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Background: Acute heart failure (AHF) is a clinical syndrome defined as the new onset or acutely decompensated heart failure (ADHF) leading to signs and symptoms of heart failure (HF). The critical cut-off values for these biomarkers that suggest high mortality are not clearly defined in previous studies. More studies are required to better understand the correlation of Pro- BNP and its association with HF. The primary objective is to study the role of Pro-BNP and critical factors in predicting outcomes in AHF patients presenting to a medical emergency. Materials and Methods: The data from the patients presented with symptoms of HF in the Department of Medical Emergency at our hospital were recorded and analysed. AHF is a clinical syndrome defined as the new onset or ADHF leading to signs and symptoms of HF, as based on the European Society of Cardiology. Results: The present study highlights the various risk factors of AHF in patients and their association with mortality. In the present study, mortality in patients with very high Pro-BNP levels ≥2000 pg/ml was significantly higher than in patients with moderately elevated Pro-BNP. The patients who survived after 5 days of hospitalization had Pro-BNP levels ≤2000 pg/ml, suggesting that very high Pro-BNP levels ≥2000 pg/ml are associated with fatal outcomes. Conclusion: To conclude, diabetes and sepsis are critical factors for the hospitalization and mortality of patients with AHF in northern India. Very high Pro-BNP levels ≥2000 pg/ml in patients with AHF requiring hospitalization and associated with fatal outcomes.

ABSTRACT: This study assessed the timing and eruption sequence of primary teeth in children of Sunsari district of Eastern Nepal and compared the eruption pattern of males & females between various, ethnic groups. Method: This cross-sectional study, included 501 subjects, aged 3 months to 60 months selected by simple random sampling method. The determinant variables such as age, gender, ethnicity, and eruption of teeth were recorded. Results: This study provides a model data on emergence of primary teeth and number of deciduous teeth in these children. This is a first study of its kind in Nepal. The findings of this study will help as a reference data for optimal use in clinical, academic, and research activities, especially for children of Eastern Nepal.

ABSTRACT Introduction: Obstructive Sleep Apnea (OSA), characterised by repetitive episodes of breathing cessation due to upper airway collapse is associated with significant morbidity and mortality. Type 2 Diabetes Mellitus (T2DM) and OSA are two common, chronic conditions that are associated with each other, in a bidirectional relationship and both share common risk factor obesity. Aim: To study the prevalence of OSA in obese patients with T2DM. Materials and Methods: Unattended polysomnography was performed in 50 obese (BMI >30 Kg/m2) and T2DM patients (symptoms of diabetes plus random blood glucose concentration ≥200 mg/dL and/or fasting plasma glucose ≥126 mg/dL, and/or Haemoglobin A1c (HbA1c) ≥6.5%, and/or 2-hour plasma glucose ≥200 mg/dL). Descriptive statistical methods were used such as computing percentage, mean, standard deviation and correlations. Results: Over 88% (N=44) of participants i.e., 64% male (N=32) and 24% female (N=12) with obesity and T2DM (Mean HbA1c 8.87±1.88) had OSA with an Apnea-Hypopnea Index (AHI) ≥5 events/h. The mean AHI was 33.57±24.88 events/h in males and 24.33±18.75 events/h in females. A total of 32% (N=16) of the participants had mild OSA (AHI 5-14), 26% (N=13) had moderate OSA (AHI 15-30), and 30% had severe OSA (AHI ≥30) (N=15). 28 out of 34 class I obese (BMI- 30-34.99 kg/m2) with T2DM, 12 out of 12 class II obese (BMI- 35-39.99 kg/m2) with T2DM and 4 out of 4 class III obese (BMI≥40 kg/m2) and T2DM patients had OSA (p-value=0.001). Conclusion: There was an exceedingly high prevalence of undiagnosed OSA in obese patients with T2DM.

Aims and objectives: Psychiatric co-morbidity in patients with diabetes mellitus (DM) is associated with higher level of functional impairment and poor self-care. This study was carried out with the aim to find out existing psychiatric morbidity in newly detected diabetic patients who were not yet started on anti-diabetic medication so that proper evaluation of mental health and comprehensive management of both the conditions can be planned. Methodology: Hundred newly detected and diagnosed type 2 DM patients attending endocrinology and psychiatry outpatient departments of Sir Sunder Lal Hospital, Institute of Medical Sciences, Banaras Hindu University, Varanasi were screened and selected for the study. Psychiatric evaluation was done on the basis of structured proforma containing socio-demographic details, physical and mental status examination, and relevant investigations pertaining to diagnosis of DM. Psychiatric diagnosis was made on the basis of the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria. Relevant rating scales (Hamilton Anxiety Rating Scale for anxiety disorder, Hamilton Depression Rating Scale for depression, Yale-Brown Obsessive Compulsive Scale [Y-BOCS] for obsessive compulsive disorder, and Brief Psychiatric Rating Scale [BPRS] for psychosis) were used for assessing severity of the conditions. Result: Majority of the patients were males (65%). Psychiatric morbidity was detected in 34% of patients – most common was major depressive disorder (21%) followed by anxiety disorder (eight per cent), dysthymic disorder (four per cent), and substance abuse (one per cent). In major depressive disorder group, moderate (ten per cent) to severe (four per cent) level of depression was detected and in anxiety disorder group, five per cent patients had moderate level of anxiety. Conclusion: Evaluation of psychiatric status at the very beginning when DM is detected ; may help in proper management of both the conditions resulting in better outcome, self-care, and maintenance therapy in follow-up.

Background: Morphological examination of the marrow requires a combination of a properly prepared bone marrow aspirate smear, a trephine biopsy section and an imprint of core biopsy. Some conditions often result in a dry tap and are best studied by marrow biopsy.The major drawbacks of biopsy sections are their thickness, precludingfine morphologic detail.The objective of this study was to compare the diagnostic accuracy, cellularity and cytomorphology from bone marrow biopsy core imprint smears with bone marrow aspiration smears.Materials and Methods: Imprint smears were prepared from 138 cases subjected to bone marrow examination. The bone marrow aspiration, imprint smears andbone marrow biopsy sections were examined and were categorized into five different groups on cytomorphological basis: Non-malignant alterations and normal marrow, Myeloid neoplasms, Plasma cell myeloma, myelo-infiltrative disease and absence of residual disease and further delineated into specific entities wherever necessary.Results: Out of 138 cases, non-malignant alterations and normal marrow was the largest subgroup (N=87, 63%), followed by myeloid neoplasms (N=26, 18.5%), Plasma cell myeloma (N=13, 9.4%), myelo-infiltrative disease (N=9, 6.5%) and absence of residual disease (N=3, 2.2%). The diagnostic accuracy of imprint smears was highest (92%) followed by biopsy sections (89.9%) and aspiration smears (87%). Kappa analysis showed strong agreement (>0.8) and p-value was statistically significant (Conclusion: Imprint smear technique is a simple, rapid, inexpensive and reliable procedure. The routine use of imprint smear in the bone marrow examination will serve as an invaluable adjunct to bone marrow aspiration and biopsy.Journal of Pathology of Nepal (2015) Vol. 5, 739-746

Introduction: Gall bladder cancer is the most common cancer of the biliary tree and one of the highly malignant tumors with poor prognosis. Although its incidence is low in west, it is common in our part of the world. There are very few studies regarding gall bladder cancer in Nepal. The incidence of gallstones in patients with gall bladder cancer is high. The aim of the study was to evaluate the clinicopathological aspect of the disease in patients with gallbladder cancer and to Asses the incidence of gallstones in patients with gall bladder cancer. Material and Methods: This was a retrospective study carried out in GI Surgery unit of National Academy of Medical Science, Bir Hospital, Kathmandu, Nepal. All patients diagnosed as gallbladder carcinomas during 12 years period from 2002 to 2014 were included in this study. Their clinical characteristics, laboratory data, tumor histopathology reports were obtained and analyzed using SPSS17. Results: Total of 47 patients who met inclusion criteria were included in the study. Male to Female ratio was 1:1.8. Age ranged from 32 to 72 years with mean age of 54. Most common presenting symptom was Pain abdomen (93.6%) followed by weight loss (51.1%) and Jaundice (46.8%). Most common finding on examination was Icterus (42.6%) followed by palpable gall bladder (34%) and Hepatomegaly (29.8%). Gall Stones were seen in 37 (72.3%) patients. Most common histopathology was Adenocarcinoma (93.6%). Conclusion: Most of the patient with gall bladder cancer remained asymptomatic until late. Pain abdomen was most common presenting symptom and icterus was most common findings. There was strong association between gall bladder cancer and gallstones. There should be high index of suspicion if patient with gallstones has constant pain in right hypochondrium and has jaundice.

Objectives: To evaluate and compare the efficacy of tamsulosin and alfuzosin as medical therapy in ureteric stones. Patients and Methods: A total of 87 patients with ureteral stones of size ≤10 mm were randomly divided into 3 groups. Group I patients (n-30) received 0.4 mg of tamsulosin daily, group II patients (n-29) received 10 mg of alfuzosin daily and group III patients (n-28) received no alpha blockers. All patients were given analgesia when needed. Follow up was done in weekly basis for 4 weeks. Results: The mean stone size (5.33±1.58, 5.79±1.84, 5.67±1.64) and age (29.1±6.3, 30.31±7.22, 29.4±7.63) were comparable in each groups. The stone expulsion rate was 83.3%, 79.3% and 50% in group I, II and III respectively. The drugs related side effects reported by patients were mild and transient. Conclusion: The use of tamsulosin and alfuzosin for the medical treatment of ureteric stones proved to be safe and effective and neither did have any significant benefits over the other

Age and tooth loss are expected to have a complex relationship with oral health-related quality of life. So the purpose of this study was to explain the impact of age and tooth loss on oral health-related quality of life using the short form 14-item oral health impact profile (OHIP-14) among two population samples of Gujarat and Rajasthan.A cross-sectional questionnaire-based survey was conducted among 1441 subjects collected from two major cities of Gujarat and Rajasthan. Both questionnaire approaches using OHIP-14 scale and clinical examination were conducted in accordance with WHO criteria using type III procedure on the same day. Chi square test, ANOVA and stepwise multiple regression analysis were applied using SPSS software version 15.0.With the increase of age, OHIP mean score in both states increased, but that among Rajasthan state was higher, depicting poor oral health. Whereas, in the remaining 23-27 number of teeth both states showed higher OHIP mean, however again the score was much higher among Rajasthan subjects showing worse oral hygiene. Hence, overall all mean OHIP score for Gujarat was lower indicating good oral health; whereas, that among Rajasthan was higher indicating poor oral health-related quality of life.Both age and tooth loss are associated with each other, but they have an independent effect on the oral health-related quality of life. Thus, all studied populations with complete natural dentition showed good oral health-related quality of life.

Purpose. Vitamin D deficiency impairs bone mineralisation and can predispose individuals to fractures. This study aimed at testing whether measurement of plasma calcium, alkaline phosphatase, and phosphate levels could detect vitamin D insufficiency. Methods. During a 10-week winter period from December 2000 to February 2001, all elderly patients presenting to a general hospital in Brighton—a British seaside town—with a fracture of the proximal femur and without known bone mineralisation problems were invited to participate in the study. Results. 23 (63.9%) of the 36 eligible patients had insufficient levels of vitamin D, with a plasma concentration of less than 30 nmol/L. The mean parathyroid hormone level was 56 pg/mL (range, 12–193 pg/mL). 11 of the 36 patients had an elevated level of parathyroid hormone and were insufficient in vitamin D. The mean plasma concentration of calcium was 2.30 mmol/L (range, 2.05–2.98 mmol/L). The mean phosphate level was 0.98 mmol/L (range, 0.40–1.79 mmol/L), and the mean alkaline phosphatase level was 91 IU/L (range, 46–127 IU/L). There was poor correlation between vitamin D insufficiency and plasma calcium, alkaline phosphatase, or phosphate levels. Conclusion. Plasma calcium, alkaline phosphatase, and phosphate testing cannot detect vitamin D insufficiency. We recommend that vitamin D and calcium supplementation be considered for patients with low-energy hip fractures.

Ifosfamide associated central nervous system toxicity has been reported in 5% to 30%of patients treated with ifosfamide. Death from irreversible encephalopathy has been reported rarely. A 52-year-old lady with carcinoma of cervix was treated with concurrent chemo-Radiatherapy, and residual disease was given with new adjuvant chemotherapy, containing regimens ifosfamide and cisplatin. Two days after the initiation of ifosfamide, the patient exhibited onset of lethal encephalopathy manifested by subacutely progressive encephlopathy then to a vegetative state and eventually to death. Brain CT-scan showed no metastatic tumor and vascular cause, blood routine examination for infection and metabolic factors was also negative; except Urea and Creatinine was increasing. Ifosfamide is known to be capable of causing acute encephalopathy that can be severe but is generally reversible. This lady showed a very atypical progressive, lethal course of ifosfamide toxicity. The possibility of this complication should be considered when kidney function is within normal limits. Key Words: ifosfamide, encephalopathy.

Abstract

ABSTRACT

The failure of cartilages to fuse, particularly in the case of articular cartilage under conditions of repair is due to morphological and structural constraints of the tissue. Factors that impede integration include, non-vascularisation, low cellularity, and proteoglycan in the surrounding extracellular matrix acting as a natural barrier to cellular migration. We hypothesised that brief activation of a catabolic cascade by cytokines followed by culture under anabolic conditions would promote tissue fusion in a ring-disk model of cartilage integration. Our results show that transient exposure to 10 ng mL-1 interleukin-1β, followed by two weeks post-culture under anabolic conditions, enhanced cartilage-cartilage integration compared to untreated explants. Quantitative PCR analysis of catabolism-related genes ADAMTS4 and MMP13 showed both were transiently upregulated and these findings correlated with evidence of extracellular matrix remodelling. At the level of histology, we observed chondrocytes readily populated the interfacial matrix between fused explants in interleukin-1β treated explants, whereas in control explants this region was relatively acellular in comparison. Catabolic cytokine treated explants exhibited 29-fold greater adhesive strength (0.859 MPa versus 0.028 MPa, P

Articular cartilage is a challenging tissue to reconstruct or replace principally because of its avascular nature; large chondral lesions in the tissue do not spontaneously heal. Where lesions do penetrate the bony subchondral plate, formation of hematomas and the migration of mesenchymal stem cells provide an inferior and transient fibrocartilagenous replacement for hyaline cartilage. To circumvent the poor intrinsic reparative response of articular cartilage several surgical techniques based on tissue transplantation have emerged. One characteristic shared by intrinsic reparative processes and the new surgical therapies is an apparent lack of lateral integration of repair or graft tissue with the host cartilage that can lead to poor prognosis. Many factors have been cited as impeding cartilage:cartilage integration including; chondrocyte cell death, chondrocyte dedifferentiation, the nature of the collagenous and proteoglycan networks that constitute the extracellular matrix, the type of biomaterial scaffold employed in repair and the origin of the cells used to repopulate the defect or lesion. This review addresses the principal intrinsic and extrinsic factors that impede integration and describe how manipulation of these factors using a host of strategies can positively influence cartilage integration.

Introduction: In India there are four distinct dengue viruses (DENVs) serotypes prevalent that can cause a full spectrum of disease from a subclinical infection to a mild self-limiting disease. The present study aimed to detect the dengue NS1 antigen by ELISA to screen the presence of dengue-specific IgM antibodies by IgM antibody capture ELISA (MAC-ELISA), and to detect dengue viral RNA in sero-positive samples and identify serotypes by one step multiplex real time reverse transcriptase-polymerase chain reaction (RT-PCR). Methodology: A hospital based observational, descriptive study was carried out on a total of 260 blood samples of clinically suspected patients with complaints of fever, myalgia, rash, and/or arthralgia. Detection of dengue NS 1 antigen and IgM antibody were done and then dengue viral RNA detection and serotype identification in seropositive samples was done to look for prevalent strain in the study area. All these methodologies were followed as per manufacturer's kit. Results: Out of 260 blood samples, a total of 82 (31.5%) samples tested positive for both sero-markers of dengue infection. Among these 82, 53 (64.6%) samples tested positive for NS1 antigen, 8 (9.8%) for IgM antibody alone, and 21 (25.6%) for both NS1 antigen and IgM antibody. PCR testing was done for these 82 seropositive patients and out of these, 75 (91.5%) tested positive on PCR testing. Of these 75 samples, 84% tested positive for dengue serotype-2 and only 16% tested positive for dengue serotype-1. Conclusion: In the study area, DENV-2 is more prevalent followed by DENV-1. None of the samples tested positive for serotype-3 and serotype-4. There was no coinfection in any sample. The information of predominant serotypes can guide in forecasting dengue outbreaks and improving control measures of vectors and thus may be helpful in the prevention of outbreaks.

Cyclooxygenase-2 (COX-2) is an enzyme that plays a crucial role in inflammation by converting arachidonic acid into prostaglandins. The overexpression of enzyme is associated with conditions such as cancer, arthritis, and Alzheimer's disease (AD), where it contributes to neuroinflammation. In silico virtual screening is pivotal in early-stage drug discovery; however, the absence of coding or machine learning expertise can impede the development of reliable computational models capable of accurately predicting inhibitor compounds based on their chemical structure. In this study, we developed an automated KNIME workflow for predicting the COX-2 inhibitory potential of novel molecules by building a multi-level ensemble model constructed with five machine learning algorithms (i.e., Logistic Regression, K-Nearest Neighbors, Decision Tree, Random Forest, and Extreme Gradient Boosting) and various molecular and fingerprint descriptors (i.e., AtomPair, Avalon, MACCS, Morgan, RDKit, and Pattern). Post-applicability domain filtering, the final majority voting-based ensemble model achieved 90.0% balanced accuracy, 87.7% precision, and 86.4% recall on the external validation set. The freely accessible workflow empowers users to swiftly and effortlessly predict COX-2 inhibitors, eliminating the need for any prior knowledge in machine learning, coding, or statistical modeling, significantly broadening its accessibility. While beginners can seamlessly use the tool as is, experienced KNIME users can leverage it as a foundation to build advanced workflows, driving further research and innovation., (© 2025 Wiley Periodicals LLC.)

Non-toxic, biocompatible, biodegradable, and bioadhesive, characteristics, of natural polysaccharides, are widely recognized and well accepted. Their usage in dietary, medicinal, biomedical, and cosmetic, applications is due to their unique and fascinating attributes. Xanthan gum, a microbial polysaccharide possesses diverse-wonderful features. It is a naturally occurring heteropolysaccharide, with large molecular weight, derived from the Gram-negative bacteria, Xanthomonas Campestris. This biopolymer has been studied extensively as a matrix for tablets, nanoparticles, microparticles, hydrogels, and various other formulation types. However, indigenous xanthan gum has its own set of restrictions, which may be overcome by chemical modification, to fine-tune the characteristics of the native gum, for attaining unmet demands. This approach has huge potential in the drug delivery and numerous other promising applications. The objective of this review is to provide a consolidated source of information on xanthan gum-based gastroretentive systems. Several approaches of floating techniques, with recent research avenues and patents, utilizing the natural polysaccharide xanthan gum is also discussed., 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 © 2024. Published by Elsevier Ltd.)

CAR T cell therapy has revolutionized how we deliver cancer treatment, most notably for hematologic cancers, by compelling T cells to recognize and kill tumor cells. Nevertheless, current obstacles to utilizing this therapy in solid tumors and overcoming cancer resistance include radicalization. This review discusses how CD95 modulation can boost CAR T cell efficacy. Traditionally, CD95 was known to execute apoptosis induction, but it plays a dual role in induced cell death or in supporting cancer cell survival. Recent data have demonstrated that cancer cells escape CD95-mediated apoptosis via the downregulation of CD95, caspase 8 mutation, or the expression of the inhibition protein cFLIP. Additionally, the immunosuppressive tumor microenvironment, containing CD95L expressing immune cells, explains CAR T cell therapy resistance. Furthermore, we characterize the therapeutic potential of CD95 targeted approaches, including CD95L inhibition (APG101) and alterations in CAR T cell manufacturing (tyrosine kinase inhibitors to mitigate fratricide). In this review, we highlight the importance of multi-path way strategies combining CD95 modulation with CAR T cell engineering to overcome resistance, specifically to target tumor cells better and sustain CAR T cell persistence to enhance treatment efficacy in solid tumors., 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 © 2024 Elsevier B.V. All rights reserved.)

Post-transcriptional and post-translational modification of transcription factors (TFs) and pathway enzymes significantly affect the stress-stimulated biosynthesis of specialized metabolites (SMs). Protein phosphorylation is one of the conserved and ancient mechanisms that critically influences many biological processes including specialized metabolism. The phosphorylation of TFs and enzymes by protein kinases (PKs), especially the mitogen-activated protein kinases (MAPKs), is well studied in plants. While the roles of MAPKs in plant growth and development, phytohormone signaling, and immunity are well elucidated, significant recent advances have also been made in understanding the involvement of MAPKs in specialized metabolism. However, a comprehensive review highlighting the significant progress in the past several years is notably missing. This review focuses on MAPK-mediated regulation of several important SMs, including phenylpropanoids (flavonoids and lignin), terpenoids (artemisinin and other terpenoids), alkaloids (terpenoid indole alkaloids and nicotine), and other nitrogen- and sulfur-containing SMs (camalexin and indole glucosinolates). In addition to MAPKs, other PKs also regulate SM biosynthesis. For comparison, we briefly discuss the regulation by other PKs, such as sucrose non-fermenting-1 (SNF)-related protein kinases (SnRKs) and calcium-dependent protein kinases (CPKs). Furthermore, we provide future perspectives in this active area of research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Conserving energy of sensor nodes and ensuring balanced workloads among them are fundamental concerns in Wireless Sensor Network (WSN) design. Clustering strategies offer a promising avenue to minimize node energy consumption, thereby prolonging network lifespan. Nevertheless, numerous multi-hop routing protocols using clustering technique face the challenge of nodes nearer to the Base Station (BS) depleting their energy faster due to forwarding data from the entire network leading to premature node failure and network partitioning known as 'hotspot problem'. The paper introduces an Energy-Efficient Mega-Cluster-Based Routing (EEMCR) protocol specially designed for expansive coverage area. The primary principle behind designing this protocol is to eliminate the hotspot problem and restrict the transmission range of nodes to the threshold distance defined by the radio energy model, thereby enhancing the overall network lifespan. The protocol adopts a centralized approach employing fixed clustering wherein the BS partitions the network into square-shaped clusters. The cluster size is determined by the threshold transmission range of the sensor radio energy model, guaranteeing that all network communication stays within this threshold distance. Four such clusters form a mega-cluster with a Mega-Cluster-Head (MCH) elected among the four Cluster Heads (CHs). The MCH role is evenly distributed among nodes of all four clusters in subsequent rounds for uniform distribution of its overhead. Implementing data aggregation at two levels (CH level as well as MCH level) leads to reduced data traffic and energy consumption throughout the network. Moreover, data collection by two data mules based on odd-even round number ensures balanced data traffic and energy distribution across the network. Analysis indicates that the proposed protocol effectively mitigates the hot-spot problem and reduces data transmission overhead of sensor nodes. In simulation, the proposed protocol on an average improves network life by 34.5%, 23.5%, 14.5% and 5.5% as compared to existing protocols FCEEC, DBSCAN, LPGCR and FBECS respectively for deployment of nodes between 600 to 1200. Also, approximately 46%, 32%, 21% and 14% of lesser sensor nodes are dead for proposed protocol in respective rounds as compared to existing protocols FCEEC, DBSCAN, LPGCR and FBECS respectively. Comparative evaluations demonstrate improved network lifetime when compared to equivalent recent routing protocols., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity and co-existence, linked to a diverse microenvironment and worse clinical outcome. However, the underlying mechanisms remain unclear. Here, by combining preclinical models, multi-center clinical, transcriptomic, proteomic, and patient bioimaging data, we identify an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic macrophages driving subtype co-existence and an immunosuppressive microenvironment. ATAC-, ChIP-, and RNA-seq analyses reveal that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory signatures in tumor cells, antagonizing cJUN/AP1 signaling, favoring a therapy-responsive classical neoplastic state. This dichotomous regulation is amplified via regional TNF-α + macrophages, which associates with a reactive phenotype and reduced CD8 + T cell infiltration in patients. Consequently, combined preclinical anti-TNF-α immunotherapy and chemotherapy reduces macrophages and promotes CD3 + /CD8 + T cell infiltration in basal-like PDAC, improving survival. Hence, tumor cell-intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In recent years, viral infections such as COVID-19, Zika virus, Nipah virus, Ebola, Influenza, Monkeypox, and Dengue have substantially impacted global health. These outbreaks have led to heightened global health initiatives and collaborative efforts to address and mitigate these significant threats effectively. Thus, developing antiviral treatments and research in this field has become highly important. Heterocycles, particularly indole motifs, have been a valuable resource in drug discovery, as they can be used as treatments or inspire the synthesis of new potent candidates. Indole-containing drugs, such as enfuvirtide (T-20), arbidol, and delavirdine, have demonstrated significant efficacy in treating viral diseases. This review aims to comprehensively assess the latest research and developments in novel indoles as potential scaffolds for antiviral activity. We have compiled detailed information about indoles as potential antivirals by conducting a thorough literature survey from the past ten years. The review includes discussions on synthetic protocols, inhibitory concentrations, SAR study, and computational study. This review shall identify new antiviral indoles that may help to combat new viral threats in the future., Competing Interests: Declaration of competing interest I, Prof Leena Khanna declare that the submitted review paper is my original work and no part of it has been published anywhere else in the past. I take full responsibility, that if in the future, the paper is found invalid according to basic rules, the last decision will be of the Authorities concerned., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Withanone (WN), a bioactive phytochemical isolated from the medicinal herb Withania somnifera, has shown multiple pharmacological and therapeutic successes, including neuroprotective and anti-cancer activities. However, detailed pharmacokinetic (PK) properties of pure WN were not well defined. Pharmacokinetic (PK) characteristics, dose proportionality, and absolute bioavailability of pure WN were explored in rats using an efficient, reliable, and sensitive LC-MS/MS assay to address this gap. The method shows excellent linearity over 0.5-500 ng/mL (r 2  ≥ 0.99), is accurate, and requires less analysis time. A dose proportionality and absolute bioavailability of pure WN were determined in Sprague-Dawley (SD) rats through three ascending oral (10, 20, and 40 mg/kg) and single intravenous (5 mg/kg) PK studies. The peak concentration (Cmax) of WN was 60.53 ± 20.33, 116.30 ± 16.89, and 91.62 ± 6.20 ng/mL, corresponding to oral dosage of 10, 20, and 40 mg/kg, respectively. WN shows poor systemic exposure upon oral administration, leading to low oral bioavailability (<15 %). Additionally, the dose proportionality studies of WN revealed its saturable bioavailability and non-proportional systemic exposure over the dosage range of 10-40 mg/kg in rats. The obtained PK findings of this study would be valuable for better understanding the pharmacological effects of WN, dose regimen optimization for future studies, and relevance for clinical reference to support its future development as a potential therapeutic molecule., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Muhammad Wahajuddin reports financial support was provided by The Council of Scientific and Industrial Research. If there are other authors, they 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 © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

This review article provides an in-depth examination of sarcoptic mange in domestic rabbits (Oryctolagus cuniculus), a widespread and highly contagious dermatological condition caused by Sarcoptes scabiei var. cuniculi mites. Sarcoptic mange poses significant health risks to rabbits and can lead to severe economic losses in commercial rabbit farming due to decreased productivity, inferior leather quality, and increased mortality rates. Clinical manifestations in rabbits include intense itching, skin lesions, hair loss, and secondary bacterial infections, which can be fatal if left untreated. The immune response in rabbits involves both innate and adaptive components, with keratinocytes playing a crucial role in initiating the response. The adaptive immune response is characterized by a mixed T helper cell profile, leading to inflammation and antibody production, which possibly play a key role in controlling mite infestations. Diagnosis of sarcoptic mange is typically based on clinical signs, supported by microscopic examination of skin scrapings and serological tests. The review emphasizes the risk of transmission to humans, especially those in close contact with infested rabbits, and explores the complex host-parasite immune interplay, detailing how S. scabiei evades the host's immune system through various mechanisms. The review also discusses advanced treatment approaches, focusing on the need for effective control measures to prevent the spread of mange in rabbit populations. The article underscores the importance of further research into the molecular mechanisms of the disease to develop targeted therapeutic interventions., Competing Interests: Declaration of Competing Interest There is no conflict of interest, according to the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Culture conditions have a profound impact on therapeutic protein production and glycosylation, a critical therapeutic-quality attribute, especially for monoclonal antibodies (mAbs). While the critical culture parameter of pH has been known since the early 1990s to affect protein glycosylation and production, detailed glycan and metabolic characterization and mechanistic understanding are critically lacking. Here, Chinese Hamster Ovary (CHO) cells were grown in bioreactors at pH 6.75, 7, and 7.25 (± 0.03) to examine how pH affects cell metabolism and site-specific N-linked glycosylation of the produced broadly neutralizing anti-HIV IgG1 mAb. VRC01 has N-linked glycosylation sites in both the Fc region and the Fab region, a situation not previously examined with respect to mAb glycosylation as affected by culture conditions. Using parsimonious Flux Balance Analysis (pFBA) and Flux Variability Analysis (FVA), we dissect and quantitate the impact of pH on cell growth, glucose/lactate metabolism, accumulation of the toxic metabolite ammonia, IgG production rates, and nonessential amino acid metabolism. pFBA revealed that beyond the established mechanism of glutamine conversion to glutamate, ammonia is also produced by the reaction converting serine to pyruvate, especially in the later phases of culture. pFBA also provided insights into the switch from ammonia production to consumption, notably due to depletion of glutamine, and consumption of glutamate and aspartate. We document that culture duration and pH alter the complex bimodal patterns (production/uptake) of several essential and non-essential amino acids. Site-specific N-linked glycan analysis using glycopeptide mapping demonstrated that pH significantly affects the glycosylation profiles of the two IgG1 sites. Fc region glycans were completely fucosylated but did not contain any sialylation. The Fab region glycans were not completely fucosylated but contained sialylated glycans. Bioreactor pH affected both the fucosylation and sialylation indexes in the Fab region and the galactosylation index of the Fc region. However, fucosylation in the Fc region was unaffected thus demonstrating that the effect of pH on site-specific N-linked glycosylation is complex., (Copyright © 2024 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Mutations in doublecortin domain-containing protein 2 (DCDC2) lead to neonatal sclerosing cholangitis (NSC), and portal hypertension (PHTN). The objective of the study was to systematically evaluate PHTN, variceal bleeding, and outcomes of patients with DCDC2-related NSC. The study included children with homozygous or compound heterozygous variants in DCDC2. All 14 children with DCDC2-related NSC had PHTN. Eight (57.1%) developed variceal bleed at a median age of 3 years (range: 1.9-5 years). Eleven (78.6%) children with high-risk varices underwent endotherapy. Varices were completely eradicated in three, downstaged to low-risk in five, and there was no response with endotherapy in three. All three children with failure to eradicate/downstage varices had rebleed, and required listing for liver transplantation (LT). The study shows that children with variants in DCDC2 have a high incidence of variceal bleed at a very young age. Variceal eradication may often be difficult and rebleed rates are high; often necessitating LT., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

This study presents the contents of α-methylenecyclopropylglycine, a potentially toxic amino acid, in the peel, pulp and seed fractions of two well-known litchi varieties, namely Shahi and China, over a span of three harvest-seasons. For analysing α-methylenecyclopropylglycine, an LC-MS/MS-based method was validated. The method-accuracies fell within 75-110 % (RSD, <15 %) at 0.1 mg/kg (LOQ) and higher levels. A comparative evaluation of the results in peel, pulp and seed at 30 days before harvest (DBH), 15-DBH, and edible-ripe stage revealed that α-methylenecyclopropylglycine content increased as the litchi seeds grew towards maturity, regardless of the cultivar. In arils, at maturity, the concentration of α-methylenecyclopropylglycine ranged from not-detected to 11.7 μg/g dry weight. The Shahi cultivar showed slightly higher α-methylenecyclopropylglycine content in comparison to China litchi. This paper presents the first known analysis of combined seasonal data on different fruit components at various growth stages for the two chosen litchi cultivars grown in India., Competing Interests: Declaration of competing interest The authors declare that there is no known conflict of interest, competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Finger millet blast caused by Pyricularia grisea hinders crop's growth and is a serious threat to economic yield. It can lead to massive yield losses i.e. up to 80%, which is a cause of major concern. In this study, we evaluated 200 accessions of finger millet at Banda University of Agriculture & Technology in Banda, India, under natural conditions to determine their resistance against leaf, neck, & finger blast diseases. Nine accessions displayed strong resistance against all forms of blast. The genetic variability analysis revealed high phenotypic & genotypic coefficients of variation. This was especially true for seed yield, plant height, & days to flowering. Most traits had heritability estimates exceeding 80%. Such results indicate a significant potential for effective selection in breeding programs. Leaf blast ratings had a significant but weaker correlation to both neck blast (r = 0.31) and finger blast (r = 0.31) whereas neck and finger blast ratings were very highly correlated and significant (r = 0.97). All types of blast had negative correlation with various agronomic traits studied. Furthermore, DNA fingerprinting of resistant genotypes with SSR markers displayed 10 polymorphic markers with an average of 2.6 alleles per locus. This points to the genetic diversity present within the germplasm. In summary, these findings provide vital insights for breeding initiatives focused on enhancing blast resistance in finger millet. Such efforts are crucial for maintaining the sustainability of this important crop for global food security., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Competing interests: Authors declare that there is no conflict of interest exists., (© 2024. The Author(s).)

The CHO VRC01 cell line produces an anti-HIV IgG1 monoclonal antibody containing N-linked glycans on both the Fab (variable) and Fc (constant) regions. Site-specific glycan analysis was used to measure the complex effects of cell culture process conditions on Fab and Fc glycosylation. Experimental data revealed major differences in glycan fractions across the two sites. Bioreactor pH was found to influence fucosylation, galactosylation, and sialylation in the Fab region and galactosylation in the Fc region. To understand the complex effects of process conditions on site-specific N-linked glycosylation, a kinetic model of site-specific N-linked glycosylation was developed. The model parameters provided mechanistic insights into the differences in glycan fractions observed in the Fc and Fab regions. Enzyme activities calculated from the model provided insights into the effect of bioreactor pH on site-specific N-linked glycosylation. Model predictions were experimentally tested by measuring glycosyltransferase-enzyme mRNA-levels and intracellular nucleotide sugar concentrations. The model was used to demonstrate the effect of increasing galactosyltransferase activity on site-specific N-linked glycan fractions. Experiments involving galactose and MnCl 2 supplementation were used to test model predictions. The model is capable of providing insights into experimentally measured data and also of making predictions that can be used to design media supplementation strategies., (© 2024 Wiley Periodicals LLC.)

Methyl donors regulate the one-carbon metabolism and have significant potential to reduce oxidative stress and inflammation. Therefore, this study aims to investigate the protective effect of methyl donors against CCl 4 -induced liver fibrosis. Liver fibrosis was induced in male Sprague Dawley rats using CCl 4 at a dose of 1 ml/kg (twice a week for a 4-week, via intraperitoneal route). Subsequently, methyl donor treatments were given orally for the next six weeks while continuing CCl 4 administration. After 10 weeks, biochemical, histopathology, immunohistochemistry, western blotting, and qRT-PCR were performed. Methyl donor treatment significantly ameliorated ALT, AST, ALP levels, and oxidative stress associated with CCl 4 -induced liver injury. The histopathological investigation also demonstrated the hepatoprotective effect of methyl donors against CCl 4 -induced liver fibrosis, showing reduced tissue damage, collagen deposition, and attenuating the expression of the COL1A1 gene. Further, methyl donors inhibited the CCl 4 -induced increase in DNMT-1 and NF-κB p65 expression with an upregulation of AMPK. Methyl donor downregulated the CCl 4 -induced increase in inflammatory and fibrosis related gene expression and inhibited the apoptosis with a downregulation of EGFR expression. Here, we provide the first evidence that methyl donor combinations prevent liver fibrosis by attenuating oxidative stress, inflammation, and fibrosis through DNMT-1 and EGFR downregulation., 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 © 2024 Elsevier Ltd. All rights reserved.)

Phthalic acid esters are pivotal plasticizers in various applications, including cosmetics, packaging materials, and medical devices. They have garnered significant attention from the scientific community due to their persistence in ecosystems. The multifaceted aspects of PAEs, encompassing leaching, transformation, and toxicity, underscore their prominence as primary components of anthropogenic waste. In this study, we conducted an extensive investigation to isolate and evaluate bacterial strains with the potential to degrade plasticizers from soil samples collected at JUHU Beach, Mumbai. The degradation capabilities of the isolates were meticulously assessed, and their characterization was performed using established microbiological protocols followed by Sanger dideoxy 16S rRNA sequencing. Four isolates demonstrating notable plasticizer degradation proficiency were subjected to in-depth examinations of their growth dynamics and tolerance thresholds. The biodegradation capabilities of these isolates were evaluated under varying pH, temperature, and plasticizer concentrations. Optimization of degradation rates was achieved through a central composite design experiment. Phenotypic characterization of the isolates was conducted through phylogenetic analysis. The isolates were identified as novel strains belonging to Brevibacillus brevis, Acinetobacter baumannii, Moraxella sp., and Halomonas sp. respectively. The novel isolates were submitted to GenBank with accession numbers OP984197, OQ690115, PP174910, and PP177540 respectively., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)