using Wearable Functional Near-infrared Spectroscopy to Measure the Sense of Self and Interpersonal Coordination in Professional Actors.

Ecologically valid research and wearable brain imaging are increasingly important in cognitive neuroscience as they enable researchers to measure neural mechanisms of complex social behaviors in real-world environments. This article presents a proof of principle study that aims to push the limits of what wearable brain imaging can capture and find new ways to explore the neuroscience of acting. Specifically, we focus on how to build an interdisciplinary paradigm to investigate the effects of taking on a role on an actor's sense of self and present methods to quantify interpersonal coordination at different levels (brain, physiology, behavior) as pairs of actors rehearse an extract of a play prepared for live performance. Participants were six actors from Flute Theatre, rehearsing an extract from Shakespeare's A Midsummer Night's Dream. Sense of self was measured in terms of the response of the pFC to hearing one's own name (compared with another person's name). Interpersonal coordination was measured using wavelet coherence analysis of brain signals, heartbeats, breathing, and behavior. Findings show that it is possible to capture an actor's pFC response to their own name and that this response is suppressed when an actor rehearses a segment of the play. In addition, we found that it is possible to measure interpersonal synchrony across three modalities simultaneously. These methods open the way to new studies that can use wearable neuroimaging and hyperscanning to understand the neuroscience of social interaction and the complex social-emotional processes involved in theatrical training and performing theater.

Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction.

Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.

Anomalies and Local Structure of Liquid Water from Boiling to the Supercooled Regime as Predicted by the Many-Body MB-pol Model.

For the past 50 years, researchers have sought molecular models that can accurately reproduce water's microscopic structure and thermophysical properties across broad ranges of its complex phase diagram. Herein, molecular dynamics simulations with the many-body MB-pol model are performed to monitor the thermodynamic response functions and local structure of liquid water from the boiling point down to deeply supercooled temperatures at ambient pressure. The isothermal compressibility and isobaric heat capacity show maxima near 223 K, in excellent agreement with recent experiments, and the liquid density exhibits a minimum at ∼208 K. A local tetrahedral arrangement, where each water molecule accepts and donates two hydrogen bonds, is found to be the most probable hydrogen-bonding topology at all temperatures. This work suggests that MB-pol may provide predictive capability for studies of liquid water's physical properties across broad ranges of thermodynamic states, including the so-called water's "no man's land" which is difficult to probe experimentally.

Water Capture Mechanisms at Zeolitic Imidazolate Framework Interfaces.

Water capture mechanisms of zeolitic imidazolate framework ZIF-90 are revealed by differentiating the water clustering and the center pore filling step, using vibrational sum-frequency generation spectroscopy (VSFG) at a one-micron spatial resolution and state-of-the-art molecular dynamics (MD) simulations. Through spectral line shape comparison between VSFG and IR spectra, the relative humidity dependence of VSFG intensity, and MD simulations, based on MB-pol, we found water clustering and center pore filling happen nearly simultaneously within each pore, with water filling the other pores sequentially. The integration of nonlinear optics with MD simulations provides critical mechanistic insights into the pore filling mechanism and suggests that the relative strength of the hydrogen bonds governs the water uptake mechanisms. This molecular-level detailed mechanism can inform the rational optimization of metal-organic frameworks for water harvesting.

Examining Health Care Access for Refugee Children and Families in the North Carolina Triangle Area.

BACKGROUND Resettled refugees are at increased risk of poor health outcomes due to acculturation challenges, logistical barriers, experiences of trauma, and other barriers to care that are poorly understood. Refugee children may be particularly vulnerable due to disruptions in health, well-being, education, and nutrition during the resettlement process.METHOD To describe the health care barriers facing refugees in the North Carolina Triangle area (comprised of Durham, Chapel Hill, Raleigh, and their surrounding areas), we conducted three focus group interviews (in Arabic, French, and Swahili) with 25 refugee parents from Syria, Iraq, Central African Republic, the Democratic Republic of the Congo, and Chad. We also administered a survey to nine organizations that provide services for refugees.RESULTS Focus group responses highlighted the multidimensional nature of health care barriers for refugee families and children, encompassing challenges with acculturation, communication, transportation, finances, and health literacy. Organizations emphasized similar challenges and described their efforts to improve access to services through increased communication, coordination, and seeking new financial support for programs.LIMITATIONS Given the geographic focus of the study, results may not be generalizable to other populations and settings. Men spoke more than women in some focus groups, and participants may have been influenced by more vocal contributors. Furthermore, this study is limited by a lack of health outcomes data.CONCLUSIONS This study suggests that the health care needs of refugees living in the North Carolina Triangle area can be better met by providing comprehensive, coordinated, and culturally relevant care. This could include minimizing the number of visits by integrating multiple services under one roof, providing trauma-informed interpreters, and offering accessible transportation services.

Hydrogen bonding structure of confined water templated by a metal-organic framework with open metal sites.

Water in confinement exhibits properties significantly different from bulk water due to frustration in the hydrogen-bond network induced by interactions with the substrate. Here, we combine infrared spectroscopy and many-body molecular dynamics simulations to probe the structure and dynamics of confined water as a function of relative humidity within a metal-organic framework containing cylindrical pores lined with ordered cobalt open coordination sites. Building upon the agreement between experimental and theoretical spectra, we demonstrate that water at low relative humidity binds initially to open metal sites and subsequently forms disconnected one-dimensional chains of hydrogen-bonded water molecules bridging between cobalt atoms. With increasing relative humidity, these water chains nucleate pore filling, and water molecules occupy the entire pore interior before the relative humidity reaches 30%. Systematic analysis of rotational and translational dynamics indicates heterogeneity in this pore-confined water, with water molecules displaying variable mobility as a function of distance from the interface.

Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome.

BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.

Disentangling Coupling Effects in the Infrared Spectra of Liquid Water.

A quantitative characterization of intermolecular and intramolecular couplings that modulate the OH-stretch vibrational band in liquid water has so far remained elusive. Here, we take up this challenge by combining the centroid molecular dynamics formalism, which accounts for nuclear quantum effects, with the MB-pol potential energy function, which accurately reproduces the properties of water across all phases, to model the infrared (IR) spectra of various isotopic water solutions with different levels of vibrational couplings, including those that cannot be probed experimentally. Analysis of the different IR OH-stretch line shapes provides direct evidence for the partially quantum-mechanical nature of hydrogen bonds in liquid water, which is emphasized by synergistic effects associated with intermolecular coupling and many-body electrostatic interactions. Furthermore, we quantitatively demonstrate that intramolecular coupling, which results in Fermi resonances due to the mixing between HOH-bend overtones and OH-stretch fundamentals, is responsible for the shoulder located at ∼3250 cm-1 of the IR OH-stretch band of liquid water.

Characterizing the transcutaneous electrical recruitment of lower leg afferents in healthy adults: implications for non-invasive treatment of overactive bladder.

BACKGROUND: As a potential new treatment for overactive bladder (OAB), we investigated the feasibility of non-invasively activating multiple nerve targets in the lower leg. METHODS: In healthy participants, surface electrical stimulation (frequency = 20 Hz, pulse width = 200 µs) was used to target the tibial nerve, saphenous nerve, medial plantar nerve, and lateral plantar nerve. At each location, the stimulation amplitude was increased to define the thresholds for evoking (1) cutaneous sensation, (2) target nerve recruitment and (3) maximum tolerance. RESULTS: All participants were able to tolerate stimulation amplitudes that were 2.1 ± 0.2 (range = 2.0 to 2.4) times the threshold for activating the target nerve. CONCLUSIONS: Non-invasive electrical stimulation can activate neural targets at levels that are consistent with evoking bladder-inhibitory reflex mechanisms. Further work is needed to test the clinical effects of stimulating one or more neural targets in OAB patients.

Wnt gene expression in human trabecular meshwork cells.

PURPOSE: The aim of this study was to examine the expression of genes related to the Wnt signaling pathway, such as beta-catenin (CTNNB1) and secreted frizzled-related protein-1 (sFRP1), in human trabecular meshwork (TM) cells. In addition, the effect of oxidative stress on Wnt signaling was evaluated. METHODS: All experiments were conducted using second- or third-passaged human TM cells. cDNA was prepared from total RNA extracted from cells by means of reverse transcription. PCR was then performed to determine the presence of Wnt genes. For oxidative stress, TM cells were treated with 1 mM of H(2)O(2) for 30 min. Actin staining was carried out to verify cell response to oxidative stress. Western blotting was used to measure Wnt-related protein levels after H(2)O(2) treatment. RESULTS: Positive PCR products were detected for a total of 25 Wnt and Wnt-related genes in human TM cells. Most of the genes identified belonged to the Wnt/beta-catenin pathway. Members of the beta-catenin-independent noncanonical pathways were also found. Oxidative stress did not result in significant changes in beta-catenin and sFRP1 protein levels. CONCLUSIONS: Genes related to canonical and noncanonical Wnt pathways are expressed in human TM cells. It appears that all three Wnt pathways are operative in the TM system. Oxidative stress, while thought to play a role in the development of glaucoma, had little effect on the Wnt activity in TM cells.

Overexpression of myocilin in cultured human trabecular meshwork cells.

The trabecular meshwork, a specialized eye tissue, is a major site for regulation of the aqueous humor outflow. Malfunctioning of the trabecular meshwork is believed to be responsible for development of glaucoma, a blinding disease. Myocilin is a gene linked to the most common form of glaucoma. Its expression is known to be upregulated by glucocorticoids in trabecular meshwork cells and the altered myocilin level may be the culprit for glaucomatous conditions such as corticosteroid-induced glaucoma. In this study, we examined the influence of myocilin overexpression on the adhesion, spreading, migration, phagocytosis, and apoptosis of human trabecular meshwork cells in culture. When the myocilin expression was increased by 3- to 4-fold, the transfectants showed a dramatic loss of actin stress fibers and focal adhesions. Cell adhesion to fibronectin and spreading were also compromised. Myocilin thus appeared to have a de-adhesive activity, similar to that reported extensively with matricellular proteins. The transfected cells in addition displayed an increased sensitivity to apoptosis. These results demonstrate that overexpression of myocilin renders trabecular meshwork cells in a de-adhesive and vulnerable state. This vulnerability may be the basis for pathologic consequences in subtypes of glaucoma.

Extracellular myocilin affects activity of human trabecular meshwork cells.

The trabecular meshwork (TM), a specialized eye tissue, is a major site for regulation of the aqueous humor outflow. Malfunctioning of this tissue is believed to be responsible for development of glaucoma, a blinding disease. Myocilin is a gene linked to the most common form of glaucoma. The protein product has been localized to both intra and extracellular sites, but its function still remains unclear. This study was to determine whether extracellular myocilin presented in the matrix affects adhesion, morphology, and migratory and phagocytic activities of human TM cells in culture. Cell adhesion assays indicated that TM cells, while adhering readily on fibronectin, failed to attach on recombinant myocilin purified from bacterial cultures. Adhesion on fibronectin was also compromised by myocilin in a dose dependent manner. Myocilin in addition triggered TM cells to assume a stellate appearance with broad cell bodies and microspikes. Loss of actin stress fibers and focal adhesions was observed. TM cell migration on fibronectin/myocilin to scratched wounds was reduced compared to fibronectin controls. Myocilin, however, had little impact on phagocytic activities of TM cells. Cell attachment on fibronectin and migration of corneal fibroblasts, a control cell type, were not altered by myocilin. These results demonstrate that extracellular myocilin elicits anti-adhesive and counter-migratory effects on TM cells. Myocilin in the matrix of tissues could be exerting a similar influence on TM cells in vivo, impacting the flexibility and resilience required for maintenance of the normal aqueous outflow.

Distribution of myocilin, a glaucoma gene product, in human corneal fibroblasts.

PURPOSE: Myocilin is a gene linked to open-angle glaucomas. In this study, the expression and distribution of myocilin in corneal fibroblasts with or without dexamethasone (DEX) treatment were investigated. METHODS: Human corneal fibroblasts were treated with 100 nM DEX for 10-14 days. Immunofluorescence staining for myocilin was performed. Cell lysates and ultracentrifugation fractions were assessed by western blotting for distribution of myocilin and its possible association with various organelles. Staurosporine was used to induce apoptosis and apoptotic cells were detected using a monoclonal single stranded DNA antibody. RESULTS: By immunofluorescence, myocilin protein was found to distribute throughout the cytoplasm of corneal fibroblasts including perinuclear regions. Myocilin distribution overlapped to varying degrees with that of the Golgi complex, endoplasmic reticulum, and mitochondria. Subsequent examination by subcellular fractionation however revealed that myocilin, while co-sedimenting with the Golgi complex, lysosomes, and endoplasmic reticulum, did not fractionate or associate with mitochondria. On western blots, protein bands at approximately 66, 57, and 55 kDa were detected and the intensity of the bands was not affected by DEX treatment in corneal fibroblasts. Apoptosis was induced by staurosporine to a similar extent in both DEX-treated and untreated corneal cultures. CONCLUSIONS: In corneal fibroblasts, myocilin expression is not enhanced by DEX treatment and the protein was not associated with mitochondria, in contrast to what were found in human trabecular meshwork (TM) cells. Such differences suggest that the expression and distribution of myocilin may be distinctive for TM cells and may explain why pathology with myocilin mutations is only evident in glaucoma even though myocilin is expressed ubiquitously in ocular and nonocular tissues.