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Abstract While TGF-β signaling is essential for microglial function, the cellular source of TGF-β1 ligand and its spatial regulation remains unclear in the adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-β1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-β1 ligands are important in the adult CNS. Astrocytes in MG-Tgfb1 inducible (i)KO mice show a transcriptome profile that is closely aligned with an LPS-associated astrocyte profile. Additionally, using sparse mosaic single-cell microglia KO of TGF-β1 ligand we established an autocrine mechanism for signaling. Here we show that MG-Tgfb1 iKO mice present cognitive deficits, supporting that precise spatial regulation of TGF-β1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

Abstract Historically, investigators have not differentiated between patients with and without hemorrhagic transformation (HT) in large core ischemic stroke at risk for life-threatening mass effect (LTME) from cerebral edema. Our objective was to determine whether LTME occurs faster in those with HT compared to those without. We conducted a two-center retrospective study of patients with ≥ 1/2 MCA territory infarct between 2006 and 2021. We tested the association of time-to-LTME and HT subtype (parenchymal, petechial) using Cox regression, controlling for age, mean arterial pressure, glucose, tissue plasminogen activator, mechanical thrombectomy, National Institute of Health Stroke Scale, antiplatelets, anticoagulation, temperature, and stroke side. Secondary and exploratory outcomes included mass effect-related death, all-cause death, disposition, and decompressive hemicraniectomy. Of 840 patients, 358 (42.6%) had no HT, 403 (48.0%) patients had petechial HT, and 79 (9.4%) patients had parenchymal HT. LTME occurred in 317 (37.7%) and 100 (11.9%) had mass effect-related deaths. Parenchymal (HR 8.24, 95% CI 5.46–12.42, p

IntroductionIllicit drug use, particularly the synthetic opioid fentanyl, presents a significant global health challenge. Previous studies have shown that fentanyl enhances viral replication; yet, the mechanisms by which it affects HIV pathogenesis remain unclear. This study investigated the impact of fentanyl on HIV replication in CD4+ T lymphocytes.MethodsCD4+ T lymphocytes from HIV-negative donors were activated, infected with HIVNL4-3, and treated with fentanyl. HIV proviral DNA and p24 antigen expression were quantified using real-time PCR and ELISA, respectively. Single-cell RNA libraries were analyzed to identify differentially expressed genes.ResultsResults indicated that fentanyl treatment increased HIV p24 expression and proviral DNA levels, and naltrexone mitigated these effects. Single-cell RNAseq analysis identified significantly altered gene expression in CD4+ T lymphocytes.DiscussionThe results of our findings suggest that fentanyl promotes HIV replication ex vivo, emphasizing the need for a deeper understanding of opioid-virus interactions to develop better treatment strategies for individuals with HIV and opioid use disorder.

BackgroundMicrosatellite instability (MSI) secondary to mismatch repair (MMR) deficiency is characterized by insertions and deletions (indels) in short DNA sequences across the genome. These indels can generate neoantigens, which are ideal targets for precision immune interception. However, current neoantigen databases lack information on neoantigens arising from coding microsatellites. To address this gap, we introduce The MicrOsatellite Neoantigen Discovery Tool (MONET).MethodMONET identifies potential mutated tumor-specific neoantigens (neoAgs) by predicting frameshift mutations in coding microsatellite sequences of the human genome. Then MONET annotates these neoAgs with key features such as binding affinity, stability, expression, frequency, and potential pathogenicity using established algorithms, tools, and public databases. A user-friendly web interface (https://monet.mdanderson.org/) facilitates access to these predictions.ResultsMONET predicts over 4 million and 15 million Class I and Class II potential frameshift neoAgs, respectively. Compared to existing databases, MONET demonstrates superior coverage (>85% vs.

This paper deals with Network Slicing-based 5G Networks. A network slice can be defined as a set of network and virtual network function (VNF) resources deployed across multiple independent infrastructure provider domains. Such multi-domain 5G deployments pose challenges since the domains would not share internal resource allocation details. Slice demands and QoS requirements tend to vary dynamically and must be satisfied by scaling the allocated VNF resources. In this paper, we use the federated learning approach in which the training data remains within the respective domains, while the system learns a shared model by aggregating locally-computed updates. Two state-of-the-art deep learning models, namely Long Short-Term Memory (LSTM) and Gated recurrent units (GRU) are used for forecasting. We present a comparison of the performance of the proposed federated system with the centralized system. Further, synthetic data in each domain has been generated using Generative Adversarial Networks (GAN) to improve the forecasting results. A Python-based discrete event simulator model of the proposed auto-scaling system was written. The experiments were used to study the performance of scaling and non-scaling systems across various workloads, and proactive approach’s effectiveness over reactive scaling. The average queue length was reduced by scaling, compared to a non-scaling system, by around 75% to 82% for different traffic type mixes. The results show that the proactive scaling system outperformed the reactive system in terms of the time required to set up new instances by around 70%.

Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.

Here, we employ polymer physics models of chromatin to investigate the 3D folding of a 2 Mb wide genomic region encompassing the human LTN1 gene, a crucial DNA locus involved in key cellular functions. Through extensive Molecular Dynamics simulations, we reconstruct in silico the ensemble of single-molecule LTN1 3D structures, which we benchmark against recent in situ Hi-C 2.0 data. The model-derived single molecules are then used to predict structural folding features at the single-cell level, providing testable predictions for super-resolution microscopy experiments.

In porous water filters, the transport and entrapment of contaminants can be modeled as a classic mass transport problem, which employs the conventional convection–dispersion equation to predict the transport of species existing in trace amounts. Using the volume-averaging method (VAM), the upscaling has revealed two possible macroscopic equations for predicting contaminant concentrations in the filters. The first equation is the classical convection–dispersion equation, which incorporates a total dispersion tensor. The second equation involves an additional transport coefficient, identified as the adsorption-induced vector. In this study, the aforementioned equations were solved in 1D for column tests using 3D unit cells. The simulated breakthrough curves (BTCs), using the proposed micro–macro-coupling-based VAM model, are compared with the direct numerical simulation (DNS) results based on BCC-type unit cells arranged one-after-another in a daisy chain manner, as well as with three previously reported experimental works, in which the functionalized zeolite and zero-valent iron fillings were used as an adsorbent to remove phosphorous and arsenic from water, respectively. The disagreement of VAM BTC predictions with DNS and experimental results reveals the need for an alternative closure formulation in VAM. Detailed investigations reveal time constraint violations in all the three cases, suggesting this as the main cause of VAM’s failure.

Abstract This paper reports on a superhydrophilic to superhydrophobic transformation of TiO2 nanoparticles doped zinc phosphate coating systems when a hydrophobic agent is applied. The objective of the reported research was to demonstrate the feasibility of a neutron imaging technique for evaluating the performance of the proposed nano-coating system and reveal the differences in water ingress mechanisms which are specific to plain, superhydrophilic, overhydrophobic, and superhydrophobic specimens. The engineered nano-coatings were designed to improve hydrophobic response with inducing the required roughness pattern and introducing the photocatalytic performance. The effectiveness of the coatings was assessed using high-resolution neutron imaging (HR-NI), SEM, CLSM, and XRD techniques. High-resolution neutron imaging revealed that the superhydrophobic coating effectively prevents water ingress into the porous ceramic substrate, whereas water imbibition was observed for superhydrophilic coating during the test duration. The moisture transport kinetics was modeled based on the Richards equation for plain ceramic and superhydrophilic specimens using obtained penetration depth values from HR-NI. SEM, CLSM, and XRD studies confirm the desired TiO2-doped zinc phosphate coatings with increased surface roughness, photocatalytic reactivity, and chemical bonding. The research results demonstrated that a two-layer superhydrophobic system is capable of creating effective water barriers on the surface with contact angles of 153°, which remained effective even after surface damage.

Background: This study aimed to investigate the level of guideline adherence for cardiometabolic health monitoring for patients prescribed antipsychotic medicines in UK primary care. Methods: In this population-based retrospective open cohort study, we used dataset of patients from the IQVIA Medical Research Data (IMRD) database between 1st January 2003 to 31st December 2018. Clinical Read codes were used to identify a cohort of adult patients with a diagnosis of Schizophrenia and at least four prescriptions of an anti-psychotic medication within 12 months of diagnosis. We then extracted data in relation to monitoring of cardiometabolic parameters (body compositions, lipids, and glucose outcomes) at baseline, then at six weeks, 12 weeks, and then 12 months. The frequency of outcome monitoring was described using descriptive statistics. Findings: A total of 11,435 patients were eligible and of them (n = 9707; 84·8%) were prescribed second-generation antipsychotics (SGAs). Only a small portion of the cohort (≈2·0%) received complete monitoring (at time points) for certain outcomes. Just over half the patients (n = 6599, 52%) had evidence of any cardiometabolic baseline testing for any of the study outcomes and the high majority had at least one abnormal lab value at baseline (n = 4627, 96·7%). Interpretation: In UK primary care, cardiometabolic monitoring practices among patients prescribed antipsychotics remain suboptimal. There is a need to promote guideline adherence to prevent adverse outcomes in antipsychotic users.

Introduction Breast cancer is the most common cancer in women in India and accounts for 14% of all cancers in women. Rise in mortality is due to lack of awareness and proper screening. Mammography and presently available serum biomarkers have low sensitivity and specificity. In our quest to identify a better biomarker, we studied mammaglobin (MAM) in patients with breast cancer and benign breast tumors.

Guava is an exotic fruit crop in India, and its occurrence in wild forests in the mid-hills of the Himalayas is a rare and unique phenomenon in its distribution. In the Ramganga valley of Pithoragarh district, Uttarakhand, a naturalized population of guava (in wild habitat) was chanced upon beside cultivated guava, hence a study was conducted to assess the population structure, phytosociology, diversity distribution patterns, and fruit variability of the guavas. Various ecological parameters like frequency, density, abundance, and A/F ratio were used to study the guava and associated species including tree seedlings in five selected sites. The highest Shannon diversity values (H = 0.367) for guava were found at Pipaltar village. Significant variability was recorded for the fruit color (pale yellow, dark yellow, pink, and whitish), fruit shape (long, round to pear-shaped), fruit length, fruit diameter, fruit weight, pulp color (white to pink), fruit maturity, and total soluble solids (TSS) content of fruits sampled from different sites. The population of maximum similarities and divergence was categorized. The present study highlights that guava is regenerating successfully in the mid-hills of Uttarakhand and that the introduction of guava in the region is not affecting the diversity of other indigenous species.

Lysophosphatidic acid (LPA) is a lipid mediator that binds to G-protein-coupled receptors, eliciting a wide variety of responses in mammalian cells. Lyso-phospholipids generated via phospholipase A2 (PLA2) can be converted to LPA by a lysophospholipase D (lyso-PLD). Secreted lyso-PLDs have been studied in more detail than membrane-localized lyso-PLDs. This study utilized in vitro enzyme assays with fluorescent substrates to examine LPA generation in membranes from multiple mammalian cell lines (PC12, rat pheochromocytoma; A7r5, rat vascular smooth muscle; Rat-1, rat fibroblast; PC-3, human prostate carcinoma; and SKOV-3 and OVCAR-3, human ovarian carcinoma). The results show that membranes contain a lyso-PLD activity that generates LPA from a fluorescent alkyl-lyso-phosphatidylcholine, as well as from naturally occurring acyl-linked lysophospholipids. Membrane lyso-PLD and PLD activities were distinguished by multiple criteria, including lack of effect of PLD2 over-expression on lyso-PLD activity and differential sensitivities to vanadate (PLD inhibitor) and iodate (lyso-PLD inhibitor). Based on several lines of evidence, including siRNA knockdown, membrane lyso-PLD is distinct from autotaxin, a secreted lyso-PLD. PC-3 cells express GDE4 and GDE7, recently described lyso-PLDs that localize to membranes. These findings demonstrate that membrane-associated lyso-D activity, expressed by multiple mammalian cell lines, can contribute to LPA production.

Background: Snakebite remains a significant public health problem worldwide, particularly in rural areas with unexpected morbidity and mortality. This study evaluated the clinical, laboratory profile and outcomes in children with snake bites from Eastern India. Methods: This was a retrospective case record-based study between January 2017 and December 2021. The clinical features, complications, laboratory profiles and outcomes were analysed. Results: Thirty children with snake bites were admitted during this study period. There was a male predominance with a ratio of 2.3:1. The mean age of presentation was 10.4 years. About 60% of bites occurred during the rainy season between July and September. Most bites (96%) were on lower limbs, predominantly showing vasculotoxic features followed by neurotoxic and a combined presentation. In this study, around 53% received anti-snake venom (ASV) before reaching our centre; the median time to reach our centre was 13 h. Complications such as acute kidney injury (AKI), cellulitis, shock and coagulation abnormalities were common in those who arrived early (before 6 h) than in those who reached late (after 6 h). Similarly, the mean duration of hospital stay was less for those seeking medical attention early as compared to those reaching late for treatment (4.7 days vs. 7.2 days). Twenty-six out of 30 (86.7%) were discharged without any sequelae, 3 (10%) children were left against medical advice and one died. Conclusions: Snakebite remains a major health problem in children causing significant morbidity and mortality. Children, in general, especially males, are particularly vulnerable because of their playful and explorative nature and considerable time spent in outdoor activities. Preventive measures, education about avoiding traditional first aid methods and early administration of ASV reduce complications, duration of hospital stay and avoid the use of antibiotics.

In 5G-and-beyond networks, the concept of Network Slicing is used to support multiple independent and co-existing logical networks on a physical network infrastructure. The infrastructure provider (InP) owns the set of virtual and physical resources that are used to support the tenant slice requests. Each slice request specifies a service level agreement (SLA) that contains the required slice-level resources (computation and communication) and the revenue provided by the tenant. Due to limited resources, the InP cannot accommodate all requests made by the tenants. In general, it has been found that tenants tend to overestimate their resource demands (e.g., for 5G Core computation) to reduce possible SLA violations. In this paper, we consider two major slice types: Elastic (low priority and low revenue) and Inelastic (high priority and high revenue). We apply the concept of overbooking, where the InP accepts more slices while considering slice priorities in order to maximize the overall revenue and utilization. We consider a multi-tenant environment and propose a slice admission system named PRLOV, which is based on Reinforcement Learning (RL) and prediction methods. The system predicts the future resource demands of Elastic slices and applies an opportunistic overbooking technique to overbook InP for accepting more slices. In addition, the admission decision is formulated as an Markov Decision Process (MDP) problem and solved using standard RL techniques (Policy Iteration, Q-Learning, DQN). The performance of our proposed work is compared against three other heuristics (Basic, Prediction, PRL) that do not use overbooking. Data traces from the Materna data center networks were used for prediction purposes. The important performance metrics measures include InP total revenue, the acceptance rate of respective slices and overall resource utilization for different slices. The results show that the proposed work significantly outperforms the other mechanisms in terms of revenue gain and resource utilization. Simulation results show that PRLOV provides a revenue gain of 6%, 26%, and 102% compared to the PRL, Prediction and Basic scheme.

Abstract Background Obstructive sleep apnea (OSA) is a serious health condition that affects approximately 30-50% of older adults and contributes to risk for cardiometabolic disorders and dementia. Despite the well-documented role of partners in treatment seeking and adherence to positive airway pressure (PAP), treatments for OSA have nearly exclusively focused on the patient and current treatments for OSA do not address co-existing sleep problems such as insomnia that are prevalent in both patients with OSA and their partners. Therefore, the goal of this study is to develop and test a novel couples-based sleep health intervention to promote adherence to PAP and improve sleep health of the couple. Methods We are conducting a two-arm, parallel group, single blind, randomized controlled pilot/feasibility trial to compare our novel couples-based sleep health intervention (We-PAP) to an information control group (IC). We-PAP is based on a transdiagnostic model and uses a dyadic approach including increasing effective partner support, communication skills, and couple-level goal-setting. We-PAP involves 3 sessions and delivered via telehealth in weekly sessions. The IC includes standardized patient educational materials. Both groups receive the usual follow-up with their medical team. The study involves assessments at pre-treatment, post-intervention (approximately 1 month after starting PAP and completing We-PAP sessions or IC) and 3 months after starting PAP. Our main outcomes are feasibility and acceptability ratings. Secondary outcomes include comparing We-PAP to IC for PAP adherence, sleep quality (self-report and objective) and cognitive measures. Discussion We-PAP is the first couples-based transdiagnostic sleep health intervention for patients with OSA and their partners. Results of this study will be used to inform the design of a subsequent fully powered clinical trial. If successful, this intervention could significantly advance current clinical practice in the treatment of OSA and sleep health more comprehensively in older adults. Moreover, this intervention may be useful for improving sleep in other aging populations with multiple sleep and other health problems, including patients with chronic illnesses or those at risk for Alzheimer’s disease and their caregivers. Trial registration NCT04759157 . Date of registration: February 8, 2021. URL of trial registry record.

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR–/–) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.

BackgroundRecent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients.MethodsNormal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled ‘Naproxen Study’ were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens.ResultsUsing data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen.ConclusionsOur findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.

This review paper delves into the nuanced world of combustion in energy generation, exploring the different kinds and their respective influences and utilization. It spans from complete type to explosive combustion, each imparting specific features, environmental implications, and technological advancements. Complete-type combustion, renowned for its cleanliness, contrasts sharply with the hazardous incomplete combustion. Whereas, rapid combustion is extremely good for enhancing engine performance, and spontaneous combustion is marked by its natural incidence without outside triggers. Explosive combustion, prominent by its rapid response rates, underscores the complexity and risks inherent in certain combustion techniques. The paper similarly investigates catalysts, fuel enhancements, and technological innovations aimed toward optimizing combustion performance and reducing environmental detriments. This complete review presents a deep dive into the combustion mechanisms, their utilization, and the ongoing research aimed at mitigating their environmental affects while enhancing efficiency in energy generation systems.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and multiple endocrine neoplasia-β (MENβ) are two long noncoding RNAs upregulated in multiple cancers, marking these RNAs as therapeutic targets. While traditional small-molecule and antisense-based approaches are effective, we report a locked nucleic acid (LNA)-based approach that targets the MALAT1 and MENβ triple helices, structures comprised of a U-rich internal stem-loop and an A-rich tract. Two LNA oligonucleotides resembling the A-rich tract (i.e., A9GCA4) were examined: an LNA (L15) and a phosphorothioate LNA (PS-L15). L15 binds tighter than PS-L15 to the MALAT1 and MENβ stem loops, although both L15 and PS-L15 enable RNA•LNA-RNA triple-helix formation. Based on UV thermal denaturation assays, both LNAs selectively stabilize the Hoogsteen interface by 5–13 °C more than the Watson–Crick interface. Furthermore, we show that L15 and PS-L15 displace the A-rich tract from the MALAT1 and MENβ stem loop and methyltransferase-like protein 16 (METTL16) from the METTL16-MALAT1 triple-helix complex. Human colorectal carcinoma (HCT116) cells transfected with LNAs have 2-fold less MALAT1 and MENβ. This LNA-based approach represents a potential therapeutic strategy for the dual targeting of MALAT1 and MENβ.

Abstract Rationale While nasal brushing transcriptomics can identify disease subtypes in chronic pulmonary diseases, it is unknown whether this is true in pediatric acute respiratory distress syndrome (PARDS). Objectives Determine whether nasal transcriptomics and methylomics can identify clinically meaningful PARDS subgroups that reflect important pathobiological processes. Methods Nasal brushings and serum were collected on days 1, 3, 7, and 14 from control and PARDS subjects from two centers. PARDS duration was the primary endpoint. Measurements and main results Twenty-four control and 39 PARDS subjects were enrolled. Two nasal methylation patterns were identified. Compared to Methyl Subgroup 1, Subgroup 2 had hypomethylation of inflammatory genes and was enriched for immunocompromised subjects. Four transcriptomic patterns were identified with temporal patterns indicating injury, repair, and regeneration. Over time, both inflammatory (Subgroup B) and cell injury (Subgroup D) patterns transitioned to repair (Subgroup A) and eventually homeostasis (Subgroup C). When control specimens were included, they were largely Subgroup C. In comparison with 17 serum biomarkers, the nasal transcriptome was more predictive of prolonged PARDS. Subjects with initial Transcriptomic Subgroup B or D assignment had median PARDS duration of 8 days compared to 2 in A or C (p = 0.02). For predicting PARDS duration ≥ 3 days, nasal transcriptomics was more sensitive and serum biomarkers more specific. Conclusions PARDS nasal transcriptome may reflect distal lung injury, repair, and regeneration. A combined nasal PCR and serum biomarker assay could be useful for predictive and diagnostic enrichment. Trial registration Clinicaltrials.gov NCT03539783 May 29, 2018.

Application of intelligent data analytics using machine learning in management of 5G networks can enable autonomous networking capabilities in 5G networks. This paper describes the design and implementation of CygNet MaSoN, a management system supporting advanced aggregation and analytics features combined with machine learning. The system supports detection of anomalous network behaviour, detection of degradation in network performance and service quality and also supports resource optimization. The main objective is to achieve self-organizing and closed loop automation functionalities expected as part of autonomous functioning of 5G networks. Details of the system architecture and components are presented. Three real-life use cases implemented on this system are then described. Machine learning models built and synthetic data generation methods adopted are presented with the features considered. The results obtained using the MaSoN system are also presented to demonstrate the effectiveness of the system in 5G network operations.

In previous study, we showed that nucleolar protein 66 (NO66) is a chromatin modifier and negatively regulates Osterix activity as well as mesenchymal progenitor differentiation. Genetic ablation of the NO66 (RIOX1) gene in cells of the Prx1-expressing mesenchymal lineage leads to acceleration of osteochondrogenic differentiation and a larger skeleton in adult mice, whereas mesenchyme-specific overexpression of NO66 inhibits osteochondrogenesis resulting in dwarfism and osteopenia. However, the impact of NO66 overexpression in cells of the osteoblast lineage in vivo remains largely undefined. Here, we generated osteoblast-specific transgenic mice overexpressing a FLAG-tagged NO66 transgene driven by the 2.3 kB alpha-1type I collagen (Col1a1) promoter. We found that overexpression of NO66 in cells of the osteoblast lineage did not cause overt defects in developmental bones but led to osteoporosis in the long bones of adult mice. This includes decreased bone volume (BV), bone volume density (bone volume/total volume, BV/TV), and bone mineral density (BMD) in cancellous compartment of long bones, along with the accumulation of fatty droplets in bone marrow. Ex vivo culture of the bone marrow mesenchymal stem/stromal cells (BMSCs) from adult Col1a1-NO66 transgenic mice showed an increase in adipogenesis and a decrease in osteogenesis. Taken together, these data demonstrate a crucial role for NO66 in adult bone formation and homeostasis. Our Col1a1-NO66 transgenic mice provide a novel animal model for the mechanistic and therapeutic study of NO66 in osteoporosis.

Summary: Previous work in our laboratory has shown that mutations in prickle (pk) cause myoclonic-like seizures and ataxia in Drosophila, similar to what is observed in humans carrying mutations in orthologous PRICKLE genes. Here, we show that pk mutant brains show elevated, sustained neuronal cell death that correlates with increasing seizure penetrance, as well as an upregulation of mitochondrial oxidative stress and innate immune response (IIR) genes. Moreover, flies exhibiting more robust seizures show increased levels of IIR-associated target gene expression suggesting they may be linked. Genetic knockdown in glia of either arm of the IIR (Immune Deficiency [Imd] or Toll) leads to a reduction in neuronal death, which in turn suppresses seizure activity, with oxidative stress acting upstream of IIR. These data provide direct genetic evidence that oxidative stress in combination with glial-mediated IIR leads to progression of an epilepsy disorder.

This article is a tribute and homage to Gerard Chaouat who invited me to contribute this article. My years in France have remained very memorable to me. Reviewed briefly is the vaccine that was made against human chorionic gonadotropin (hCG) to prevent unwanted pregnancy in sexually active women. It has now been developed as a genetically engineered recombinant vaccine and passed onto industry for its production under good manufacturing practices (GMP) conditions for confirmatory trials. The trials have received the approval of the Drugs Controller General of India. The trials have started but have been interrupted by the coronavirus disease 2019 (COVID-19) pandemic. This vaccine is likely to have another highly beneficial application in the treatment of cancers expressing ectopically hCG.

A simple and efficient protocol for the construction of 1-aminoisoquinolines was achieved by treating 2-(2-oxo-2-phenylethyl)benzonitriles with amines in the presence of Me3Al. The reaction proceeds via a domino nucleophilic addition with subsequent intramolecular cyclisation. This method provides a wide variety of substituted 1-aminoisoquinolines with good functional group tolerance. Furthermore, the synthetic utility of this protocol was demonstrated in the successful synthesis of the antitumor agent CWJ-a-5 in gram scale.

Aims: Periodontal disease and domestic abuse (DA) are significant public health problems. Previous cross-sectional evidence indicates an association between DA exposure and development of periodontal disease. There have been no large-scale cohort studies exploring this relationship in a UK-setting. Our aim was to conduct a population-based retrospective open cohort study to explore the association between DA exposure and the subsequent development of general practitioner (GP)-coded periodontal disease. Materials and methods: We undertook a retrospective open-cohort study using the IQVIA Medical Research Database (IMRD) UK database between the 1st January 1995 to 31st January 2021. Women (aged 18 years and over) exposed to DA were matched by age, deprivation, and smoking status to up to 4 unexposed women, all of whom had no pre-existing record of periodontal disease. Cox regression analysis was used to calculate crude and adjusted hazard ratios (HRs) to describe the risk of developing periodontal disease in the exposed group. Results: 23429 exposed patients were matched to 69815 unexposed patients. During the study period, 78 exposed patients had developed GP-recorded periodontal disease compared to 154 in the unexposed group, translating to an IR of 94.18 per 100,000 person years (py) and 54.67 per 100,000 py respectively. Following adjustment for key covariates, this translated to an aHR of 1.74 (95% CI 1.31–2.32), which was robust during our sensitivity analysis. Conclusions: Our results provide further evidence that DA exposure is associated with increased risk of developing periodontal disease. There is a need for swift implementation of public health policies to improve surveillance, reporting, and prevention of DA.

Abstract A ‘shadow pandemic’ of domestic violence and abuse (DVA) has emerged secondary to strict public health measures containing the spread of SARS-CoV-2. Many countries have implemented policies to allow the free movement of DVA survivors in attempts to minimise their exposure to abusive environments. Although these policies are well received, as a result there is a possibility of increased COVID-19 transmission within this vulnerable group who are not currently prioritised for vaccination. Therefore, we aimed to compare the risk of developing suspected or confirmed COVID-19 in women (aged over 16 years) exposed to DVA against age-sex-matched unexposed controls, following adjustment for known COVID-19 risk factors. A population-based retrospective open cohort study was undertaken between the 31 January 2020 and 28 February 2021 using ‘The Health Improvement Network’ database. We identified 10,462 eligible women exposed to DVA who were matched to 41,467 similarly aged unexposed women. Following adjustment for key covariates, women exposed to DVA were at an increased risk (aHR 1.57; 95% CI 1.29–1.90) of suspected/confirmed COVID-19 compared to unexposed women. These findings support previous calls for positive policy action improving DVA surveillance and prioritising survivors for COVID-19 vaccination.

SARS-CoV-2 vaccines are needed to fight the pandemic. Here, authors show protective efficacy and immunogenicity of the inactivated SARS-CoV-2 vaccine BBV152 in rhesus macaques. This vaccine is currently in clinical development.

Abstract This study focuses on the improvement of the power quality in interconnected power distribution systems using connected microgrids. The power quality issues at the secondary distribution level are addressed using a unified power quality conditioner, which aids in controlling voltage imbalances and current harmonics. Further, a power control method, adaptive network‐based fuzzy inference system, is proposed as a global solution by installing independent compensating devices at the point of common coupling. The proposed strategy can improve the power quality in traditional installations because the proposed unified power quality conditioner method maximizes power utilization and improves the efficiency of the system. The microgrids integrate renewable energy sources, which generate green energy with low loss. Case studies, a prototype, and simulations via MATLAB/Simulink are used to validate the proposed method, and the results prove the enhancement in power quality control. The proposed control strategy had a response time of 0.3 s, reduced peak voltage distortions, and restored the voltage at the interconnecting point to a normal level. The total harmonic distortion of currents decreased from 21.13% to 14.74% when a PI technique was used to control the UPQC‐P, and the proposed adaptive network‐based fuzzy inference system‐based UPQC‐P reduced the harmonic content to 2.43% from 21.13%.

Solid dispersion of poorly soluble APIs is known to be a promising strategy to improve dissolution and oral bioavailability. To facilitate the development and commercialization of a successful solid dispersion formulation, understanding of intermolecular interactions between APIs and polymeric carriers is essential. In this work, first, we assessed the molecular interactions between various delayed-release APIs and polymeric excipients using molecular dynamics (MD) simulations, and then we formulated API solid dispersions using a hot melt extrusion (HME) technique. To assess the potential API–polymer pairs, three quantities were evaluated: (a) interaction energy between API and polymer [electrostatic (Ecoul), Lenard-Jones (ELJ), and total (Etotal)], (b) energy ratio (API–polymer/API–API), and (c) hydrogen bonding between API and polymer. The Etotal quantities corresponding to the best pairs: NPX-Eudragit L100, NaDLO–HPMC(P), DMF–HPMC(AS) and OPZ–HPMC(AS) were −143.38, −348.04, −110.42, and −269.43 kJ/mol, respectively. Using a HME experimental technique, few API–polymer pairs were successfully extruded. These extruded solid forms did not release APIs in a simulated gastric fluid (SGF) pH 1.2 environment but released them in a simulated intestinal fluid (SIF) pH 6.8 environment. The study demonstrates the compatibility between APIs and excipients, and finally suggests a potential polymeric excipient for each delayed-release API, which could facilitate the development of the solid dispersion of poorly soluble APIs for dissolution and bioavailability enhancement.

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm3 and 2.83 mm3, respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans.

Introduction: Recently, Dental Council of India directed all the teaching dental institutions in the country to set up tobacco cessation centers (TCC). International experiences suggest that there are many barriers for the provision of tobacco cessation counseling at dental clinics. In this context, it is important to understand the dental students' attitudes toward this initiative of tobacco cessation counseling at dental settings. Materials and Methods: This qualitative study to document the dental students' perspectives toward the provision of tobacco cessation counseling using focus group interviews was conducted in two teaching dental institutions in the state of Andhra Pradesh, India. 133 house surgeons from two dental institutions participated in the study and were interviewed as 13 focus groups. MAXQDA (version 12, VERBI GmbH, Berlin, Germany) was used for data analysis. All the interviews were audio recorded and the transcripts were open coded by three independent investigators. Results: The response rate in this study was 78.45%. The following themes were extracted from the views and opinions shared by the students: the reluctance of patients to discuss tobacco-related problems; tobacco use among students discouraging them to actively participate in counseling; an opinion that dental clinics are not suitable for the provision of tobacco cessation counseling; belief among students that they are not qualified enough. Conclusion: The directives given by the Ministry of Health and Family Welfare in association with Dental council of India to set up TCC at every teaching dental institution are laudable and demonstrate the commitment at policy level toward bringing down tobacco consumption in the country. However, few reforms need to be made in the curriculum to better execute the delegated responsibilities, which include orientation programs for dental students on the scope of the dental profession and workshops on tobacco cessation counseling.

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.

Summary: Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genome stability and transcription. Heat-induced reduction in H4K16ac was detected in humans, Drosophila, and yeast, indicating that this is a highly conserved response. The examination of histone deacetylase recruitment to chromatin after heat-shock identified SIRT1 as the major deacetylase subsequently enriched at gene-rich regions. Heat-induced SIRT1 recruitment was antagonized by chromatin remodeler SMARCAD1 depletion and, like hyperthermia, the depletion of the SMARCAD1 or combination of the two impaired DNA end resection and increased replication stress. Altered repair protein recruitment was associated with heat-shock-induced γ-H2AX chromatin changes and DSB repair processing. These results support a novel mechanism whereby hyperthermia impacts chromatin organization owing to H4K16ac deacetylation, negatively affecting the HR-dependent DSB repair.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

The northward migration of the intertropical convergence zone (ITCZ) is a significant feature of the West African (WA) monsoon. An accurate simulation of ITCZ migration is essential for the realistic representation of WA precipitation in global coupled models. In this study, we employ the energetics and dynamics framework with a subset of CMIP6 models to investigate the bias in the simulated WA precipitation. Models were found to simulate more local positive (negative) shortwave cloud radiative forcing (SWCRF) in the Southeastern Atlantic Ocean (over the African continent). The effect of the excess local SWCRF is linked to the stagnation of the ITCZ latitudinal migration and the associated biases in the asymmetry index of precipitation. In the models, there is more (less) moist static energy in the lower (mid and upper) troposphere than in the reanalysis. The worst models have a stronger bias, especially over land. The vertical transport of moisture is confined to the boundary layer in the worst model ensemble. In most cases, the high-resolution coupled models show substantial northward migration of the ITCZ compared to the low-resolution models. Furthermore, the best-performing models capture local circulation and energetic processes more accurately than the worst-performing models.

Proliferative Diabetic Retinopathy (PDR) is a retinal disease that can affect people with diabetes and cause visual loss if left untreated. Detecting neovascularization, an abnormal growth of veins in the retina, can be difficult due to its irregular pattern and small size. To improve detection, deep learning algorithms, such as MobileNet, are being used to automate complex object recognition. In a neovascularization affirmation technique based on transfer learning, multiple pre-trained models were built during the training phase, including MobileNet, CNN with SVM, AlexNet, GoogleNet, ResNet, ResNet18, and ResNet and GoogleNet models. Machine learning models for HOG feature extraction were also implemented, such as Random Forest, Decision Tree, Gradient Boosting, Support Vector Classifier, and Voting Classifier. MobileNet performed the best and was used to build the model for predicting results from user-uploaded images.

Abstract Aerodigestive tract fish bones are common and often utilize significant hospital resources. Some pharyngeal fish bones can be retrieved with basic equipment thus clinicians should exhaust all simple techniques including that described in this paper.

Summary: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation. : In this article, Laflamme and colleagues show that the transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) partially remuscularizes the scar of infarcted and appropriately immunosuppressed pigs. hESC-CM recipients exhibited frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. These graft-related tachyarrhythmias were found to be due to focal mechanisms rather than macro-reentry. Keywords: human embryonic stem cell-derived cardiomyocytes, pluripotent stem cells, myocardial infarction, ventricular tachyarrhythmias, electroanatomical mapping, MRI

(E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo [d]imidazole-5-carbohydrazides (5a-r) have been synthesized from 7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbohydrazide (3) by condensing with different aromatic aldehydes (4a-r). Title compounds (5a-r) were evaluated for in vitro antioxidant activity and based on their potential for antioxidant property, selected compounds 5d and 5m-p were screened for in vivo anti-inflammatory and analgesic activity. The results indicate that the compound 5o and 5p are effective against anti-inflammatory and analgesic activity. The biological data was further supported by molecular docking studies, which revealed the binding pattern and the affinity of the molecules in the active site of COX-2.

Anita Nath,1 Shubhashree Venkatesh,1 Sheeba Balan,1 Chandra S Metgud,2 Murali Krishna,3 Gudlavalleti Venkata Satyanarayana Murthy4,51Indian Institute of Public Health Hyderabad-Bangalore Campus, Public Health Foundation of India, Bangalore, Karnataka, India; 2Department of Community Medicine, J.N. Medical College, KLE University, Belgavi, Karnataka, India; 3FRAMe, Mysore, Karnataka, India; 4Indian Institute of Public Health Hyderabad, Public Health Foundation of India, Hyderabad, Telangana, India; 5Department of Clinical Research, International Center for Evidence in Disability, London School of Hygiene and Tropical Medicine, London, UKBackground: A pregnant woman undergoes physiological as well as psychological changes during this phase of life during which anxiety is a commonly faced mental condition. There is sufficient evidence on the association of pregnancy specific anxiety with adverse pregnancy outcomes. Studies on anxiety during pregnancy from low and middle income countries are limited.Methods: This study included 380 pregnant women, having a confirmed pregnancy of less than 24 weeks without any obstetric complication, who were availing of antenatal care at a public sector hospital in Bangalore city. Pregnancy-related thoughts (PRT) scale was used to screen for anxiety. Details pertaining to sociodemographic data, obstetric history, psychosocial factors including social support, marital discord, domestic violence, consanguinity, history of catastrophic events, history of mental illness, current presence of depression and anxiety was obtained by means of electronic data capture using an Android-based App.Results: Out of 380 pregnant women, 195 (55.7%) were found to have pregnancy-related anxiety. Lower socioeconomic status, low social support and depression emerged as significant determinants of anxiety.Conclusion: The prevalence of anxiety was fairly high in the study population and isp therefore an important public health concern. Pregnancy-related anxiety must be identified early during routine antenatal care to prevent any untoward pregnancy outcomes.Keywords: anxiety, pregnancy, prevalence, determinants, India

Context: Oral submucous fibrosis (OSMF) is characterized by excessive collagen production in the submucosa leading to progressive fibrosis of the oral mucosa and atrophic changes of the epithelium. Aim: To clinically evaluate the efficacy of intralesional injections of placental extract (2ml) in comparison to intralesional injections of triamcinolone acetonide (40mg/ml; 1ml) in the management of OSMF patients. Methodology: This randomized, parallel-group, single-blinded outcome-based study, consisted of 40 diagnosed cases of OSMF. The patients were divided into two groups of 20 each in placental extract group and triamcinolone acetonide group. Patients were administered test medications weekly in respective groups by intralesional mode for a period of 10 weeks. Parameters taken into consideration and compared weekly were burning sensation, pain, mouth opening, tongue protrusion, and cheek flexibility. Result: The data so obtained was tabulated and subjected to statistical analysis using Chi-square test, Mann–Whitney test, Wilcoxon ranked test, and t-test by means of SPSS version 20 software to reach conclusive results. There was significant improvement in burning sensation, pain, mouth opening, tongue protrusion, and cheek flexibility in both groups. Better and faster improvement in tongue protrusion and cheek flexibility was achieved in triamcinolone group as against placental extract group. Conclusion: The intralesional triamcinolone acetonide was found to be a superior intralesional drug in comparison to placental extract.

Most living organisms have in their genome a sizable proportion of DNA sequences capable of mobilization; these sequences are commonly referred to as transposons, transposable elements (TEs), or jumping genes. Although long thought to have no biological significance, advances in DNA sequencing and analytical technologies have enabled precise characterization of TEs and confirmed their ubiquitous presence across all forms of life. These findings have ignited intense debates over their biological significance. The available evidence now supports the notion that TEs exert major influence over many biological aspects of organismal life. Transposable elements contribute significantly to the evolution of the genome by giving rise to genetic variations in both active and passive modes. Due to their intrinsic nature of mobility within the genome, TEs primarily cause gene disruption and large-scale genomic alterations including inversions, deletions, and duplications. Besides genomic instability, growing evidence also points to many physiologically important functions of TEs, such as gene regulation through cis-acting control elements and modulation of the transcriptome through epigenetic control. In this review, we discuss the latest evidence demonstrating the impact of TEs on genome stability and the underling mechanisms, including those developed to mitigate the deleterious impact of TEs on genomic stability and human health. We have also highlighted the potential therapeutic application of TEs.