Risk factors associated with driving after marijuana use among West Virginia college students during the COVID-19 pandemic.

OBJECTIVES: The purpose of this study was to assess sociodemographic and behavioral risk factors associated with driving after marijuana use (DAMU) among West Virginia college students. METHODS: Participants were recruited from West Virginia University between September and November 2022. The study sample was restricted to students who were ≥18 years of age; reported recently driving; possessed a current, valid driver's license from any US state; and were enrolled for at least one credit hour in the Fall 2022 semester. RESULTS: Among respondents (N = 772), 28.9% reported DAMU. Students who had a GPA of B (adjusted odds ratio [AOR]: 2.17, 95% confidence interval [CI]: 1.06-4.42), smoked or ingested marijuana in the past year (AOR: 26.51, 95% CI: 10.27-68.39), drove after drinking (AOR: 2.38, 95% CI: 1.18-4.79), and used both marijuana and alcohol concurrently and then drove (AOR: 10.39, 95% CI: 2.32-46.54) associated with DAMU. Individuals who felt the behavior was somewhat dangerous or not dangerous or thought their peers approved of DAMU showed significant associations with DAMU. CONCLUSIONS: As DAMU was prevalent, future interventions that raise awareness of the danger and potential consequences of DAMU may be needed to reduce this risky behavior on college campuses.

Cannabis use among adolescents and young adults during the COVID-19 pandemic: A systematic review.

Background: A systematic review of the literature was performed to summarize cannabis use among adolescents and young adults during the COVID-19 pandemic. Special focus was given to the prevalence of cannabis use during COVID-19, as well as factors that may explain changes in cannabis consumption patterns. Methods: The protocol of this systematic review was registered. Articles from seven publication databases were searched in January 2022. The inclusion criteria for studies were as follows: 1) published in English; 2) study instruments needed to include items on COVID-19; 3) conducted after January 1st, 2020; 4) published in a peer-reviewed journal, dissertation, or thesis; 5) study population ≤25 years of age; 6) study designs were limited to observational analytical studies; 7) measured cannabis use. This review excluded other reviews, editorials, and conference abstracts that were not available as full text manuscripts. Independent review, risk of bias assessment, and data abstraction were performed by two authors. Results: Fifteen articles from the United States (n=11) and Canada (n=4) were included in this review. The findings of this review showed that the prevalence of cannabis use during the pandemic among adolescents and young adults were mixed. Some mental health symptoms, including depression and anxiety, were identified as the most commonly reported reasons for increased cannabis use during the pandemic. Conclusions: This review highlights the inconsistencies in the prevalence of cannabis use among adolescents and young adults during the pandemic. Therapeutic interventions for mental health and continued public health surveillance should be conducted to understand the long-term effects of cannabis use among adolescents and young adults.

An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission.

Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15+ macrophages, PRDM16+ dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of TH17 cells. Ligand-receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9+IL-4+IL-13+ TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4+ TRM cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.

Time-dependent ultrastructural changes during venous thrombogenesis and thrombus resolution.

BACKGROUND: Deep vein thrombosis is a common vascular event that can result in debilitating morbidity and even death due to pulmonary embolism. Clinically, patients with faster resolution of a venous thrombus have improved prognosis, but the detailed structural information regarding changes that occur in a resolving thrombus over time is lacking. OBJECTIVES: To define the spatial-morphologic characteristics of venous thrombus formation, propagation, and resolution at the submicron level over time. METHODS: Using a murine model of stasis-induced deep vein thrombosis along with scanning electron microscopy and immunohistology, we determine the specific structural, compositional, and morphologic characteristics of venous thrombi formed after 4 days and identify the changes that take place during resolution by day 7. Comparison is made with the structure and composition of venous thrombi formed in mice genetically deficient in plasminogen activator inhibitor type 1. RESULTS: As venous thrombus resolution progresses, fibrin exists in different structural forms, and there are dynamic cellular changes in the compositions of leukocytes, platelet aggregates, and red blood cells. Intrathrombus microvesicles are present that are not evident by histology, and red blood cells in the form of polyhedrocytes are an indicator of clot contraction. Structural evidence of fibrinolysis is observed early during thrombogenesis and is accelerated by plasminogen activator inhibitor type 1 deficiency. CONCLUSION: The results reveal unique, detailed ultrastructural and compositional insights along with documentation of the dynamic changes that occur during accelerated resolution that are not evident by standard pathologic procedures and can be applied to inform diagnosis and effectiveness of thrombolytic treatments to improve patient outcomes.

Health Service Utilization in Adolescents Following a First Arrest: The Role of Antisocial Behavior, Callous-Unemotional Traits, and Juvenile Justice System Processing.

Previous research indicates that youth exhibiting antisocial behavior are at risk for utilizing a disproportionate amount of health services compared to youth without these problems. The present study investigates whether being processed by the juvenile justice system and showing callous-unemotional (CU) traits independently predict health service utilization (medical and mental health service use and out-of-home placement) over and above the severity of antisocial behavior across adolescence. A total of 766 participants who had been arrested for the first time in adolescence provided data at ten appointments over a period of seven years. Results showed that self-reported antisocial behavior at the time of arrest predicted increased use of most health service use types over the next seven years (i.e. medicine prescriptions, tests for sexually transmitted infections, mental health service appointments, and out-of-home placements). All except prescription medication use remained significant when controlling for justice system processing and CU traits. Further, justice system processing added significantly to the prediction of medical service appointments. Whereas CU traits were associated with mental health service appointments and out-of-home placements, these did not remain significant when controlling for severity of antisocial behavior. These findings are consistent with prior research documenting the health care costs of antisocial behavior.

Retinoic acid-loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T-cell development in vitro.

The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.

A Hybrid Type 1 trial of a multi-component mHealth intervention to improve post-hospital transitions of care for patients with serious mental illness: Study protocol.

BACKGROUND: The transition from acute (e.g., psychiatric hospitalization) to outpatient care is associated with increased risk for rehospitalization, treatment disengagement, and suicide among people with serious mental illness (SMI). Mobile interventions (i.e., mHealth) have the potential to increase monitoring and improve coping post-acute care for this population. This protocol paper describes a Hybrid Type 1 effectiveness-implementation study, in which a randomized controlled trial will be conducted to determine the effectiveness of a multi-component mHealth intervention (tFOCUS) for improving outcomes for adults with SMI transitioning from acute to outpatient care. METHODS: Adults meeting criteria for schizophrenia-spectrum or major mood disorders (n = 180) will be recruited from a psychiatric hospital and randomized to treatment-as-usual (TAU) plus standard discharge planning and aftercare (CHECK-IN) or TAU plus tFOCUS. tFOCUS is a 12-week intervention, consisting of: (a) a patient-facing mHealth smartphone app with daily self-assessment prompts and targeted coping strategies; (b) a clinician-facing web dashboard; and, (c) mHealth aftercare advisors, who will conduct brief post-hospital clinical calls with patients (e.g., safety concerns, treatment engagement) and encourage app use. Follow-ups will be conducted at 6-, 12-, and 24-weeks post-discharge to assess primary and secondary outcomes, as well as target mechanisms. We also will assess barriers and facilitators to future implementation of tFOCUS via qualitative interviews of stakeholders and input from a Community Advisory Board throughout the project. CONCLUSIONS: Information gathered during this project, in combination with successful study outcomes, will inform a potential tFOCUS intervention scale-up across a range of psychiatric hospitals and healthcare systems. CLINICALTRIALS: govregistration: NCT05703412.

Barriers and Attitudes Toward Seeking Mental Health Services Among Collegiate Marching Band Artists.

CONTEXT: Marching band (MB) artists experience stressors impacting their physical, mental, and emotional health warranting medical support; and they face challenges like other college students and athletes. Mental health illnesses exist in college and MB settings, but there are barriers impacting access to treatment. OBJECTIVE: To examine perceived barriers and attitudes of MB artists toward seeking care from mental health professionals. The secondary aim will examine barriers and attitudes across gender and history with seeking mental health counseling. DESIGN: Cross-sectional. SETTING: Online survey. PARTICIPANTS: A total of 534 MB artists (women: n=312; men: n=222; age: 19.7±1.4 years) participated in the study. MAIN OUTCOME MEASURES: Participants completed surveys with demographics, past medical history, the Barriers to Help Seeking Checklist (BHSC), the Mental Help Seeking Attitudes Scale (MHSAS), and the Attitudes Toward Seeking Professional Psychological Help Scale (ATSPPH-SF). Descriptive statistics examined demographic data. Crosstabulations and Chi-squares examined individual barriers (BHSC) across gender. Scores were assessed on a scale of 1-7 and 10-30 on MHSAS and ATSPPH-SF respectively, and a one-way ANOVA assessed differences in total mean score on the ATSPPH-SF across gender. RESULTS: The highest barrier reported was "lack of time to seek services" (69.1%; n=369), followed by 47.6% (n=254) for "services not available during my free time". The average score on the MHSAS was 4.0±.4 (indicating neutral attitudes to seeking help) and 17.97±5.48 (indicating slightly positive attitudes to seeking help). There were no significant differences across the total mean scores for the MHSAS and ATSPPH-SF across gender. CONCLUSION: MB artists' barriers and attitudes toward mental healthcare influence their ability to seek care in times of need and have some similarities to collegiate athletes. Awareness of the obstacles MB artists face in receiving mental health care will assist healthcare providers in advocating for improved care in this setting.

Contribution of speech rhythm to understanding speech in noisy conditions: Further test of a selective entrainment hypothesis.

Previous work by McAuley et al. Attention, Perception, & Psychophysics, 82, 3222-3233, (2020), Attention, Perception & Psychophysics, 83, 2229-2240, (2021) showed that disruption of the natural rhythm of target (attended) speech worsens speech recognition in the presence of competing background speech or noise (a target-rhythm effect), while disruption of background speech rhythm improves target recognition (a background-rhythm effect). While these results were interpreted as support for the role of rhythmic regularities in facilitating target-speech recognition amidst competing backgrounds (in line with a selective entrainment hypothesis), questions remain about the factors that contribute to the target-rhythm effect. Experiment 1 ruled out the possibility that the target-rhythm effect relies on a decrease in intelligibility of the rhythm-altered keywords. Sentences from the Coordinate Response Measure (CRM) paradigm were presented with a background of speech-shaped noise, and the rhythm of the initial portion of these target sentences (the target rhythmic context) was altered while critically leaving the target Color and Number keywords intact. Results showed a target-rhythm effect, evidenced by poorer keyword recognition when the target rhythmic context was altered, despite the absence of rhythmic manipulation of the keywords. Experiment 2 examined the influence of the relative onset asynchrony between target and background keywords. Results showed a significant target-rhythm effect that was independent of the effect of target-background keyword onset asynchrony. Experiment 3 provided additional support for the selective entrainment hypothesis by replicating the target-rhythm effect with a set of speech materials that were less rhythmically constrained than the CRM sentences.

Aberrant neutrophil degranulation in hospitalized patients with COVID-19 partially remains for 6 months.

Neutrophils are important players in COVID-19, contributing to tissue damage by release of inflammatory mediators, including ROS and neutrophil elastase. Longitudinal studies on the effects of COVID-19 on neutrophil phenotype and function are scarce. Here, we longitudinally investigated the phenotype and degranulation of neutrophils in COVID-19 patients (28 nonhospitalized and 35 hospitalized patients) compared with 17 healthy donors (HDs). We assessed phenotype, degranulation, CXCL8 (IL-8) release, and ROS generation within 8 days, at one or 6 month(s) after COVID-19 diagnosis. For degranulation and ROS production, we stimulated neutrophils, either with ssRNA and TNF or granulocyte-macrophage colony-stimulating factor and N-Formylmethionyl-leucyl-phenylalanine. During active COVID-19, neutrophils from hospitalized patients were more immature than from HDs and were impaired in degranulation and ROS generation, while neutrophils from nonhospitalized patients only demonstrated reduced CD66b+ granule release and ROS production. Baseline CD63 expression, indicative of primary granule release, and CXCL8 production by neutrophils from hospitalized patients were elevated for up to 6 months. These findings show that patients hospitalized due to COVID-19, but not nonhospitalized patients, demonstrated an aberrant neutrophil phenotype, degranulation, CXCL8 release, and ROS generation that partially persists up to 6 months after infection.

Early Weight-bearing Following Surgical Treatment of Ankle Fractures Without Trans-syndesmotic Fixation Is Safe and Improves Short-term Outcomes.

OBJECTIVES: The objective of this study was to ascertain outcome differences after fixation of unstable rotational ankle fractures allowed to weight-bear 2 weeks postoperatively compared with 6 weeks. DESIGN: Prospective case-control study. SETTING: Academic medical center; Level 1 trauma center. PATIENT SELECTION CRITERIA: Patients with unstable ankle fractures (OTA/AO:44A-C) undergoing open reduction internal fixation (ORIF) were enrolled. Patients requiring trans-syndesmotic fixation were excluded. Two surgeons allowed weight-bearing at 2 weeks postoperatively (early weight-bearing [EWB] cohort). Two other surgeons instructed standard non-weight-bearing until 6 weeks postoperatively (non-weight-bearing cohort). OUTCOME MEASURES AND COMPARISONS: The main outcome measures included the Olerud-Molander questionnaire, the SF-36 questionnaire, and visual analog scale at 6 weeks, 3 months, 6 months, and 12 months postoperatively and complications, return to work, range of ankle motion, and reoperations at 12 months were compared between the 2 cohorts. RESULTS: One hundred seven patients were included. The 2 cohorts did not differ in demographics or preinjury scores ( P > 0.05). Six weeks postoperatively, EWB patients had improved functional outcomes as measured by the Olerud-Molander and SF-36 questionnaires. Early weight-bearing patients also had better visual analog scale scores (standardized mean difference -0.98, 95% confidence interval [CI] -1.27 to -0.70, P < 0.05) and a greater proportion returning to full capacity work at 6 weeks (odds ratio = 3.42, 95% CI, 1.08-13.07, P < 0.05). One year postoperatively, EWB patients had improved pain measured by SF-36 (standardized mean difference 6.25, 95% CI, 5.59-6.92, P < 0.01) and visual analog scale scores (standardized mean difference -0.05, 95% CI, -0.32 to 0.23, P < 0.01). There were no differences in complications or reoperation at 12 months ( P > 0.05). CONCLUSIONS: EWB patients had improved early function, final pain scores, and earlier return to work, without an increased complication rate compared with those kept non-weight-bearing for 6 weeks. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium.

The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendants in vitro , resulting in the differentiation of mature tuft cells at the expense of ionocytes. Consistent with this model of mature tuft cell differentiation, we identify mature tuft cells in a patient who died from an asthma flare. Overall, our findings suggest that the immune signaling pathways active in asthma and CF may skew the composition of disease-relevant rare cells and illustrate how deep atlases are required for identifying physiologically-relevant scarce cell populations.

Treble or Trouble: Mental Health Experiences of Gender Diverse Collegiate Marching Band Artists.

CONTEXT: For gender diverse (GD) college marching band (MB) artists, the risk for anxiety and depression may be higher as they navigate the demands. OBJECTIVE: To examine the risk of anxiety and depression across GD MB artists and to explore their barriers and attitudes toward seeking mental health (MH) care. DESIGN: Cross-sectional study. SETTING: Online survey. PARTICIPANTS: 78 GD individuals (transgender=12, non-binary=66, age=19±1 y). OUTCOME MEASURES: A survey was used to assess demographics, anxiety risk using the State-Trait Anxiety Inventory (STAI), depression risk using the Center for Epidemiological Studies Depression Scale (CES-D), and barriers and attitudes using the Barriers Towards Seeking Help Checklist, the Mental Health Seeking Attitudes Scale (MHSAS), and the Attitudes Towards Seeking Professional Psychological Help Scale-Short Form (ATSPPH-SF). Descriptive statistics and univariate analyses determined scores, risk, and differences between MH and receiving assistance. RESULTS: Participants had high state-anxiety (mean=52.0±112.1), trait-anxiety (mean=55.2±10.0), and symptoms of depression (mean=30.4±12.0) using the STAI and CESD. Overall, 78.2% (n=61/78) of GD MB artists were considered at risk for both state- and trait-anxiety and depression. Of these, 61 GD individuals were at risk for all 3 conditions, and 18% (n=11/61) did not seek help from an MH professional. GD MB artists cited lack of time (82.1%; n=64/78) as the primary barrier to seeking professional help. The mean score on the ATSPPH-SF for all GD artists was 19.5 ± 5.0, and the total score for the MHSAS was 47.8±9.2 which indicated more favorable attitudes toward seeking professional help. CONCLUSIONS: We identified high rates of clinical symptoms 26 for depression and anxiety among GD MB artists. The data is consistent with other minority populations and above the normative values for cisgender students. The lack of help-seeking behaviors in nearly 15% of at-risk participants highlights the need for specialized resources for GD patients and/or participation in MB.

The Military Health System: Minimizing Disparities in Breast Cancer Treatment.

BACKGROUND: The Military Health System (MHS) is a universal health care system, in which health care disparities are theoretically minimized. This study aimed to identify disparities and assess their impact on the initiation of timely treatment for breast cancer within a universally insured population. METHODS: A retrospective cohort study was performed to evaluate the treatment of female breast cancer patients ≥18 years of age within the MHS from January 1, 2014, to December 31, 2018. Incident breast cancer was defined as ≥2 breast cancer diagnoses without a prior diagnosis of breast cancer during the three continuous years before index diagnosis. Time from index diagnosis to initial treatment was calculated and dichotomized as receiving treatment within a clinically acceptable time course. Poisson regression was used to estimate relative risk (RR) with 95% CIs. RESULTS: Among the 30,761 female breast cancer patients identified in the MHS, only 6% of patients had a prolonged time to initial treatment. Time to initial treatment decreased during the study period from a mean (SD) of 63.2 (152.0) days in 2014 to 37.1 (28.8) days in 2018 (P < 0.0001). Age, region, and military characteristics remained significantly associated with receiving timely treatment even after the adjustment of confounders. Patients 70-79 years old were twice as likely as 18-39 years olds to receive timely treatment (RR: 2.0100, 95% CI, 1.52-2.6563, P < 0.0001). Senior officers and their dependents were more likely to receive timely initial treatment compared to junior enlisted patients and their dependents (RR: 1.5956, 95% CI, 1.2119-2.1005, P = 0.004). CONCLUSIONS: There have been significant improvements in the timely initiation of breast cancer treatment within the MHS. However, demographic and socioeconomic disparities can be identified that affect the timely initiation of therapy.

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.

In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of MMP12 + dendritic cells (DCs), mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19 + IL4I1 + fibroblasts, and clonally expanded IL13 + IL22 + IL26 + T cells with overlapping type 2 and type 17 characteristics. Cell subsets within this immune and stromal multicellular community were connected by multiple inter-cellular positive feedback loops predicted to impact community assembly and maintenance. AD GWAS gene expression was enriched both in disrupted cornified keratinocytes and in cell subsets from the lesional immune and stromal multicellular community including IL13 + IL22 + IL26 + T cells and ILCs, suggesting that epithelial or immune dysfunction in the context of the observed cellular communication network can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation.

Matriptase drives dissemination of ovarian cancer spheroids by a PAR-2/PI3K/Akt/MMP9 signaling axis.

The transmembrane serine protease matriptase is a key regulator of both barrier-disruptive and protective epithelial cell-cell interactions. Elevated matriptase is a consistent feature of epithelial ovarian cancers (OvCa), where multicellular spheroids shed from the primary tumor into the peritoneal cavity are critical drivers of metastasis. Dynamic cell-to-cell adhesive contacts are required for spheroid formation and maintenance. Here, we show that overactive matriptase, reflected in an increased ratio of matriptase to its inhibitor hepatocyte growth factor activator inhibitor 1 (HAI-1), disrupts cell-cell contacts to produce loose prometastatic spheroids that display increased mesothelial cell adhesion and submesothelial invasion. We show that these activities are dependent on the matriptase activation of a protease-activated receptor-2 (PAR-2) signaling pathway involving PI3K/Akt and MMP9-induced disruption of cell-cell adhesion by the release of the soluble E-cadherin ectodomain. These data reveal a novel pathological connection between matriptase activation of PAR-2 and disruption of cell-cell adhesion, and support the clinical investigation of this signaling axis as a therapeutic strategy for aggressive metastatic OvCa.

Toward a correct treatment of core properties with local hybrid functionals.

In local hybrid functionals (LHs), a local mixing function (LMF) determines the position-dependent exact-exchange admixture. We report new LHs that focus on an improvement of the LMF in the core region while retaining or partly improving upon the high accuracy in the valence region exhibited by the LH20t functional. The suggested new pt-LMFs are based on a Padé form and modify the previously used ratio between von Weizsäcker and Kohn-Sham local kinetic energies by different powers of the density to enable flexibly improved approximations to the correct high-density and iso-orbital limits relevant for the innermost core region. Using TDDFT calculations for a set of K-shell core excitations of second- and third-period systems including accurate state-of-the-art relativistic orbital corrections, the core part of the LMF is optimized, while the valence part is optimized as previously reported for test sets of atomization energies and reaction barriers (Haasler et al., J Chem Theory Comput 2020, 16, 5645). The LHs are completed by a calibration function that minimizes spurious nondynamical correlation effects caused by the gauge ambiguities of exchange-energy densities, as well as by B95c meta-GGA correlation. The resulting LH23pt functional relates to the previous LH20t functional but specifically improves upon the core region.