The emerging role of PI3K inhibitors for solid tumour treatment and beyond.

Phosphoinositide 3-kinases (PI3Ks) play a central role in tumourigenesis with recurrent activating mutations of its p110α subunit (PIK3CA) identified in several tumours. Although several PI3K inhibitors are approved for haematological malignancies, only alpelisib was approved in solid tumours and for the treatment of PIK3CA-related overgrowth spectrum (PROS) syndrome. Traditional PI3K inhibitors inhibit both wild-type and mutant PI3K with almost equal potency, thus limiting their efficacy due to on-target toxicity. Since the initiation of phase I clinical trials investigating next generation allosteric mutant and isoform selective PIK3CA inhibitors, there has been a surge in interest in PIK3CA targeting in solid tumours. Preclinical characterisation of these compounds showed that maximal mutant protein inhibition fails to elicit metabolic and glucose homoeostasis dysregulation, one of the dose limiting toxicities of both selective and pan PI3K inhibitors. While extreme selectivity can be hypothesised to grant activity and safety advantage to these novel agents, on the other hand reduced benefit can be speculated for patients harbouring multiple or rare PIK3CA mutations. This review summarises the current understanding of PI3K alterations and the state-of-the-art treatment strategies in PI3K driven solid tumours, while also exploring the potential intrinsic and acquired resistance mechanisms to these agents, and the emerging role of mutant selective PIK3CA inhibitors.

The PCOS-NAFLD Multidisease Phenotype Occurred in Medaka Fish Four Generations after the Removal of Bisphenol A Exposure.

As a heterogeneous reproductive disorder, polycystic ovary syndrome (PCOS) can be caused by genetic, diet, and environmental factors. Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease (NAFLD) due to direct exposure; however, whether these phenotypes persist in future unexposed generations is not currently understood. In a previous study, we observed that transgenerational NAFLD persisted in female medaka for five generations (F4) after exposure to an environmentally relevant concentration (10 µg/L) of BPA. Here, we demonstrate PCOS in the same F4 generation female medaka that developed NAFLD. The ovaries contained immature follicles, restricted follicular progression, and degenerated follicles, which are characteristics of PCOS. Untargeted metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage fish, whereas transcriptomic analysis revealed 292 genes abnormally expressed, which were similar to human patients with PCOS. Metabolomic-transcriptomic joint pathway analysis revealed activation of the cancerous pathway, arginine-proline metabolism, insulin signaling, AMPK, and HOTAIR regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results suggest that ancestral BPA exposure can lead to PCOS phenotypes in the subsequent unexposed generations and warrant further investigations into potential health risks in future generations caused by initial exposure to EDCs.

Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson's Disease.

Neurological ailments, including stroke, Alzheimer's disease (AD), epilepsy, Parkinson's disease (PD), and other related diseases, have affected around 1 billion people globally to date. PD stands second among the common neurodegenerative diseases caused as a result of dopaminergic neuron loss in the midbrain's substantia nigra regions. It affects cognitive and motor activities, resulting in tremors during rest, slow movement, and muscle stiffness. There are various traditional approaches for the management of PD, but they provide only symptomatic relief. Thus, a survey for finding new biomolecules or substances exhibiting the therapeutic potential to patients with PD is the main focus of present-day research. Medicinal plants, herbal formulations, and natural bioactive molecules have been gaining much more attention in recent years as synthetic molecules orchestrate a number of undesired effects. Several in vitro, in vivo, and in silico studies in the recent past have demonstrated the therapeutic potential of medicinal plants, herbal formulations, and plant-based bioactives. Among the plant-based bioactives, polyphenols, terpenes, and alkaloids are of particular interest due to their potent anti-inflammatory, antioxidant, and brain-health-promoting properties. Further, there are no concise, elaborated articles comprising updated mechanism-of-action-based reviews of the published literature on potent, recently investigated (2019-2023) medicinal plants, herbal formulations, and plant based-bioactive molecules, including polyphenols, terpenes, and alkaloids, as a method for the management of PD. Therefore, we designed the current review to provide an illustration of the efficacious role of various medicinal plants, herbal formulations, and bioactives (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host. This information can be further utilized in the future to develop several value-added formulations and nutraceutical products to achieve the desired safety and efficacy for the management of PD.

Is histopathological examination of sleeve gastrectomy specimens necessary in areas endemic for gastric cancer?

Background: The value of histopathological examination of a laparoscopic sleeve gastrectomy (LSG) specimen in areas endemic for Helicobacter pylori (H. pylori) and gastric cancer is not known. We assessed the histopathological findings of LSG specimens to determine whether routine histopathological examination of these would be useful in patients with normal preoperative upper gastrointestinal endoscopy findings in an area endemic for gastric cancer. Methods: We did a retrospective analysis of the histopathological findings of LSG specimens in patients who underwent the procedure between March 2015 and March 2017. We ascertained the association of positive histopathological findings with the clinical profile of patients and preoperative upper gastrointestinal endoscopy findings. Results: Twenty-six patients (16 females) with a mean age of 37.5 years underwent LSG during the study period. On preoperative upper gastrointestinal endoscopy, 18 patients had unremarkable findings. Of the three patients with gastric or duodenal erosions on upper gastrointestinal endoscopy, two had H. pylori infection. On histopathological examination, 14 patients had unremarkable findings. Chronic gastritis with or without follicle formation was the most common finding (n=7). None of the patients with normal upper gastrointestinal endoscopy findings had significant histopathological findings or evidence of H. pylori infection. No significant association was found between age, gender, body mass index, smoking and alcohol intake with positive histopathological findings (p=0.64, 0.91, 0.90, 0.10 and 0.94, respectively). Conclusions: We did not find clinically important histopathological findings on routine examination of the LSG specimen in bariatric patients with normal preoperative upper gastrointestinal endoscopy findings.

Evaluation of some in vitro probiotic properties of Lactobacillus fermentum Strains.

This study aimed to check the in vitro probiotic properties of eleven Lactobacillus fermentum strains previously isolated from fermented dairy products and infant faeces. These cultures were tested for their tolerance to different pH such as 2.0, 2.5, 3.0, 3.5 and 6.5, bile salt hydrolysis and cell surface hydrophobicity. All the strains were persistent at pH 3.5 for 3 h whereas only faecal origin isolates such as L. fermentum BIF-19, BIF-20, BIF-18 and MTCC 8711 had shown considerable growth at pH 2.5. The strains NCDC-400, MTCC 8711, BIF-18, BIF-19 and BIF-20 showed slight to intense precipitation zone of bile salt hydrolase activity by agar plate assay. The strain L. fermentum BIF-19 exhibited best preliminary probiotic properties was selected for the adhesion to Caco-2 cell lines, which shows similar adhesion to that observed for standard probiotic Lactobacillus rhamnosus GG.

Heterogeneous CD3 expression levels in differing T cell subsets correlate with the in vivo anti-CD3-mediated T cell modulation.

The tolerogenic anti-CD3ε monoclonal Abs (anti-CD3) are promising compounds for the treatment of type 1 diabetes. Anti-CD3 administration induces transient T cell depletion both in preclinical and in clinical studies. Notably, the said depletion mainly affects CD4(+) but not CD8(+) T cells. Moreover, type 1 diabetes reversal in preclinical models is accompanied by the selective expansion of CD4(+)Foxp3(+) T regulatory (Treg) cells, which are fundamental for the long-term maintenance of anti-CD3-mediated tolerance. The mechanisms that lead to this immune-shaping by affecting mainly CD4(+) T effector cells while sparing CD4(+)Foxp3(+) Treg cells have still to be fully elucidated. This study shows that CD3 expression levels differ from one T cell subset to another. CD4(+)Foxp3(-) T cells contain higher amounts of CD3 molecules than do CD4(+)Foxp3(+) and CD8(+) T cells in both mice and humans. The said differences correlate with the anti-CD3-mediated immune resetting that occurs in vivo after anti-CD3 administration in diabetic NOD mice. Additionally, transcriptome analysis demonstrates that CD4(+)Foxp3(+) Treg cells are significantly less responsive than are CD4(+)Foxp3(-) T cells to anti-CD3 treatment at a molecular level. Thus, heterogeneity in CD3 expression seems to confer to the various T cell subsets differing susceptibility to the in vivo tolerogenic anti-CD3-mediated modulation. These data shed new light on the molecular mechanism that underlies anti-CD3-mediated immune resetting and thus may open new opportunities to improve this promising treatment.

Dynamic regulation of the transcription initiation landscape at single nucleotide resolution during vertebrate embryogenesis.

Spatiotemporal control of gene expression is central to animal development. Core promoters represent a previously unanticipated regulatory level by interacting with cis-regulatory elements and transcription initiation in different physiological and developmental contexts. Here, we provide a first and comprehensive description of the core promoter repertoire and its dynamic use during the development of a vertebrate embryo. By using cap analysis of gene expression (CAGE), we mapped transcription initiation events at single nucleotide resolution across 12 stages of zebrafish development. These CAGE-based transcriptome maps reveal genome-wide rules of core promoter usage, structure, and dynamics, key to understanding the control of gene regulation during vertebrate ontogeny. They revealed the existence of multiple classes of pervasive intra- and intergenic post-transcriptionally processed RNA products and their developmental dynamics. Among these RNAs, we report splice donor site-associated intronic RNA (sRNA) to be specific to genes of the splicing machinery. For the identification of conserved features, we compared the zebrafish data sets to the first CAGE promoter map of Tetraodon and the existing human CAGE data. We show that a number of features, such as promoter type, newly discovered promoter properties such as a specialized purine-rich initiator motif, as well as sRNAs and the genes in which they are detected, are conserved in mammalian and Tetraodon CAGE-defined promoter maps. The zebrafish developmental promoterome represents a powerful resource for studying developmental gene regulation and revealing promoter features shared across vertebrates.

Age-related changes in the brain antioxidant status: modulation by dietary supplementation of Decalepis hamiltonii and physical exercise.

The synergistic effects of physical exercise and diet have profound benefits on brain function. The present study was aimed to determine the effects of exercise and Decalepis hamiltonii (Dh) on age-related responses on the antioxidant status in discrete regions of rat brain. Male Wistar albino rats of 4 and 18 months old were orally supplemented with Dh extract and swim trained at 3 % intensity for 30 min/day, 5 days/week, for a period of 30 days. Supplementation of 100 mg Dh aqueous extract/kg body weight and its combination with exercise significantly elevated the antioxidant enzyme activities irrespective of age. Age-related and region-specific changes were observed in superoxide levels, and protein carbonyl and malondialdehyde contents, and were found to be decreased in both trained and supplemented groups. Levels of total thiols, protein, and nonprotein thiols decreased with age and significantly increased in the SW-T(+100 mg) groups. Our results demonstrated that the interactive effects of two treatments enhanced the antioxidant status and decreased the risk of protein and lipid oxidation in the rat brain.

Direct ChIP-Seq significance analysis improves target prediction.

BACKGROUND: Chromatin immunoprecipitation followed by sequencing of protein-bound DNA fragments (ChIP-Seq) is an effective high-throughput methodology for the identification of context specific DNA fragments that are bound by specific proteins in vivo. Despite significant progress in the bioinformatics analysis of this genome-scale data, a number of challenges remain as technology-dependent biases, including variable target accessibility and mappability, sequence-dependent variability, and non-specific binding affinity must be accounted for. RESULTS AND DISCUSSION: We introduce a nonparametric method for scoring consensus regions of aligned immunoprecipitated DNA fragments when appropriate control experiments are available. Our method uses local models for null binding; these are necessary because binding prediction scores based on global models alone fail to properly account for specialized features of genomic regions and chance pull downs of specific DNA fragments, thus disproportionally rewarding some genomic regions and decreasing prediction accuracy. We make no assumptions about the structure or amplitude of bound peaks, yet we show that our method outperforms leading methods developed using either global or local null hypothesis models for random binding. We test prediction performance by comparing analyses of ChIP-seq, ChIP-chip, motif-based binding-site prediction, and shRNA assays, showing high reproducibility, binding-site enrichment in predicted target regions, and functional regulation of predicted targets. CONCLUSIONS: Given appropriate controls, a direct nonparametric method for identifying transcription-factor targets from ChIP-Seq assays may lead to both higher sensitivity and higher specificity, and should be preferred or used in conjunction with methods that use parametric models for null binding.

Food protein-derived bioactive peptides in management of type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D), one of the major common human health problems, is growing at an alarming rate around the globe. Alpha-glucosidase and dipeptidyl peptidase IV (DPP-IV) enzymes play a significant role in development of T2D. Hence, reduction or inhibition of their activity can be one of the important strategies in management of T2D. Studies in the field of bioactive peptides have shown that dietary proteins could be natural source of alpha-glucosidase and DPP-IV inhibitory peptides. PURPOSE: The purpose of this review is to provide an overview of food protein-derived peptides as potential inhibitors of alpha-glucosidase and DPP-IV with major focus on milk proteins. METHODS: Efforts have been made to review the available information in literature on the relationship between food protein-derived peptides and T2D. This review summarizes the current data on alpha-glucosidase and dipeptidyl peptidase IV inhibitory bioactive peptides derived from proteins and examines the potential value of these peptides in the treatment and prevention of T2D. In addition, the proposed modes of inhibition of peptide inhibitors are also discussed. RESULTS: Studies revealed that milk and other food proteins-derived bioactive peptides play a vital role in controlling T2D through several mechanisms, such as the satiety response, regulation of incretin hormones, insulinemia levels, and reducing the activity of carbohydrate degrading digestive enzymes. CONCLUSIONS: The bioactive peptides could be used in prevention and management of T2D through functional foods or nutraceutical supplements. Further clinical trials are necessary to validate the findings of in vitro studies and to confirm the efficiency of these peptides for applications.

A high-resolution anatomical atlas of the transcriptome in the mouse embryo.

Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.

Sex-specific expression of the human NAFLD-NASH transcriptional signatures in the liver of medaka with a history of ancestral bisphenol A exposure.

The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish who were not directly exposed but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% DEGs were downregulated and 20% DEGs were upregulated. Off all DEGs, 52.31% DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.

A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain.

The transient receptor potential (TRP) superfamily of ion channels in humans comprises voltage-gated, non-selective cation channels expressed both in excitable as well as non-excitable cells. Four TRP channel subunits associate to create functional homo- or heterotetramers that allow the influx of calcium, sodium, and/or potassium. These channels are highly abundant in the brain and kidney and are important mediators of diverse biological functions including thermosensation, vascular tone, flow sensing in the kidney and irritant stimuli sensing. Inherited or acquired dysfunction of TRP channels influences cellular functions and signaling pathways resulting in multifaceted disorders affecting skeletal, renal, cardiovascular, and nervous systems. Studies have demonstrated the involvement of these channels in the generation and transduction of pain. Based on the multifaceted role orchestrated by these TRP channels, modulation of the activity of these channels presents an important strategy to influence cellular function by regulating intracellular calcium levels as well as membrane excitability. Therefore, there has been a remarkable pharmaceutical inclination toward TRP channels as therapeutic interventions. Several candidate drugs influencing the activity of these channels are already in the clinical trials pipeline. The present review encompasses the current understanding of TRP channels and TRP modulators in pain and pain management.

Knowledge, attitude, and perception of dental undergraduates towards mobile and digital learning methods in India: A cross-sectional study.

BACKGROUND: Internet-based education is having few advantages since it increases an emphasis on the education system based on problems by incorporation of both visual as well as interactive tools. Also, some contributions to practical skills can be made using pictorial as well as video-based knowledge. The present study aimed to assess the knowledge, attitude, and perception of dental undergraduates towards mobile and digital learning methods in India. MATERIALS AND METHODS: This was a cross-sectional questionnaire-based study conducted after obtaining Institutional Ethical Review Board permission. Before commencing the study, the purpose of the study was explained to the study participants and written informed consent was obtained. About 200 undergraduate students of dentistry in a single institution were selected as a convenient sample. Information obtained from responses was entered into an Excel sheet (Microsoft Corporation) and was further analyzed. Data collection was done for a period of one month. Statistical analysis: Obtained data were recorded and subjected to statistical analysis by use of statistical SPSS software (version 20.0, IBM). Descriptive statistical data were recorded as frequencies or percentages. Chi-square statistical test was used for the assessment of responses obtained from dental undergraduate students. The level of significance was fixed at a probability of <0.05. RESULTS AND OBSERVATIONS: On statistically analyzing, 99% of students were found to possess knowledge regarding the use of mobile phones for digital education. A good statistical correlation was obtained between attitude and perception regarding accessing digital learning using mobile phones. CONCLUSION: In the present study, good knowledge, attitude, and perception regarding the use of digital learning using phones were found among Indian dental undergraduates.

Effects of Yoga therapy in teaching oral hygiene practice and tooth brushing skills in patients with Parkinson's disease: A qualitative study.

BACKGROUND: Parkinson's disease is a chronic neurodegenerative disorder associated with heterogeneous symptoms. Though it is characterized by means of four distinct motor symptoms such as resting tremors, muscular rigidity, bradykinesia, and postural instability. These patients also have deficits in fine motor skills while performing simple tasks such as brushing their own teeth, taking bath, remembering small details, and writing skills. The study aimed to qualitatively evaluate the effectiveness of Yoga therapy in teaching oral hygiene practice and subsequently, on tooth brushing skills in patients who were diagnosed with Parkinson's disease. MATERIALS AND METHODS: This qualitative study was conducted on 100 patients diagnosed with Parkinson's disease. Institutional ethical committee permission was obtained prior to commencing the study. Written informed consent was obtained from patients or their caregivers before conducting this study. Detailed clinical history was recorded and gender characteristics were noted down. In the present study, there were 67 female and 33 male participants. Yoga exercises were taught to Parkinson's patients by a qualified yoga instructor. Improvements in toothbrushing skills were noted down by a single operator and oral hygiene status was analyzed using gingival index and plaque index on follow-up durations at 1, 2, 3, and 6 months. Yoga exercises comprised of warming up, stretching, yoga breathing exercises or pranayama, and/or relaxation process. Statistical analysis was performed by use of IBM SPSS Version 20.0. (IBM Corp., Armonk, NY) software designed for Windows. Intra-group comparison between categorical variables was done by statistical test-paired student 't-test'. RESULTS: On comparing plaque indices, the mean ± SD plaque index at 1st, 2nd, 3rd, and 6th months were 1.89 ± 0.02, 1.72 ± 0.01, 1.42 ± 0.12, and 0.56 ± 0.02, respectively. Mean ± SD gingival index scores at 1st month, 2nd month, 3rd month, and 6th-month durations, scores were 1.76 ± 0.06, 1.57 ± 0.12, 1.23 ± 0.02, and 0.76 ± 0.01, respectively. Statistical significance difference was noted on comparing the indices scores. CONCLUSION: Yoga practice has been shown to improve toothbrushing skills and oral hygiene in Parkinson's disease patients.

Evaluation of visual pedagogy teaching method for improving oral hygiene practice in children with Autism: An interventional study.

BACKGROUND: Evaluation of visual pedagogy teaching method for improving oral hygiene practice in children with Autism: An interventional study: Visual pedagogy is a relatively newer approach to improve dental care in autistic children. The present study aimed to evaluate visual pedagogy in the practice of oral hygiene in autistic children. MATERIALS AND METHODS: This interventional and prospective study was conducted in the Department of Paediatric and Preventive Dentistry. Required approval was obtained from Institutional Ethical Board. Written informed consent was obtained from parents/caregivers. The age range was 5-12 years which included 100 participants (40 males and 60 females). Improvement of oral hygiene was evaluated by recording the tooth brushing technique and ability to follow instructions as presented in the educational video shown on smartphones with Wi-Fi/mobile data. Inclusion criteria: (1) Accessibility and (2) Age range between 5 to 12 years. Exclusion criteria: (1) Non-cooperative children, (2) Children receiving medicines that influence oral health, and (3) Inability to follow-ups. Fones technique was used for brushing teeth in video recording demonstrating it in simple structured steps. Statistical analysis was performed using Chi-square and Independent t tests. RESULTS: Statistically significant improvement was observed in oral hygiene (plaque index) after training patients with visual pedagogy. CONCLUSION: In the present study, the use of visual pedagogy showed improvement in the oral hygiene scores of autistic children.

NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown. Objective: NFκB1 is preferentially expressed at a high level in ILC2s. We examined the role of NFkB1 in memory induction and memory-driven effector function in a mouse model of asthma. Methods: Intranasal administration of Alternaria, flexivent, ELISA, histology, real-time PCR, western blot, flow cytometry and immunofluorescence staining. Results: NFκB1 was essential for the effector phase of memory-driven asthma. NFκB1 was critical for IL33 production, ILC2 generation, and production of type-2 cytokines, which resulted in eosinophilic inflammation and other features of asthma. NFκB1 induction of type-2 cytokines in ILC2s was independent of GATA3. NFκB1 was important for allergen induction of ILC3s and FoxP3+ Tregs. NFκB1 did not affect Th2 cells or their cytokine production. In contrast to its protagonistic role in the effector phase, NFκB1 had an antagonistic role in the memory phase. NFκB1 inhibited allergen-induced upregulation of memory-associated repressor and preparedness genes in ILC2s. NFκB1 upregulated RUNX1. NFκB1 formed a heterodimer with RUNX1 in ILC2s. Conclusions: NFκB1 positively regulated the effector phase but inhibited the induction phase of memory. The foregoing pointed to an interdependent antagonism between the memory induction and the memory effector processes. The NFκB1-RUNX1 heterodimer represented a non-canonical transcriptional activator of type-2 cytokines in ILC2s.

Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis.

Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.

Correlation of serum cornitine levels with bone mineral density among Indian male tobacco users.

It is of interest to assess levels of serum cornitine in male tobacco users and also find its correlation with bone mineral density. Assessment for serum cotinine levels was done using commercially available Enzyme Linked Immunosorbent Assay (ELISA Kit). While bone mineral density was measured using bone densitometry through ultrasound in the wrist region. Karl Pearson's coefficient was used to assess correlation between BMD values and serum cotinine (ng/ml) levels. Inter group BMD association was measured using Chi square test. The present study showed that the first 3 groups had a low BMD level compared to control group, indicative of osteopenia. BMD values were lesser for chewers from group II as compared to smokers from group I and individuals using both smoked and smokeless form of tobacco from Group III. In group III (both forms of tobacco), osteopenic individuals were more. Thus, data shows effect of tobacco usage on bone mineral density. Smokeless form of tobacco has relatively serious effects on bone density.

Accurate and fast clade assignment via deep learning and frequency chaos game representation.

BACKGROUND: Since the beginning of the coronavirus disease 2019 pandemic, there has been an explosion of sequencing of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, making it the most widely sequenced virus in the history. Several databases and tools have been created to keep track of genome sequences and variants of the virus; most notably, the GISAID platform hosts millions of complete genome sequences, and it is continuously expanding every day. A challenging task is the development of fast and accurate tools that are able to distinguish between the different SARS-CoV-2 variants and assign them to a clade. RESULTS: In this article, we leverage the frequency chaos game representation (FCGR) and convolutional neural networks (CNNs) to develop an original method that learns how to classify genome sequences that we implement into CouGaR-g, a tool for the clade assignment problem on SARS-CoV-2 sequences. On a testing subset of the GISAID, CouGaR-g achieved an $96.29\%$ overall accuracy, while a similar tool, Covidex, obtained a $77,12\%$ overall accuracy. As far as we know, our method is the first using deep learning and FCGR for intraspecies classification. Furthermore, by using some feature importance methods, CouGaR-g allows to identify k-mers that match SARS-CoV-2 marker variants. CONCLUSIONS: By combining FCGR and CNNs, we develop a method that achieves a better accuracy than Covidex (which is based on random forest) for clade assignment of SARS-CoV-2 genome sequences, also thanks to our training on a much larger dataset, with comparable running times. Our method implemented in CouGaR-g is able to detect k-mers that capture relevant biological information that distinguishes the clades, known as marker variants. AVAILABILITY: The trained models can be tested online providing a FASTA file (with 1 or multiple sequences) at https://huggingface.co/spaces/BIASLab/sars-cov-2-classification-fcgr. CouGaR-g is also available at https://github.com/AlgoLab/CouGaR-g under the GPL.