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This article deals with existence of solutions to the following fractional pp-Laplacian system of equations: (−Δp)su=∣u∣ps*−2u+γαps*∣u∣α−2u∣v∣βinΩ,(−Δp)sv=∣v∣ps*−2v+γβps*∣v∣β−2v∣u∣αinΩ,\left\{\begin{array}{l}{\left(-{\Delta }_{p})}^{s}u={| u| }^{{p}_{s}^{* }-2}u+\frac{\gamma \alpha }{{p}_{s}^{* }}{| u| }^{\alpha -2}u{| v| }^{\beta }\hspace{0.33em}\hspace{0.33em}\hspace{0.1em}\text{in}\hspace{0.1em}\hspace{0.33em}\Omega ,\hspace{1.0em}\\ {\left(-{\Delta }_{p})}^{s}v={| v| }^{{p}_{s}^{* }-2}v+\frac{\gamma \beta }{{p}_{s}^{* }}{| v| }^{\beta -2}v{| u| }^{\alpha }\hspace{0.33em}\hspace{0.33em}\hspace{0.1em}\text{in}\hspace{0.1em}\hspace{0.33em}\Omega ,\hspace{1.0em}\end{array}\right. where s∈(0,1)s\in \left(0,1), p∈(1,∞)p\in \left(1,\infty ) with N>spN\gt sp, α,β>1\alpha ,\beta \gt 1 such that α+β=ps*≔NpN−sp\alpha +\beta ={p}_{s}^{* }:= \frac{Np}{N-sp} and Ω=RN\Omega ={{\mathbb{R}}}^{N} or smooth bounded domains in RN{{\mathbb{R}}}^{N}. When Ω=RN\Omega ={{\mathbb{R}}}^{N} and γ=1\gamma =1, we show that any ground state solution of the aforementioned system has the form (λU,τλV)\left(\lambda U,\tau \lambda V) for certain τ>0\tau \gt 0 and UU and VV are two positive ground state solutions of (−Δp)su=∣u∣ps*−2u{\left(-{\Delta }_{p})}^{s}u={| u| }^{{p}_{s}^{* }-2}u in RN{{\mathbb{R}}}^{N}. For all γ>0\gamma \gt 0, we establish existence of a positive radial solution to the aforementioned system in balls. When Ω=RN\Omega ={{\mathbb{R}}}^{N}, we also establish existence of positive radial solutions to the aforementioned system in various ranges of γ\gamma .

Background: As per National Education Policy (NEP) report, the gross enrolment ratio for class 6-8, class 9-10 and class 11-12 was 91%, 79%and 57% respectively. Education plays crucial role in development of economic, social and income of a country. Dropping out leads to under employments, mental health, delinquency and a lower quality of life for young people. Objective: To assess the determinants of school dropouts among adolescent and factor associated with it among adolescent. Methodology: A cross- sectional study was conducted for 3 months from the month of November 2023 to January 2024. Multistage random sampling was done. Participants were interviewed using pre- tested semi- structed questionnaire. Data was analyzed using SPSS in the Department of Community Medicine, MKCG Medical College, and Hospital. Results: All of the study population belonged to Hinduism, 64.29% were boys and 35.71% were girls. School dropouts were significantly less among adolescent whose mother were educated (65%) than in uneducated. The likelihood of dropout among older boys are 2times more than in younger boys who consumed any substances. Lack of interest in studies (38%), family reasons (29%) and paid work (22%) were predominant reasons among adolescents. Conclusion: There is need to improve socio- economic status, delay of marital ages of girls, and enhanced government incentives for education and spread awareness.

Background: Adolescence is a pivotal phase marked by significant physical, emotional, and cognitive changes. The lifestyle choices made during this period can profoundly affect the quality of life (QOL) of adolescents. However, research on this topic is limited, especially within the unique context of urban slums. Objective: This cross-sectional study aims to investigate the impact of physical activity and sedentary behaviour on QOL among adolescents residing in the urban slums of Berhampur, Ganjam. Methodology: A multistage cluster sampling method was employed to select adolescents aged 12-18 living in urban slum areas. WHO-QOL were utilized to collect data on physical activity, sedentary behaviour, and QOL using validated instruments. Data analysis encompassed descriptive statistics, inferential analyses, and regression models to explore the relationships between physical activity, sedentary behaviour, and QOL. Socio-demographic variables were also considered. Results: Preliminary findings reveal diverse physical activity patterns among adolescents, with a notable proportion engaging in insufficient levels of physical activity. Sedentary behaviours, particularly prolonged screen time, were prevalent. QOL assessments identified variations in physical, emotional, and social well-being domains. Regression analyses indicated a positive association between higher levels of physical activity and improved QOL, while sedentary behaviour, especially extensive screen time, was associated with decreased QOL. Socio-demographic factors, including gender and socio- economic status, were identified as influential factors in these associations. Conclusion: This study underscores the significant interplay between physical activity, sedentary behaviour, and QOL among adolescents residing in urban slums. It emphasizes the need for targeted interventions aimed at promoting healthier lifestyles within this underserved population. The findings provide essential insights for policymakers, healthcare providers, and educators to develop evidence-based strategies that can enhance the well-being of adolescents in similar contexts worldwide. Addressing the unique health challenges faced by adolescents in urban slums is crucial for improving their overall QOL and health outcomes.

Background: Breastfeeding is one of the most effective ways to ensure a child’s health and survival. Contrary to WHO recommendations, fewer than half of infants under 6 months old are exclusively breastfed. Although we know about breastfeeding practices in urban and rural populations, very little knowledge is available about breastfeeding practices and their correlates among the tribal population. Objectives: 1. To assess the knowledge, attitude and practices prevailing among tribal women about breastfeeding 2. To explore the facilitators and barriers to infant breastfeeding practices amongst women in tribal areas. Methodology: Study design- Mixed method study. Study period- May, 2023 to July, 2023 Study population- tribal women of Koraput district. Study setting- villages in Koraput Inclusion criteria- 1. Women belonging to Scheduled Tribe communities. 2. Having at least one living issue. 3. Residing in their respective villages during the study period. Exclusion criteria- 1. Those who did not consent to the study. 2. Not residing in their respective villages. Sampling- Multistage sampling. Sample size- 500. Results: 78.6% of mothers belong to the age group 21-30 years, 93.4% were literate whereas 6.6% were illeterate, 88% were housewives with 78.8% belonging from joint family. Majority of them had good knowledge regarding breastfeeding, though they lacked clarity on the concept of exclusive breastfeeding. Majority of their knowledge about breastfeeding was from relatives or neighbours and healthcare workers. having multiple children in quick succession serves as a major barrier to exclusive breastfeeding. Conclusion: The findings can form targeted interventions and policy initiatives to reduce the barriers and promote the facilitating factors for optimal breastfeeding practices within this unique cultural setting, ultimately contributing to improved maternal and child health outcomes.

This paper deals with existence and multiplicity of positive solutions to the following class of nonlocal equations with critical nonlinearity:

We study positive solutions to the fractional Lane-Emden system

Comments on several medical related issues. Proposals of Health Department to produce full-time salaried service for medical consultants in Great Britain; Increase of the prevalence of Hemophilus influenzae in the elderly; Association of pericarditis and peritonitis with practolol therapy.

Introduction: Optimal outcomes during childhood cancer treatment require effective management of toxicities, often called supportive care. A lack of agreement on what comprises supportive care limits the development and provision of comprehensive guidance (for this work, we have defined supportive care as any disease- or treatment-related condition experienced by children with cancer, excluding psychosocial conditions, palliative care, survivorship, or procedural topics). To address this gap, we conducted a consensus-building exercise among global experts to define and prioritize topics for supportive care., Methods: Two rounds of brainstorming and prioritization exercises were conducted. A multidisciplinary panel nominated by professional societies and cooperative groups was formed to ensure geographic and resource representation using snowball sampling. An internal expert panel generated an initial list of supportive care topics. In round one, the multidisciplinary panel reviewed the initial list and recommended additional topics, followed by prioritization in round two using a seven-point Likert scale. Results were summarized using descriptive statistics., Results: The multidisciplinary panel consisted of 57 members representing 32 countries. The initial list included 46 topics; 161 additional topics were suggested. After removing duplicates and out-of-scope additions, the final list contained 62 topics. Febrile neutropenia, sepsis, bloodstream infections, and pain were ranked highest priority. Mortality, morbidity, and frequency of the event were identified as the most important factors influencing prioritization., Conclusion: Through a multidisciplinary and globally representative process, we identified core supportive care topics and factors influencing their prioritization for childhood cancer. Outputs from this work will inform efforts to generate resource-adapted recommendations for a global audience. This supports ongoing WHO CureAll work to develop a health systems-level policy brief of supportive care requirements in the management of children with cancer., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background Postpartum depression (PPD) is a complex mix of physical, emotional, and behavioral changes that happen in some women after giving birth. Objectives The aim of the study is to determine the prevalence of PPD using the Edinburgh Postnatal Depression Scale (EPDS) and evaluate the predisposing factors for PPD. Methodology The present observational study was conducted in the Department of Community Medicine, Maharaja Krushna Chandra Gajapati (MKCG) Medical College and Hospital, Brahmapur, Odisha, India from May 2022 to November 2022. Using the EPDS, participants were assessed for postnatal depression. Every subject additionally filled out a risk factor questionnaire covering important sociodemographic and obstetric parameters. The prevalence of an EPDS score of 12 or above is the primary outcome measure. Results The study encompassed 121 mothers, with 8.26% scoring above the depression cutoff of 12 and 6.61% falling within the borderline range. Notably, all mothers surpassing the cutoff were from joint families, contrasting with those from nuclear families. A predominant portion of the depressive group was in their 20s, while the borderline group primarily consisted of mothers in their 30s. Urban residency and government hospital care were universal among the samples. Mode of delivery showed significance, with a higher prevalence of PPD observed among those who underwent a lower segment cesarean section. Additionally, maternal age, anemia, mode of delivery, educational status, adverse life events, and lack of partner support significantly correlated with depression scores. Notably, maternal age emerged as the most influential factor, followed by anemia and mode of delivery. Spearman correlation analysis revealed moderate negative associations between various aspects of maternal depression and the ages of their babies, indicating that younger infants were associated with greater maternal distress. However, the correlation between feeling sad or miserable and the baby's age was negligible. These findings emphasize the multifaceted nature of PPD, highlighting the interplay between sociodemographic factors, maternal well-being, and infant age., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee, Maharaja Krushna Chandra Gajapati (MKCG) Medical College and Hospital issued approval 1336. The Institutional Ethics Committee has approved the protocol titled "Assessing the Prevalence and Risk Factors of Postpartum Depression: A Cross-Sectional Study Conducted in the Urban Areas of Ankuli in Southern Odisha" of Dr. Madhumita Bhakta, a postgraduate student in the Department of Community Medicine, to be conducted for six months at Maharaja Krushna Chandra Gajapati (MKCG) Medical College and Hospital, Brahmapur, Odisha, India. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bhakta et al.)

Background: Chronic inflammation brought on by oxidative stress can result in several immunopathologies. Natural compounds with antioxidant characteristics, like quercetin, have shown effectiveness in reducing oxidative damage and regulating the immune response., Purpose: The commonly used food additive monosodium glutamate (M) causes immunosuppression by disrupting redox equilibrium and inducing oxidative stress. The goal of this work is to examine the therapeutic potential of quercetin against immunotoxicity brought on by M, revealing the molecular route implicated in such immunopathology by targeting the thymus and spleen, to support the development of future anti-inflammatory and antioxidant therapies., Study Design and Methods: M-fed rats were employed as an immunotoxicity model and were supplemented with quercetin for four weeks. Hematological and biochemical parameters were measured; H&E staining, immunohistochemistry, flow cytometry, real-time quantitative PCR, and western blotting were performed., Results: Based on the findings, TLR4 was activated by M to cause oxidative stress-mediated inflammation, which was alleviated by the supplementation of quercetin by modulating redox homeostasis to neutralize free radicals and suppress the inflammatory response. To prevent M-induced inflammation, quercetin demonstrated anti-inflammatory functions by blocking NF-kB activation, lowering the production of pro-inflammatory cytokines, and increasing the release of anti-inflammatory cytokines. By normalizing lipid profiles and lowering the potential risk of immunological deficiency caused by M, quercetin also improves lipid metabolism. Additionally, it has shown potential for modifying insulin levels, suggesting a possible function in controlling M-induced alteration in glucose metabolism. The addition of quercetin to M enhanced the immune response by improving immunoglobulin levels and CD4/CD8 expression in the thymus and spleen. Additionally, quercetin inhibited apoptosis by controlling mitochondrial caspase-mediated cellular signaling, suggesting that it may be able to halt cell death in M-fed rats., Conclusion: The results of this study first indicate that quercetin, via modulating redox-guided cellular signaling, has a promising role in reducing immune disturbances. This study illuminates the potential of quercetin as a safe, natural remedy for immunopathology caused by M, including thymic hypoplasia and/or splenomegaly, and paves the way for future anti-inflammatory and antioxidant supplements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare and devastating childhood-onset lysosomal storage disease caused by complete loss of function of the lysosomal hydrolase α-N-acetylglucosaminidase. The lack of functional enzyme in MPS IIIB patients leads to the progressive accumulation of heparan sulfate throughout the body and triggers a cascade of neuroinflammatory and other biochemical processes ultimately resulting in severe mental impairment and early death in adolescence or young adulthood. The low prevalence and severity of the disease has necessitated the use of animal models to improve our knowledge of the pathophysiology and for the development of therapeutic treatments. In this study, we took a systematic approach to characterizing a classical mouse model of MPS IIIB. Using a series of histological, biochemical, proteomic and behavioral assays, we tested MPS IIIB mice at two stages: during the pre-symptomatic and early symptomatic phases of disease development, in order to validate previously described phenotypes, explore new mechanisms of disease pathology and uncover biomarkers for MPS IIIB. Along with previous findings, this study helps provide a deeper understanding of the pathology landscape of this rare disease with high unmet medical need and serves as an important resource to the scientific community., (© 2023. Springer Nature Limited.)

It is essential to revisit the global biodiversity, search for ethnopharmacologically relevant plants, and unveil their untapped potential to overcome the complications associated while treating infections triggered by multiple antibiotic-resistant Staphylococcus aureus . Catharanthus roseus (L.) G. Don of the Apocynaceae family is a medicinal plant used for remedial purposes against infectious diseases from ancient times. In this study, we intended to evaluate the mechanism by which the ethanolic extract of C . roseus root (EECRR) causes the reversal of ampicillin resistance in S. aureus . To achieve this goal, we have stained EECRR-treated S. aureus with acridine orange, analysed DNA damage by comet assay, and studied the alteration of plasmid band pattern and expression of penicillin-binding protein 2a (PBP2a) protein. Experiments revealed better S. aureus killing efficiency of EECRR at its minimum inhibitory concentration (MIC) doses due to DNA damage and reducing plasmid band intensities along with a decline in the expression of PBP2a in EECRR-treated cells at half-MIC dose. EECRR proved to be an efficient growth inhibitor of S. aureus that reduces the expression of PBP2a. Therefore, EECRR can also render ampicillin-resistant S. aureus susceptible to the antibiotic., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

The current work is an extensive review addressing the effects of heavy metals in major pulse crops such as Chickpea ( Cicer arietinum L.), Pea ( Pisum sativum L.), Pigeonpea ( Cajanus cajan L.), Mung bean ( Vigna radiata L.), Black gram ( Vigna mungo L.) and Lentil ( Lens culinaris Medik.). Pulses are important contributors to the global food supply in the world, due to their vast beneficial properties in providing protein, nutritional value and health benefits to the human population. Several studies have reported that heavy metals are injurious to plants causing inhibition in plant germination, a decrease in the root and shoot length, reduction in respiration rate and photosynthesis. Properly disposing of heavy metal wastes has become an increasingly difficult task to solve in developed countries. Heavy metals pose one of the substantial constraints to pulse crops growth and productivity even at low concentrations. This article attempts to present the morphological, biochemical and various physiological changes induced on the pulse crops grown under various heavy metal stress such as As, Cd, Cr, Cu, Pb, and Ni., (© King Abdulaziz City for Science and Technology 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Alternative Lengthening of Telomeres (ALT) is an aberrant DNA recombination pathway which grants replicative immortality to approximately 10% of all cancers. Despite this high prevalence of ALT in cancer, the mechanism and genetics by which cells activate this pathway remain incompletely understood. A major challenge in dissecting the events that initiate ALT is the extremely low frequency of ALT induction in human cell systems. Guided by the genetic lesions that have been associated with ALT from cancer sequencing studies, we genetically engineered primary human pluripotent stem cells to deterministically induce ALT upon differentiation. Using this genetically defined system, we demonstrate that disruption of the p53 and Rb pathways in combination with ATRX loss-of-function is sufficient to induce all hallmarks of ALT and results in functional immortalization in a cell type-specific manner. We further demonstrate that ALT can be induced in the presence of telomerase, is neither dependent on telomere shortening nor crisis, but is rather driven by continuous telomere instability triggered by the induction of differentiation in ATRX-deficient stem cells., (© 2023. The Author(s).)

Comprehensive cis-regulatory landscapes are essential for accurate enhancer prediction and disease variant mapping. Although cis-regulatory element (CRE) resources exist for most tissues and organs, many rare - yet functionally important - cell types remain overlooked. Despite representing only a small fraction of the heart's cellular biomass, the cardiac conduction system (CCS) unfailingly coordinates every life-sustaining heartbeat. To globally profile the mouse CCS cis-regulatory landscape, we genetically tagged CCS component-specific nuclei for comprehensive assay for transposase-accessible chromatin-sequencing (ATAC-Seq) analysis. Thus, we established a global CCS-enriched CRE database, referred to as CCS-ATAC, as a key resource for studying CCS-wide and component-specific regulatory functions. Using transcription factor (TF) motifs to construct CCS component-specific gene regulatory networks (GRNs), we identified and independently confirmed several specific TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validated numerous CCS-enriched enhancer elements and suggested gene targets based on CCS single-cell RNA-Seq data. Furthermore, we leveraged CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominated a potential enhancer-target pair that was dysregulated by a specific SNP. Collectively, our results established a CCS-regulatory compendium, identified novel CCS enhancer elements, and illuminated potential functional associations between human genomic variants and CCS component-specific CREs.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging., Competing Interests: Declaration of interests D.A.S. is a consultant, inventor, board member, and in some cases an investor in Life Biosciences (developing reprogramming medicines), InsideTracker, Zymo, EdenRoc Sciences/Cantata/Dovetail/Metrobiotech, Caudalie, Galilei, Immetas, Animal Biosciences, Tally Health, and more. See https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. E.M.M., M. Blanchette, and M. Bhakta are employees of Catata Bio/Dovetail. Y.C.C., W.G., and X.Y. are employees of Zymo Research. A.J.W. advises Kate Therapeutics and Frequency Therapeutics and is a co-founder, adviser, and equity holder of Elevian, which sponsors Wagers Lab research. L.S. was an employee of Vium. Y.R.L. and L.A.R. are equity owners of Life Biosciences. M.S.B. and D.L.V. advise EdenRoc Sciences. A patent application was filed on the reprogramming methods., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mayaro virus (MAYV) is an emerging arbovirus with an increasing circulation across the Americas. In the present study, we evaluated the potential antiviral activity of the following natural compounds against MAYV and other arboviruses: Sanguinarine, (R)-Shikonin, Fisetin, Honokiol, Tanshinone IIA, and α-Mangostin. Sanguinarine and Shikonin showed significant cytotoxicity, whereas Fisetin, Honokiol, Tanshinone IIA, and α-Mangostin were well tolerated in all the cell lines tested. Honokiol and α-Mangostin treatment protected Vero-E6 cells against MAYV-induced damage and resulted in a dose-dependent reduction in viral progeny yields for each of the MAYV strains and human cell lines assessed. These compounds also reduced MAYV viral RNA replication in HeLa cells. In addition, Honokiol and α-Mangostin disrupted MAYV infection at different stages of the virus life cycle. Moreover, Honokiol and α-Mangostin decreased Una, Chikungunya, and Zika viral titers and downmodulated the expression of E1 and nsP1 viral proteins from MAYV, Una, and Chikungunya. Finally, in Honokiol- and α-Mangostin-treated HeLa cells, we observed an upregulation in the expression of type I interferon and specific interferon-stimulated genes, including IFN α , IFN β, MxA , ISG15 , OAS2 , MDA-5 , TNF α , and IL-1β, which may promote an antiviral cellular state. Our results indicate that Honokiol and α-Mangostin present potential broad-spectrum activity against different arboviruses through different mechanisms.

Introduction: Numerous inflammatory markers may serve a role in prognostication of patients hospitalized with COVID-19 infection. Early in the pandemic, our health system created an admission order set which included daily d-dimer, c-reactive protein (CRP), lactate dehydrogenase (LDH), and ferritin. Given more available outcomes data, limiting standing order of labs that do not affect daily management could result in significant cost savings to the health system without adverse patient outcomes. The purpose of this study was to determine ordering and utilization patterns of inflammatory markers by physicians caring for patients hospitalized with COVID-19 infection., Methods: An anonymous 10-question survey was distributed to 125 physicians (Infectious Disease, Hospitalist, Pulmonary and Critical Care faculty). Responses were tallied and values greater than 50% were identified as the majority of the surveyed group., Results: Of the 125 physicians surveyed, 77 (62%) responded. A total of 57.1% (44/77) of physicians reported ordering daily inflammatory markers for 3 - 10 days from admission. Another 31.2% (24/77) ordered markers until clinical improvement or hospital discharge. D-dimer was used for care decisions by 83.1% (64/77) of respondents; 93.8% (60/64) of those reported utilizing it in determining anticoagulation dose. CRP was used by 61% (47/77) of physicians to help identify a secondary infection or determine steroid dose or duration. LDH and ferritin were not used for management decisions by the majority of physicians. Inflammatory markers were not used routinely after isolation precautions had been discontinued, even when ongoing care required mechanical ventilation., Conclusions: Of the markers studied, both d-dimer and CRP were considered useful by most respondents. LDH and ferritin were used less frequently and were not considered as useful in guiding medical decision making. Discontinuation of standing daily LDH and ferritin orders is believed to have potential to result in cost savings to the health care system with no adverse patient outcomes., (© 2022 The University of Kansas Medical Center.)

The cardiac conduction system (CCS) ensures regular contractile function, and injury to any of its components can cause cardiac dysrhythmia. Although all cardiomyocytes (CMs) originate from common progenitors, the CCS is composed of biologically distinct cell types with unique functional and developmental characteristics. In contrast to ventricular cardiomyocytes, which continue to proliferate after birth, most CCS cells terminally exit the cell cycle during fetal development. Although the CCS should thus provide a poor substrate for postnatal injury repair, its regenerative capacity remains untested. Here, we describe a genetic system for ablating CMs that reside within the atrioventricular conduction system (AVCS). Adult mouse AVCS ablation resulted in regenerative failure characterized by persistent atrioventricular conduction defects and contractile dysfunction. In contrast, AVCS injury in neonatal mice led to recovery in a subset of these mice, thus providing evidence for CCS plasticity. Furthermore, CM proliferation did not appear to completely account for the observed functional recovery, suggesting that mechanisms regulating recovery from dysrhythmia are likely to be distinct from cardiac regeneration associated with ventricular injury. Taken together, we anticipate that our results will motivate further mechanistic studies of CCS plasticity and enable the exploration of rhythm restoration as an alternative therapeutic strategy.

Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition and their effect on cancer cells for the first time. A 15-fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC 50 values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC 50 of 2.93±0.07 μM in a cellular model of triple-negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as-yet-undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple-negative breast cancer., (© 2020 Wiley-VCH GmbH.)

Background: The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP - fremanezumab, galcanezumab and eptinezumab - and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature., Methods: To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays., Results: Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY 1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY 1 receptor while fremanezumab did not affect amylin responses., Conclusion: The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.

Phosphoglycerate kinase (PGK) is glycolytic enzyme critical in the creation of adenosine triphosphate. Mutations in the gene for this enzyme, PGK1, are associated with PGK deficiency, which is characterized by neurologic symptoms, nonhereditary spherocytic hemolytic anemia, and myopathy. We present a 20-year-old male with a novel c.461T>C (p.L154P) PGK1 mutation and clinical disease complicated by anemia and neurological symptoms. There is no recommended treatment for PGK deficiency. Because of our patient's advanced disease progression, we initiated serial blood transfusions and report significant subjective improvement in the patient's physical condition before his passing from PGK deficiency-related complications.

We propose an integrated structural approach to search potential aptamer molecules for targeting cancer receptor proteins. We used the outer cellular domain of the B-lymphocyte antigen, CD19, as the target for this study. First, using available protein-aptamer structures deposited in the protein data bank as resources, structural annotation was performed to seek the most probable binding aptamer and its potential initial configuration to the CD19 structure. Using this initial structure, molecular dynamics (MD) simulations were performed for adjustment of the aptamer-binding. During this process, we observed an "aptamer walking" mechanism of the binding of the single-stranded RNA-aptamer to CD19: the aptamer molecule gradually adjusts its configurations and shifts toward favorable binding positions. However, the target molecule CD19 maintained a relatively stable conformation during this process. The interface area between the RNA-aptamer and CD19 increased from less than 8 nm 2 to over 12 nm 2 during a 2-μs MD simulation. Using a stable binding pose as the starting structure, we manually mutated the RNA-aptamer to a DNA-aptamer and found that the interface area was further increased to over 16 nm 2 , indicating a stronger affinity compared to the RNA-aptamer. The RNA- and DNA-aptamers and their stable binding-poses to the CD19 molecule may be used as templates in designing potential aptamer molecules that target the B-cell marker molecule CD19 with enhanced specificity and stability., (© 2020 American Institute of Chemical Engineers.)

Herbicide resistance is a recurrent evolutionary event that has been reported across many species and for all major herbicide modes of action. The synthetic auxinic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) has been widely used since the 1940s, however the genetic variation underlying naturally evolving resistance remains largely unknown. In this study, we used populations of the forage legume crop red clover (Trifolium pratense L.) that were recurrently selected for 2,4-D resistance to detect genome-wide signatures of adaptation. Four susceptible and six derived resistant populations were sequenced using a less costly approach by combining targeted sequencing (Capture-Seq) with pooled individuals (Pool-Seq). Genomic signatures of selection were identified using: (i) pairwise allele frequency differences; (ii) genome scan for overly differentiated loci; and (iii) genome-wide association. Fifty significant SNPs were consistently detected, most located in a single chromosome, which can be useful for marker assisted selection. Additionally, we searched for candidate genes at these genomic regions to gain insights into potential molecular mechanisms underlying 2,4-D resistance. Among the predicted functions of candidate genes, we found some related to the auxin metabolism, response to oxidative stress, and detoxification, which are also promising for further functional validation studies.