AagingBase: a comprehensive database of anti-aging peptides.

The process of aging is an intrinsic and inevitable aspect of life that impacts every living organism. As biotechnological advancements continue to shape our understanding of medicine, peptide therapeutics have emerged as a promising strategy for anti-aging interventions. This is primarily due to their favorable attributes, such as low immunogenicity and cost-effective production. Peptide-based treatments have garnered widespread acceptance and interest in aging research, particularly in the context of age-related therapies. To effectively develop anti-aging treatments, a comprehensive understanding of the physicochemical characteristics of anti-aging peptides is essential. Factors such as amino acid composition, instability index, hydrophobic areas and other relevant properties significantly determine their efficacy as potential therapeutic agents. Consequently, the creation of 'AagingBase', a comprehensive database for anti-aging peptides, aims to facilitate research on aging by leveraging the potential of peptide therapies. AagingBase houses experimentally validated 282 anti-aging peptides collected from 54 research articles and 236 patents. Employing state-of-the-art computational techniques, the acquired sequences have undergone rigorous physicochemical calculations. Furthermore, AagingBase presents users with various informative analyses highlighting atomic compositions, secondary structure fractions, tertiary structure, amino acid compositions and frequencies. The database also offers advanced search and filtering options and similarity search, thereby aiding researchers in understanding their biological functions. Hence, the database enables efficient identification and prioritization of potential peptide candidates in geriatric medicine and holds immense potential for advancing geriatric medicine research and innovations. AagingBase can be accessed without any restriction. Database URL: https://project.iith.ac.in/cgntlab/aagingbase/.

Organelles are miscommunicating: Membrane contact sites getting hijacked by pathogens.

Membrane Contact Sites (MCS) are areas of close apposition of organelles that serve as hotspots for crosstalk and direct transport of lipids, proteins and metabolites. Contact sites play an important role in Ca2+ signalling, phospholipid synthesis, and micro autophagy. Initially, altered regulation of vesicular trafficking was regarded as the key mechanism for intracellular pathogen survival. However, emerging studies indicate that pathogens hijack MCS elements - a novel strategy for survival and replication in an intracellular environment. Several pathogens exploit MCS to establish direct contact between organelles and replication inclusion bodies, which are essential for their survival within the cell. By establishing this direct control, pathogens gain access to cytosolic compounds necessary for replication, maintenance, escaping endocytic maturation and circumventing lysosome fusion. MCS components such as VAP A/B, OSBP, and STIM1 are targeted by pathogens through their effectors and secretion systems. In this review, we delve into the mechanisms which operate in the evasion of the host immune system when intracellular pathogens hostage MCS. We explore targeting MCS components as a novel therapeutic approach, modifying molecular pathways and signalling to address the disease's mechanisms and offer more effective, tailored treatments for affected individuals.

p53 directly represses human LINE1 transposons.

p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5'UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.

Morphophysiological and biochemical response of mungbean [Vigna radiata (L.) Wilczek] varieties at different developmental stages under drought stress.

The present study was conducted to assess the morphophysiological and biochemical responses during different developmental stages in mungbean varieties subjected to drought stress, and to screen the varieties for drought tolerance. A field experiment was performed according to a completely randomized design on 25 mungbean varieties with 3 replicates per variety. Stress treatment was applied at 3 levels: control (no stress), vegetative stage (25 days after sowing), and reproductive stage (35 days after sowing). According to combined analysis of variance, there were significant effects from drought stress on relative water content (RWC), membrane stability index (MSI), protein and proline content of leaves, leaf area, plant height, and yield traits. MSI, RWC, protein content, leaf area, plant height, and yield traits were decreased during drought stress, while proline content was increased under drought stress conditions. The results showed that the vegetative stage was more sensitive to drought stress, which was further supported by correlation analysis. Taken together, Vigna sublobata, MCV-1, PLM-32, LGG-407, LGG-450, TM-96-2, and Sattya varieties were identified as drought tolerant as they maintained the higher values of RWC, MSI, protein, proline content, leaf area, plant height, and yield traits. These varieties could be used in breeding programs for better physiological drought tolerance traits.

Drosophila p53 directs nonapoptotic programs in postmitotic tissue.

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RErpr) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RErpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation-seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.

Transposons, p53 and Genome Security.

p53, the most commonly mutated tumor suppressor, is a transcription factor known to regulate proliferation, senescence, and apoptosis. Compelling studies have found that p53 may prevent oncogenesis through effectors that are unrelated to these canonical processes and recent findings have uncovered ancient roles for p53 in the containment of mobile elements. Together, these developments raise the possibility that some p53-driven cancers could result from unrestrained transposons. Here, we explore evidence linking conserved features of p53 biology to the control of transposons. We also show how p53-deficient cells can be exploited to probe the behavior of transposons and illustrate how unrestrained transposons incited by p53 loss might contribute to human malignancies.

Identification of genes associated with stress tolerance in moth bean [Vigna aconitifolia (Jacq.) Marechal], a stress hardy crop.

Moth bean is the most drought and heat tolerant cultigens among Asian Vigna. We performed comparative transcriptome analysis of moth bean cultivar "Marumoth" under control and stress condition. De novo transcriptome assembly was carried out by using Velvet followed by Oases softwares. Differential expression analyses, SSR identification and validation and mapping of pathways and transcription factors were conducted. A total of 179,979 and 201,888 reads were generated on Roche 454 platform and 48,617,205 and 45,449,053 reads were generated on ABI Solid platform for the control and stressed samples. Combined assembly from Roche and ABI Solid platforms generated 16,090 and 15,096 transcripts for control and stressed samples. We found 1287 SSRs and 5606 transcripts involved in 179 pathways. The 55 transcription factor families represented 19.42% of total mothbean transcripts. In expression profiling, ten transcripts were found to be up-regulated and 41 down-regulated while 490 showed no major change under moisture stress condition. Stress inducible genes like Catalase, Cyt P450 monooxygenase, heat shock proteins (HSP 90 and HSP 70), oxidoreductase, protein kinases, dehydration responsive protein (DRP), universal stress protein and ferridoxin NADH oxidoreductase genes were up-regulated in stressed sample. Genes which might be involved in moisture stress tolerance in moth bean were identified and these might be useful for stress tolerance breeding in moth bean and other related crops.

Retrotransposons Mimic Germ Plasm Determinants to Promote Transgenerational Inheritance.

Retrotransposons are a pervasive class of mobile elements present in the genomes of virtually all forms of life [1, 2]. In metazoans, these are preferentially active in the germline, which, in turn, mounts defenses that restrain their activity [3, 4]. Here we report that certain classes of retrotransposons ensure transgenerational inheritance by invading presumptive germ cells before they are formed. Using sensitized Drosophila and zebrafish models, we found that diverse classes of retrotransposons migrate to the germ plasm, a specialized region of the oocyte that prefigures germ cells and specifies the germline of descendants in the fertilized egg. In Drosophila, we found evidence for a "stowaway" model, whereby Tahre retroelements traffic to the germ plasm by mimicking oskar RNAs and engaging the Staufen-dependent active transport machinery. Consistent with this, germ plasm determinants attracted retroelement RNAs even when these components were ectopically positioned in bipolar oocytes. Likewise, vertebrate retrotransposons similarly migrated to the germ plasm in zebrafish oocytes. Together, these results suggest that germ plasm targeting represents a fitness strategy adopted by some retrotransposons to ensure transgenerational propagation.

The Mycobacterium tuberculosis protein pair PE9 (Rv1088)-PE10 (Rv1089) forms heterodimers and induces macrophage apoptosis through Toll-like receptor 4.

Toll-like receptor (TLR)-mediated interactions of Mycobacterium tuberculosis (M. tb) with macrophages are major determinant in the outcome of innate immune defence and subsequent adaptive immune responses. Here we report a novel interaction of the M. tb protein pair PE9 (Rv1088)-PE10 (Rv1089) with the macrophage TLR4 leading to apoptosis and modulation of cytokine levels. We demonstrate that the two proteins physically interact, and that PE9 is required for the cell wall localization of PE10 in Mycobacterium smegmatis. Interaction of the PE9-PE10 complex with TLR4 in THP-1 macrophages was associated with increased levels of phospho-IRF-3, which correlated with an increase in transcript levels of its target gene interferon-ß. THP-1 macrophages treated with PE9-PE10 complex showed multiple hallmarks of apoptosis and modulation of interleukin (IL)-1b and IL-10 levels. All of these effects were abrogated when cells were treated either with an antibody to PE10 or an anti-TLR4 antibody, indicating that the complex specifically interacts with TLR4 through PE10, establishing this protein pair as a TLR4 ligand. This novel observation of two proline-glutamate (PE) proteins forming functional heterodimers represents a considerable expansion of the PE_PPE repertoire in the context of receptor engagement and the concomitant modulation of host responses by this unique class of proteins.

An immunomodulatory role for the Mycobacterium tuberculosis region of difference 1 locus proteins PE35 (Rv3872) and PPE68 (Rv3873).

The pathogenesis of Mycobacterium tuberculosis involves the coordinate action of multiple bacillary components that modulate host immune responses to ensure its survival. One such group of factors is the multigenic PE_PPE protein family, several members of which have been implicated in host immune evasion. Here we investigate the function of the PE-PPE gene pair PE35 (Rv3872)-PPE68 (Rv3873), located in the region of difference 1, encoding a specialized mycobacterial secretion system that is deleted in all vaccine strains of Mycobacterium bovis BCG. We report that this gene pair is co-operonic in M. tuberculosis, and demonstrate that its gene products interact with each other. Stimulation of THP-1 macrophages with recombinant PE35 and PPE68, singly or in combination, led to a dose-dependent increase in levels of the anti-inflammatory cytokine interleukin (IL)-10 and the chemokine monocyte chemoattractant protein-1, and caused a reciprocal decrease in levels of the proinflammatory cytokine IL-12. PE35/PPE68-stimulated production of IL-10 and monocyte chemoattractant protein-1 was observed to be dependent on toll-like receptor 2, as receptor blockade caused a significant reduction in their levels. Pharmacological inhibition indicated that this induction involved activation of the mitogen-activated protein kinase signalling axis. In a transwell migration assay, culture supernatants from PE35/PPE68-treated THP-1 cells were observed to stimulate the migration of monocytes. Our findings suggest that the PE35-PPE68 gene pair plays an important immunomodulatory role in regulating the pathophysiology of M. tuberculosis. STRUCTURED DIGITAL ABSTRACT: TLR2 physically interacts with PPE68 by anti bait coimmunoprecipitation (View interaction) PE35 binds to PPE68 by pull down (View interaction) PE35 physically interacts with PPE68 by anti tag coimmunoprecipitation (View interaction) TLR2 physically interacts with PE35 by anti bait coimmunoprecipitation (View interaction) PPE68 and PE35 physically interact by dihydrofolate reductase reconstruction (View interaction).

The Mycobacterium tuberculosis PE proteins Rv0285 and Rv1386 modulate innate immunity and mediate bacillary survival in macrophages.

The unique PE/PPE multigene family of proteins occupies almost 10% of the coding sequence of Mycobacterium tuberculosis (M.tb), the causative agent of human tuberculosis. Although some members of this family have been shown to be involved in pathways essential to M.tb pathogenesis, their precise physiological functions remain largely undefined. Here, we investigate the roles of the conserved members of the 'PE only' subfamily Rv0285 (PE5) and Rv1386 (PE15) in mediating host-pathogen interactions. Recombinant Mycobacterium smegmatis strains expressing PE5 and PE15 showed enhanced survival vs controls in J774.1 and THP-1 macrophages - this increase in viable counts was correlated with a reduction in transcript levels of inducible nitric oxide synthase. An up-regulation of anti- and down-regulation of pro-inflammatory cytokine levels was also observed in infected macrophages implying an immuno-modulatory function for these proteins. Induction of IL-10 production upon infection of THP-1 macrophages was associated with increased phosphorylation of the MAP Kinases p38 and ERK1/2, which was abolished in the presence of the pharmacological inhibitors SB203580 and PD98059. The PE5-PPE4 and PE15-PPE20 gene pairs were observed to be co-operonic in M.tb, hinting at an additional level of complexity in the functioning of these proteins. We conclude that M.tb exploits the PE proteins to evade the host immune response by altering the Th1 and Th2 type balance thereby favouring in vivo bacillary survival.