Explore the vast range of titles available.

The highest density of microbes resides in human gastrointestinal tract, known as “Gut microbiome”. Of note, the members of the genus Lactobacillus that belong to phyla Firmicutes are the most important probiotic bacteria of the gut microbiome. These gut-residing Lactobacillus species not only communicate with each other but also with the gut epithelial lining to balance the gut barrier integrity, mucosal barrier defence and ameliorate the host immune responses. The human body suffers from several inflammatory diseases affecting the gut, lungs, heart, bone or neural tissues. Mounting evidence supports the significant role of Lactobacillus spp. and their components (such as metabolites, peptidoglycans, and/or surface proteins) in modulatingimmune responses, primarily through exchange of immunological signals between gastrointestinal tract and distant organs. This bidirectional crosstalk which is mediated by Lactobacillus spp. promotes anti-inflammatory response, thereby supporting the improvement of symptoms pertaining to asthma, chronic obstructive pulmonary disease (COPD), neuroinflammatory diseases (such as multiple sclerosis, alzheimer’s disease, parkinson’s disease), cardiovascular diseases, inflammatory bowel disease (IBD) and chronic infections in patients. The metabolic disorders, obesity and diabetes are characterized by a low-grade inflammation. Genus Lactobacillus alleviates metabolic disorders by regulating the oxidative stress response and inflammatory pathways. Osteoporosis is also associated with bone inflammation and resorption. The Lactobacillus spp. and their metabolites act as powerful immune cell controllers and exhibit a regulatory role in bone resorption and formation, supporting bone health. Thus, this review demonstrated the mechanisms and summarized the evidence of the benefit of Lactobacillus spp. in alleviating inflammatory diseases pertaining to different organs from animal and clinical trials. The present narrative review explores in detail the complex interactions between the gut-dwelling Lactobacillus spp. and the immune components in distant organs to promote host’s health.

p53, a tumor suppressor protein, has been proven to regulate the cell cycle, apoptosis, and DNA repair to prevent malignant transformation. MDM2 regulates activity of p53 and inhibits its binding to DNA. In the present study, we elucidated the MDM2 inhibition potential of polyphenols (Apigenin, Fisetin, Galangin and Luteolin) by MD simulation and MM/PBSA free energy calculations. All polyphenols bind to hydrophobic groove of MDM2 and the binding was found to be stable throughout MD simulation. Luteolin showed the highest negative binding free energy value of -173.80 kJ/mol followed by Fisetin with value of -172.25 kJ/mol. It was found by free energy calculations, that hydrophobic interactions (vdW energy) have major contribution in binding free energy.

Mapping biological processes in brain tissues requires piecing together numerous histological observations of multiple tissue samples. We present a direct method that generates readouts for a comprehensive panel of biomarkers from serial whole-brain slices, characterizing all major brain cell types, at scales ranging from subcellular compartments, individual cells, local multi-cellular niches, to whole-brain regions from each slice. We use iterative cycles of optimized 10-plex immunostaining with 10-color epifluorescence imaging to accumulate highly enriched image datasets from individual whole-brain slices, from which seamless signal-corrected mosaics are reconstructed. Specific fluorescent signals of interest are isolated computationally, rejecting autofluorescence, imaging noise, cross-channel bleed-through, and cross-labeling. Reliable large-scale cell detection and segmentation are achieved using deep neural networks. Cell phenotyping is performed by analyzing unique biomarker combinations over appropriate subcellular compartments. This approach can accelerate pre-clinical drug evaluation and system-level brain histology studies by simultaneously profiling multiple biological processes in their native anatomical context. It is challenging to map complex processes in brain tissue. Here the authors report a toolkit enabling large-scale multiplexed IHC and automated cell classification whereby they use a conventional epifluorescence microscope and deep neural networks to phenotype all major cell classes of the brain.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, manifests as accumulation of amyloid-beta-42 (Aβ42) plaques and intracellular accumulation of neurofibrillary tangles (NFTs) that results in microtubule destabilization. Targeted expression of human Aβ42 ( GMR  >  Aβ42 ) in developing Drosophila eye retinal neurons results in Aβ42 plaque(s) and mimics AD-like extensive neurodegeneration. However, there remains a gap in our understanding of the underlying mechanism(s) for Aβ42-mediated neurodegeneration. To address this gap in information, we conducted a forward genetic screen, and identified N-acetyltransferase 9 (Mnat9) as a genetic modifier of GMR > Aβ42 neurodegenerative phenotype. Mnat9 is known to stabilize microtubules by inhibiting c-Jun-N- terminal kinase (JNK) signaling. We found that gain-of-function of Mnat9 rescues GMR  >  Aβ42 mediated neurodegenerative phenotype whereas loss-of-function of Mnat9 exhibits the converse phenotype of enhanced neurodegeneration. Here, we propose a new neuroprotective function of Mnat9 in downregulating the JNK signaling pathway to ameliorate Aβ42-mediated neurodegeneration, which is independent of its acetylation activity. Transgenic flies expressing human NAT9 (hNAT9), also suppresses Aβ42-mediated neurodegeneration thereby suggesting functional conservation in the interaction of fly Mnat9 or hNAT9 with JNK-mediated neurodegeneration. These studies add to the repertoire of molecular mechanisms that mediate cell death response following accumulation of Aβ42 and may provide new avenues for targeting neurodegeneration.

Safe structures are the backbone of human coping capacity towards healthy living that can contribute significantly in reducing risk during hazards. However, due to various natural and anthropogenic activities, about 12.6% of land areas (excluding snow-covered area) in India are prone to landslide posing threat to life and property. Moreover, many structures in the hilly terrain of India are non-engineered which results in high vulnerability of buildings. Therefore, assessment of physical vulnerability is a fundamental step in reducing landslide risk. The study aims to present a methodology to assess vulnerability of the buildings using indicator-based approach at site-specific scale. Several studies to assess vulnerability of buildings due to landslides have been carried out by researchers from European countries. But these methodologies cannot be implemented successfully in India because of different geological and climatic condition. The different components of the discussed methodology for physical vulnerability of buildings exposed to landslides such as landslide intensity (a function of landslide velocity and volume) and resistance of buildings (a function of structural and non-structural features) are worked out and suggested by different researchers. However, putting them together, to present as a framework (specifically in Indian scenario) is the novelty of the present work. Further, consideration of the concept of ‘proximity of buildings to landslides’ in the process of site-specific vulnerability assessment is newly proposed. To address this issue, fifteen potential indicators contributing to vulnerability of buildings have been identified and a systematic form for documentation of data during field survey has also been prepared (keeping in view the construction bye-laws and techniques followed in India). The methodology discussed is further successfully implemented in ward number 10 of Gopeshwar Township (Chamoli District), Uttarakhand, India.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes. Epilepsy is a brain network disorder with associated genetic risk factors. Here, the authors show that spatial patterns of transcriptomic vulnerability co-vary with structural brain network alterations in focal and generalized epilepsy.

Background Mosquito-borne diseases threaten over half the world’s human population, making the need for environmentally-safe mosquito population control tools critical. The sterile insect technique (SIT) is a biological control method that can reduce pest insect populations by releasing a large number of sterile males to compete with wild males for female mates to reduce the number of progeny produced. Typically, males are sterilized using radiation, but such methods can reduce their mating competitiveness. The method is also most effective if only males are produced, but this requires the development of effective sex-sorting methods. Recent efforts to use transgenic methods to produce sterile male mosquitoes have increased interest in using SIT to control some of our most serious disease vectors, but the release of genetically modified mosquitoes will undoubtedly encounter considerable delays as regulatory agencies deal with safety issues and public concerns. Methods Testis genes in the dengue vector Aedes aegypti were identified using a suppression subtractive hybridization technique. Mosquito larvae were fed double-stranded RNAs (dsRNAs) that targeted both the testis genes and a female sex determination gene ( doublesex ) to induce RNA interference (RNAi) -mediated sterility and inhibition of female development. Fertility and mating competiveness of the treated males were assessed in small-scale mating competition experiments. Results Feeding mosquito larvae dsRNAs targeting testis genes produced adult males with greatly reduced fertility; several dsRNAs produced males that were highly effective in competing for mates. RNAi-mediated knockdown of the female-specific isoform of doublesex was also effective in producing a highly male-biased population of mosquitoes, thereby overcoming the need to sex-sort insects before release. Conclusions The sequence-specific gene-silencing mechanism of this RNAi technology renders it adaptable for species-specific application across numerous insect species. We envisage its use for traditional large-scale reared releases of mosquitoes and other pest insects, although the technology might also have potential for field-based control of mosquitoes where eggs deposited into a spiked larval site lead to the release of new sterile males.

The genome of Mycobacterium tuberculosis , the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca 2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism. IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease. Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.

The effectiveness of current treatments for opioid use disorder (OUD) varies by sex. Our understanding of the neurobiological mechanisms mediating negative states during withdrawal is lacking, particularly with regard to sex differences. Based on preclinical research in male subjects, opioid withdrawal is accompanied by increased gamma-aminobutyric acid (GABA) release probability at synapses onto dopamine neurons in the ventral tegmental area (VTA). It is unclear, however, if the physiological consequences of morphine that were originally elucidated in male rodents extend to females. The effects of morphine on the induction of future synaptic plasticity are also unknown. Here, we show that inhibitory synaptic long-term potentiation (LTP GABA ) is occluded in the VTA in male mice after repeated morphine injections and 1 day of withdrawal, while morphine-treated female mice maintain the ability to evoke LTP GABA and have basal GABA activity similar to controls. Our observation of this physiological difference between male and female mice connects previous reports of sex differences in areas upstream and downstream of the GABA-dopamine synapse in the VTA during opioid withdrawal. The sex differences highlight the mechanistic distinctions between males and females that can be targeted when designing and implementing treatments for OUD.

The human brain is divided into various anatomical regions that control and coordinate unique functions. The prefrontal cortex (PFC) is a large brain region that comprises a range of neuronal and non-neuronal cell types, sharing extensive interconnections with subcortical areas, and plays a critical role in cognition and memory. A timely appearance of distinct cell types through embryonic development is crucial for an anatomically perfect and functional brain. Direct tracing of cell fate development in the human brain is not possible, but single-cell transcriptome sequencing (scRNA-seq) datasets provide the opportunity to dissect cellular heterogeneity and its molecular regulators. Here, using scRNA-seq data of human PFC from fetal stages, we elucidate distinct transient cell states during PFC development and their underlying gene regulatory circuitry. We further identified that distinct intermediate cell states consist of specific gene regulatory modules essential to reach terminal fate using discrete developmental paths. Moreover, using in silico gene knock-out and over-expression analysis, we validated crucial gene regulatory components during the lineage specification of oligodendrocyte progenitor cells. Our study illustrates unique intermediate states and specific gene interaction networks that warrant further investigation for their functional contribution to typical brain development and discusses how this knowledge can be harvested for therapeutic intervention in challenging neurodevelopmental disorders.