Orthogonal Persulfide Generation through Precision Tools Provides Insights into Mitochondrial Sulfane Sulfur.

The sulfane sulfur pool, comprised of persulfide (RS-SH) and polysulfide (RS-SnH) derived from hydrogen sulfide (H2S), has emerged as a major player in redox biochemistry. Mitochondria, besides energy generation, serve as significant cellular redox hubs, mediate stress response and cellular health. However, the effects of endogenous mitochondrial sulfane sulfur (MSS) remain largely uncharacterized as compared with their cytosolic counterparts, cytosolic sulfane sulfur (CSS). To investigate this, we designed a novel artificial substrate for mitochondrial 3-mercaptopyruvate sulfurtransferase (3-MST), a key enzyme involved in MSS biosynthesis. Using cells expressing a mitochondrion-localized persulfide biosensor, we demonstrate this tool's ability to selectively enhance MSS. While H2S was previously known to suppress human immunodeficiency virus (HIV-1), we found that MSS profoundly affected the HIV-1 life cycle, mediating viral reactivation from latency. Additionally, we provide evidence for the role of the host's mitochondrial redox state, membrane potential, apoptosis, and respiration rates in managing HIV-1 latency and reactivation. Together, dynamic fluctuations in the MSS pool have a significant and possibly conflicting effect on HIV-1 viral latency. The precision tools developed herein allow for orthogonal generation of persulfide within both mitochondria and the cytosol and will be useful in interrogating disease biology.

A study on microstructural, mechanical properties, and optimization of wear behaviour of friction stir processed AZ31/TiC composites using response surface methodology.

The primary objective of this study is to investigate the microstructural, mechanical, and wear behaviour of AZ31/TiC surface composites fabricated through friction stir processing (FSP). TiC particles are reinforced onto the surface of AZ31 magnesium alloy to enhance its mechanical properties for demanding industrial applications. The FSP technique is employed to achieve a uniform dispersion of TiC particles and grain refinement in the surface composite. Microstructural characterization, mechanical testing (hardness and tensile strength), and wear behaviour evaluation under different operating conditions are performed. Response surface methodology (RSM) is utilized to optimize the wear rate by considering the effects of process parameters. The results reveal a significant improvement in hardness (41.3%) and tensile strength (39.1%) of the FSP-TiC composite compared to the base alloy, attributed to the refined grain structure (6-10 µm) and uniform distribution of TiC particles. The proposed regression model accurately predicts the wear rate, with a confirmation test validating an error percentage within ± 4%. Worn surface analysis elucidates the wear mechanisms, such as shallow grooves, delamination, and oxide layer formation, influenced by the applied load, sliding distance, and sliding velocity. The enhanced mechanical properties and wear resistance are attributed to the synergistic effects of grain refinement, particle-accelerated nucleation, the barrier effect of TiC particles, and improved interfacial bonding achieved through FSP. The optimized FSP-TiC composites exhibit potential for applications in industries demanding high strength, hardness, and wear resistance.

Empowerment of Lay Mental Health Workers and Junior Psychologists Online in a Task-Shared, Rural Setting in Kerala, India.

BACKGROUND: Patients with severe mental health issues who live in isolated rural areas are difficult to reach and treat. Providing effective treatment is difficult because mental health problems are complex and require specialized knowledge from a range of professionals. Task-sharing with lay mental health workers (LMHWs) has potential but requires proper training and supervision to be effective. This article reports on the challenges and facilitators experienced in empowering LMHWs in their role, with the help of a technology supported supervision group. The study sought to understand the functioning of the Empowering Supervisory Group (ESG) in the context of junior psychologists and LMHWs in rural India, and investigate how they experienced it by exploring challenges, lessons and empowerment. METHODS: Qualitative analysis of interviews with the 22 ESG participants and their supervisors. RESULTS: A total of three discrete phases of supervision were identified where supervisors responded to the changing needs of the group. This began with building trust at a baseline level, tackling issues with competence and autonomy and finally experiencing meaning and impact through self-determination. The experience of empowerment even in an online setting was very beneficial given the challenges of working in rural areas. CONCLUSION: Empowerment based supervision of LMHWs and junior psychologists online enables a level of engagement that positions them to engage in community mental health practices with greater independence and confidence.

Rotational dynamics of CNCN by p-H2 and o-H2 collision at interstellar temperatures.

The rotational dynamics of isocyanogen (CNCN) is studied for its collision with para (p-) and ortho (o-) hydrogen (H2) in the temperature range of 1-100 K. These temperatures correspond to the cold dense molecular clouds in the interstellar medium where molecular hydrogen is the primary collider. An ab initio 4D potential energy surface (PES) is constructed keeping the two molecules under rigid rotor approximation. The PES is generated using the CCSD(T)-F12b/AVTZ level of theory. The 4D PES is further fitted into a neural network (NN) model, which can augment the surface and account for missing data points within spectroscopic accuracy. This NN-fitted PES is then expanded over a bispherical harmonics function to get radial terms, which are expressed into analytic functions. Thereafter, the cross sections (σ) are computed for rotational transitions of CNCN (j → j') using the close-coupling and centrifugal sudden methods for both p-H2 (jc = 0) and o-H2 (jc = 1) collision till 194 cm-1. In addition, p-H2 (jc = 0, 2) cross sections are also computed using the centrifugal sudden approximation method. The collisional rates are achieved by taking the Boltzmann distribution of σ over the translational energy of H2 till 100 K. Finally, the CNCN-H2 rates are compared to CNCN-He and NCCN-H2 collisional rates. Comparing even and odd transitions for the CNCN-H2 rates show a propensity toward higher rates for even transitions especially for o-H2 collisions considering low-order transitions.

Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs).

A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1H-imidazo[4,5-c]quinolin-4-amines) allosterically increase the Emax of A3AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A3ARs. The chain length, functionality, and attachment position were varied to modulate A3AR PAM activity. For example, 26 (MRS8247, p-alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's Emax and potency ([35S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A3AR PAM activity through rational design based on an extrahelical, lipidic binding site.

Sex Differences Across the Lifespan: A Focus on Cardiometabolism.

Women's health and sex differences research remain understudied. In 2022, to address the topic of sex differences, the Ludeman Family Center for Women's Health Research (LFCWHR) at the University of Colorado (LudemanCenter.org) held its third National Conference, "Sex Differences Across the Lifespan: A Focus on Metabolism." The research presentations and discussions from the 2022 conference addressed cardiometabolic sex differences across the lifespan and included sessions focusing on scientific methods with which to study sex differences, effects of estrogen on metabolism, and sex differences in cardiovascular disease-implications for women and policy among others. Over 100 participants, including basic scientists, clinical scientists, policymakers, advocacy group leaders, and federal agency leadership participated. The meeting proceedings reveal that although exciting advances in the area of sex differences have taken place, significant questions and gaps remain about women's health and sex differences in critical areas of health. Identifying these gaps and the subsequent research that will result may lead to important breakthroughs.

New species of Chalciporus and Tylopilus from India, with keys to the known species.

Two new species, Chalciporus rubrostipitatus and Tylopilus purpureus, are proposed from India based on morphological and molecular data. Chalciporus rubrostipitatus is characterized by basidiomata having purplish red to reddish pileus with subtomentose to rugose surface, whitish pileal context, round to angular pores, and reddish orange to red stipe, which is pruinose toward the apex. Tylopilus purpureus produces basidiomata having a purple to vinaceous purple pileus, whitish pore surface that changes to reddish brown on bruising, and a minutely pubescent purplish stipe. Morphological descriptions and comparisons, taxonomic keys, and results of phylogenetic analyses using sequences of the ITS (internal transcribed spacer), 28S (28S rRNA), and RPB2 (second largest subunit of RNA polymerase II) gene regions are presented.

Nickel-ion substituted hydroxyapatite matrices for metal-affinity chromatographic purification of recombinant proteins.

Hydroxyapatite (HAp) is a calcium phosphate ceramic, widely used as a matrix for protein chromatography. The crystal structure of HAp is amenable to a wide range of substitutions, thus allowing for the alteration of its properties. In this study, nickel-ion substituted HAp (NiSHAp) was synthesized using a wet-precipitation method, followed by spray drying. This resulted in the structural incorporation of nickel ions within well-defined microspheres, which were suitable for chromatographic applications. The chromatographic experiments were conducted with NiSHAp and compared with spray-dried hydroxyapatite (SHAp) matrices. Protein purification experiments were conducted using refolded recombinant L-asparaginase (L-Asp), which was produced as inclusion bodies in Escherichia coli. The results showed that NiSHAp effectively adsorbed L-Asp, which was selectively eluted using a phosphate buffer, surpassing the efficiency of imidazole-based elution. In contrast, SHAp showed weaker binding and lower selectivity. The significance of this study lies in developing a scalable NiSHAp matrix for protein purification, especially for large-scale applications. The NiSHAp matrix offers a cost-effective alternative to commercial immobilized metal affinity chromatography (IMAC) adsorbents, especially for purifying His-tagged proteins. This innovative approach exhibits the advantages of mixed-mode chromatography by combining the properties of hydroxyapatite and IMAC in a single matrix, with the potential of improved industrial-scale protein purification.

12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi after Subarachnoid Hemorrhage in Mice.

Background and Purpose: Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus 12/15-LOX is an important target to prevent delayed cerebral ischemia. Methods: SAH was induced in C57BL/6 and 12/15-LOX-/- mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. Results: In SAH mice, 12/15-LOX was upregulated in brain vascular cells and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Conclusions: Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.

Amplification of temperature extremes in Arabian Peninsula under warmer worlds.

The Paris Agreement and the Special Report on Global Warming of 1.5 °C from the Intergovernmental Panel on Climate Change (IPCC) highlighted the potential risks of climate change across different global warming levels (GWLs). The increasing occurrence of extreme high-temperature events is linked to a warmer climate that is particularly prevalent in the Arabian Peninsula (AP). This study investigates future changes in temperatures and related extremes over AP, under four GWLs, such as 1.5 °C, 2.0 °C, 3.0 °C, and 4.0 °C, with three different Shared Socioeconomic Pathways (SSPs: SSP1-2.6, SSP2-4.5, and SSP5-8.5). The study uses high-resolution datasets of 27 models from the NASA Earth Exchange Global Daily Downscaled Projections of the Coupled Model Intercomparison Project Phase 6 (NEX-GDDP-CMIP6). The results showed that the NEX-GDDP-CMIP6 individual models and their multi-model means reasonably captured the extreme temperature events. The summer maximum and winter minimum temperatures are projected to increase by 0.11-0.67 °C and 0.09-0.70 °C per decade under the selected SSPs. Likewise, the projected temperature extremes exhibit significant warming with varying degrees across the GWLs under the selected SSPs. The warm temperature extremes are projected to increase, while the cold extremes are projected to decrease under all GWLs and the selected SSPs. Overall, the findings provide a comprehensive assessment of temperature changes over AP in response to global warming, which can be helpful in the development of climate adaptation and mitigation strategies.

Enhancing brain tumor detection in MRI with a rotation invariant Vision Transformer.

Background: The Rotation Invariant Vision Transformer (RViT) is a novel deep learning model tailored for brain tumor classification using MRI scans. Methods: RViT incorporates rotated patch embeddings to enhance the accuracy of brain tumor identification. Results: Evaluation on the Brain Tumor MRI Dataset from Kaggle demonstrates RViT's superior performance with sensitivity (1.0), specificity (0.975), F1-score (0.984), Matthew's Correlation Coefficient (MCC) (0.972), and an overall accuracy of 0.986. Conclusion: RViT outperforms the standard Vision Transformer model and several existing techniques, highlighting its efficacy in medical imaging. The study confirms that integrating rotational patch embeddings improves the model's capability to handle diverse orientations, a common challenge in tumor imaging. The specialized architecture and rotational invariance approach of RViT have the potential to enhance current methodologies for brain tumor detection and extend to other complex imaging tasks.

Eating Speed Measurement Using Wrist-Worn IMU Sensors Towards Free-Living Environments.

Eating speed is an important indicator that has been widely investigated in nutritional studies. The relationship between eating speed and several intake-related problems such as obesity, diabetes, and oral health has received increased attention from researchers. However, existing studies mainly use self-reported questionnaires to obtain participants' eating speed, where they choose options from slow, medium, and fast. Such a non-quantitative method is highly subjective and coarse at the individual level. This study integrates two classical tasks in automated food intake monitoring domain: bite detection and eating episode detection, to advance eating speed measurement in near-free-living environments automatically and objectively. Specifically, a temporal convolutional network combined with a multi-head attention module (TCN-MHA) is developed to detect bites (including eating and drinking gestures) from IMU data. The predicted bite sequences are then clustered into eating episodes. Eating speed is calculated by using the time taken to finish the eating episode to divide the number of bites. To validate the proposed approach on eating speed measurement, a 7-fold cross validation is applied to the self-collected fine-annotated full-day-I (FD-I) dataset, and a holdout experiment is conducted on the full-day-II (FD-II) dataset. The two datasets are collected from 61 participants with a total duration of 513 h, which are publicly available. Experimental results show that the proposed approach achieves a mean absolute percentage error (MAPE) of 0.110 and 0.146 in the FD-I and FD-II datasets, respectively, showcasing the feasibility of automated eating speed measurement in near-free-living environments.

A pilot study of childhood-onset Takayasu arteritis using whole exome sequencing suggests oligogenic inheritance involving classical complement, collagen, and autoinflammatory pathways.

Takayasu arteritis (TA) is a chronic granulomatous inflammatory disease affecting the aorta and its branches. Paediatric TA (pTA) may present from 6 months after birth till the adolescent age group. Genetics and pathogenesis of pTA are not fully understood. Earlier studies reported monogenic mutation in NOD2, XIAP, and STAT1 genes in patients with pTA. TA, a relatively rare disease, is more common in geographical pockets, including India. We hypothesized that South Asian patients with pTA, namely, those of Indian subcontinent origin, may have clinically relevant and unique pathogenic variants involving one or more genes, especially those linked to genetically driven vasculitic illnesses, including autoinflammatory pathologies. Children with pTA fulfilling EULAR/PRINTO/PReS classification criteria and presenting with clinical symptoms to the Paediatric Rheumatology clinic of Christian Medical College, Vellore, were included. Blood samples were collected after getting informed consent from parents or guardians and assent forms from children. DNA was extracted from whole blood using the Qiagen DNA extraction kit. Initially, the common variant in Indian population, namely, ADA2 c.139G > A; p.Gly47Arg, was screened, followed by whole exome sequencing. Fourteen children were recruited for the study. Median age of patients was 11 years (4 months-14 years) with a male-to-female ratio of 4:10. Distribution of angiographic subsets by Numano's classification of included children were as follows: type 5 (n = 7), type 4 (n = 5), and type 3 (n = 2). We identified novel variants in ten different genes. This include variants in genes of classical complement pathway, namely, C2, C3, C6, C7, and C9, and other genes, namely, CYBA, SH3BP2, GUCY2C, CTC1, COL5A1, and NLPR3. Two of 14 patients have heterozygous pathogenic variants; this implies that combination of heterozygous variants in C3 and COL5A1 might lead to disease development, suggesting digenic inheritance. One patient has a homozygous variant in CYBA. None of the patients were identified to have ADA2 variants. Whole exome sequencing reveals combination of rare variants in genes C3, COL5A1, and CYBA associated with disease development in children with Takayasu Arteritis. Key Points • We identified novel variants in genes of classical complement pathway, namely, C2, C3, C6, C7, and C9, and other genes, namely, CYBA, SH3BP2, GUCY2C, CTC1, COL5A1, and NLPR3. • Two of 14 patients have heterozygous pathogenic variants in C3 and COL5A1; this may have implications in disease development, suggesting digenic inheritance. • One patient has homozygous variant in CYBA. • None of the patients were identified to have ADA2 variants.

Photoredox Catalysis by 21-Thiaporphyrins: A Green and Efficient Approach for C-N Borylation and C-H Arylation.

Photoredox catalysis provides a green and sustainable alternative for C-H activation of organic molecules that eludes harsh conditions and use of transition metals. The photocatalytic C-N borylation and C-H arylation mostly depend on the ruthenium and iridium complexes or eosin Y and the use of porphyrin catalysts is still in infancy. A series of novel 21-thiaporphyrins (A2B2 and A3B type) were synthesized having carbazole/phenothiazine moieties at their meso-positions and screened as catalysts for C-N borylation and C-H arylation. This paper demonstrates the 21-thiaporphyrin catalyzed C-N borylation and het-arylation of anilines under visible light. The method utilizes only 0.1 mol % of 21-thiaporphyrin catalyst under blue light for the direct C-N borylation and het-arylation reactions. A variety of substituted anilines were used as source for expensive and unstable aryl diazonium salts in the reactions. The heterobiaryls and aryl boronic esters were obtained in decent yields (up to 88 %). Versatility of the 21-thiaporphyrin catalyst was tested by thiolation and selenylation of anilines under similar conditions. Mechanistic insight was obtained from DFT studies, suggesting that 21-thiaporphyrin undergo an oxidative quenching pathway. The photoredox process catalyzed by 21-thiaporphyrins offers a mild, efficient and metal-free alternative for the formation of C-C, C-S, and C-Se bonds in aryl compounds; it can also be extended to borylation reaction.

Correction: Hybrid optimal-FOPID based UPQC for reducing harmonics and compensate load power in renewable energy sources grid connected system.

[This corrects the article DOI: 10.1371/journal.pone.0300145.].

Effectiveness of Plaque Removal Using Different Toothbrushes in Children - A Comparative Study.

BACKGROUND: Effective plaque control is essential for improved oral health. Advancements in mechanical plaque removal using toothbrushes still continue. One such sophisticated intervention is the app-based toothbrush, a new innovative technology that helps to track the child's brushing habits. AIM: The aim of this study is to evaluate the plaque removal efficacy of three different toothbrushes in children aged 6-8 years. METHODS: A randomized controlled clinical trial was conducted among primary school children with decayed missing filled teeth (dmft) score of ≤2. Baseline plaque score was collected using Turesky modification of the Quigley and Hein Index 1 week after oral prophylaxis. Children were randomly divided into three groups. Group I received conventional toothbrush (n = 25), group II received powered toothbrush (n = 25), and group III received app-based toothbrush (n = 25). Post-intervention plaque score, toothbrush wear and bite mark scores were done at the 15th, 30th, 45th and 90th day. Participant's opinion on their toothbrushes was evaluated using a questionnaire. RESULTS AND CONCLUSION: App-based toothbrush showed maximum plaque reduction followed by powered and conventional toothbrush. Significant reduction in plaque score was seen at 30th-, 45th- and 90th-day follow-up in group II (<0.001) and group III (<0.001). There was no appreciable difference in the toothbrush wear and bite mark score between the three groups. Children preferred app-based toothbrush in spite of the complex nature of using it.

Community pharmacists as antimicrobial resistance stewards: a narrative review on their contributions and challenges in low- and middle-income countries.

Antimicrobial resistance (AMR) is a global public health crisis that impedes the therapeutic effectiveness of available antimicrobial agents. Due to the high burden of infectious diseases and limited resources, especially trained healthcare professionals, low- and middle-income countries (LMICs) are particularly susceptible to the detrimental effects of AMR. Sometimes, as the first and last point of contact for patients seeking treatment for infections, community pharmacists can play a pivotal role in the stewardship required for AMR. This review aims to highlight the contributions made by community pharmacists in LMICs as AMR stewards. The review considers the challenges from the perspectives of limited resources, inadequate training, a lack of policies and regulations, and issues related to patient behavior. Community pharmacists in LMICs could optimize their advocacy contributions by focusing on One Health AMR stewardship. Transformational and actionable patient and population-centric antimicrobial stewardship (AMS) is feasible with the synergy of policymakers and other healthcare providers in the implementation of AMS policies and programs that support community pharmacists in their efforts to promote rational antimicrobial use.

Impact of Social Determinants of Health on Predictive Models for Outcomes After Congenital Heart Surgery.

BACKGROUND: Despite documented associations between social determinants of health and outcomes post-congenital heart surgery, clinical risk models typically exclude these factors. OBJECTIVES: The study sought to characterize associations between social determinants and operative and longitudinal mortality as well as assess impacts on risk model performance. METHODS: Demographic and clinical data were obtained for all congenital heart surgeries (2006-2021) from locally held Congenital Heart Surgery Collaborative for Longitudinal Outcomes and Utilization of Resources Society of Thoracic Surgeons Congenital Heart Surgery Database data. Neighborhood-level American Community Survey and composite sociodemographic measures were linked by zip code. Model prediction, discrimination, and impact on quality assessment were assessed before and after inclusion of social determinants in models based on the 2020 Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model. RESULTS: Of 14,173 total index operations across New York State, 12,321 cases, representing 10,271 patients at 8 centers, had zip codes for linkage. A total of 327 (2.7%) patients died in the hospital or before 30 days, and 314 children died by December 31, 2021 (total n = 641; 6.2%). Multiple measures of social determinants of health explained as much or more variability in operative and longitudinal mortality than clinical comorbidities or prior cardiac surgery. Inclusion of social determinants minimally improved models' predictive performance (operative: 0.834-0.844; longitudinal 0.808-0.811), but significantly improved model discrimination; 10.0% more survivors and 4.8% more mortalities were appropriately risk classified with inclusion. Wide variation in reclassification was observed by site, resulting in changes in the center performance classification category for 2 of 8 centers. CONCLUSIONS: Although indiscriminate inclusion of social determinants in clinical risk modeling can conceal inequities, thoughtful consideration can help centers understand their performance across populations and guide efforts to improve health equity.