Survey of Dopamine Receptor D2 Antagonists as Retinal Antifibrotics.

Purpose: To evaluate the potency and efficacy of a library of dopamine receptor D2 (D2R) antagonists in the mitigation of fibrotic activation in retinal pigment epithelial (RPE) cells. Methods: ARPE-19 cells were cultured and treated with methotrexate or 27 district D2R antagonists using a fibronectin deposition assay. The most potent compounds were then further assessed in assays measuring cellular proliferation, cellular migration, and profibrotic gene expression. Results: The previously established antifibrotic D2R antagonist loxapine exerted a robust and dose-dependent inhibition of fibronectin deposition, whereas methotrexate exerted minimal inhibition. The most potent D2R antagonist identified, fluphenazine, effectively blocked in vitro models of fibrosis at 300-1,000 nM concentrations. Conclusions: Here we found multiple FDA-approved D2R antagonists that potently block RPE cell fibrogenesis. These findings further support the potential of D2R antagonism as a potential therapeutic for retinal fibrotic disease.

Modeling item-level variance of polysyllabic word reading in developing readers: Exploring semantically related child, word, and child-by-word predictors.

Across word reading development, there are important and evolving relationships between oral and written semantic knowledge. Recent research has focused on these relationships, with accumulating evidence supporting the role of word knowledge and related word characteristics as important factors influencing polysyllabic word reading abilities. The purpose of this study was to investigate how semantic-related effects across child-level skills (e.g., general vocabulary knowledge), word-level properties (e.g., age of acquisition), child-by-word-level familiarity (e.g., item-level familiarity), and interactions between key child attributes and word characteristics (e.g., word reading skill by age of acquisition) contribute to polysyllabic word reading. Specifically, we emphasize the semantic contributions of word-level features to word reading development, which have been relatively underexplored in the literature. A sample of elementary school students oversampled for word reading difficulty (N = 92) in Grades 3 to 5 read a set of polysyllabic words (J = 45) and completed a battery of reading and language-related measures. Using cross-classified random-effects models and accounting for various control variables, semantic-related variables representing item-level familiarity; child-level set for variability; and word-level age of acquisition and number of morphemes were significant predictors in the main-effects model. A significant interaction between sight word efficiency and age of acquisition indicated higher probabilities of correctly reading polysyllabic words at lower levels of acquisition for better readers. Results indicate important semantic-related influences on polysyllabic word reading at the child, word, and child-by-word levels, suggesting meaningful relationships between knowledge of the orthographic form of a word and semantic knowledge in developing readers.

Systematic evidence mapping of potential correlates of exposure for per- and poly-fluoroalkyl substances (PFAS) based on measured occurrence in biomatrices and surveys of dietary consumption and product use.

Per- and poly-fluoroalkyl substances (PFAS) are widely observed in environmental media and often are found in indoor environments as well as personal-care and consumer products. Humans may be exposed through water, food, indoor dust, air, and the use of PFAS-containing products. Information about relationships between PFAS exposure sources and pathways and the amounts found in human biomatrices can inform source-contribution assessments and provide targets for exposure reduction. This work collected and collated evidence for correlates of PFAS human exposure as measured through sampling of biomatrices and surveys of dietary consumption and use of consumer products and articles. A systematic evidence mapping approach was applied to perform a literature search, conduct title-abstract and full-text screening, and to extract primary data into a comprehensive database for 16 PFAS. Parameters of interest included: sampling dates and locations, cohort descriptors, PFAS measured in a human biomatrix, information about food consumption in 11 categories, use of products/articles in 11 categories, and reported correlation values (and their statistical strength). The literature search and screening process yielded 103 studies with information for correlates of PFAS exposures. Detailed data were extracted and compiled on measures of PFAS correlations between biomatrix concentrations and dietary consumption and other product/article use. A majority of studies (61/103; 59%) were published after 2015 with few (8/103; 8%) prior to 2010. Studies were most abundant for dietary correlates (n = 94) with fewer publications reporting correlate assessments for product use (n = 56), while some examined both. PFOA and PFOS were assessed in almost all studies, followed by PFHxS, PFNA, and PFDA which were included in >50% of the studies. No relevant studies included PFNS or PFPeS. Among the 94 studies of dietary correlates, significant correlations were reported in 83% of the studies for one or more PFAS. The significant dietary correlations most commonly were for seafood, meats/eggs, and cereals/grains/pulses. Among the 56 studies of product/article correlates, significant correlations were reported in 70% of the studies. The significant product/article correlations most commonly were for smoking/tobacco, cosmetics/toiletries, non-stick cookware, and carpet/flooring/furniture and housing. Six of 11 product/article categories included five or fewer studies, including food containers and stain- and water-resistant products. Significant dietary and product/article correlations most commonly were positive. Some studies found a mix of positive and negative correlations depending on the PFAS, specific correlate, and specific response level, particularly for fats/oils, dairy consumption, food containers, and cosmetics/toiletries. Most of the significant findings for cereals/grains/pulses were negative correlations. Substantial evidence was found for correlations between dietary intake and biomatrix levels for several PFAS in multiple food groups. Studies examining product/article use relationships were relatively sparse, except for smoking/tobacco, and would benefit from additional research. The resulting database can inform further assessments of dietary and product use exposure relationships and can inform new research to better understand PFAS source-to-exposure relationships. The search strategy should be extended and implemented to support living evidence review in this rapidly advancing area.

Effect of wheat middling incorporation into wet corn distillers grains with solubles on apparent diet digestibility and ruminal fermentation characteristics in growing and finishing diets.

Two separate cross-over experiments were conducted to evaluate the effects of incorporating wheat middlings into wet corn distillers grains with solubles (WDGS) on apparent diet digestibility and ruminal fermentation characteristics in growing and finishing diets. In experiment 1, four ruminally cannulated heifers (313 ±â€…42.9 kg) were limit fed a high-energy growing diet that included WDGS (CON) or WDGS + wheat middlings (CON + WM) at 40% of diet dry matter (DM). The diet also contained (DM basis) 39.5% dry-rolled corn, 7.5% supplement, and 13% warm-season grass hay. In experiment 2, four ruminally cannulated Holstein steers (321 ±â€…17.4 kg) were fed a finishing diet that included WDGS (CON) or WDGS + wheat middlings (CON + WM) at 30% of diet DM. The diet also contained (DM basis) 60.3% dry-rolled corn, 2.7% supplement, and 7.0% warm-season grass hay. Experiments consisted of two 15-d periods that were conducted concurrently. Each period included 10 d of diet adaptation, 4 d of fecal collection, and 1 d of ruminal fluid collection. Fecal samples were collected on days 11 to 14 of each period and composite samples were analyzed for chromium to estimate apparent diet digestibility. On day 15, ruminal fluid samples were collected prior to feeding and again at 2, 4, 6, 8, 12, 18, and 24-h post-feeding. In experiment 1, DM, organic matter (OM), neutral detergent fiber (NDF), and acid detergent fiber (ADF) intake did not differ (P ≥ 0.11) between diets; however, starch intake was greater (P = 0.03) for heifers fed CON + WM compared with CON. Apparent DM, OM, NDF, and starch digestibilities were similar between diets (P ≥ 0.13), but feeding CON + WM tended to lead to lesser (P = 0.06) apparent ADF digestibility. Ruminal pH and total volatile fatty acid concentrations did not differ between diets (P ≥ 0.16); however, ruminal ammonia concentrations tended to be less (P = 0.09) for CON + WM compared with CON. In experiment 2, DM intake did not differ (P = 0.65) between diets. Apparent DM digestibility was greater (P = 0.01) for CON + WM compared with CON but the difference was small. Intake and apparent digestibility of OM, NDF, ADF, and starch did not differ (P ≥ 0.25) between diets. Ruminal ammonia concentrations were lesser (P = 0.03) while ruminal pH was greater (P = 0.02) for CON + WM compared with CON. Overall, incorporation of wheat middlings into WDGS had minimal impacts on feed intake, apparent diet digestibility, and ruminal fermentation characteristics when fed to growing and finishing cattle.

Mosquito Species Diversity and Abundance Patterns in Plots with Contrasting Land Use and Land Cover in Bloomington, Indiana.

Land use and land cover (LULC) gradients are associated with differences in mosquito species composition and the entomological risk of mosquito-borne disease. Here, we present results from a season-long study of mosquito species richness and abundance with samples collected at 9 locations from 2 plots with contrasting LULC, an urban farm and a forest preserve, in Bloomington, IN, a city in the midwestern USA. With a total sampling effort of 234 trap-nights, we collected 703 mosquitoes from 9 genera and 21 species. On the farm, we collected 15 species (285 mosquitoes). In the preserve, we collected 19 species (418 mosquitoes). Thirteen species were common in both study plots, 2 were exclusive to the farm, and 6 were exclusive to the forest preserve. In both plots, we collected Aedes albopictus and Ae. japonicus. In the farm, the most common mosquito species were Culex restuans/Cx. pipiens and Coquillettidia perturbans. In the preserve, Ae. japonicus and Ae. triseriatus were the 2 most common mosquito species. Time series analysis suggests that weather factors differentially affected mosquito species richness and mosquito abundance in the plots. Temperature, relative humidity (RH), and precipitation were positively associated with richness and abundance at the farm, while increases in the SD of RH decreased both richness and abundance at the preserve. Our results highlight the importance that LULC has for mosquito species diversity and abundance and confirm the presence of Ae. albopictus and Ae. japonicus in southwestern Indiana.

Almond hulls and shells as an alternative fiber source in limit-fed growing beef cattle diets.

Almond hulls and shells are a by-product of almond production that can be incorporated as a feed ingredient in beef cattle diets. Three experiments were conducted to determine the effects of hammermill screen size on almond hull and shell bulk density and inclusion of ground or non-ground almond hulls and shells in limit-fed growing diets on growth performance, diet digestibility, and ruminal fermentation characteristics of beef cattle. In experiment 1, almond hulls and shells were ground with a laboratory-scale hammermill using no screen, a 11.1-mm screen, a 19.1-mm screen, or a 25.4-mm screen. Each screen-size treatment was ground at three separate time points (n= 3 replications/treatment). Grinding almond hulls and shells with no screen increased bulk density by 111% and minimized proportions of fine particles; therefore, almond hulls and shells ground using no screen were included as a treatment in the following experiments. In experiment 2, 364 steers (initial body weight [BW]: 257±â€…20.7 kg) were blocked by truckload (n = 4), stratified by BW, and assigned to pen within block. Pens were randomly assigned to 1 of 4 experimental diets (n= 10 pens/treatment). The control diet (CON) contained (DM basis) 39.5% dry-rolled corn, 7.5% supplement, 40% wet-corn gluten feed, and 13% prairie hay. Non-ground (13AH) or ground (13GAH) almond hulls and shells replaced prairie hay and were fed at 13% of diet DM or non-ground almond hulls and shells were fed at 26% of diet DM and replaced 13% prairie hay and 13% dry-rolled corn (26AH). Diets were limit-fed at 2.2% of BW daily (DM basis) for 56 d. Overall average daily gains (ADG) were greater (P ≤ 0.05) for CON, 13AH, and 13GAH compared with 26AH. In addition, ADG from days 14 to 56 were greater (P= 0.03) for 13GAH and tended to be greater (P = 0.09) for 13AH compared with CON. Experiment 3 was a 4 × 4 replicated Latin square in which 8 ruminally cannulated heifers (initial BW = 378 ±â€…44.0 kg) were fed diets from experiment 2. Apparent dry matter digestibility did not differ (P = 0.21) among treatments. Total ruminal volatile fatty acid concentrations were greater (P ≤ 0.03) for 13GAH and 13AH compared with 26AH and tended (P = 0.06) to be greater for 13GAH compared with CON. Overall, almond hulls and shells can be utilized as an alternative to prairie hay in limit-fed growing diets without negatively influencing rates of gain or diet digestibility.

The Effects of poly-GA and poly-PR C9orf72 Dipeptide Repeats on Sleep Patterns in Drosophila melanogaster.

C9orf72 is the most common familial gene associated with amyotrophic lateral sclerosis (ALS). Dipeptide repeats (DPRs) encoded by an expanded nucleotide repeat sequence in the C9orf72 gene were found in the sleep-related neurons of patients, indicating a role of DPRs in ALS-associated sleep disruptions. Poly-GA or poly-PR DPRs were expressed in male Drosophila melanogaster to study their effect on sleep . Poly-PR expression caused sleep disruptions while poly-GA expression did not. This study validates the use of Drosophila as an in vivo model system for exploring the roles of DPRs in perturbing the underlying molecular mechanisms in sleep regulation.

Integration of Total Worker Health ® Training for Occupational Health and Safety Professionals With Efforts to Promote Worker Health, Safety, and Well-being in Mexico.

OBJECTIVE: We sought to test whether a 2-week Total Worker Health (TWH) training mapped to TWH education competencies could be administered to a Mexican audience of occupational safety and health professionals and could lead to positive changes to knowledge and behaviors. METHODS: This study used robust program evaluation methods collected before and after each of the nine training days and at the end of the course. RESULTS: Overall course quality received a mean score of 4.6 (SD = 0.6) and 98.8% of participants agreed that their TWH knowledge increased. All participants intended to make at least one change to their professional practice, most frequently helping companies assess their organizational culture to support health, safety, and well-being. CONCLUSIONS: This TWH training was well received and led to positive self-reported increase in knowledge and abilities to influence workers' health, safety, and well-being.

Advances in cholera research: from molecular biology to public health initiatives.

The aquatic bacterium Vibrio cholerae is the etiological agent of the diarrheal disease cholera, which has plagued the world for centuries. This pathogen has been the subject of studies in a vast array of fields, from molecular biology to animal models for virulence activity to epidemiological disease transmission modeling. V. cholerae genetics and the activity of virulence genes determine the pathogenic potential of different strains, as well as provide a model for genomic evolution in the natural environment. While animal models for V. cholerae infection have been used for decades, recent advances in this area provide a well-rounded picture of nearly all aspects of V. cholerae interaction with both mammalian and non-mammalian hosts, encompassing colonization dynamics, pathogenesis, immunological responses, and transmission to naïve populations. Microbiome studies have become increasingly common as access and affordability of sequencing has improved, and these studies have revealed key factors in V. cholerae communication and competition with members of the gut microbiota. Despite a wealth of knowledge surrounding V. cholerae, the pathogen remains endemic in numerous countries and causes sporadic outbreaks elsewhere. Public health initiatives aim to prevent cholera outbreaks and provide prompt, effective relief in cases where prevention is not feasible. In this review, we describe recent advancements in cholera research in these areas to provide a more complete illustration of V. cholerae evolution as a microbe and significant global health threat, as well as how researchers are working to improve understanding and minimize impact of this pathogen on vulnerable populations.

Semi-automated micro-computed tomography lung segmentation and analysis in mouse models.

Computed Tomography (CT) is a standard clinical tool utilized to diagnose known lung pathologies based on established grading methods. However, for preclinical trials and toxicity investigations in animal models, more comprehensive datasets are typically needed to determine discriminative features between experimental treatments, which oftentimes require analysis of multiple images and their associated differential quantification using manual segmentation methods. Furthermore, for manual segmentation of image data, three or more readers is the gold standard of analysis, but this requirement can be time-consuming and inefficient, depending on variability due to reader bias. In previous papers, microCT image manual segmentation was a valuable tool for assessment of lung pathology in several animal models; however, the manual segmentation approach and the commercial software used was typically a major rate-limiting step. To improve the efficiency, the semi-manual segmentation method was streamlined, and a semi-automated segmentation process was developed to produce:•Quantifiable segmentations: using manual and semi-automated analysis methods for assessing experimental injury and toxicity models,•Deterministic results and efficiency through automation in an unbiased and parameter free process, thereby reducing reader variance, user time, and increases throughput in data analysis,•Cost-Effectiveness: portable with low computational resource demand, based on a cross-platform open-source ImageJ program.

Methodologic challenges and lessons learned through conducting a hospital-based Salmonella Javiana case-control study.

OBJECTIVE: Determine the food(s) most likely contaminated by Salmonella Javiana associated with a salmonellosis outbreak involving 2 hospitals in North Carolina that were within 50 miles of each other in November 2021. METHODS: A 2:1 matched case-control study was conducted. Food histories were obtained from hospital food orders and potential confounder covariates were collected from patient medical records. Attack rates and conditional logistic regression odds ratios (OR) were estimated at the 80% confidence interval (CI) for each food exposure and salmonellosis. RESULTS: There were 21 cases and 42 controls included. Fruit cups had the strongest association with salmonellosis (matched and adjusted OR = 7.9 80% CI: 2.7, 23.6). Hospital-specific ORs varied for several food items, but attack rates analyses provided additional evidence that fruit cups were a likely common source. CONCLUSION: Our analyses implicated fruit cups in an outbreak of salmonellosis in 2 hospitals. Other methodologic challenges included selection of controls among sick patients, heterogeneity of food exposures, reliance on food orders rather than foods consumed, and retention of food history records. Understanding and anticipating these challenges through changes to policies and operational procedures is critical for conducting efficient and effective case-control studies in the hospital setting.

Regulation of Helicobacter pylori Urease and Acetone Carboxylase Genes by Nitric Oxide and the CrdRS Two-Component System.

Helicobacter pylori colonizes the human gastric mucosa and causes various gastroduodenal diseases, including peptic ulceration and gastric cancer. Colonization requires the actions of two-component systems (TCSs) to sense and respond to changes in the host environment. In this study, we evaluated gene regulation mediated by the CrdRS TCS. Few studies have evaluated this TCS, leaving the signal(s) yet to be exhaustively determined and a need for a more complete regulon to be delineated. We performed RNA sequencing (RNA-Seq) on three isogenic H. pylori 26695 mutants: a control, a mutant with deletion of the sensory histidine kinase, ΔcrdS, and a mutant with deletion of the response regulator, ΔcrdR. Comparison of the RNA-Seq results from these mutants established a 40-gene regulon putatively controlled by the CrdRS TCS. Quantitative reverse transcriptase PCR (RT-qPCR) was used to validate 7 of 11 putative regulon members selected for analysis. We further investigated 6 confirmed CrdRS regulon genes by using phospho-incompetent H. pylori 26695 CrdR D53A and CrdS H173A mutants. These experiments further confirmed the role of CrdRS in regulation of urease, acetone carboxylase, hofD, and HP1440. Expression of these CrdRS regulon genes was also evaluated under 10 µM nitric oxide (NO) conditions. This revealed that ureA, acxA, hofD, and HP1440 expression is affected by NO in a CrdRS-dependent manner. Importantly, three of these genes (ureA, acxA, and hofD) are known to play important roles in H. pylori colonization of the stomach. IMPORTANCE The molecular strategies used by Helicobacter pylori to colonize and persist in the harsh environment of the human stomach are a critical area of study. Our study identified several genes in this gastric pathogen, including ureA, a gene encoding a protein essential to the survival of H. pylori, that are regulated via the CrdRS two-component system (TCS) in response to nitric oxide (NO). NO is a product of the innate immune system of the human host. The identification of these genes whose expression is regulated by this molecule may give insights to novel therapeutics. Two genes (ureA and acxA) determined in this study to be regulated by NO via CrdRS have been previously determined to be regulated by other TCSs, indicating that the expression of these genes may be of critical importance to H. pylori.

Cognitive Component Structure of a Neuropsychological Battery Administered to Cognitively-Normal Adults in the SIU Longitudinal Cognitive Aging Study.

We used principal component analysis (PCA) to examine the component structure of a neuropsychological test battery administered to 943 cognitively-normal adults enrolled in the Southern Illinois University (SIU) Longitudinal Cognitive Aging Study (LCAS). Four components explaining the most variance (63.9%) in the dataset were identified: speed/cognitive flexibility, visuospatial skills, word-list learning/memory, and story memory. Regression analyses confirmed that increased age was associated with decreased component scores after controlling for gender and education. Our identified components differ slightly from previous studies using PCA on similar test batteries. Factors such as the demographic characteristics of the study sample, the inclusion of mixed patient and control samples, the inclusion of different test measures in previous studies, and the fact that many neuropsychological test measures assess multiple cognitive processes simultaneously, may help to explain these inconsistencies.

Bunk space requirements for growing beef cattle limit-fed a high-energy corn and corn co-product diet.

Bunk requirements for optimal growth performance of growing calves limit-fed high-energy corn and corn co-product diets have not been widely evaluated. Three-hundred eighty-five crossbred steers (initial body weight = 215 ± 25 kg) were purchased in Texas, transported to the Kansas State Beef Stocker Unit, and weighed at arrival. Steers were stratified by body weight and randomly assigned to 1 of 28 pens containing 12 to 14 head. Within block, pens were randomly assigned to one of four bunk allotment treatments: 25.4, 38.1, 50.8, or 63.5 cm of bunk per head for a 58-d receiving period. Calves were fed at 0700 h once daily at 1.8% of bodyweight (dry matter basis) from February 2 to March 13, 2021; thereafter the daily feed allotment was increased to 2.0% of bodyweight. The diet contained (dry matter basis) 39.5% dry-rolled corn, 7.5% supplement, 40% wet corn gluten feed, and 13% prairie hay. Steers were individually weighed on days 29 and 58 and pen weights were measured weekly to determine feed offered for the following week. Body weights on days 29 and 58, dry matter intake, or gain-to-feed ratio during the receiving period did not differ (P ≥ 0.34) between treatments. During the first 29 d, average daily gain (ADG) increased linearly as bunk space increased (P = 0.03); however, no treatment effects were observed thereafter. In addition, ADG standard deviation from days 0 to 29 responded quadratically (P = 0.05) where ADG standard deviation tended to be greater in the 38.1-cm allotment and was greater in the 50.8-cm allotment compared to the 25.4-cm allotment (P = 0.07 and P = 0.04, respectively). Bunk score tended to decrease linearly as bunk allotment decreased (P = 0.06). Following the receiving period, steers were blocked by bunk treatment and randomly assigned to 1 of 18 pastures. Steers were grazed for 90-d from May to August at a targeted stocking density of 280 kg live-weight ˖ ha-1. During the grazing season, ADG increased linearly with reduced (P < 0.01) bunk allotment; however, body weights did not differ (P = 0.91) between bunk treatments at the completion of the grazing period. In addition, overall total body weight gains and ADG from the receiving and grazing periods did not differ (P > 0.57) between bunk treatments. We interpreted our data to suggest that bunk space allotments of 25.4 to 63.5 cm per head had minimal impact on growth performance during a 58-d receiving period and did not affect final body weights following a 90-d grazing season.

Spontaneous Uterine Vessel Rupture During Pregnancy or in the Puerperium: A Review of the Literature.

Importance: Spontaneous perinatal rupture of a uterine vessel is a rare occurrence that may lead to severe hemorrhage and requires prompt identification and management. Objective: The aim of this study was to examine the etiologies, locations, diagnostic tools, treatment options, and risks in subsequent pregnancies when spontaneous rupture of a uterine vessel occurs in pregnancy. Evidence Acquisition: A literature search was performed by university research librarians using the PubMed, CINAHL, and Web of Science search engines. Identified were 78 cases of perinatal spontaneous uterine vessel rupture and formed the basis for this review. Results: Increased uterine blood flow during pregnancy may alter the integrity of pelvic vessels leading to increased risk of spontaneous rupture. The uterine artery is the most common site of vessel rupture; the second most common site is the uterine-ovarian plexus. The most common presentation is abdominal or pelvic pain, maternal vital sign abnormalities, and an absence of vaginal bleeding. Exploratory laparotomy and embolization (interventional radiology) have been reported as management options. Conclusions: Spontaneous rupture of uterine vessels is a rare but potentially life-threatening complication of pregnancy that should be included in the differential diagnosis of pregnant patients presenting with an acute abdomen. Relevance: Our aim is to increase the awareness of spontaneous vessel rupture during pregnancy to improve detection, management, and perinatal outcomes.

Engineering adoptive T cell therapy to co-opt Fas ligand-mediated death signaling in ovarian cancer enhances therapeutic efficacy.

BACKGROUND: In the USA, more than 50% of patients with ovarian cancer die within 5 years of diagnosis, highlighting the need for therapeutic innovations. Mesothelin (MSLN) is a candidate immunotherapy target; it is overexpressed by ovarian tumors and contributes to malignant/invasive phenotypes, making tumor antigen loss disadvantageous. We previously showed that MSLN-specific T cell receptor (TCR)-engineered T cells preferentially accumulate within established tumors, delay tumor growth, and significantly prolong survival in the ID8VEGF mouse model that replicates many aspects of human disease. However, T cell persistence and antitumor activity were not sustained. We therefore focused on Fas/FasL signaling that can induce activation-induced cell death, an apoptotic mechanism that regulates T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature has been detected in the tumor microenvironment (TME) of human and murine ovarian cancers, can induce apoptosis in infiltrating, Fas (CD95) receptor-expressing lymphocytes, and can protect ovarian cancers from tumor-infiltrating lymphocytes. METHODS: To overcome potential FasL-mediated immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. Murine T cells were engineered to express an MSLN-specific TCR (TCR1045), alone or with the IFP, transferred into ID8VEGF tumor-bearing mice and evaluated for persistence, proliferation, cytokine production and efficacy. Human T cells were similarly engineered to express an MSLN-specific TCR (TCR530) alone or with a truncated Fas receptor or a Fas-4-1BB IFP and evaluated for cytokine production and tumor lysis. RESULTS: Relative to murine T cells expressing only TCR1045, T cells expressing both TCR1045 and a Fas-4-1BB IFP preferentially persisted in the TME of tumor-bearing mice, with improved T cell proliferation and survival. Moreover, TCR1045/IFP+ T cells significantly prolonged survival in tumor-bearing mice, compared with TCR1045-only T cells. Human T cells expressing TCR530 and a Fas-4-1BB IFP exhibit enhanced functional activity and viability compared with cells with only TCR530. CONCLUSIONS: As many ovarian tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may be used to enhance engineered adoptive T cell therapy for patients.

Maternal Nanomaterial Inhalation Exposure: Critical Gestational Period in the Uterine Microcirculation is Angiotensin II Dependent.

Maternal inhalation exposure to engineered nanomaterials (ENM) has been associated with microvascular dysfunction and adverse cardiovascular responses. Pregnancy requires coordinated vascular adaptation and growth that are imperative for survival. Key events in pregnancy hallmark distinct periods of gestation such as implantation, spiral artery remodeling, placentation, and trophoblast invasion. Angiotensin II (Ang II) is a critical vasoactive mediator responsible for adaptations and is implicated in the pathology of preeclampsia. If perturbations occur during gestation, such as those caused by ENM inhalation exposure, then maternal-fetal health consequences may occur. Our study aimed to identify the period of gestation in which maternal microvascular functional and fetal health are most vulnerable. Additionally, we wanted to determine if Ang II sensitivity and receptor density is altered due to exposure. Dams were exposed to ENM aerosols (nano-titanium dioxide) during three gestational windows: early (EE, gestational day (GD) 2-6), mid (ME, GD 8-12) or late (LE, GD 15-19). Within the EE group dry pup mass decreased by 16.3% and uterine radial artery wall to lumen ratio (WLR) increased by 25.9%. Uterine radial artery response to Ang II sensitivity increased by 40.5% in the EE group. Ang II receptor density was altered in the EE and LE group with decreased levels of AT2R. We conclude that early gestational maternal inhalation exposures resulted in altered vascular anatomy and physiology. Exposure during this time-period results in altered vascular reactivity and changes to uterine radial artery WLR, leading to decreased perfusion to the fetus and resulting in lower pup mass.

Pliocene decoupling of equatorial Pacific temperature and pH gradients.

Ocean dynamics in the equatorial Pacific drive tropical climate patterns that affect marine and terrestrial ecosystems worldwide. How this region will respond to global warming has profound implications for global climate, economic stability and ecosystem health. As a result, numerous studies have investigated equatorial Pacific dynamics during the Pliocene (5.3-2.6 million years ago) and late Miocene (around 6 million years ago) as an analogue for the future behaviour of the region under global warming1-12. Palaeoceanographic records from this time present an apparent paradox with proxy evidence of a reduced east-west sea surface temperature gradient along the equatorial Pacific1,3,7,8-indicative of reduced wind-driven upwelling-conflicting with evidence of enhanced biological productivity in the east Pacific13-15 that typically results from stronger upwelling. Here we reconcile these observations by providing new evidence for a radically different-from-modern circulation regime in the early Pliocene/late Miocene16 that results in older, more acidic and more nutrient-rich water reaching the equatorial Pacific. These results provide a mechanism for enhanced productivity in the early Pliocene/late Miocene east Pacific even in the presence of weaker wind-driven upwelling. Our findings shed new light on equatorial Pacific dynamics and help to constrain the potential changes they will undergo in the near future, given that the Earth is expected to reach Pliocene-like levels of warming in the next century.

The impact of airborne endotoxin exposure on rheumatoid arthritis-related joint damage, autoantigen expression, autoimmunity, and lung disease.

Airborne biohazards are risk factors in the development and severity of rheumatoid arthritis (RA) and RA-associated lung disease, yet the mechanisms explaining this relationship remain unclear. Lipopolysaccharide (LPS, endotoxin) is a ubiquitous inflammatory agent in numerous environmental and occupational air pollutant settings recognized to induce airway inflammation. Combining repetitive LPS inhalation exposures with the collagen induced arthritis (CIA) model, DBA1/J mice were assigned to either: sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS 100 ng inhalation), or CIA + LPS for 5 weeks. Serum anti-citrullinated (CIT) protein antibody (ACPA) and anti-malondialdehyde-acetaldehyde (MAA) antibodies were strikingly potentiated with co-exposure (CIA + LPS). CIT- and MAA-modified lung proteins were increased with co-exposure and co-localized across treatment groups. Inhaled LPS exacerbated arthritis with CIA + LPS > LPS > CIA versus sham. Periarticular bone loss was demonstrated in CIA and CIA + LPS but not in LPS alone. LPS induced airway inflammation and neutrophil infiltrates were reduced with co-exposure (CIA + LPS). Potentially signaling transition to pro-fibrotic processes, there were increased infiltrates of activated CD11c+CD11b+ macrophages and transitioning CD11c+CD11bint monocyte-macrophage populations with CIA + LPS. Moreover, several lung remodeling proteins including fibronectin and matrix metalloproteinases as well as complement C5a were potentiated with CIA + LPS compared to other treatment groups. IL-33 concentrations in lung homogenates were enhanced with CIA + LPS with IL-33 lung staining driven by LPS. IL-33 expression was also significantly increased in lung tissues from patients with RA-associated lung disease (N = 8) versus controls (N = 7). These findings suggest that patients with RA may be more susceptible to developing interstitial lung disease following airborne biohazard exposures enriched in LPS.

Speech motor control and orofacial point pressure sensation in adults with ADHD.

Attention-Deficit Hyperactivity Disorder (ADHD) is a predominant neurobehavioral disorder of childhood with motor and sensory symptoms often persisting into adulthood. Motor control theories highlight the importance of the bidirectional relationship between sensation and movement for maintaining skilled behaviors like speech. The impact of ADHD on speech in adults has not been well established. The purpose of this study is to assess group differences in quantitative speech and oral somatosensory measures in adults with and without ADHD and to describe the relationship between ADHD symptomology and speech production. A total of 50 adults (18-26 years) were recruited and divided in two groups based on diagnosis: those with (n = 28) and those without (n = 22) ADHD. All participants provided a speech sample to measure articulatory accuracy and speech rate and completed quantitative point-pressure testing using tactile detection and discrimination on bilateral sites on the lower lip and lateral edge of the tongue tip. Independent t-tests corrected for multiple comparisons identified significant group differences using FDR corrected q values in speech production for correct syllables per second and overall speech rate (q<.05). Additionally, there were significant group differences (q<.05) for detection and discrimination threshold estimates at one testing location. Bivariate correlations identified a relationship between several speech measures and self-reported ADHD symptoms such that as symptom severity increased, speech accuracy for correct syllables per second decreased. Young adults with ADHD have subtle differences in speech production compared to non-ADHD control participants. Speech scientists might consider screening for ADHD when collecting normative data samples.