Although all human tissues carry out common processes, tissues are distinguished by gene expression patterns, implying that distinct regulatory programs control tissue specificity. In this study, we ...investigate gene expression and regulation across 38 tissues profiled in the Genotype-Tissue Expression project. We find that network edges (transcription factor to target gene connections) have higher tissue specificity than network nodes (genes) and that regulating nodes (transcription factors) are less likely to be expressed in a tissue-specific manner as compared to their targets (genes). Gene set enrichment analysis of network targeting also indicates that the regulation of tissue-specific function is largely independent of transcription factor expression. In addition, tissue-specific genes are not highly targeted in their corresponding tissue network. However, they do assume bottleneck positions due to variability in transcription factor targeting and the influence of non-canonical regulatory interactions. These results suggest that tissue specificity is driven by context-dependent regulatory paths, providing transcriptional control of tissue-specific processes.
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•Regulatory network connections are more tissue specific than nodes (genes and transcription factors)•Tissue-specific function is not solely regulated by transcription factor expression•Tissue-specific genes assume bottleneck positions in their corresponding networks•Tissue specificity is driven by context-dependent, non-canonical regulatory paths
Understanding gene regulation is important for many fields in biology and medicine. Sonawane et al. reconstruct and investigate regulatory networks for 38 human tissues. They find that regulation of tissue-specific function is largely independent of transcription factor expression and that tissue specificity appears to be mediated by tissue-specific regulatory network paths.
Dietary proteins can influence the maturation of the immune system, particularly the gut-associated lymphoid tissue, when consumed from weaning to adulthood. Moreover, replacement of dietary proteins ...by amino acids at weaning has been shown to impair the generation of regulatory T cells in the gut as well as immune activities such as protective response to infection, induction of oral and nasal tolerance as well as allergic responses. Polymeric and elemental diets are used in the clinical practice, but the specific role of intact proteins and free amino acids during the intestinal inflammation are not known. It is plausible that these two dietary nitrogen sources would yield distinct immunological outcomes since proteins are recognized by the immune system as antigens and amino acids do not bind to antigen-recognition receptors but instead to intracellular receptors such as mammalian target of rapamycin (mTOR). In this study, our aim was to evaluate the effects of consumption of an amino acid-containing diet (AA diet) versus a control protein-containing diet in adult mice at steady state and during colitis development. We showed that consumption of a AA diet by adult mature mice lead to various immunological changes including decrease in the production of serum IgG as well as increase in the levels of IL-6, IL-17A, TGF-β, and IL-10 in the small and large intestines. It also led to changes in the intestinal morphology, to increase in intestinal permeability, in the number of total and activated CD4+ T cells in the small intestine as well as in the frequency of proliferating cells in the colon. Moreover, consumption of AA diet during and prior to development of dextran sodium sulfate-induced colitis exacerbated gut inflammation. Administration of rapamycin during AA diet consumption prevented colitis exacerbation suggesting that mTOR activation was involved in the effects triggered by the AA diet. Therefore, our study suggests that different outcomes can result from the use of diets containing either intact proteins or free amino acids such as elemental, semielemental, and polymeric diets during intestinal inflammation. These results may contribute to the design of nutritional therapeutic intervention for inflammatory bowel diseases.
The midfoot joint complex (MFJC) is related to the mechanics and efficiency of the walking propulsive phase and low midfoot passive stiffness may require compensatory foot and ankle joint moments to ...avoid excessive pronation and inefficient propulsion. This study aimed to investigate the kinematics and kinetics of the MFJC and ankle during the propulsive phase of walking in subjects with larger and smaller midfoot passive stiffness. MFJC passive stiffness of 20 healthy adult participants, and the kinematics and kinetics of the MFJC (forefoot-rearfoot) and ankle (rearfoot-shank) during the stance phase of walking were measured. The participants were divided equally into two groups according to the MFJC passive stiffness. Ranges of motion (ROM) and mean joint moments were computed for the late stance. Independent t-tests (α = 0.05) revealed that subjects with lower midfoot passive stiffness showed an increased MFJC sagittal ROM (flattened longitudinal arch) (p = 0.002), increased ankle frontal ROM (more everted positions) (p = 0.002), increased MFJC frontal ROM (more inverted positions) (p = 0.019), as well as a tendency for larger ankle sagittal ROM (p = 0.056). They also showed increased MFJC (p = 0.021) and ankle (p = 0.018) moments in the sagittal plane, increased MFJC moment in the frontal plane (p = 0.047) and a tendency for a predominant ankle moment in the frontal (p = 0.058). Foot and ankle joint moments are possible strategies to reduce pronation and improve propulsion, but not sufficient to prevent the altered kinematics related to low midfoot stiffness. Therefore, midfoot passive stiffness is critical for foot and ankle kinematics and kinetics during walking propulsive phase and is a potential target of interventions.
Although convincing experimental evidence indicates that Na
/K
/Cl
cotransporter 1 (NKCC1) is involved in spinal nociceptive information processing and in the generation of hyperalgesia and allodynia ...in chronic pain states, the cellular distribution of NKCC1 in the superficial spinal dorsal horn is still poorly understood. Because this important piece of knowledge is missing, the effect of NKCC1 on pain processing is still open to conflicting interpretations. In this study, to provide the missing experimental data, we investigated the cellular distribution of NKCC1 in the superficial spinal dorsal horn by immunohistochemical methods. We demonstrated for the first time that almost all spinal axon terminals of peptidergic nociceptive primary afferents express NKCC1. In contrast, virtually all spinal axon terminals of nonpeptidergic nociceptive primary afferents were negative for NKCC1. Data on the colocalization of NKCC1 with axonal and glial markers indicated that it is almost exclusively expressed by axon terminals and glial cells in laminae I-IIo. In lamina IIi, however, we observed a strong immunostaining for NKCC1 also in the dendrites and cell bodies of PV-containing inhibitory neurons and a weak staining in PKCγ-containing excitatory neurons. Our results facilitate further thinking about the role of NKCC1 in spinal pain processing.
The Pantanal region in South America is one of the world's largest wetlands. Since 2019, the Pantanal has suffered a prolonged drought that has spelled disaster for the region, and subsequent fires ...have engulfed hundreds of thousands of hectares. The lack of rainfall during the summers of 2019 and 2020 was caused by reduced transport of warm and humid summer air from Amazonia into the Pantanal. Instead, a predominance of warmer and drier air masses from subtropical latitudes contributed to a scarcity of summer rainfall at the peak of the monsoon season. This led to prolonged extreme drought conditions across the region. This drought had severe impacts on the hydrology of the Pantanal. Hydrometric levels fell all along the Paraguay River. In 2020, river levels reached extremely low values, and in some sections of this river, transportation had to be restricted. Very low river levels affected the mobility of people and shipping of soybeans and minerals to the Atlantic Ocean by the
Hidrovia -Paraná
-
Paraguai
(Paraná-Paraguay Waterway). This study is directed to better understand the hydroclimatic aspects of the current drought in the Brazilian Pantanal and their impacts on natural and human systems. As a consequence of the drought, fires spread and affected natural biodiversity as well as the agribusiness and cattle ranching sectors. While fires had serious socioecological and economic consequences, we do not intend to investigate the effect of the downstream low-level waters on the Pantanal ecosystems or the drought in the risk of fire.
•We investigated the antioxidant capacity of Lantana camara L. and Lantana montevidensis Briq.•Phenolic compounds were identified and quantified by HPLC-DAD.•The species exhibited strong antioxidant ...activity in assay systems: inhibition of production of thiobarbituric acid reactive substances (TBARS), iron-chelating activity, deoxyribose degradation and ferric-reducing antioxidant power (FRAP).
There is currently a growing interest of the industry to replace synthetic products by natural ones with bioactive properties. The aim of this work is the phytochemical analysis of phenolic compounds and antioxidant activities of Lantana camara and Lantana montevidensis. ethanolic extracts. Folin–Ciocalteu and aluminum chloride methods were used for the analysis of the phenolic compounds, checking higher concentrations in the extracts of the leaves of both species. Phenolic compounds such as quercetin, rutin, gallic acid, chlorogenicacid and caffeic acid were identified and quantified by HPLC-DAD. Antioxidant activity of these species was determined using assay systems: inhibition of production of thiobarbituric acid reactive substances (TBARS), iron-chelating activity, deoxyribose degradation and ferric-reducing antioxidant power (FRAP). The ethanolic extracts exhibited more antioxidant activity recording major activities in TBARS and FRAP, being more effective extracts of leaves toward the root extracts. The results suggest the potential use of L. camara and L. montevidensis for the treatment of several diseases due to its ability to act as an antioxidant.
Diazinon (DZN) is a broad-spectrum insecticide extensively used to control pests in crops and animals. Several investigators demonstrated that DZN produced tissue toxicity especially to the liver. In ...addition, the mitochondrion was implicated in DZN-induced toxicity, but the precise role of this organelle remains to be determined. The aim of this study was thus to examine the effects of DZN (50 to 150 μM) on the bioenergetics and mitochondrial permeability transition (MPT) associated processes in isolated rat liver mitochondria. DZN inhibited state-3 respiration in mitochondria energized with glutamate plus malate, substrates of complex I, and succinate, substrate of complex II of the respiratory chain and decreased the mitochondrial membrane potential resulting in inhibition of ATP synthesis. MPT was estimated by the extent of mitochondrial swelling, in the presence of 10 µM Ca
2+
. DZN elicited MPT in a concentration-dependent manner, via a mechanism sensitive to cyclosporine A, EGTA, ruthenium red and N-ethylmaleimide, which was associated with mitochondrial Ca
2+
efflux and cytochrome c release. DZN did not result in hydrogen peroxide accumulation or glutathione oxidation, but this insecticide oxidized endogenous NAD(P)H and protein thiol groups. Data suggest the involvement of mitochondria, via apoptosis, in the hepatic cytotoxicity attributed to DZN.
Infectious pancreatic necrosis virus (IPNV) is a non-enveloped virus belonging to the Birnaviridae family. IPNV produces an acute disease in salmon fingerlings, with high mortality rates and ...persistent infection in survivors. Although there are reports of IPNV binding to various cells, the viral receptor and entry pathways remain unknown. The aim of this study was to determine the endocytic pathway that allows for IPNV entry. We observed that IPNV stimulated fluid uptake and virus particles co-localysed with the uptake marker dextran in intracellular compartments, suggesting a role for macropinocytosis in viral entry. Consistent with this idea, viral infection was significantly reduced when the Na+/H+ exchanger NHE1 was inhibited with 5-(N-Ethyl-N-isopropyl) amiloride (EIPA). Neither chlorpromazine nor filipin complex I affected IPNV infection. To examine the role of macropinocytosis regulators, additional inhibitors were tested. Inhibitors of the EGFR pathway and the effectors Pak1, Rac1 and PKC reduced viral infection. Together, our results indicate that IPNV is mainly internalized into CHSE-214 cells by macropinocytosis.
Objective
The purpose of the study was to develop a novel diet based on standard AIN93G diet that would be able to induce experimental obesity and impair immune regulation with high concentrations of ...both carbohydrate and lipids.
Methods
To compare the effects of this high sugar and butter (HSB) diet with other modified diets, male C57BL/6 mice were fed either mouse chow, or AIN93G diet, or high sugar (HS) diet, or high-fat (HF) diet, or high sugar and butter (HSB) diet for 11 weeks ad libitum. HSB diet induced higher weight gain. Therefore, control AIN93G and HSB groups were chosen for additional analysis. Regulatory T cells were studied by flow cytometry, and cytokine levels were measured by ELISA.
Results
Although HF and HSB diets were able to induce a higher weight gain compatible with obesity in treated mice, HSB-fed mice presented the higher levels of serum glucose after fasting and the lowest frequency of regulatory T cells in adipose tissue. In addition, mice that were fed HSB diet presented higher levels of cholesterol and triglycerides, hyperleptinemia, increased resistin and leptin levels as well as reduced adiponectin serum levels. Importantly, we found increased frequency of CD4
+
CD44
+
effector T cells, reduction of CD4
+
CD25
+
Foxp3
+
and Th3 regulatory T cells as well as decreased levels of IL-10 and TGF-β in adipose tissue of HSB-fed mice.
Conclusion
Therefore, HSB represents a novel model of obesity-inducing diet that was efficient in triggering alterations compatible with metabolic syndrome as well as impairment in immune regulatory parameters.
Clostridium difficile is an important nosocomial pathogen that has become a major cause of antibiotic-associated diarrhea. There is a general consensus that C. difficile spores play an important role ...in C. difficile pathogenesis, contributing to infection, persistence, and transmission. Evidence has demonstrated that C. difficile spores have an outermost layer, termed the exosporium, that plays some role in adherence to intestinal epithelial cells. Recently, the protein encoded by CD1067 was shown to be present in trypsin-exosporium extracts of C. difficile 630 spores. In this study, we renamed the CD1067 protein Clostridium difficile exosporium cysteine-rich protein (CdeC) and characterized its role in the structure and properties of C. difficile spores. CdeC is expressed under sporulation conditions and localizes to the C. difficile spore. Through the construction of an ΔcdeC isogenic knockout mutant derivative of C. difficile strain R20291, we demonstrated that (i) the distinctive nap layer is largely missing in ΔcdeC spores; (ii) CdeC is localized in the exosporium-like layer and is accessible to IgGs; (iii) ΔcdeC spores were more sensitive to lysozyme, ethanol, and heat treatment than wild-type spores; and (iv) despite the almost complete absence of the exosporium layer, ΔcdeC spores adhered at higher levels than wild-type spores to intestinal epithelium cell lines (i.e., HT-29 and Caco-2 cells). Collectively, these results indicate that CdeC is essential for exosporium morphogenesis and the correct assembly of the spore coat of C. difficile.
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