Factors Associated with High Prevalence of Multibacillary Leprosy in West Bengal: A Case-Control Study.

BACKGROUND: High proportion of multibacillary (MB) among newly diagnosed leprosy cases poses a public health challenge. OBJECTIVES: This study aimed to find out the factors associated with the high burden of MB leprosy in West Bengal. MATERIALS AND METHODS: This case-control study was conducted from August 2020 to December 2022 in three high-endemic districts (annual new case detection rate ≥10/lakh) of West Bengal. OBJECTIVES: MB cases registered under the National Leprosy Eradication Programme were considered as case and paucibacillary (PB) cases were considered as control. Weighted sample sizes for cases and controls in each of the three districts were selected using simple random sampling from the list of registered leprosy patients. Requisite data were collected through structured interview with a validated questionnaire in Bengali. R, version 4.1.1 (R Foundation for Statistical Computing, 2021, Vienna, Austria) was used for data analysis. A binary logistic regression model was prepared with the type of leprosy as a dependent variable. RESULTS: Three hundred and ninety-eight individuals, 204 MB and 194 PB, participated in this study with 1.97% nonresponse rate. Gender, marital status, and diagnostic delay (adjusted odds ratio = 2.75 [1.66,4.65]) were associated with developing MB. Not perceiving the symptoms seriously (90, 56% [PB], 97, 51% [MB]), lack of knowledge about the disease and its complications (47, 29% [PB], 53, 28% [MB]), delayed referral by the private practitioners (11, 7% [PB], 22, 12% [MB]) were the major reasons of delay. CONCLUSION: This study identified a vulnerable group - married and migrated males. Changing from annual screening to quarterly screening along with capacity building and awareness generation of the targeted population is the need of the hour for eradicating the disease.

Impact of HMGB1 on cancer development and therapeutic insights focused on CNS malignancy.

The present study explores the complex roles of High Mobility Group Box 1 (HMGB1) in the context of cancer development, emphasizing glioblastoma (GBM) and other central nervous system (CNS) cancers. HMGB1, primarily known for its involvement in inflammation and angiogenesis, emerges as a multifaceted player in the tumorigenesis of GBM. The overexpression of HMGB1 correlates with glioma malignancy, influencing key pathways like RAGE/MEK/ERK and RAGE/Rac1. Additionally, HMGB1 secretion is linked to the maintenance of glioma stem cells (GSCs) and contributes to the tumor microenvironment's (TME) vascular leakiness. Henceforth, our review discusses the bidirectional impact of HMGB1, acting as both a promoter of tumor progression and a mediator of anti-tumor immune responses. Notably, HMGB1 exhibits tumor-suppressive roles by inducing apoptosis, limiting cellular proliferation, and enhancing the sensitivity of GBM to therapeutic interventions. This dualistic nature of HMGB1 calls for a nuanced understanding of its implications in GBM pathogenesis, offering potential avenues for more effective and personalized treatment strategies. The findings underscore the need to explore HMGB1 as a prognostic marker, therapeutic target, and a promising tool for stimulating anti-tumor immunity in GBM.

Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.

Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future.

Addressing the interaction of stem bromelain with different anionic surfactants, below, at and above the critical micelle concentration (cmc) in phosphate buffer at pH 7: Physicochemical, spectroscopic, & molecular docking study.

The structural stability and therapeutic activity of Stem Bromelain (BM) have been explored by unravelling the interaction of stem BM in presence of two different types of anionic surfactants namely, bile salts, NaC and NaDC and the conventional anionic surfactants, SDDS and SDBS, below, at and above the critical micelle concentration (cmc) in aqueous phosphate buffer of pH 7. Different physicochemical parameters like, surface excess (Γcmc), minimum area of surfactants at air water interface (Amin) etc. are calculated from tensiometry both in absence and presence of BM. Several inflection points (C1, C2 and C3) have been found in tensiometry profile of surfactants in presence of BM due to the conformational change of BM assisted by surfactants. Similar observation also found in isothermal titration calorimetry (ITC) profiles where the enthalpy of micellization (ΔH0obs) of surfactants in absence and presence of BM have calculated. Further, steady state absorption and fluorescence spectra monitoring the tryptophan (Trp) emission of free BM and in presence of all the surfactants at three different temperatures (288.15 K, 298.15 K, and 308.15 K) reveal the nature of fluorescence quenching of BM in presence of bile salts/surfactants. Time resolved fluorescence studies at room temperature also support to determine the several quenching parameters. The binding constant (Kb) of BM with all the surfactants and free energy of binding (∆G0 of bile salts/surfactants with BM at different temperatures have been calculated exploiting steady state fluorescence technique. It is observed that, the binding of NaC with BM is greater as compared to other surfactants while Stern-Volmer quenching constant (KSV) is found greater in presence of SDBS as compared with others which supports the surface tension and ITC data with the fact that surface activity of surfactant(s) is decreasing with the binding of the surfactants at the core or binding pocket of BM. Circular Dichroism (CD) study shows the stability of secondary structure of BM in presence of NaC and NaDC below C3, while BM lost its structural stability even at very low surfactant concentration of SDDS and SDBS which also supports the more involvement of bile salts in binding rather than surfactants. The molecular docking studies have also been substantiated for better understanding the several experimental investigations interaction of BM with the bile salts/surfactants.

Automated radiosynthesis of [11C]CPPC for in-human PET imaging applications.

The macrophage colony-stimulating factor 1 receptor (CSF1R) is almost exclusively expressed in microglia, representing a biomarker target for imaging of microglia availability. [11C]CPPC has specific binding affinity to CSF1R and suitable kinetic properties for in vivo PET imaging of microglia. However, previous studies reported a low radiochemical yield, motivating additional research to optimize [11C]CPPC radiochemistry. In this work, we report an automated radiosynthesis of [11C]CPPC on a Synthra MeIPlus module with improved radiochemical yield. The final [11C]CPPC product was obtained with excellent chemical/radiochemical purities and molecular activity, facilitating high-quality in-human PET imaging applications.

Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.

Cannabichromene (CBC) is a nonpsychoactive phytocannabinoid well-known for its wide-ranging health advantages. However, there is limited knowledge regarding its human metabolism following CBC consumption. This research aimed to explore the metabolic pathways of CBC by various human liver cytochrome P450 (CYP) enzymes and support the outcomes using in vivo data from mice. The results unveiled two principal CBC metabolites generated by CYPs: 8'-hydroxy-CBC and 6',7'-epoxy-CBC, along with a minor quantity of 1″-hydroxy-CBC. Notably, among the examined CYPs, CYP2C9 demonstrated the highest efficiency in producing these metabolites. Moreover, through a molecular dynamics simulation spanning 1 µs, it was observed that CBC attains stability at the active site of CYP2J2 by forming hydrogen bonds with I487 and N379, facilitated by water molecules, which specifically promotes the hydroxy metabolite's formation. Additionally, the presence of cytochrome P450 reductase (CPR) amplified CBC's binding affinity to CYPs, particularly with CYP2C8 and CYP3A4. Furthermore, the metabolites derived from CBC reduced cytokine levels, such as IL6 and NO, by approximately 50% in microglia cells. This investigation offers valuable insights into the biotransformation of CBC, underscoring the physiological importance and the potential significance of these metabolites.

Metastatic Neuroblastoma in the Testis: Report of a Case with Review of Literature.

Neuroblastoma is the most common extracranial malignant solid tumor in childhood. Neuroblastoma is known to metastasize in certain niche areas such as the bone, bone marrow, liver, and skin. Testicular metastasis of neuroblastoma is uncommon, and only a few cases have been reported. In this communique, we describe an infant with neuroblastoma presenting with testicular metastasis. Testicular metastasis of neuroblastoma, although uncommon, should be considered a differential of testicular masses in children.

4'-C-Acetamidomethyl-2'-O-methoxyethyl Nucleic Acid Modifications Improve Thermal Stability, Nuclease Resistance, Potency, and hAgo2 Binding of Small Interfering RNAs.

In this study, we designed the 4'-C-acetamidomethyl-2'-O-methoxyethyl (4'-C-ACM-2'-O-MOE) uridine and thymidine modifications, aiming to test them into small interfering RNAs. Thermal melting studies revealed that incorporating a single 4'-C-ACM-2'-O-MOE modification in the DNA duplex reduced thermal stability. In contrast, an increase in thermal stability was observed when the modification was introduced in DNA:RNA hybrid and in siRNAs. Thermal destabilization in DNA duplex was attributed to unfavorable entropy, which was mainly compensated by the enthalpy factor to some extent. A single 4'-C-ACM-2'-O-MOE thymidine modification at the penultimate position of the 3'-end of dT20 oligonucleotides in the presence of 3'-specific exonucleases, snake venom phosphodiesterase (SVPD), demonstrated significant stability as compared to monomer modifications including 2'-O-Me, 2'-O-MOE, and 2'-F. In gene silencing studies, we found that the 4'-C-ACM-2'-O-MOE uridine or thymidine modifications at the 3'-overhang in the passenger strand in combination with two 2'-F modifications exhibited superior RNAi activity. The results suggest that the dual modification is well tolerated at the 3'-end of the passenger strand, which reflects better siRNA stability and silencing activity. Interestingly, 4'-C-ACM-2'-O-MOE-modified siRNAs showed considerable gene silencing even after 96 h posttransfection; it showed that our modification could induce prolonged gene silencing due to improved metabolic stability. Molecular modeling studies revealed that the introduction of the 4'-C-ACM-2'-O-MOE modification at the 3'-end of the siRNA guide strand helps to anchor the strand within the PAZ domain of the hAgo2 protein. The overall results indicate that the 4'-C-ACM-2'-O-MOE uridine and thymidine modifications are promising modifications to improve the stability, potency, and hAgo2 binding of siRNAs.

N-terminal ectodomain of BTNL2 inhibits T cell activation via a non-canonical interaction with its putative receptor that results in a delayed progression of DSS-induced ulcerative colitis.

Butyrophilin-like 2 (BTNL2) is a T cell inhibitory molecule that interacts with unknown binding partners to modulate the immune response in a number of inflammatory and autoimmune diseases. In this study, we found that the inhibitory effects of BTNL2 on T cell activation and effector functions can be executed by its N-terminal IgV domain (BTNL2 IgV1) alone. Structure-guided mutation of key residues on BTNL2 IgV1 based on known receptor-ligand interfaces involving immunoglobulin superfamily members revealed that BTNL2 uses a non-canonical binding interface with its putative receptor. A high avidity BTNL2 IgV1 probe revealed that in an inducible model of ulcerative colitis, severe colitis was accompanied by a selective enrichment of BTNL2-receptor expressing effector-memory CD4+ and CD8+ T cells in the Peyer's patches. Intraperitoneal administration of BTNL2 IgV1 resulted in a significant delay in the progression of DSS-induced colitis and also showed reduced activation of the BTNL2-receptor-expressing T cells in the Peyer's patches. Thus, this study demonstrates that the BTNL2-receptor-expressing T cells in the Peyer's patches participate in the disease pathogenesis and can serve as a novel therapeutic target in ulcerative colitis, which can be modulated by BTNL2 IgV1.

In-silico identification of novel DDI2 inhibitor in glioblastoma via repurposing FDA approved drugs using molecular docking and MD simulation study.

Glioblastoma, the most severe form of brain tumor and a leading cause of death within a year of diagnosis, is characterized by excessive protein synthesis and folding in the lumen of the endoplasmic reticulum (ER), leading to increased ER stress in the cells of GBM tissues. To mitigate this stress the cancer cells have intelligently adopted a plethora of response mechanisms and Unfolded Protein Response (UPR) is one of those. To bear with this exhaustive situation cells upregulate a strong protein degradation system in form of 26S proteasome and blocking of proteasomal gene synthesis may be a potential therapeutic action against GBM. Proteasomal gene synthesis is exclusively dependent on the transcription factor Nuclear respiratory factor 1 (NRF1) and its activating enzyme DNA damage inducible 1 homolog 2 (DDI2). Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.

Liquid marbles: review of recent progress in physical properties, formation techniques, and lab-in-a-marble applications in microreactors and biosensors.

Liquid marbles (LMs) are nonsticking droplets whose surfaces are covered with low-wettability particles. Owing to their high mobility, shape reconfigurability, and widely accessible liquid/particle possibilities, the research on LMs has flourished since 2001. Their physical properties, fabrication mechanisms, and functionalisation capabilities indicate their potential for various applications. This review summarises the fundamental properties of LMs, the recent advances (mainly works published in 2020-2023) in the concept of LMs, physical properties, formation methods, LM-templated material design, and biochemical applications. Finally, the potential development and variations of LMs are discussed.

Direct organocatalytic transfer hydrogenation and C-H oxidation: high-yielding synthesis of 3-hydroxy-3-alkyloxindoles.

Readily available 3-alkylideneoxindoles were effectively reduced to 3-alkyloxindoles through transfer hydrogenation using Hantzsch ester as a reducing agent at ambient temperature and the greenness/sustainability of this protocol was assessed by correlation with Pd/C-mediated hydrogenation with hydrogen gas. Furthermore, an organocatalytic method was developed to access drug-like 3-alkyl-3-hydroxyoxindoles by C-H oxidation of 3-alkyl-indolin-2-one, using a catalytic amount of 1,1,3,3-tetramethylguanidine (TMG) as an organic base and dissolved oxygen in THF as an oxidant at room temperature. Key reaction intermediates were observed by controlled on-line ESI-HRMS experiments and identified by their corresponding mass (m/z) analysis. This two-step high-yielding transfer hydrogenation/C-H oxidation protocol was used for the total synthesis of medicinally important 3-cyanomethyl-3-hydroxyoxindole and formal total synthesis of (±)-alline and (±)-CPC-I in very good overall yields compared to previous methods.

Apple-like Shape of Freezing Paraffin Wax Droplets and Its Origin.

Paraffin wax stores energy in the form of latent heat at a nearly constant temperature during melting and releases this energy during solidification. This effect is used in industrial energy storage. At the same time, the possible deformation of even small volumes of material as a result of phase change is insufficiently studied. In this paper, the physical nature of such deformation, probably for the first time, is studied on the example of a droplet of paraffin wax. An unusual change in the shape of a melted droplet of paraffin wax placed on a relatively cold glass plate was observed in the laboratory experiments. As the droplet solidifies, its upper surface becomes nearly flat, and a dimple is formed in the center of this surface, making the droplet look like a fruit (pumpkins are more commonly shaped like this, but the authors prefer apples). A series of experiments, as well as physical and numerical modeling of the droplet's thermal state, taking into account the formation of a mushy zone between liquidus and solidus, made it possible to understand the role of gravity and gradual increase in viscosity and density of paraffin wax on changing the droplet shape and, in particular, to clarify the mechanism of formation of the dimple on its upper. It was shown that the mushy zone between the liquidus and solidus of the paraffin wax is responsible for the dimple formation.

Yolk Sac Tumour Arising in the Glans Penis an Achondroplasic Child: A Case Report with Summary of Prior Published Cases.

BACKGROUND: Yolk sac tumors (YST) are commonly encountered gonadal germ cell tumors in children, especially in the prepubertal age group. In addition to gonadal primary, it can occur in multiple extragonadal sites, of which sacrococcygeal, retroperitoneum, gastric and mediastinum are the commonest. There are 4 previous reports of primary penile YST. CASE REPORT: We describe a primary penile yolk sac tumor in a child with achondroplasia. CONCLUSION: Yolk sac tumor can occur in the penis during the prepubertal period. Penile yolk sac tumor associated with achondroplasia has not been previously reported, but this could be incidental.

Isolation of Multidrug-Resistant Organisms in Surveillance Stool Culture at Diagnosis Fails to Predict Mortality or Subsequent Sepsis due to Multidrug-Resistant Organisms in Children with Acute Leukemia: A Single-Center, Prospective, Observational Study.

The utility of surveillance stool culture (SSC) to guide antibiotics for febrile neutropenia (FN) is unresolved in non-transplant settings. The prospective study explored the prevalence of multidrug-resistant organisms (MDRO) in SSCs, its correlation with mortality, and the concordance of SSCs with cultures obtained during subsequent episodes of FN amongst children with acute leukemia. SSCs were obtained at presentation and 2 mo into chemotherapy. Seventy-nine patients (mean age: 5.9±3.2 y) with acute lymphoblastic leukemia (ALL) (80%), acute myeloid leukemia (AML) (16%), or biphenotypic leukemia (4%) were enrolled. MDROs were isolated from 14 (17.5%) patients in the first SSCs, including E.coli (80%), K. pneumoniae (10%), and E. faecium (10%). Three (3.8%) patients developed MDRO sepsis; none concorded with the SSCs. Eleven (14%) patients died; 4/14 (28.5%) with MDRO-colonization vis-à-vis 7/66 (10.6%) without MDRO-colonization (OR: 3.37, 95% CI: 0.8-13.6; p = 0.095). MDRO-colonization failed to predict MDRO-sepsis, bloodstream infection, or mortality. SSC failed to guide the choice of antibiotics for FN in children with acute leukemia.