Skeletal Muscle Mitochondrial Dysfunction Mediated by Pseudomonas aeruginosa Quorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum sensing (QS) transcription factor MvfR by interrogating five days post-infection its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs ATP generation, oxidative phosphorylation (OXPHOS), and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR- mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.

The L-lactate dehydrogenases of Pseudomonas aeruginosa are conditionally regulated but both contribute to survival during macrophage infection.

Pseudomonas aeruginosa is an opportunistic pathogen that thrives in environments associated with human activity, including soil and water altered by agriculture or pollution. Because L-lactate is a significant product of plant and animal metabolism, it is available to serve as a carbon source for P. aeruginosa in the diverse settings it inhabits. Here, we evaluate P. aeruginosa's production and use of its redundant L-lactate dehydrogenases, termed LldD and LldA. We confirm that the protein LldR represses lldD and identify a new transcription factor, called LldS, that activates lldA; these distinct regulators and the genomic contexts of lldD and lldA contribute to their differential expression. We demonstrate that the lldD and lldA genes are conditionally controlled in response to lactate isomers as well as to glycolate and - hydroxybutyrate, which, like lactate, are -hydroxycarboxylates. We also show that lldA is induced when iron availability is low. Our examination of lldD and lldA expression across depth in biofilms indicates a complex pattern that is consistent with the effects of glycolate production, iron availability, and cross-regulation on enzyme preference. Finally, macrophage infection assays revealed that both lldD and lldA contribute to persistence within host cells, underscoring the potential role of L-lactate as a carbon source during P. aeruginosa-eukaryote interactions. Together, these findings help us understand the metabolism of a key resource that may promote P. aeruginosa's success as a resident of contaminated environments and animal hosts.

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages' mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from a decrease in pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (MPC1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (ERRα). Consequently, ERRα exhibits weakened binding to the MPC1 promoter. This outcome arises from the impaired interaction between ERRα and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and consequently reduced ATP production in tolerized macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of MPC1 and ERR-α and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedent mechanism of host tolerance to infection involving the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings paving the way for developing treatments to bolster resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

Exploiting N-Centered Umpolung Reactivity of α-Iminomalonates for the Synthesis of N-Sulfenylimines and Sulfonamides.

An efficient and interesting N-centered umpolung method has been disclosed to construct beneficial S-N bonds, furnishing N-sulfenylimines, which can readily be converted into the corresponding sulfonamide derivatives in a one-pot sequential operation. N-Sulfenylimines are potent intermediates in organic synthesis, whereas sulfonamides are of major molecular interest due to their rich biological activities and wide applicability in medicinal chemistry. Owing to the simple reaction conditions and setup, this protocol displays a broad and versatile substrate scope, resulting in excellent functional group tolerability toward the synthesis of both N-sulfenylimines and sulfonamides. A density functional theory (DFT) computed and experimentally supported convenient mechanism has been proposed for this unique method.

C(sp3)-C(sp3) Radical-Cross-Coupling Reaction via Photoexcitation.

The photoexcitation of 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) in the presence of a base triggers the single-electron-transfer-mediated desulfonative radical-cross-coupling (RCC) reaction without the need for any metal or photocatalyst. 4-Alkyl-substituted 1,4-DHPs as the electron donor (reductant) and alkyl sulfones as the electron acceptor (oxidant) are chosen strategically as the two best-matched modular radical precursors for the construction of C(sp3)-C(sp3) bonds. Ultraviolet light-emitting diodes (365 nm) have proven to be adequate for inducing single-electron transfer between two radical precursors in the excited state. Following this designed strategy, a diverse collection of primary, secondary, and tertiary persistent alkyl radicals from both radical precursors have been used to forge C(sp3)-C(sp3) bonds. This blueprint features good functional group compatibility, a broad scope, and detailed mechanistic investigation.

Novel Insight into the Cellular and Molecular Signalling Pathways on Cancer Preventing Effects of Hibiscus sabdariffa: A Review.

A category of diseases known as cancer includes abnormal cell development and the ability to infiltrate or spread to other regions of the body, making them a major cause of mortality worldwide. Chemotherapy, radiation, the use of cytotoxic medicines, and surgery are the mainstays of cancer treatment today. Plants or products produced from them hold promise as a source of anti-cancer medications that have fewer adverse effects. Due to the presence of numerous phytochemicals that have been isolated from various parts of the Hibiscus sabdariffa (HS) plant, including anthocyanin, flavonoids, saponins, tannins, polyphenols, organic acids, caffeic acids, citric acids, protocatechuic acid, and others, extracts of this plant have been reported to have anti-cancer effects. These compounds have been shown to reduce cancer cell proliferation, induce apoptosis, and cause cell cycle arrest. They also increase the expression levels of the cell cycle inhibitors (p53, p21, and p27) and the pro-apoptotic proteins (BAD, Bax, caspase 3, caspase 7, caspase 8, and caspase 9). This review highlights various intracellular signalling pathways involved in cancer preventive potential of HS.

Associations Between Autism Spectrum Quotient and Integration of Visual Stimuli in 9-year-old Children: Preliminary Evidence of Sex Differences.

PURPOSE: The dorsal stream vulnerability hypothesis posits that the dorsal stream, responsible for visual motion and visuo-motor processing, may be particularly vulnerable during neurodevelopment. Consistent with this, autism spectrum disorder (ASD) has been associated with deficits in global motion integration, though deficits in ventral stream tasks, such as form identification, have also been reported. In the current study, we examined whether a similar pattern of results is found in a cohort of 381 children born with neurodevelopmental risk factors and exhibiting a wide spectrum of caregiver-reported autistic traits. METHODS: We examined the associations between global motion perception, global form perception, fine motor function, visual-motor integration, and autistic traits (autism spectrum quotient, AQ) using linear regression, accounting for possible interactions with sex and other factors relevant to neurodevelopment. RESULTS: All assessments of dorsal stream function were significantly associated with AQ such that worse performance predicted higher AQ scores. We also observed a significant sex interaction, with worse global form perception associated with higher AQ in boys (n = 202) but not girls (n = 179). CONCLUSION: We found widespread associations between dorsal stream functions and autistic traits. These associations were observed in a large group of children with a range of AQ scores, demonstrating a range of visual function across the full spectrum of autistic traits. In addition, ventral function was associated with AQ in boys but not girls. Sex differences in the associations between visual processing and neurodevelopment should be considered in the designs of future studies.

Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis.

Macrophages are crucial components of the host's defense against pathogens. Recent studies indicate that macrophage functions are influenced by lipid metabolism. However, knowledge of how bacterial pathogens exploit macrophage lipid metabolism for their benefit remains rudimentary. We have shown that the Pseudomonas aeruginosa MvfR-regulated quorum-sensing (QS) signaling molecule 2-aminoacetophenone (2-AA) mediates epigenetic and metabolic changes associated with this pathogen's persistence in vivo. We provide evidence that 2-AA counteracts the ability of macrophages to clear the intracellular P. aeruginosa, leading to persistence. The intracellular action of 2-AA in macrophages is linked to reduced autophagic functions and the impaired expression of a central lipogenic gene, stearoyl-CoA desaturase 1 (Scd1), which catalyzes the biosynthesis of monounsaturated fatty acids. 2-AA also reduces the expression of the autophagic genes Unc-51-like autophagy activating kinase 1 (ULK1) and Beclin1 and the levels of the autophagosomal membrane protein microtubule-associated protein 1, light chain 3 isoform B (LC3B) and p62. Reduced autophagy is accompanied by the reduced expression of the lipogenic gene Scd1, preventing bacterial clearance. Adding the SCD1 substrates palmitoyl-CoA and stearoyl-CoA increases P. aeruginosa clearance by macrophages. The impact of 2-AA on lipogenic gene expression and autophagic machinery is histone deacetylase 1 (HDAC1) mediated, implicating the HDAC1 epigenetic marks at the promoter sites of Scd1 and Beclin1 genes. This work provides novel insights into the complex metabolic alterations and epigenetic regulation promoted by QS and uncovers additional 2-AA actions supporting P. aeruginosa sustainment in macrophages. These findings may aid in designing host-directed therapeutics and protective interventions against P. aeruginosa persistence. IMPORTANCE This work sheds new light on how P. aeruginosa limits bacterial clearance in macrophages through 2-aminoacetophenone (2-AA), a secreted signaling molecule by this pathogen that is regulated by the quorum-sensing transcription factor MvfR. The action of 2-AA on the lipid biosynthesis gene Scd1 and the autophagic genes ULK1 and Beclin1 appears to secure the reduced intracellular clearance of P. aeruginosa by macrophages. In support of the 2-AA effect on lipid biosynthesis, the ability of macrophages to reduce the intracellular P. aeruginosa burden is reinstated following the supplementation of palmitoyl-CoA and stearoyl-CoA. The 2-AA-mediated reduction of Scd1 and Beclin1 expression is linked to chromatin modifications, implicating the enzyme histone deacetylase 1 (HDAC1), thus opening new avenues for future strategies against this pathogen's persistence. Overall, the knowledge obtained from this work provides for developing new therapeutics against P. aeruginosa.

Determining human-coronavirus protein-protein interaction using machine intelligence.

The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) virus spread the novel CoronaVirus -19 (nCoV-19) pandemic, resulting in millions of fatalities globally. Recent research demonstrated that the Protein-Protein Interaction (PPI) between SARS-CoV-2 and human proteins is accountable for viral pathogenesis. However, many of these PPIs are poorly understood and unexplored, necessitating a more in-depth investigation to find latent yet critical interactions. This article elucidates the host-viral PPI through Machine Learning (ML) lenses and validates the biological significance of the same using web-based tools. ML classifiers are designed based on comprehensive datasets with five sequence-based features of human proteins, namely Amino Acid Composition, Pseudo Amino Acid Composition, Conjoint Triad, Dipeptide Composition, and Normalized Auto Correlation. A majority voting rule-based ensemble method composed of the Random Forest Model (RFM), AdaBoost, and Bagging technique is proposed that delivers encouraging statistical performance compared to other models employed in this work. The proposed ensemble model predicted a total of 111 possible SARS-CoV-2 human target proteins with a high likelihood factor ≥70%, validated by utilizing Gene Ontology (GO) and KEGG pathway enrichment analysis. Consequently, this research can aid in a deeper understanding of the molecular mechanisms underlying viral pathogenesis and provide clues for developing more efficient anti-COVID medications.

COVID-19 vaccination does not affect male sexual functions.

BACKGROUND: COVID-19 infection has been linked with erectile dysfunction, which has also raised apprehensions about the impact of COVID-19 vaccination on male sexual functions. The purpose of this study was to investigate the impact of COVID-19 vaccination on male sexual functions, such as erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. METHODS: We used International Index of Erectile Function (IIEF) questionnaire for data collection. Mixed methods were adopted for this study, which consisted of Google online form distribution and the distribution of hard copies of the form to those who were not internet friendly. All data were entered in a spreadsheet and scores were assigned to each response according to the standard scores given in the IIEF questionnaire. Fifteen questions, one corresponding to each question in the IIEF questionnaire, were included to assess the impact of COVID-19 vaccination on each sexual function. RESULTS: In the first part of analysis, we calculated sexual function scores and men reporting low sexual function scores (~ 15%) were excluded, providing us with 465 individuals for further analysis. Regarding the impact of COVID-19 vaccination on male sexual functions, 71% individuals reported no impact, 3% reported a decline, 2.7% reported an improvement, and 23.3% could not assess the impact. We also performed analysis on the basis of age-groups of the participants and the duration after vaccination, finding that there was no impact irrespective of the age of subjects or the length of period after vaccination. CONCLUSIONS: COVID-19 vaccination does not affect male sexual functions, including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satisfaction.

A PREVENTIVE TOOL FOR PREDICTING BLOODSTREAM INFECTIONS IN CHILDREN WITH BURNS.

ABSTRACT: Introduction: Despite significant advances in pediatric burn care, bloodstream infections (BSIs) remain a compelling challenge during recovery. A personalized medicine approach for accurate prediction of BSIs before they occur would contribute to prevention efforts and improve patient outcomes. Methods: We analyzed the blood transcriptome of severely burned (total burn surface area [TBSA] ≥20%) patients in the multicenter Inflammation and Host Response to Injury ("Glue Grant") cohort. Our study included 82 pediatric (aged <16 years) patients, with blood samples at least 3 days before the observed BSI episode. We applied the least absolute shrinkage and selection operator (LASSO) machine-learning algorithm to select a panel of biomarkers predictive of BSI outcome. Results: We developed a panel of 10 probe sets corresponding to six annotated genes ( ARG2 [ arginase 2 ], CPT1A [ carnitine palmitoyltransferase 1A ], FYB [ FYN binding protein ], ITCH [ itchy E3 ubiquitin protein ligase ], MACF1 [ microtubule actin crosslinking factor 1 ], and SSH2 [ slingshot protein phosphatase 2 ]), two uncharacterized ( LOC101928635 , LOC101929599 ), and two unannotated regions. Our multibiomarker panel model yielded highly accurate prediction (area under the receiver operating characteristic curve, 0.938; 95% confidence interval [CI], 0.881-0.981) compared with models with TBSA (0.708; 95% CI, 0.588-0.824) or TBSA and inhalation injury status (0.792; 95% CI, 0.676-0.892). A model combining the multibiomarker panel with TBSA and inhalation injury status further improved prediction (0.978; 95% CI, 0.941-1.000). Conclusions: The multibiomarker panel model yielded a highly accurate prediction of BSIs before their onset. Knowing patients' risk profile early will guide clinicians to take rapid preventive measures for limiting infections, promote antibiotic stewardship that may aid in alleviating the current antibiotic resistance crisis, shorten hospital length of stay and burden on health care resources, reduce health care costs, and significantly improve patients' outcomes. In addition, the biomarkers' identity and molecular functions may contribute to developing novel preventive interventions.

Molecular mediators of angiogenesis and neurogenesis after ischemic stroke.

The mechanisms governing neurological and functional recovery after ischemic stroke are incompletely understood. Recent advances in knowledge of intrinsic repair processes of the CNS have so far translated into minimal improvement in outcomes for stroke victims. Better understanding of the processes underlying neurological recovery after stroke is necessary for development of novel therapeutic approaches. Angiogenesis and neurogenesis have emerged as central mechanisms of post-stroke recovery and potential targets for therapeutics. Frameworks have been developed for conceptualizing cerebral angiogenesis and neurogenesis at the tissue and cellular levels. These models highlight that angiogenesis and neurogenesis are linked to each other and to functional recovery. However, knowledge of the molecular framework linking angiogenesis and neurogenesis after stroke is limited. Studies of potential therapeutics typically focus on one mediator or pathway with minimal discussion of its role within these multifaceted biochemical processes. In this article, we briefly review the current understanding of the coupled processes of angiogenesis and neurogenesis after stroke. We then identify the molecular mediators and signaling pathways found in pre-clinical studies to upregulate both processes after stroke and contextualizes them within the current framework. This report thus contributes to a more-unified understanding of the molecular mediators governing angiogenesis and neurogenesis after stroke, which we hope will help guide the development of novel therapeutic approaches for stroke survivors.

Forecasting adversities of COVID-19 waves in India using intelligent computing.

The second wave of the COVID-19 pandemic outburst triggered enormously all over India. This ill-fated and fatal brawl affected millions of Indian citizens, with many active and infected Indians struggling to recover from this deadly disease to date, leading to a grief situation. The present situation warrants developing a robust and sound forecasting model to evaluate the adversities of the epidemic with reasonable accuracy to assist officials in curbing this hazard. Consequently, we employed Auto-ARIMA, Auto-ETS, Auto-MLP, Auto-ELM, AM, MLP and proposed ELM methods for assessing accumulative infected COVID-19 individuals by the end of July 2021. We made 90 days of advanced forecasting, i.e., up to 24 July 2021, for the number of cumulative infected COVID-19 cases of India using all seven methods in 15 days' intervals. We fine-tuned the hyper-parameters to enhance the prediction performance of these models and observed that the proposed ELM model offers satisfactory accuracy with MAPE of 5.01, and it rendered better accuracy than the other six models. To comprehend the dataset's nature, five features are extracted. The resulting feature values encouraged further investigation of the models for an updated dataset, where the proposed model provides encouraging results.

Transcranial random noise stimulation and exercise do not modulate ocular dominance plasticity in adults with normal vision.

Short-term deprivation of one eye by monocular patching causes a temporary increase in the contribution of that eye to binocular vision when the eye patch is removed. This effect, known as ocular dominance plasticity, provides a model of neuroplasticity within the human binocular visual system. We investigated whether physical exercise and the non-invasive brain stimulation technique transcranial random noise stimulation (tRNS), two interventions that may increase visual cortex neuroplasticity, enhance ocular dominance plasticity when delivered individually or in combination. Ocular dominance was measured using a grating rivalry test and a dichoptic letter contrast polarity judgment test. We observed robust ocular dominance changes for both outcome measures following 2-hour monocular deprivation; however, the magnitude of the effect was not influenced by exercise or tRNS. Ocular dominance plasticity may already be maximal after 2 hours of monocular deprivation in those with normal vision and therefore cannot be augmented by interventions designed to enhance neuroplasticity.

Family-acquired photographs for the evaluation of pediatric head shape via telemedicine: an analysis of photograph quality.

OBJECTIVE: Telemedicine can be an effective tool for the evaluation of the pediatric patient with a cranial deformity, but it increases the reliance of neurosurgical providers on data provided by patients and families. Family-acquired photographs, in particular, can be used to augment the evaluation of pediatric head shape abnormalities via telemedicine, but photographs of sufficient quality are necessary. Here, the authors systematically reviewed the quality and utility of family-acquired photographs for patients referred to their pediatric neurosurgery clinic for telemedicine-based head shape evaluations. METHODS: All telemedicine encounters that were completed for head shape abnormalities at the authors' institution between May 2020 and December 2021 were retrospectively reviewed. Instructions were sent to families prior to each visit with examples of ideal photographs. Three orthogonal views of the patient's head-frontal, lateral, and vertex-were requested. Data were collected regarding demographics, diagnosis, follow-up, and photograph quality. Quality variables included orthogonality of each requested view, appropriate distance, appropriate lighting, presence of distracting elements, and whether hair obscured the head shape. RESULTS: Overall, 565 patients had 892 visits during the study period. A total of 1846 photograph requests were made, and 3335 photographs were received for 829 visits. Of 2676 requested orthogonal views, 1875 (70%) were received. Of these, 1826 (97%) had adequate lighting, 1801 (96%) had appropriate distance, and 1826 (97%) had no distracting features. Hair did not obscure the head shape on the vertex view in 557 visits with orthogonal vertex views (82%). In-person follow-up was requested for further medical evaluation in 40 visits (5%). CONCLUSIONS: The family-acquired photographs in this series demonstrated high rates of adequate lighting and distance, without distracting features. Lack of orthogonality and obscuration of the head shape by hair, however, were more common issues. Family education prior to the visit may improve the quality of family-acquired photographs but requires an investment of time by medical staff. Efforts to further improve photographic quality will facilitate efforts to perform craniometric evaluations through telemedicine visits.

Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis.

Visceral leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, in a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/- mice correlated with increased plasma gammaglobulin level, incidence of liver granuloma, and disorganization of splenic white pulp. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a proinflammatory cytokine bias. Taken together our results indicate that while depletion of Wnt5A promotes susceptibility to visceral leishmaniasis, revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of disease.

How surface and fomite infection affect contagion dynamics: a study with self-propelled particles.

Self-propelled particles have been a tool of choice for many studies for understanding spatial interaction of people and propagation of infectious diseases. Other than the direct contagion process through face-to-face contacts with an infected agent, in some diseases, like COVID-19, the disease can spread by indirect ways, through contaminated object surfaces and puff-clouds created by the infected individual. However, this dual spreading process and the impact of these indirect infections in the entire dynamics are not properly explored. In this work, we consider epidemic spreading in an artificial society, with realistic parameters and movements of people, along with the possibilities of indirect exposure through contaminated surfaces and puff-clouds. This particular simulation based infectious disease dynamics is associated with the movements of some self-propelled free agents executing random motion which is investigated in conjunction with the rules of a realistic contagion process. With mathematical formulation and extensive computational studies, we have accommodated the indirect infection possibilities into the dynamics by incorporating an infectious 'tail' with the infected individuals. Analytical expressions of survival distance and infection probability of individuals have been explicitly calculated and reported. Results of precise and comparative simulation study have revealed the seriousness of indirect infections in connection with several dynamical parameters. Using this framework, interpretation of multiple waves in local as well as global scenarios have been established for COVID-19 infection statistics. Furthermore, the importance of indirect infections are also pointed out through data fitting, showing that ignoring this component might cause a misinterpretation of the dynamical parameters, like, imposed restrictions.

Possible Association Between Polymorphisms in ESR1, COL1A2, BGLAP, SPARC, VDR, and MMP2 Genes and Dental Fluorosis in a Population from an Endemic Region of West Bengal.

Dental fluorosis (DF) is the most prevalent form of fluorosis in India affecting millions of people all over the country. As estrogen receptor 1 (ESR1), collagen type 1 alpha 2 (COL1A2), bone γ-carboxyglutamic acid protein (BGLAP), secreted protein acidic and cysteine-rich (SPARC), vitamin D receptor (VDR), and matrix metallopeptidase 2 (MMP2) genes play critical roles in bone metabolism, bone formation, mineral metabolism, and mineralization, variants in these genes could influence susceptibility to DF. The present study was aimed at evaluating the association between 15 single-nucleotide polymorphisms (SNPs) in the six candidate genes (namely, ESR1, COL1A2, BGLAP, SPARC, VDR, and MMP2) and DF among 132 individuals (case = 71 and control = 61) living in a fluoride endemic region of West Bengal, India. No statistically significant association with disease risk was found when the genotypes and allele frequencies of each of the 15 SNPs was analyzed individually using odd's ratio with 95% confidence interval. "CC" and "AG" haplotypes of the COL1A2 gene showed a borderline association with DF. The present study is the first in India to use multifactor dimensionality reduction (MDR) analysis for identifying gene-gene and gene-environment interactions in fluorosis. The biomarker of serum fluoride showed a significant association with the disease state among the 17 attributes (15 SNPs and 2 biomarkers of urine fluoride and serum fluoride) (P value = 0.011). The best model of MDR analysis with maximized testing accuracy involved two SNPs from the ESR1 gene (rs9340799 and rs2077647) and one SNP from BGLAP gene (rs1543294) (P value < 0.0001).

Epigenetic modifications from arsenic exposure: A comprehensive review.

Arsenic is a notorious element with the potential to harm exposed individuals in ways that include cancerous and non-cancerous health complications. Millions of people across the globe (especially in South and Southeast Asian countries including China, Vietnam, India and Bangladesh) are currently being unknowingly exposed to precarious levels of arsenic. Among the diverse effects associated with such arsenic levels of exposure is the propensity to alter the epigenome. Although a large volume of literature exists on arsenic-induced genotoxicity, cytotoxicity, and inter-individual susceptibility due to active research on these subject areas from the last millennial, it is only recently that attention has turned on the ramifications and mechanisms of arsenic-induced epigenetic changes. The present review summarizes the possible mechanisms involved in arsenic induced epigenetic alterations. It focuses on the mechanisms underlying epigenome reprogramming from arsenic exposure that result in improper cell signaling and dysfunction of various epigenetic components. The mechanistic information articulated from the review is used to propose a number of novel therapeutic strategies with a potential for ameliorating the burden of worldwide arsenic poisoning.

Relationship between visual and neurodevelopmental measures at 2 years with visual acuity and stereopsis at 4.5 years in children born at risk of neonatal hypoglycaemia.

PURPOSE: Mild to moderate vision loss affects many children and can negatively impact a child's early literacy and academic achievement. Nevertheless, there is no consensus on which factors present in early childhood indicate the need for long-term ophthalmic follow up, particularly in children with a history of perinatal adversity. This study identified the relationship between visual, cognitive, motor and demographic factors at 2 years of age and visual acuity (VA) and stereoacuity at 4.5 years of age. METHODS: Five hundred sixteen children identified as being at risk of neonatal hypoglycaemia were recruited soon after birth. At 2 years of age, binocular VA, stereoacuity and non-cycloplegic refraction were measured and a clinical neuro-developmental assessment with the Bayley Scales of Infant Development III (BSID-III) was conducted by a trained examiner. Monocular VA and stereoacuity were measured at 4.5 years of age. RESULTS: Three hundred twenty-eight children completed both the 2 and 4.5 year vision and neurodevelopmental assessments. Multiple linear regression showed oblique astigmatism and motor function at 2 years were significantly associated with VA at 4.5 years of age, while spherical equivalent refraction, motor scores and stereoacuity at 2 years were significantly associated with stereoacuity at 4.5 years of age. BSID-III motor scores had the best sensitivity (81.8%) and specificity (51.5%) for identifying impaired stereoacuity at 4.5 years. However, all measures at 2 years were poorly associated with VA at 4.5 years old. CONCLUSION: Vision and neurodevelopmental measures at 2 years were poorly associated with visual function at 4.5 years of age. However, lower scores on tests of motor function at 2 years may be associated with vision abnormalities, particularly reduced stereopsis, at 4.5 years of age and referral for comprehensive vision assessment for these children may be warranted.