Bacteroides is increased in an autism cohort and induces autism-relevant behavioral changes in mice in a sex-dependent manner.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition which is defined by decreased social communication and the presence of repetitive or stereotypic behaviors. Recent evidence has suggested that the gut-brain axis may be important in neurodevelopment in general and may play a role in ASD in particular. Here, we present a study of the gut microbiome in 96 individuals diagnosed with ASD in Israel, compared to 42 neurotypical individuals. We determined differences in alpha and beta diversity in the microbiome of individuals with ASD and demonstrated that the phylum Bacteroidetes and genus Bacteroides were the most significantly over-represented in individuals with ASD. To understand the possible functional significance of these changes, we treated newborn mice with Bacteroides fragilis at birth. B. fragilis-treated male mice displayed social behavior dysfunction, increased repetitive behaviors, and gene expression dysregulation in the prefrontal cortex, while female mice did not display behavioral deficits. These findings suggest that overabundance of Bacteroides, particularly in early life, may have functional consequences for individuals with ASD.

Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.

Heparanase accelerates the proliferation of both hepatocytes and endothelial cells early after partial hepatectomy.

BACKGROUND AND AIMS: Heparanase (HPSE) is an endo-ß-D-glucuronidase, which cleaves heparan sulfate in the extracellular matrix (ECM) and has pro-angiogenic and pro-proliferative properties. The aim of this investigation was to study the effect of HPSE on hepatocytes and endothelial cells (EC) during liver regeneration. METHODS: Following 70% hepatectomy (PHP), rats were injected daily with 1-50µg HPSE/rat. Liver samples were stained with H&E and anti-bromodeoxyuridine (BrdU) antibody. mRNAs of hepatocyte growth factor (HGF), stem cell factor, tumor necrosis factor (TNF)-α, interleukin(IL)-6, and cyclinD1 were tested by real-time qPCR. Matrix metalloproteinases (MMPs) were tested by gel zymography. RESULTS: Compared to the saline control, HPSE increased hepatocyte proliferation 24h, 48h and 72h after PHP, with the maximal effect found at 24h with 50µg HPSE (40.9±2.5% vs. 8.6±4.3%, p<0.01 for BrdU staining; 5.5±0.9% vs. 0.8±0.5%, p<0.05 for mitosis). Proliferation of the sinusoidal and the portal vein radical ECs was also increased (p<0.05). HPSE caused a twofold increase in cyclinD1 mRNA (p<0.05) and in pro-MMP-9 levels (p<0.05). HPSE at all doses also caused significant reductions of TNF-α mRNA (p<0.05) and IL-6 mRNA, and no change in HGF mRNA. CONCLUSIONS: HPSE enhances liver regeneration by inducing proliferation of hepatocytes and both sinusoidal and vascular ECs. Since the effect of HPSE on hepatocytes occurred earlier than that observed in ECs, this effect is not related to HPSE's effect on ECs. The mechanism of HPSE action is probably indirect and is mediated by HPSE-dependent ECM cleavage and the release of pre-existing enzymes.

Differential expression of small heat shock protein genes Hsp23 and Hsp40, and heat shock gene Hsr-omega in fruit flies (Drosophila melanogaster) along a microclimatic gradient.

We examined the role of small Hsp genes (Hsp23 and Hsp40) and heat shock gene Hsr-omega in the thermoadaptation of Drosophila melanogaster inhabiting a highly heterogeneous microsite (Nahal Oren canyon, Carmel massif, Israel). We tested whether interslope differences in Drosophila thermoadaptation, revealed in our previous studies, are associated with the differential expression of these genes. Our results demonstrate an increased expression of the Hsp40 gene in thermotolerant lines subjected to mild heat shock treatment (P < 10(-6), analysis of variance test). A high positive correlation was found between the levels of Hsp40 expression and scores of basal (R = 0.74; P < 0.001, based on the Spearman rank correlation test) and induced thermotolerance (R = 0.78; P < 0.0001), implying a significant contribution of Hsp40 gene in thermoadaptation.

Cellularized biosynthetic microhydrogel polymers for intravascular liver tissue regeneration therapy.

INTRODUCTION: The liver is the natural microenvironment for hepatocytes transplantation but unfortunately engraftment efficiency is low. Cell-laden microhydrogels made of fibrinogen attached to poly(ethylene glycol) (PEG)-diacrylate side chains, were used as a cell carrier, for intravascular transplantation. This approach may reduce shear stress and immediate immunological pressure after intravascular transplantation and provide biomatrix for environmental support. AIMS: In vitro assessment of HuH-7 viability and function after polymerization within PEGylated fibrinogen-hydrogel. In vivo assessment of intraportal transplantation of cell-laden microhydrogels with rat adult parenchymal cells. METHODS: (1) In vitro assessment of HuH-7 cell viability and function, after cell-laden hydrogel (hydrogel volume 30 µL) fabrication, by propidium iodide (PI)/fluorescein diacetate (FDA), and MTT assays, albumin concentration and CYP1A activity. (2) Fabrication of cell-laden microhydrogels and their intraportal transplantion. Engraftment efficiency in vivo was evaluated by real-time qPCR of Y chromosome (SRY gene) and histology. RESULTS: The viability of cells in hydrogels in culture was comparable to viability of not embedded cells during the first 48 h. However, the viability of cells in hydrogels was reduced after 72 h compared with not embedded cells. Activity of CYP1A in hydrogel was comparable to that of not embedded cells (4.33±1 pmole/µg DNA/4 h vs. 5.13±1 pmole/µg DNA/4 h, respectively). Albumin concentration increased at day 3 in hydrogels to 1.4±0.6 µg/10(4)/24 h and was greater to that of free cells, 0.3±0.1 µg/10(4)/24 h. Cell-laden microhydrogels at a size of 150-150-600 µm (6×10(6) cells/rat) showed better engraftment efficiency at 21 days post-transplantation, compared with isolated cell transplantation (54.6%±5% vs. 1.8%±1.2%, p<0.001). CONCLUSIONS: The in vitro HuH-7 viability and function after polymerization in PEGylated fibrinogen hydrogel was comparable to cells without the hydrogel. Long-term survival and engraftment efficiency of intravascular transplanted adult hepatocytes is much better in within cell-laden microhydrogels compared with isolated cells. The overall efficiency of the procedure needs to be improved.

Activity of lung neutrophils and matrix metalloproteinases in cyclophosphamide-treated mice with experimental sepsis.

Sepsis in patients receiving chemotherapy may result in acute respiratory distress syndrome, despite decreased number of blood neutrophils [polymorphonuclear neutrophils (PMNs)]. In the present study, we investigated the correlation of cyclophosphamide (CY)-induced neutropenia with the destructive potential of lung PMN in respect to formation of septic acute lung injury (ALI). Mice were treated with 250 mg/kg of CY or saline (control) and subjected to cecal ligation and puncture (CLP) or sham operation. ALI was verified by histological examination. Lung PMNs and matrix metalloproteinases (MMPs) were assessed by flow cytometry and gelatin zymography. CLP in CY-treated mice induced a typical lung injury. Despite profound neutropenia, CY treatment did not attenuate CLP-induced ALI. This might relate to only a partial suppression of PMN: CY has significantly reduced PMN influx into the lungs (P = 0.008) and suppressed their oxidative metabolism, but had no suppressive effect on degranulation (P = 0.227) and even induced MMP-9 activity (P = 0.0003). In CY-untreated animals, peak of CLP-induced ALI coincided with massive PMN influx (P = 0.013), their maximal degranulation (P = 0.014) and activation of lung MMP-9 (P = 0.002). These findings may indicate an important role of the residual lung PMN and activation of MMP-9 in septic lung injury during CY chemotherapy.