Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex.

Background/aimsWistar rat dams exposed to limited nesting stress (LNS) from post-natal days (PND) 2 to 10 display erratic maternal behavior, and their pups show delayed maturation of the hypothalamic-pituitary-adrenal axis and impaired epithelial barrier at PND10 and a visceral hypersensitivity at adulthood. Little is known about the impact of early life stress on the offspring before adulthood and the influence of sex. We investigated whether male and female rats previously exposed to LNS displays at weaning altered corticosterone, intestinal permeability, and microbiota.MethodsWistar rat dams and litters were maintained from PND2 to 10 with limited nesting/bedding materials and thereafter reverted to normal housing up to weaning (PND21). Control litters had normal housing. At weaning, we monitored body weight, corticosterone plasma levels (enzyme immunoassay), in vivo intestinal to colon permeability (fluorescein isothiocyanate-dextran 4 kDa) and fecal microbiota (DNA extraction and amplification of the V4 region of the 16S ribosomal RNA gene).ResultsAt weaning, LNS pups had hypercorticosteronemia and enhanced intestinal permeability with females > males while body weights were similar. LNS decreased fecal microbial diversity and induced a distinct composition characterized by increased abundance of Gram positive cocci and reduction of fiber-degrading, butyrate-producing, and mucus-resident microbes.ConclusionsThese data indicate that chronic exposure to LNS during the first week post-natally has sustained effects monitored at weaning including hypercorticosteronemia, a leaky gut, and dysbiosis. These alterations may impact on the susceptibility to develop visceral hypersensitivity in adult rats and have relevance to the development of irritable bowel syndrome in childhood

Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts.

ObjectiveTo compare faecal microbial composition in patients with systemic sclerosis (SSc) from 2 independent cohorts with controls and to determine whether certain genera are associated with SSc-gastrointestinal tract (GIT) symptoms.DesignAdult patients with SSc from the University of California, Los Angeles (UCLA) and Oslo University Hospital (OUH) and healthy controls participated in this study (1:1:1). All participants provided stool specimens for 16S rRNA sequencing. Linear discriminant analysis effect size demonstrated genera with differential expression in SSc. Differential expression analysis for sequence count data identified specific genera associated with GIT symptoms as assessed by the GIT 2.0 questionnaire.ResultsThe UCLA-SSc and OUH-SSc cohorts were similar in age (52.1 and 60.5 years, respectively), disease duration (median (IQR): 6.6 (2.5-16.4) and 7.0 (1.0-19.2) years, respectively), gender distribution (88% and 71%, respectively), and GIT symptoms (mean (SD) total GIT 2.0 scores of 0.7 (0.6) and 0.6 (0.5), respectively). Principal coordinate analysis illustrated significant microbial community differences between SSc and controls (UCLA: p=0.001; OUH: p=0.002). Patients with SSc had significantly lower levels of commensal genera deemed to protect against inflammation, such as Bacteroides (UCLA and OUH), Faecalibacterium (UCLA), Clostridium (OUH); and significantly higher levels of pathobiont genera, such as Fusobacterium (UCLA), compared with controls. Increased abundance of Clostridium was associated with less severe GIT symptoms in both cohorts.ConclusionsThe present analysis detected specific aberrations in the lower GIT microbiota of patients with SSc from 2 geographically and ethnically distinct cohorts. These findings suggest that GIT dysbiosis may be a pathological feature of the SSc disease state

Circulating C3 is Necessary and Sufficient for Induction of Autoantibody-Mediated Arthritis in a Mouse Model

Objective. For the inflammation characteristic of rheumatoid arthritis, the relative contribution of mediators produced locally in the synovium versus those circulating systemically is unknown. Complement factor C3 is made in rheumatoid synovium and has been proposed to be a crucial driver of inflammation. The aim of this study was to test, in a mouse model of rheumatoid arthritis, whether C3 synthesized within the synovium is important in promoting inflammation. Methods. Radiation bone marrow chimeras between normal and C3−/− mice were constructed in order to generate animals that expressed or lacked expression of C3 only in hematopoietic cells. Parabiotic mice were made by surgically linking C3−/− mice to irradiated wild-type mice to obtain animals having C3 only in the circulation. Arthritis was induced by injection of serum from arthritic K/BxN mice.Results In bone marrow chimeras, synthesis of C3 by radioresistant cells was necessary and sufficient to confer susceptibility to serum-transferred arthritis. Parabionts having C3 only in the circulation remained sensitive to arthritis induction, and the cartilage of these arthritic mice contained deposits of C3. Conclusion. In a mouse model in which the alternative pathway of complement activation is critical to the induction of arthritis by autoantibodies, circulating C3 was necessary and sufficient for arthritis induction.Stem Cell and Regenerative Biolog

Development of the Infant Gut Microbiome Predicts Temperament Across the First Year of Life

Perturbations to the gut microbiome are implicated in altered neurodevelopmental trajectories that may shape life span risk for emotion dysregulation and affective disorders. However, the sensitive periods during which the microbiome may influence neurodevelopment remain understudied. We investigated relationships between gut microbiome composition across infancy and temperament at 12 months of age. In 67 infants, we examined if gut microbiome composition assessed at 1–3 weeks, 2, 6, and 12 months of age was associated with temperament at age 12 months. Stool samples were sequenced using the 16S Illumina MiSeq platform. Temperament was assessed using the Infant Behavior Questionnaire-Revised (IBQ-R). Beta diversity at age 1–3 weeks was associated with surgency/extraversion at age 12 months. Bifidobacterium and Lachnospiraceae abundance at 1–3 weeks of age was positively associated with surgency/extraversion at age 12 months. Klebsiella abundance at 1–3 weeks was negatively associated with surgency/extraversion at 12 months. Concurrent composition was associated with negative affectivity at 12 months, including a positive association with Ruminococcus-1 and a negative association with Lactobacillus. Our findings support a relationship between gut microbiome composition and infant temperament. While exploratory due to the small sample size, these results point to early and late infancy as sensitive periods during which the gut microbiome may exert effects on neurodevelopment

Contact with Caregivers is Associated with Composition of the Infant Gastrointestinal Microbiome in the First 6 Months of Life

Objectives Little is known about how physical contact at birth and early caregiving environments influence the colonization of the infant gastrointestinal microbiome. We investigated how infant contact with caregivers at birth and within the first 2 weeks of life relates to the composition of the gastrointestinal microbiome in a sample of U.S. infants (n = 60). Methods Skin-to-skin and physical contact with caregivers at birth and early caregiving environments were surveyed at 2 weeks postpartum. Stool samples were collected from infants at 2 weeks, 2, 6, and 12 months of age and underwent 16S rRNA sequencing as a proxy for the gastrointestinal microbiome. Associations between early caregiving environments and alpha and beta diversity, and differential abundance of bacteria at the genus level were assessed using PERMANOVA, and negative binomial mixed models in DEseq2. Results Time in physical contact with caregivers explained 10% of variation in beta diversity at 2 weeks\u27 age. The number of caregivers in the first few weeks of life explained 9% of variation in beta diversity at 2 weeks and the number of individuals in physical contact at birth explained 11% of variation in beta diversity at 6 months. Skin-to-skin contact on the day of birth was positively associated with the abundance of eight genera. Infants held for by more individuals had greater abundance of eight genera. Discussion Results reveal a potential mechanism (skin-to-skin and physical contact) by which caregivers influence the infant gastrointestinal microbiome. Our findings contribute to work exploring the social transmission of microbes

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

Optimal local implementation of non-local quantum gates

We investigate the minimal resources that are required in the local implementation of non-local quantum gates in a distributed quantum computer. Both classical communication requirements and entanglement consumption are investigated. We present general statements on the minimal resource requirements and present optimal procedures for a number of important gates, including CNOT and Toffoli gates. We show that one bit of classical communication in each direction is both necessary and sufficient for the non-local implementation of the quantum CNOT, while in general two bits in each direction is required for the implementation of a general two bit quantum gate. In particular, the state-swapper requires this maximum classical communication overhead. Extensions of these ideas to multi-party gates are presented.Comment: 7 pages, 5 figures; Replaced with published version, correcting minor typo

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one\u27s own body