bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Inflammatory Responses In Tobacco Smoke‐Exposed Mice That Over‐Express The Tight Junctional Protein Claudin‐6
Authors: Lewis Joshua B , Bodine Jared , Milner Dallin , Lewis Adam , Dunaway Todd , Egbert Kaleb , Albright Scott , Merrill Brigham , Monson Troy , Watson Mark , Burstedt Nathan , Smith Quinn , Gassman Jason , Jergensen Tyson , Chavarria Bryan , Broberg Dallin , Thomas Daniel , Arroyo Juan , Reynolds Paul R 
Published: November 2023

It has long been understood that increased epithelial permeability contributes to mucosal inflammation associated with many respiratory diseases including COPD, emphysema, and acute lung injury (ALI). Recently, evidence has revealed that environmental exposures to noxious material such as air pollution, allergens, and cigarette smoke reduces tight junction barrier integrity, thus contributing to inflammatory conditions. Cldn6 is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To elucidate the role of Cldn6, we utilized the Tet‐O inducible system to conditionally over‐express Clnd6 within the distal lung. Cldn6 TG and control mice were continuously provided doxycycline from postnatal day (PN) 30 until sacrifice date at PN 90 and lung biology was assessed. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS) via a nose only inhalation system (Sireq industries) from PN30‐90. On the sacrifice date, lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cells and molecules. qPCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up‐regulation in TG mice. Immunohistochemistry and immunoblotting confirmed the differential expression of Cldn6 and a host of cell‐specific and inflammatory markers (TNF‐alpha, IL‐1beta, Pro‐SPC, CCSP, FOXJ1, and MAC3). As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal captivating information suggesting a role for Cldn6 in lungs exposed to tobacco smoke and further research is necessary in order to fully explain roles for TJ components such as Cldn6 in lungs coping with exposure.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).
Th1 Effector T cells Induce Cardiac Fibroblasts Transition to Myofibroblasts and Contribute to Pressure Overload Induced Cardiac Fibrosis
Authors: Nevers Tania , Salvador Ane M , Velazquez Francisco , Aronovitz Mark , Blanton Robert , Alcaide Pilar 
Published: November 2023

Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. It is known that various inflammatory mediators such as T cells and pro‐fibrotic cytokines play an important part in triggering fibrosis in many different organ systems. We recently demonstrated that T cells represent a major subset of heart infiltrating cells in pressure overload induced heart failure, and contribute to cardiac fibrosis and HF progression. In fact, mice deficient in T cells (TCRa−/− mice) or pharmacological depletion of T cells in WT mice resulted in blunted cardiac fibrosis and preserved cardiac function. However the mechanism by which T cells contribute to cardiac fibrosis and the pathogenesis of non‐ischemic HF is still unclear. Thus, we hypothesize that heart infiltrated T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix‐producing cardiac myofibroblasts. To test this hypothesis we used in vitro approaches and the thoracic aortic constriction (TAC) mouse model of pressure overload induced heart failure. Co‐culture of various CD4 T cell subsets with cardiac fibroblasts demonstrated that Th1 cells, in contrast to naïve T cells, adhered directly to cardiac fibroblasts and induced fibroblast to myofibroblast transition, enhancing collagen secretion and regulating the synthesis of extracellular matrix proteins shown to be implicated in fibrosis. Supernatants of Th1 cells only slightly induced myofibroblast transition, indicating the requirement of Th1 cells cross‐talk to cardiac fibroblasts to promote fibrosis. Adoptive transfer of Th1 cells into TCRa−/− mice at 48 hours and 2 weeks post TAC surgery resulted in T cell LV infiltration and was sufficient to induce left ventricular fibrosis, and this was not observed after adoptive transfer of naïve T cells in the onset of TAC. Our data suggest that Th1 cells and cardiac fibroblasts reciprocally influence cardiac fibrosis and the pathogenesis of heart failure. These findings provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of cardiac fibrosis in non ischemic heart failure.Support or Funding InformationNIH HL094706 and AHA 13GRNT14560068 (PA), HL6977(RHK )
High glucose culture medium downregulates production of human β‐defensin‐2 (HBD‐2) in human amniotic epithelial cells (HAEC)
Authors: Szukiewicz Dariusz , Alkhalayla Habib , Pyzlak Michal , Szewczyk Grzegorz 
Published: November 2023

Protection of materno‐placento‐fetal unit significantly depends on production of β‐defensins, including HBD‐2, by the HAEC. Regulation of innate and adaptive immunity by HBD‐2 is related to its action against gram‐negative bacteria and chemoattraction of immature dendritic cells. Despite the fact that diabetes induces placental genes for chronic stress and inflammatory pathways, the fetus is at higher risk of transplacental transmission of infection. Here we examined influence of a high glucose environment on production of HBD‐2 in cultured HAEC. Immediately postpartum, HAEC were isolated using trypsin‐based method at 37 degrees C from the amnions obtained after 48 normal full‐term pregnancies. The material was equally divided among the two groups: group I (N = 48) – cultured in high glucose culture medium (280 mg/dl), and the control group II (N = 48) – cultured in the standard medium containing 100 mg/dl glucose, in normoxia (20% O2). After pretreatment with LPS (1 mcg/ml), HBD‐2 concentrations in the HAEC culture supernatant were assessed at determined time points (120, 132, 144, and 156 hours) using ELISA. Nonparametric Wilcoxon rank‐sum test was used and the differences between the groups were considered statistically significant if p < 0.05. We observed that high glucose environment in group I was correlated with 1.1 to 2.7‐fold decrease over time in HBD‐2 concentration in the culture supernatant, compared to group II (p < 0.05). The mean viability of cells in both groups did not differ significantly at the consecutive time points. Thus, immunosupression due to hyperglycemia in poorly controlled diabetes may predispose to perinatal infections. Further studies are needed to examine whether this inhibition of HBD‐2 production is correlated with high glucose‐induced changes in the local expression of toll‐like receptors (TLRs).Support or Funding InformationSupported by WUM grant: 2M2‐W1‐15
Insulin Signaling Regulation of Sortilin 1 and Glut4 Storage Vesicle Formation in NIH 3T3‐L1 Adipocytes and Mouse Adipose Tissue
Authors: Li Jibiao , Matye David , Wang Yifeng , Li Tiangang 
Published: November 2023

Type‐II diabetes is associated with impaired insulin‐stimulated glucose uptake into the muscle and adipose tissues. Insulin regulates glucose uptake in adipocytes and muscle cells by promoting the plasma membrane translocation of the glucose transporter 4 (Glut4)‐containing storage vesicles, which is defective in type‐II diabetes. The intracellular trafficking receptor Sortilin 1 is an essential component of the Glut4 storage vesicles in adipocytes and mediates the insulin responsiveness of Glut4 translocation to the plasma membrane. Knockdown of Sortilin 1 impaired Glut4 storage vesicle formation and resulted in Glut4 degradation in NIH 3T3‐L1 cells. The objective of this study is to investigate the effect and molecular mechanism of insulin regulation of Sortilin 1 in differentiated 3T3‐L1 adipocytes and in mouse adipose tissue. Adipose Sortilin 1 and Glut4 protein levels were determined in obese and diabetic mice. The effects of insulin and insulin signaling inhibitors on Sortilin 1 mRNA and protein levels were determined in differentiated 3T3‐L1 adipocytes. The potential role of Sortilin 1 phosphorylation in mediating insulin regulation of Sortilin 1 was further investigated. Results showed that insulin induced Sortilin 1 protein, but not mRNA, in 3T3‐L1 adipocytes. Treatment of PI3K or AKT inhibitors decreased Sortilin 1 protein, but not mRNA in 3T3‐L1 cells. In addition, treatment of pro‐inflammatory cytokine TNFα impaired Insulin signaling and decreased Sortilin 1 protein in 3T3‐L1 adipocytes. Consistently, Sortilin 1 protein was down‐regulated in the white and brown adipose of obese and diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. In addition, intraperitoneal injection of a PI3K inhibitor in lean mice caused rapid downregulation of Sortilin 1 protein in the adipose tissue without alteration of Sortilin 1 mRNA levels. LC‐MS/MS analysis further revealed novel serine phosphorylation sites on Sortilin 1 protein. Additional mechanistic studies suggest that Sortilin 1 phosphorylation affects Sortilin1 protein trafficking function and stability, and potentially mediates insulin regulation of Sortilin 1. In conclusion, we have identified Sortilin 1 as a novel target of insulin signaling in adipose tissue, and suggest that insulin resistance may be responsible for the Sortilin 1 downregulation and impaired Glut4 storage vesicle formation in obesity and diabetes.Support or Funding InformationAmerican Diabetes Association, NIDDK
Pancreatic Trypsin and Insulin Receptor Cleavage in High Fat Diet Rats
Authors: Courelli Asimina S. , Mazor Rafi , Schmid‐Schonbein Geert W. 
Published: November 2023

The mechanisms for insulin resistance with type 2 diabetes have been studied extensively, but there is no generally accepted consensus about its etiology. In spontaneously hypertensive rats, we have shown that cleavage of the extracellular domain of the insulin receptors destroys its ability to signal after insulin binding, generating insulin resistance and reduced glucose uptake. Recent evidence suggests that insulin resistance in obese diabetic patients and in the spontaneously hypertensive rat is associated with increased proteolytic (e.g., MMP‐9 and elastase) activity in the blood. We hypothesized that rats given high fat diet (HFD) develop increased intestinal permeability allowing pancreatic trypsin to escape the intestinal lumen and cleave insulin receptors. We examined the insulin receptor and trypsin levels in the intestine, the liver, and the plasma in rats consuming normal diet (ND) and HFD. Immunohistochemistry (IHC) showed a decrease in submucosal and intestinal wall extracellular insulin receptor subunit IRa and an increase in submucosal and intestinal wall trypsin in HFD versus ND rats. In the liver, similar trends were observed, with increase in trypsin levels and decrease in IRa levels in HFD rats. Western blots of the blood plasma showed a marginal increase in plasma trypsin (p‐value=0.06) and IRa levels (p‐value=0.065) in HFD rats. The increase of trypsin in the intestine and liver of HFD rats suggests that a high fat diet alters intestinal permeability to allow digestive trypsin to escape out of the lumen into the blood stream, and cleave IRa in the intestinal wall and the liver.Support or Funding InformationSupported by HL 10881.
Early Childhood Predictors of Life course BMI Latent Class Trajectories in a Guatemalan Cohort
Authors: Ford Nicole D. , Ramirez‐Zea Manuel , Martorell Reynaldo , Stein Aryeh D. 
Published: November 2023

ObjectiveIn recent years, Latin America has experienced dramatic increases in obesity. Programming to address under‐nutrition can also potentially affect obesity trends – especially among children outside the critical window of the first 1,000 days. We examined the role of early childhood factors on the timing and rate of body mass index (BMI) gain using latent class trajectories in a Guatemalan cohort.MethodsStudy participants (741 men, 711 women) were born in the El Progreso department of Guatemala from 1962–77 and have been followed prospectively since participating in a nutrition supplementation trial as children. Sex‐specific BMI latent class trajectories were derived from 22 possible measures of height and weight: 5 from 1–12 months; 3 from 13–23 months; 5 from 24–50 months; 3 from 51–84 months; 2 from 10–20y; and 4 from 21–42y. We estimated the role of the type of nutrition supplement (Atole vs. control beverage), timing of exposure (conception through age 2 y vs. other), and their interaction (using a difference‐in‐difference interaction test), and childhood household socioeconomic status (SES) on BMI latent class using multinomial logistic regression.ResultsWe identified 3 BMI latent classes (low (39%), medium (46%), and high (14%)) in men and 2 classes (low (57%) and high (43%)) in women. Atole status and timing of exposure differed significantly by BMI latent class in both men (p<.01) and women (p<.0001). High SES tertile was associated with increased odds of high BMI latent class membership in both men (OR 2.07; 95% CI 1.19, 3.59) and women (OR 1.92; 95% CI 1.29, 2.84) relative to the lowest tertile. Among women, middle SES tertile was also associated with increased odds of high BMI latent class membership (OR 1.60; 95% CI 1.07, 2.38) relative to the lowest tertile. Exposure to Atole during the first 1,000 days was not significantly associated with BMI latent class membership (difference‐in‐difference test ‐ p>0.2 for men; p>0.6 for women).ConclusionExposure to Atole during the first 1,000 days was not significantly associated with BMI latent class membership, suggesting that programs to improve nutritional status are unlikely to adversely affect BMI trajectories. Childhood household SES was associated with increased odds of high BMI latent class membership – the pathways through which this operates still need to be explored.Support or Funding InformationFunding: This research was funded by the National Institutes of Health.
Protein intake, breastfeeding frequency and breastfeeding duration affect BMI from infancy to mid‐childhood
Authors: Wright Melecia , Sotres‐Alvarez Daniela , Mendez Michelle , Adair Linda 
Published: November 2023

BackgroundProtein intake (PI) is an important determinant of growth, but excess protein in infancy has been associated with increased risk of obesity. Few studies have explored age‐specific associations of PI with BMI from infancy to adulthood.ObjectiveTo analyze how PI and breastfeeding relate to infant and toddler BMI, and how breastfeeding history and PI relate to BMI from age 2 to 22 yr using 24‐hour dietary recalls and anthropometric data from the Cebu Longitudinal Health and Nutrition birth cohort.MethodsRandom‐effects longitudinal regression models were used to estimate 1) the joint association of daily breastfeeding frequency (BF) and dietary protein residuals with concurrent BMI Z‐scores measured bi‐monthly from 2 to 24 months (n=2899), and 2) the association of breastfeeding history and protein residuals with concurrent BMI measured at ages 2, 11, 15, 19 and 22 years (n=2435). Where appropriate, models included statistical interactions (PI*energy, energy*age, BF*energy, BF*age), and were adjusted for socio‐demographic and anthropometric confounders (maternal education, maternal height and maternal age at baseline, offspring sex, birth weight and age‐2 BMI, and time‐varying household assets, urbanicity, offspring age and offspring education).Results1) Relative to not being breastfed the previous day, breastfeeding was associated with higher zBMI, though this effect ameliorated with time (Beta=0.524 at 6mo & 0.138 at 18mo). An additional 5 breast milk feedings in the previous day contributed to higher zBMI in younger infants (B=0.030 at 6mo) and lower zBMI in later infancy (B=−0.075 at 18mo). Compared to those at the 25th percentile of protein intake, being at the 75th percentile of protein intake was positively associated with zBMI regardless of age, however, the magnitudes of these associations were highest in non‐breastfed and older infants (at 6 mo: B=0.019 vs 0.005, at 18 mo: B=0.024 vs 0.012 for non‐breastfed vs breastfed infants respectively). 2) In post‐infancy analyses, 15 months of breastfeeding duration was inversely associated with BMI at age 11 (Beta=−0.145). Protein residuals were not significantly associated with BMI in the post‐infancy analyses. (All shown betas were statistically significant, p<0.05.)ImplicationsBreastfeeding frequency, dietary protein intake and breastfeeding duration are significant contributors to concurrent BMI in infancy and childhood.Support or Funding InformationHoward Hughes Medical Institute International Student Research Fellowship
Low Plasma Concentrations of High‐Density Lipoprotein Cholesterol (HDL‐C) Associated with Shorter Duration of Pregnancy: A Nested Cohort Study in Ghana
Authors: Oaks Brietta M , Stewart Christine P , Laugero Kevin D , Adu‐Afarwuah Seth , Lartey Anna , Vosti Stephen A , Ashorn Per , Dewey Kathryn G 
Published: November 2023

BackgroundRecent studies have suggested that low serum cholesterol is associated with preterm birth (birth < 37 wk gestation), however results are mixed and research has been limited primarily to populations from high‐income countries.ObjectiveTo determine whether maternal blood lipid concentrations, at ≤ 20 wk or 36 wk gestation, are associated with duration of gestation.MethodsWe performed a nested cohort (n=320) study of pregnant Ghanaian women ≤ 20 wk gestation enrolled in a large randomized controlled trial. Total cholesterol, high density lipoprotein cholesterol (HDL‐C), low density lipoprotein cholesterol (LDL‐C), and triglycerides were analyzed in plasma samples, and gestational age was determined by ultrasound at baseline. A linear regression model examined the association between each blood lipid and duration of gestation. Blood lipids were examined both as continuous variables and categorically as low (<10th percentile), referent (10–90th percentile), and high (>90th percentile).ResultsAt baseline, blood lipid concentrations were not associated with duration of gestation. At 36 wk gestation, higher HDL‐C was associated with a longer duration of gestation (β‐coefficient ± SE: 1.8 ± 0.7 days/mmol/L, p=0.02), independent of assigned group in trial, gestational age at enrollment, maternal baseline BMI, woman's age, parity, infant gender, asset index, season at enrollment, and time between sample collection and last meal. Among women with low HDL‐C at 36 wk gestation, duration of gestation was 5.9 days shorter when compared with the referent group (10–90th percentile) (p = 0.02) and 8.5 days shorter when compared with the high HDL‐C group (p = 0.003). LDL‐C was not significantly associated with duration of gestation at 36 wk gestation in linear regression analyses (adjusted β‐coefficient ± SE: −1.2 ± 0.7 days/mmol/L, p=0.08). Among women with low LDL‐C at 36 wk gestation, duration of gestation was 4.9 days longer when compared with the referent group (p = 0.051). Total cholesterol and triglycerides were not significantly associated with pregnancy duration.ConclusionLow HDL‐C in the third trimester of pregnancy is associated with a shorter duration of pregnancy in this study population of Ghanaian women.Support or Funding InformationBill & Melinda Gates Foundation.
Evaluating the Impact of Pre‐Matriculation Instruction on Academic Performance in the Anatomical and Physiological Sciences
Authors: Chico Diane E , Smith Sherry , Chen Wei‐Jung A , Peterson Thomas V , Hairrell Angela 
Published: November 2023

The Texas A&M Health Science Center College of Medicine recently implemented a pre‐matriculation program (MedCamp) for a selected group of first year students. This study was conducted to correlate the MedCamp experience with academic performance in the first‐year biomedical science disciplines in gross anatomy, histology and physiology. The exam performance of students who participated in MedCamp (“MedCampers”) was compared with that of students who did not participate in MedCamp. The components of this 4‐week MedCamp included: providing a head‐start on acculturating to the medical community; taking select first‐year curriculum courses such as anatomy, histology, physiology, and molecular medicine (including quizzes and exams); experiencing simulated clinical encounters; developing professionalism skills; providing requisite academic support and tutoring; and having a current M2 student, a staff member, and a faculty member serve as mentors. All of these activities were geared toward preparing students for the rigor of the curriculum, social and professional expectations as medical students, and insight into areas for improvement. Twenty‐four students who met the selecting criteria for this program participated voluntarily in MedCamp. Students ranged in age from 21–51, with 10 females and 14 males that represented many ethnic groups, and had an average MCAT score of 29.17 and overall BCPM (biology, chemistry, physics, and math) GPA of 3.61. Data analysis is ongoing, but qualitative results were extremely positive from the participants, especially regarding social support needed for academic success. Preliminary quantitative analyses of written, laboratory practical, and overall exam performance indicated that the MedCampers performed well and did not show a significant difference in performance when compared with their peers (two tailed t‐tests, α=0.05). Our findings suggested that the MedCamp pre‐matriculation program was effective in preparing students who have been traditionally identified in the literature as having pre‐admission factors associated with difficulties in medical school. These findings align with findings of other pre‐matriculation programs in regard to medical school academic performance.Support or Funding InformationThe Minority Health Research and Education Grant Program (Higher Education Coordinating Board)