bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological effects of Lactobacillus johnsonii N6.2 in healthy adults: A double‐blind, randomized trial
Authors: Lorca Graciela L , Marcial Guillermo , Ford Amanda , Gezan Salvador , Perry Daniel , Haller Michael , Wasserfall Clive , Brusko Todd , Atkinson Mark , Gonzalez Claudio , Dahl Wendy 
Published: November 2023

The intestinal environment may play a central role in the development of Type 1 Diabetes (T1D). However, the use of bacteria to alleviate the onset of this disease has been restricted to studies in rodent models. To date, the ability of a Lactobacillus probiotic to prevent T1D onset in humans has not been evaluated. L. johnsonii N6.2 mitigated the onset of T1D when administered to Biobreeding diabetes‐prone rats by altering the activity of intestinal indoleamine 2,3‐dioxygenase‐1 (IDO), correlating with a Th17 bias in the mesenteric lymph nodes of animals protected from T1D onset. Translating this work toward the prevention of T1D in humans required a pilot study in healthy individuals. We performed a human trial to evaluate the immunological response in healthy individuals (n=42; F=30, M=12; 23.2±5.5 y). The 13‐week study was divided into three phases: 1‐week pre‐baseline, 8‐week intervention (1 capsule/d of L. johnsonii N6.2 at 108 CFU or placebo), and 4‐week wash‐out. Blood samples were collected and analyzed throughout the study. Leukocyte subpopulations were assessed at baseline, treatment, and washout by immunophenotyping using flow cytometry and serum blood markers were quantified by ELISAs. Consumption of the L. johnsonii N6.2 did not affect the B cells, dendritic cells or regulatory T cells subsets. However, significant changes were observed in Monocytes, Natural Killer cells, T cells, T effector and follicular helper T cells in the L. johnsonii group. Specifically, the administration of L. johnsonii N6.2 increased the population of activated effector T cells, Th1 (CD45RO+, CD183+, CD196−) after 8 weeks of treatment, an effect that was maintained after the wash‐out period (12 weeks). Based on these results, the concentrations of IL2, IL6, TNFa, INFa, IFNg, sCD25 (IL2Ra), C reactive protein, insulin and IgA were quantified in blood samples. It was found that the concentrations of IgA increased significantly over the time in the L. johnsonii group while no changes were observed for the others. In this study, we identified several biomarkers as a result of L. johnsonii N6.2 consumption in healthy subjects. The results of this pilot study provide a solid foundation for an investigation into prevention of T1D onset by L. johnsonii N6.2 in an at‐risk human population.Support or Funding InformationThese studies were funded by grants from the JDRF (1‐INO‐2014‐176‐A‐V to GLL and a Career Development Award 2‐2012‐280 to TMB) and grants from the National Institutes of Health P01 AI42288 (to MAA and TMB.).
Administration of Fluoxetine or a Small Molecule TPH1 Inhibitor Affects Litter Size, Pup Mortality, and Milk Yield During Murine Pregnancy and Lactation
Authors: Weaver Samantha , Fricke Hannah , Hernandez Laura 
Published: November 2023

Non‐neuronal serotonin regulates milk synthesis in an autocrine‐paracrine manner during lactation. Selective Serotonin Reuptake Inhibitors (SSRI), including Fluoxetine, are the most commonly prescribed antidepressants during pregnancy and lactation in the United States. SSRI increase local activity of serotonin in both neuronal and non‐neuronal tissues, including the mammary gland. The objective of this study was to examine the effects of SSRI administration during lactation on milk yield, pup weight, pup mortality, and litter size. As a negative control, we used a small‐molecule inhibitor of the rate‐limiting enzyme in serotonin synthesis, tryptophan hydroxylase 1 (Tph1). Beginning the day after pregnancy (d1 after cervical plug), C57Bl/6J dams were administered 20 mg/kg of either saline or fluoxetine daily via intraperitoneal injection through d21 of lactation. Additionally, on d1 of pregnancy, dams were either maintained on a control diet or loaded on a control diet fortified with a small‐molecule inhibitor of Tph1. There were three treatment groups: injected with saline and receiving control chow (CON; n=15), fluoxetine/control chow (FLX; n=11), saline/Tph1 inhibitor chow (TPH1; n=14). Litter size on d0 was recorded, as was pup mortality throughout lactation. Milk yield per pup was determined using the weigh‐suckle‐weigh method and pup weight gain was recorded. Of all dams enrolled in the study (19 CON, 34 FLX, 26 TPH1), a certain proportion were excluded because all pups were found dead. By treatment, 21.1% (4/19) of CON dams, 67.6% (23/34) of FLX dams, and 46.2% (12/26) of TPH1 dams were excluded due to a dead/killed litter. Of those dams that kept all pups, FLX dams had smaller litters (P=0.01; 6.5 ± 0.4 vs. 4.6 ± 0.5 vs. 6.4 ± 0.5 pups for CON, FLX, and TPH1) and tended to have more dead pups (P=0.06; 0.7 ± 0.2 vs. 0.9 ± 0.3 vs. 0.2 ± 0.1 dead pups for CON, FLX, and TPH1) than CON or TPH1 dams. FLX dams also produced less milk (P=0.03) than TPH1 or CON dams and subsequently had pups that gained less weight throughout lactation (P<0.0001; 4.9 ± 0.5 vs. 4.4 ± 0.5 vs. 4.7 ± 0.5 g/pup for CON, FLX, and TPH1). Collectively, this data suggests that FLX administration throughout pregnancy and lactation may have adverse effects on pup development both in utero and during lactation. While previous literature has established that SSRI are the safest antidepressants due to minimal side effects, our data suggests that FLX treatment affects the dam's gestational and lactational capacity and therefore pup growth during pregnancy and lactation.Support or Funding InformationKaros PharmaceuticalsNational Science Foundation Graduate Research Fellowship Grant No. DGE‐1256259
Novel Plasma Proteins in Nepalese School‐aged Children Are Associated with a Small Head at Birth
Authors: Lee Sun Eun , West Keith P. , Cole Robert N. , Schulze Kerry , Yager James D. , Groopman John , Christian Parul 
Published: November 2023

BackgroundFetal growth restriction may have long‐term effects on health and function mediated by permanent changes in cell size or number and modification of gene expression and organ structure. Yet, little is known about protein biomarkers of fetal metabolic programming that persist into childhood.ObjectiveWe explored the plasma proteome of school‐aged children to identify proteins that may be differentially abundant by size at birth and reflect a sustained proteomic phenotype of intrauterine growth restriction.MethodsPlasma proteins were profiled using tandem mass spectrometry in a cohort of 500 6–8 year old children living in the southern plains of Nepal on whom weight, length, and head circumference had been measured at birth. Small birth size was defined by weight, length, weight‐for‐length or head circumference (HC) being < ‐2 Z‐scores of the WHO growth standards. We estimated differences in relative abundance of proteins between children born small vs normal (≥ ‐2 Z‐scores) in size. Pathway analysis using the Gene Ontology database was performed to identify functional protein clusters associated with birth size. Significance was defined by a false discovery rate (q) < 0.10.ResultsAmong 982 plasma proteins detected in >10% of children, 21 proteins were differentially abundant in children with a small vs normal HC at birth. No proteins differed by other indicators of birth size (q ≥0.10). After adjusting for gestational age at birth, child sex, current anthropometry and maternal and household characteristics, 19 proteins differed by HC at birth (q <0.10), with 18 being 8–22% less abundant in plasma of children with a small HC at birth: i.e., HC < ‐2 Z‐scores (□ 32 cm) at birth. Affected proteins were mostly actin (α‐actin), actin filament organizing molecules (α‐actinin, talin, filamin, transgelin‐2, tropomyosin 3 and 4, etc.), actin‐binding motor protein (myosin 6), and cytoskeleton‐binding glycolytic enzymes (glyceraldehyde‐3‐phosphate dehydrogenase). A correlation matrix revealed high, positive correlations among these cytoskeletal proteins (average r=0.68). One protein, angiopoietin‐like 6, recently reported to be elevated in malnutrition and metabolic disorders, was elevated by 22% in children with a small vs normal head size at birth. Pathway analysis confirmed cytoskeleton protein sets such as cellular morphogenesis and muscle contraction were over‐represented in the proteins associated with a small HC (Bonferroni corrected p<0.05).ConclusionsA novel cluster of plasma proteins of actin cytoskeletal origin assessed in childhood that regulate fundamental developmental processes was negatively associated with small head size at birth. The childhood plasma proteome stably reflects specific aspects of poor growth early in life which may have prognostic value for later life disease risk.Support or Funding InformationGrant funding: Bill and Melinda Gates Foundation (OPP5241 and GH614).
Supplemental Zinc Decreases Fractional Zinc Absorption and Increases Lean Tissue Mass among Vietnamese Children with Tuberculosis
Authors: Hall Andrew G , Hoang Nga Thu , Hoang Van Thanh , Woodhouse Leslie , Tu Ngu , King Janet C , Vo Phuc Hanh 
Published: November 2023

Childhood tuberculosis (TB) is a major health concern in Vietnam. Dietary Zn absorption is greater in children recovering from TB, possibly due to increased demand of Zn for immune function. Zn supplementation, therefore, may improve the effectiveness of TB treatment. Our objective was to determine changes in Zn homeostasis in response to Zn supplements among children admitted for treatment of TB at the National Lung Hospital in Hanoi, Vietnam.After baseline, children matched by sex were randomized to 10 mg Zn/d (n=10) or placebo (n=11) for the first 2 mo of TB treatment. At baseline and after 2 mo, fractional Zn absorption (FZA) and exchangeable Zn pool size (EZP) were determined using Zn stable isotopes during an 8 d controlled‐diet metabolic study. After each of 3 meals on d 2, the child received 0.33 mg 67Zn orally and, 1 h following dinner, 0.1 mg 70Zn intravenously. FZA was determined from urinary Zn tracer‐tracee ratios (TTRs) in samples collected 5–7 d post isotope administration. EZP was estimated from the y‐intercept of the log‐transformed linear regression of urinary 70Zn TTRs. Height, weight, body mass index (BMI), mid‐upper arm circumference (MUAC), triceps skinfold thickness (TSK), and subscapular skinfold thickness (SSK) were determined. Mid‐upper arm muscle area (MUAM) and mid‐upper arm fat area (MUAF) were derived from MUAC and TSK.21 children 9 to 15 y, 11 male and 10 female, enrolled. 14 had pulmonary TB. Height‐ and BMI‐for‐age z‐scores were −1.2 (−1.9, −0.6) and −1.7 (−2.4, −1.0), respectively. After 2 mo, controlling for baseline values, FZA was significantly lower among Zn‐supplemented children vs. placebo: 25.8% (21.5, 30.1%) vs. 32% (27.7, 36.3%), p < 0.05. EZP tended to be higher with Zn compared with placebo: 83.3 mg (69.2, 97.5 mg) vs. 70.1 mg (55.2, 85 mg), p = 0.19 (NS). No differences in weight, height, or BMI were observed. MUAC was higher among Zn supplemented, 21.1 cm (20.2, 22 cm), vs. placebo, 19.5 cm (18.7, 20.3 cm), p < 0.05. MUAM was also higher among Zn supplemented, 19.6 cm2 (17.3, 22.2 cm2) vs. 15.7 cm2 (13.9, 17.6 cm2) placebo, p < 0.05.In sum, 10 mg Zn/d led to a homeostatic response and improved lean tissue gain in Vietnamese children with TB, and thus should further be evaluated as part of their treatment. Given the sensitivity of MUAC and MUAM, these indicators should be included for monitoring the TB recovery process in future studies.Support or Funding InformationInternational Atomic Energy Agency, Contract 15859
The SELENOF Selenoprotein Localizes to the Outer Plasma Membrane in Human Prostatic Tissue and its Levels are Reduced in Prostate Cancer
Authors: Ekoue Dede , Ansong Emmanuel , Macias Virgilia , Deaton Ryan , Kajdacsy‐Balla Andre , Liu Li , Latcher Craig , Picklo Matthew , Nonn Larisa , Gann Peter , Freeman Vincent , Diamond Alan 
Published: November 2023

SELENOF (also referred to as Sep15) is a selenium containing protein shown to reside in the endoplasmic reticulum (ER). Previous studies have linked polymorphisms in SELENOF to prostate cancer mortality. To investigate the role of SELENOF inprostate cancer, human prostatic tissue obtained from patients following prostatectomy was examined by immunohistochemistry. Unlike what we observe inhuman cancer‐derived cell lines, SELENOF partitioned predominantly to the outercell membrane in histologically benign glands distal to the tumor. Similarly, outer membrane staining was observed when primary human epithelial cells were examined by confocal microscopy. The pattern of expression in tumors was dramatically different than that observed in benign tissue with the levels of the protein being significantly lower and generally not in the outer membrane. AfricanAmerican men are at an increased risk of prostate cancer. A functional polymorphism in SELENOF expected to result in lower SELENOF levels is approximately 5‐fold more prevalent in African Americans. Therefore, the levels of SELENOF were compared between tumor tissue obtained from African Americans(n=33) and Caucasians (n=295). SELENOF levels were lower in tumor cells from African Americans when the signals were evaluated from the entire cell (P<0.02). These results indicate that SELENOF may have a non‐ER function in normal prostate epithelia and lower levels in tumor tissue may be contributing to prostate cancer risk. Tissue SELENOF levels are likely to be responsive to an individual's selenium status and SELENOF genotype. Selenium levels in plasma obtained from 129 men who had undergone a prostatectomy and participated in a Chicago‐based study were genotyped for SELENOF and plasma selenium levels were evaluated. The genetic data obtained confirmed the higher frequency of the allele likely to result in lower SELENOF levels in AfricanAmericans and this allele was associated with both higher levels of the Prostate Specific Antigen (P<0.05) and the Gleason Score, a measure of prostate cancer aggressiveness and prognosis. The selenium status of AfricanAmerican men (115.24 ±3.04 ng/mL) in this cohort was also significantly lower (P<0.01) than that determined for Caucasians (139.18 ±2.41 ng/mL). Collectively, the data obtained from these two approaches indicates that the SELENOF genotype and the selenium status of individuals may be contributing to the disparate incidence and outcome of prostate cancer experienced by African American men.Support or Funding InformationThis work was supported by grants from the National Institutes of Health [Grant # RO1CA127943, R21CA182103] and a Research Supplement to Promote Diversity in Health‐Related Research to AMD.
Serum 25‐Hydroxyvitamin D Concentration and Leukocyte Telomere Length in US Adults: A Nationwide Population‐Based Study
Authors: Bao Wei , Oleson Jacob J. , Snetselaar Linda G. 
Published: November 2023

BackgroundVitamin D status has been associated with a variety of health outcomes, beyond bone health. The role of vitamin D in aging and longevity remains controversial. We examined the association between serum 25‐hydroxyvitamin D (25[OH]D) concentration and telomere length, an indicator of cellular aging and biological longevity, in US adults.MethodsWe used data from a nationally representative subsample of 4215 adults in the 2001‐2002 National Health and Nutrition Examination Survey (NHANES). This was the only NHANES cycle when both serum 25(OH)D and leukocyte telomere length were measured. Serum 25(OH)D concentration was measured using a radioimmunoassay method. The leukocyte telomere length relative to standard reference DNA (T/S ratio) was measured in purified DNA samples using the quantitative polymerase chain reaction method. We used linear regression to estimate the relationship between serum 25(OH)D levels and telomere length. Both serum 25(OH)D levels and telomere length were log‐transformed prior to modeling to satisfy regression assumptions. The model was adjusted for covariates including age, gender, race/ethnicity, education, family income to poverty ratio, smoking status, alcohol intake, physical activity, total energy intake, and body mass index. Survey weights, strata, and primary sampling units were used in all analyses to account for the complex sampling design.ResultsAfter adjustment for covariates, although there was no main effect (β [SE] 0.017 [0.014], P=0.24), the relationship between serum 25(OH)D levels and leukocyte telomere length differed by age. Specifically, there was a significant association between serum 25(OH)D levels and leukocyte telomere length in adults of 45–64 years old (0.086 [0.022], P=0.001), but not in adults of 20–44 years old (−0.024 [0.021], P=0.26) or adults ≥ 65 years old (−0.004 [0.027], P=0.87). We observed no effect modification on the association by gender or race/ethnicity.ConclusionsIn this large nationwide population‐based study, we observed a significant association between serum 25(OH)D levels and leukocyte telomere length in middle‐aged adults, but not in younger or elder adults.
Adducin regulates migration and invasion of normal lung epithelial cells and lung cancer cells
Authors: Lechuga Susana , Amin Parth H , Ivanov Andrei I 
Published: November 2023

Epithelial cell migration represents a critical mechanism underlying normal tissue morphogenesis and disease‐related processes such as epithelial restitution and tumor metastasis. In the lungs, epithelial cell migration is essential to repair the airways damaged by environmental and inflammatory insults. Furthermore, this process is critical for metastasis of non‐small cell lung cancer (NSCLC) cells. Migration of epithelial cells depends on orchestrated dynamics of the plasma membrane and the underlying actin cytoskeleton, which implicates the membrane/cytoskeleton interface in cell motility. The plasma membrane is linked to the actin cytoskeleton by a spectrin‐adducin polymeric lattice. The aim of this study was to investigate the roles of adducin in migration and invasion of normal lung epithelial cells and NSCLC cells. We used 16HBE14o immortalized lung epithelial cells and two NSCLC cell lines, H1573 and H1299, which express two different isoforms of adducin, ADD1 and ADD3. CRISPR/Cas9 mediated knockout of either ADD1, or ADD3 significantly increased Boyden chamber migration of individual16HBE14o and NCI‐H1573 cells without affecting their collective motility in a wound closure assay. Overexpression of ADD1 in H1299 cells significantly decreased their wound healing, Boyden chamber migration, and Matrigel invasion. The described effects of adducin knockout and overexpression on epithelial cell migration were not due to changes in cell proliferation. ADD1‐overexpressing H1299 cells demonstrated markedly accelerated cell adhesion and spreading on the collagen matrix. These effects were accompanied by the increased size of focal adhesions at the spreading cell edges, higher Src phosphorylation, and the assembly of long filopodia‐like protrusions enriched in F‐actin and non‐muscle myosin IIB. The protrusions had a slow rate of contraction and detachment from the matrix. Our findings reveal a novel function of adducin as a negative regulator of migration and invasion of normal lung epithelial cells and NSCLC cells by mechanisms, involving remodeling of the actin cytoskeleton, and modulation of cell adhesion to the extracellular matrix.Support or Funding InformationSuported by NIH R01 grant DK108278 to AII.
Tryptophan Metabolite Activation of the Aryl Hydrocarbon Receptor in Intestinal Epithelia Promotes Mucosal Healing
Authors: Lanis Jordi M , Alexeev Erica , Colgan Sean 
Published: November 2023

Inflammatory bowel disease (IBD) is a chronic inflammation of the intestine affecting more 1 million people in the United States. The pathogenesis of IBD is not completely understood, but complex risk factors such as genetics, environmental exposures, diet, and changes to the microbiota all play a role in the establishment of this disease. Regardless of the triggering factors, it is clear that the response of intestinal epithelia to the various inflammatory signals is crucial to restore homeostasis. Significant shifts in tissue metabolism are detected during inflammation and include a notable increase in tryptophan (Trp) metabolites. In vivo work has demonstrated that inflammation stimulates the induction of epithelial indoleamine 2,3‐dioxygenase (IDO1), the enzyme that catalyzes the conversion of Trp to kynurenine (Kyn). Consequently, elevated levels of intracellular kynurenine trigger activation of the Aryl Hydrocarbon Receptor (AHR). Numerous pathways are mediated by the transcription factor AHR, but preliminary data suggests that AHR activation during colonic inflammation is important for IL10 receptor (IL10R1) expression and wound healing. Based on these findings, we hypothesized that epithelial AHR signaling is protective in colitis. To that end, in vivo studies have revealed that Kyn mediates protective actions via the AHR to ameliorate colitis in an IL10R1 dependent manner. In contrast, colitis in intestinal epithelia conditional AHR knockout mice is not improved with exogenous Kyn, and the isolated colonic epithelial cells are deficient in IL10R1. Together, these results provide evidence on the importance of AHR signaling in intestinal epithelia and implicate AHR in the regulation of IL10R1 expression in the colon.Support or Funding InformationThis work was supported by NIH grants DK099452, DK50189, DK095491, VA Merit BX002182 and by the Crohn's and Colitis Foundation of America.
Neutrophils Induce Pro‐angiogenic T cells with a Regulatory Phenotype in Pregnancy
Authors: Nadkarni Suchita , Smith Joanne , Sferruzzi‐Perri Amanda , Kishore Madhav , Mauro Claudio , Williams David , Marelli‐Berg Federica , Perretti Mauro 
Published: November 2023

Whilst fundamental in controlling innate immune responses, the role of neutrophils in regulating adaptive immunity is just being appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T‐cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil‐induced (ni)T‐cells produce IL‐10, IL‐17 and VEGF, and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal‐maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT‐cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT‐cells and their regulatory function occurs via transfer of apoptotic neutrophil‐derived proteins including FOXO1 to T‐cells. Unlike in healthy pregnancies, neutrophils from blood and placental samples of pre‐eclamptic women fail to induce niT‐cells as a direct consequence of their inability to transfer FOXO1 to T‐cells. Finally, neutrophil‐selective FOXO1 knockdown leads to defective placentation and compromised embryo development similar to that resulting from neutrophil depletion. These data define a novel, non‐redundant function of neutrophil‐T‐cell interactions in the regulation of vascularisation at the maternal‐fetal interface.Support or Funding InformationSN and MP were supported by the Wellcome Trust (Programme 086867/Z/08/Z). FMB is supported by the British Heart Foundation (CH/15/2/32064).