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.

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.

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.

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.

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.

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.

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.

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.

Resolvins Lipid Mediators: Potential Therapeutic Targets in Alzheimer and Parkinson Disease.

Inflammation and resolution are highly programmed processes involving a plethora of immune cells. Lipid mediators synthesized from arachidonic acid metabolism play a pivotal role in orchestrating the signaling cascades in the game of inflammation. The majority of the studies carried out so far on inflammation were aimed at inhibiting the generation of inflammatory molecules, whereas recent research has shifted more towards understanding the resolution of inflammation. Owing to chronic inflammation as evident in neuropathophysiology, the resolution of inflammation together with the class of lipid mediators actively involved in its regulation has attracted the attention of the scientific community as therapeutic targets. Both omega-three polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, orchestrate a vital regulatory role in inflammation development. Resolvins derived from these fatty acids comprise the D-and E-series resolvins. A growing body of evidence using in vitro and in vivo models has revealed the pro-resolving and anti-inflammatory potential of resolvins. This systematic review sheds light on the synthesis, specialized receptors, and resolution of inflammation mediated by resolvins in Alzheimer's and Parkinson's disease.

Polyphenols and Their Nanoformulations: Protective Effects against Human Diseases.

Polyphenols are the secondary metabolites synthesized by the plants as a part of defense machinery. Owing to their antioxidant, anti-inflammatory, anticancerous, antineoplastic, and immunomodulatory effects, natural polyphenols have been used for a long time to prevent and treat a variety of diseases. As a result, these phytochemicals may be able to act as therapeutic agents in treating cancer and cardiovascular and neurological disorders. The limited bioavailability of polyphenolic molecules is one issue with their utilization. For the purpose of increasing the bioavailability of these chemicals, many formulation forms have been developed, with nanonization standing out among them. The present review outlines the biological potential of nanoformulated plant polyphenolic compounds. It also summarizes the employability of various polyphenols as nanoformulations for cancer and neurological and cardiovascular disease treatment. Nanoencapsulated polyphenols, singular or in combinations, effective both in vitro and in vivo, need more investigation.

A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility.

BACKGROUND: Over 200 genetic loci have been associated with multiple sclerosis (MS) explaining ~ 50% of its heritability, suggesting that additional mechanisms may account for the "missing heritability" phenomenon. OBJECTIVE: To analyze a large cohort of Italian individuals to identify markers associated with MS with potential functional impact in the disease. METHODS: We studied 2571 MS and 3234 healthy controls (HC) of continental Italian origin. Discovery phase included a genome wide association study (1727 MS, 2258 HC), with SNPs selected according to their association in the Italian cohort only or in a meta-analysis of signals with a cohort of European ancestry (4088 MS, 7144 HC). Top associated loci were then tested in two Italian cohorts through array-based genotyping (903 MS, 884 HC) and pool-based target sequencing (588 MS, 408 HC). Finally, functional prioritization through conditional eQTL and mQTL has been performed. RESULTS: Top associated signals overlap with already known MS loci on chromosomes 3 and 17. Three SNPs (rs4267364, rs8070463, rs67919208), all involved in the regulation of TBKBP1, were prioritized to be functionally relevant. CONCLUSIONS: No evidence of novel signal of association with MS specific for the Italian continental population has been found; nevertheless, two MS loci seems to play a relevant role, raising the interest to further investigations for TBKBP1 gene.

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.

Comparative Evaluation of Changes in Microflora in Delayed and Immediate Implant Placement: An In vivo Study.

AIM: This study is aimed to compare and evaluate the changes in the microflora in immediate and delayed placed implants. MATERIALS AND METHODS: In this study, the implant site sample was taken and assessed during different phases of treatment for delayed and immediate implants. They were looked for Streptococcus, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, and Fusobacterium nucleatum. RESULTS: The results showed that Streptococci were found in a higher number in all the phases of the treatment. The presence of pathogenic organisms such as P. gingivalis and Fusobacterium, in considerable amounts, was seen in both the groups. CONCLUSION: Thus, we conclude that implant mode of placement, delayed or immediate placement does not alter the flora of the oral cavity. Organisms present remains the same in all the phase of the treatment. To prevent the disease, one must continuously monitor the implant, with the increasing age changes, the microflora is continually changing in the oral cavity. The periodontal health should be assessed before the placement of the implant, followed by follow-ups after a set period for a better prognosis.

Efficacy of Transdermal Diclofenac Patch and Ketoprofen Patch as Postoperative Analgesia after Extraction of First Premolars Bilaterally in Both Arches for Orthodontic Purpose: A Comparative Study.

AIM: The aim of the study was to compare the efficacy of transdermal diclofenac patch with ketoprofen patch as postoperative analgesia after extraction of first premolars bilaterally in both arches for orthodontic purpose. MATERIALS AND METHODS: A split-mouth technique was used in 52 patients with the age group of 15-25 years for extracting maxillary and mandibular first premolars bilaterally for orthodontic reason. A single ketoprofen patch was used after the extraction of premolars from first and fourth quadrant, whereas for the extraction of second and third quadrant premolars, diclofenac patch was used. All the extractions were performed under local anesthesia. The data were compiled and statistically analyzed using the student's t-test. RESULTS: Mean visual analog scale score for diclofenac and ketoprofen patch was 2.05 (0.75) and 1.09 (0.3), respectively. Thirteen patients required additional medication (25%) and 1 (1.9%) patient with diclofenac and ketoprofen patch, respectively. No major complication or adverse effects were observed in any of the groups. CONCLUSION: Both diclofenac and ketoprofen transdermal patches are helpful in relieving pain after orthodontic extraction. Patients with diclofenac patch required more additional analgesia within 24 h compared to that with ketoprofen patch. None of the drugs showed any significant adverse effects and were well tolerated by the patients.

Fabrication and in vitro Evaluation of 4-HIA Encapsulated PLGA Nanoparticles on PC12 Cells.

PURPOSE: 4-Hydroxyisophthalic acid (4-HIA) is a bioactive compound present in the roots of Decalepis hamiltonii, which has attracted considerable attention in attenuating oxidative stress-related neurodegenerative diseases. However, its efficacy is limited because of its low solubility and bioavailability. Therefore, the present study aimed to encapsulate 4-HIA using biocompatible copolymer polylactide-co-glycolide (PLGA) and evaluate its antioxidant and neuroprotective potential. METHODS: The nanoparticles (NPs) were fabricated by solid/oil/water (s/o/w) emulsion technique and characterized using XRD, SEM, HR-TEM, and FTIR spectroscopy. Antioxidant assays such as 1,1 diphenyl-2-picrylhydrazyl (DPPH), superoxide, and hydroxyl radical scavenging ability were performed to assess the antioxidant potential of the fabricated NPs. RESULTS: The bioactive component, 4-HIA, was efficiently encapsulated by the PLGA polymer and was found to be spherical and smooth with a size <10nm. 4-HIA showed better scavenging capability in DPPH and superoxide assays as compared to 4-HIA encapsulated PLGA and butylated hydroxytoluene (BHT). In contrast, 4-HIA encapsulated PLGA NPs exhibited a significant hydroxyl radical scavenging activity than 4-HIA and BHT alone. Further, the encapsulated NPs efficiently curtailed hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. CONCLUSION: Our findings indicate that 4-HIA encapsulated PLGA NPs might be a therapeutic intervention towards the effective management of oxidative stress as it has exhibited efficient neuroprotective potential against H2O2-induced oxidative stress in PC12 cells.

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility.

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c+, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.

High throughput screening identifies SOX2 as a super pioneer factor that inhibits DNA methylation maintenance at its binding sites.

Binding of mammalian transcription factors (TFs) to regulatory regions is hindered by chromatin compaction and DNA methylation of their binding sites. Nevertheless, pioneer transcription factors (PFs), a distinct class of TFs, have the ability to access nucleosomal DNA, leading to nucleosome remodelling and enhanced chromatin accessibility. Whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Using a highly parallelized approach to investigate PF ability to bind methylated DNA and induce DNA demethylation, we show that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs displaying pioneering activity; while some PFs do not affect the methylation status of their binding sites, we identified PFs that can protect DNA from methylation and others that can induce DNA demethylation at methylated binding sites. We call the latter super pioneer transcription factors (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Finally, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation, an activity enhanced by the co-binding of OCT4. This finding suggests that SPFs could interfere with epigenetic memory during DNA replication.