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We report a case of 32-year-old man with progressive, asymmetric, proximal weakness of both upper limbs for 14 months. On examination, he had gynecomastia and wasting and weakness of his deltoid, supraspinatus, infraspinatus, pectoralis, biceps, and triceps muscles, along with sensory loss of his left C5-C8 dermatomes. Deep tendon reflexes were depressed in the upper limbs and normal in the lower limbs. There was a history of a road traffic accident 2 years ago without any neurologic deficits. We discuss the clinical approach, differential diagnosis, investigations, and treatment options for bibrachial weakness.

4-Hydroxy-3,5-dinitropyrazole (HODNP) was investigated as a precursor for synthesizing two thermally stable, insensitive zwitterionic energetic materials. The ability of the hydroxy functionality to carry negative charge was leveraged and further covalently bonded with two positively charged moieties (3,4-diamino-1,2,4-triazole and acetimidamide) via N-functionalization to form zwitterions 2 and 3 . Structural characterization and a study of the energetic performance were carried out. The zwitterionic nature of compound 3 was confirmed by single-crystal analysis.

Magnetic resonance imaging (MRI) plays an important role in imaging of penile pathologies due to its excellent soft tissue resolution and multiplanar imaging capabilities. This imaging review describes the MRI protocols and anatomical considerations in penile pathologies. MRI not only serves as a complementary tool to ultrasound in evaluation of trauma, infections, inflammatory diseases, and malignancies, but is also used as the definitive imaging modality for evaluation of penile prosthesis and complex cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The global urge to adopt sustainable chemistry has resulted in the development of more environmentally benign strategies (EBS) that use CO 2 and CO 2 -derived chemicals in a step-economic manner. In this context, we investigated a dual C-H methylation and (C═O)-methoxylation of indole derivatives using dimethyl carbonate (DMC) in the presence of catalytic amounts of Cs 2 CO 3 . Mechanistic insights include DMF-assisted, DMC-induced cooperative ionic catalysis, which allows DMC to act as both a nucleophilic and an electrophilic precursor, resulting in (C═O)-methoxylation and C-H methylation of N -benzylindolyl ketones.

Mammary gland carcinoma is one of the most prevalent and deadly diseases among women globally. It is a type of solid malignant tumor. In this malignant tumor, the microenvironment becomes hypoxic in rapidly proliferating cancer cells. These cells undergo adaptive changes through the expression of hypoxia-inducible factor-1alpha (HIF-1α) which is regulated by factor inhibiting HIF-1α (FIH-1). Considering this, we hypothesized that the chemical activation of FIH-1 would inhibit the hypoxic activity of HIF-1α in mammary gland carcinoma. A library of 67,609 chemical compounds was virtually screened against FIH-1 based on Lipinski's rule from the ZINC database. The BBAP-8 has been selected based on an excellent docking score (-8.352 Kcal/mol), favorable ADMET, and potential FIH-1 activator profile. Further, its in-vitro cytotoxicity and apoptotic activity were scrutinized against MCF-7 cells and in-vivo activity against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinoma in Wistar rats. It exhibited significant cytotoxicity (IC50 = 16.59 ± 0.49 μM) and activated apoptosis when scrutinized through DAPI, AO/EB, and JC-1 staining. Also, oral administration of BBAP-8 restored hemodynamic changes, normalized tissue architecture, and corrected metabolic abnormalities. The western blot analysis and mRNA expression analysis validated that BBAP-8 has the potential to activate FIH-1 with the downregulation of GLUT-1, VEGF, and Twist-1. Moreover, BBAP-8 fostered apoptosis, when evaluated through BCL-2, BAX, Caspase-8, and Caspase-3. Based on research findings, this implies that BBAP-8 activates FIH-1 and can be effective in chemotherapeutic treatment of mammary gland carcinoma., (© 2024 Wiley Periodicals LLC.)

This article discusses the preparation of different grades of single-ion conducting quasi-solid polymer electrolytes (q-SPE) material (Chit-g-SPA-IL) based on biopolymer (chitosan), polyacrylic acid and DBU-acetate (DBUH + AcO - ) ionic liquid. Chit-SPA-60 %-IL exhibited the highest conductivity within the range of 10 -4  S/cm. TGA analysis demonstrated the stability of electrolytes up to a temperature of 120 °C. SEM-EDS analysis unveiled the porous nature of the electrolyte and even distribution of ions throughout the matrix. It exhibited an electrochemical stability window (EWS) of 2.53 V with significant current density and an ionic transference number (ITN) of ~99.9 %. The temperature-dependent conductivity established an Arrhenius-type conduction mechanism with an activation energy of 0.149 eV for ion movement within the electrolyte matrix. The AC conductivity analysis emphasized the time-temperature independence of the ionic conduction mechanism. Dielectric analysis highlighted the capacitive nature of the electrolyte, underlining its substantial capacitance, while modulus studies indicated minimal influence from the electrode-electrolyte interface. Chit-SPA-60 %-IL at 30 °C included a self-diffusion coefficient of 4.57 × 10 -5  m 2 /s, ionic mobility of 1.75 × 10 -3  m 2 /Vs, and drift ionic velocity of 0.44 m/s. These findings makes SPE as a promising candidate for sodium-ion-based energy storage devices., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Appropriate selection of surgical approach for associated fractures of the acetabulum that involves both columns is still elusive. Therefore, present study aimed to assess the quality of life of complex acetabulum fracture managed with combined anterior and posterior approach (dual approach) as well as the association of postoperative reduction and patient reported outcomes., Material and Methods: This retrospective study was performed on 42 associated acetabular fracture patients with involvement of both columns, who were treated with a dual approach including combined anterior modified ilio-inguinal approach in combination with posterior Kocher-Langenbeck (K-L) approach in a single anaesthetic session having minimum two years follow-up. Postoperative reduction and radiological outcomes were assessed using Matta criteria. Functional outcome was assessed by a score system developed by Merle d'Aubigné-Postel. Patient-reported outcomes were assessed using the 36-Item Short Form Survey (SF-36)., Results: The mean age of participants was 47.9 ± 11.95 years and mean follow-up period was 2.8 ± 0.49 years. Anatomical reduction was achieved in 32 (76.19%) cases in postoperative period. 8 (19.04%) cases had congruent and 2 (4.76%) had incongruent reduction. Radiological and functional outcome was excellent/good n  = 35 (83.33%) cases. Patient-reported outcome on domains physical function and role physical showed a significant improvement between 6 to 24 months period ( p  < 0.001)., Conclusions: The dual approach for complex acetabulum fracture with mid-term follow-up showed good to excellent radiological and functional outcomes. A significant improvement in patient-reported outcomes on Physical function and Role physical domains of SF-36 was also seen over the follow-up period., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The field of Machine Learning (ML) has garnered significant attention, particularly in healthcare for predicting disease severity. Recently, the pharmaceutical sector has also adopted ML techniques in various stages of drug development. Tablets are the most common pharmaceutical formulations, with their efficacy influenced by the physicochemical properties of active ingredients, in-process parameters, and formulation components. In this study, we developed ML-based prediction models for disintegration time, friability, and water absorption ratio of fast disintegration tablets. The model development process included data visualization, pre-processing, splitting, ML model creation, and evaluation. We evaluated the models using root mean square error (RMSE) and R-squared score (R 2 ). After hyperparameter tuning and cross-validation, the voting regressor model demonstrated the best performance for predicting disintegration time (RMSE: 21.99, R 2 : 0.76), surpassing previously reported models. The random forest regressor achieved the best results for friability prediction (RMSE: 0.142, R 2 : 0.7), and the K-nearest neighbor (KNN) regressor excelled in predicting the water absorption ratio (RMSE: 10.07, R 2 : 0.94). Notably, predicting friability and water absorption ratio using ML models is unprecedented in the literature. The developed models were deployed in a web app for easy access by anyone. These ML models can significantly enhance the tablet development phase by minimizing experimental iterations and material usage, thereby reducing costs and saving time., 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.)

Genome editing is recognized as a powerful tool in agriculture and research, enhancing our understanding of genetic function, diseases, and productivity. However, its progress in buffaloes has lagged behind other mammals due to several challenges, including long gestational periods, single pregnancies, and high raising costs. In this study, we aimed to generate MSTN-edited buffaloes, known for their distinctive double-muscling phenotype, as a proof of concept. To meet our goal, we used somatic cell nuclear transfer (SCNT) and zygotic electroporation (CRISPR-EP) technique. For this, we firstly identified the best transfection method for introduction of RNP complex into fibroblast which was further used for SCNT. For this, we compared the transfection, cleavage efficiency and cell viability of nucleofection and lipofection in adult fibroblasts. The cleavage, transfection efficiency and cell viability of nucleofection group was found to be significantly (P ≤ 0.05) higher than lipofection group. Four MSTN edited colony were generated using nucleofection, out of which three colonies was found to be biallelic and one was monoallelic. Further, we compared the efficacy, embryonic developmental potential and subsequent pregnancy outcome of SCNT and zygotic electroporation. The blastocyst rate of electroporated group was found to be significantly (P ≤ 0.05) higher than SCNT group. However, the zygotic electroporation group resulted into two pregnancies which were confirmed to be MSTN edited. Since, the zygotic electroporation does not require complex micromanipulation techniques associated with SCNT, it has potential for facilitating the genetic modification in large livestock such as buffaloes. The present study lays the basis for inducing genetic alternation with practical or biological significance., Competing Interests: Declaration of competing interest There are no conflict of interest for any of the authors that there has been no duplicate publication or submission elsewhere of this work that all authors have read and approved the manuscript, are aware of the submission for publication and agree to be listed as co-authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is great interest in fabricating devices that can detect and remove water pollutants, especially heavy metal ions and dyes from wastewater, to promote sustainable water use. In this study, an extract of Borassus flabellifer leaves (BoF-LE) was used to synthesize silver nanoparticles (BoF-AgNPs), with the BoF-LE serving as a reducing and capping agent. The sensitivity and selectivity of BoF-AgNPs for Mn(II) ions were tested by comparing with the control sample and other competent metal ions. Our results showed that BoF-AgNPs are extremely sensitive and selective in detecting Mn(II) ions, with a detection limit of 0.3 ppb. HR-TEM, UV-Vis spectroscopy, and DLS investigations were used to confirm that BoF-AgNPs detect Mn(II) ions by an aggregation-based mechanism. Additionally, it was found that BoF-AgNPs are effective in rapidly decolorizing MB dye, as demonstrated by their ability to decolorize MB by 92.66% within 7 min. This study is the first to report successful synthesis of BoF-AgNPs and their two applications, which are enabled with an Inhibit-AND logic gate. Using BoF-AgNPs to detect and degrade water pollutants may promote sustainable water use., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Kritika S. Sharma reports financial support was provided by Department of Science and Technology (DST), Ministry of Science & Technology, India. 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 © 2024 Elsevier B.V. All rights reserved.)

Atmospheric aerosols have a serious impact on altering the radiation balance of the vulnerable Himalayan atmosphere. Organic aerosol (OA), one of the least resolved aerosol fractions in the Himalayas, constrain our competence to assess their climate impacts on the region. Here we investigate water-soluble OA molecules in PM 10 samples collected from March to May 2019 at Lachung (27.4°N and 88.4°E), a high-altitude location (2700 m a.s.l.) in the eastern Himalaya, to elucidate their origin and formation process. The dominance of oxalic acid (C 2 ) reveals that water-soluble OA in the eastern Himalaya are atmospherically processed. Backward air mass trajectories and mass concentration ratios of organic tracers as well as relationships with inorganic species (K + , SO 4 2- , NH 4 + ) suggest an anthropogenic origin of water-soluble OA with significant atmospheric processing during long-range transport to the eastern Himalayan region. We used the thermodynamic prediction of aerosol liquid water (ALW) to examine the formation mechanism of secondary OA (SOA) such as oxalic acid. Correlations of ALW with SO 4 2- and water-soluble organic matter show that ALW is sensitive to both anthropogenic sulfate and water-soluble organic compounds in Himalayan aerosols. A strong positive relationship of C 2 acid with predicted ALW provides evidence of extensive SOA formation from precursors via aqueous phase photochemical processes. This inference is supported by positive correlations of C 2 acid relative abundance with diagnostic mass concentration ratios of C 2 acid to precursor molecules. Our findings underscore the importance of anthropogenic sources and ALW in SOA formation through aqueous phase processes in the eastern Himalaya., 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.)

Lung cancer is a complex and heterogeneous disease, which has been associated with various molecular alterations, including the overexpression and mutations of the epidermal growth factor receptor (EGFR). In this study, designed a library of 1843 benzimidazole-1,2,3-triazole hybrids and carried out pharmacophore-based screening to identify potential EGFR inhibitors. The 164 compounds were further evaluated using molecular docking and molecular dynamics simulations to understand the binding interactions between the compounds and the receptor. In-si-lico ADME and toxicity studies were also conducted to assess the drug-likeness and safety of the identified compounds. The results of this study indicate that benzimidazole-1,2,3-triazole hybrids BENZI-0660, BENZI-0125, BENZI-0279, BENZI-0415, BENZI-0437, and BENZI-1110 exhibit dock scores of -9.7, -9.6, -9.6, -9.6, -9.6, -9.6 while referencing molecule -7.9 kcal/mol for EGFR (PDB ID: 4HJO), respectively. The molecular docking and molecular dynamics simulations revealed that the identified compounds formed stable interactions with the active site of EGFR, indicating their potential as inhibitors. The in-silico ADME and toxicity studies showed that the compounds had favorable drug-likeness properties and low toxicity, further supporting their potential as therapeutic agents. Finally, performed DFT studies on the best-selected ligands to gain further insights into their electronic properties. The findings of this study provide important insights into the potential of benzimidazole-1,2,3-triazole hybrids as promising EGFR inhibitors for the treatment of lung cancer. This research opens up a new avenue for the discovery and development of potent and selective EGFR inhibitors for the treatment of lung cancer.Communicated by Ramaswamy H. Sarma.

The peculiarity of Indian cattle lies in milk quality, resistance to diseases and stressors as well as adaptability. The investigation addressed selection signatures in Gir and Tharparkar cattle, belonging to arid ecotypes of India. Double digest restriction-site associated DNA sequencing (ddRAD-seq) yielded nearly 26 million high-quality reads from unrelated seven Gir and seven Tharparkar cows. In all, 19,127 high-quality SNPs were processed for selection signature analysis. An approach involving within-population composite likelihood ratio (CLR) statistics and between-population F ST statistics was used to capture selection signatures within and between the breeds, respectively. A total of 191 selection signatures were addressed using CLR and F ST approaches. Selection signatures overlapping 86 and 73 genes were detected as Gir- and Tharparkar-specific, respectively. Notably, genes related to production (CACNA1D, GHRHR), reproduction (ESR1, RBMS3), immunity (NOSTRIN, IL12B) and adaptation (ADAM22, ASL) were annotated to selection signatures. Gene pathway analysis revealed genes in insulin/IGF pathway for milk production, gonadotropin releasing hormone pathway for reproduction, Wnt signalling pathway and chemokine and cytokine signalling pathway for adaptation. This is the first study where selection signatures are identified using ddRAD-seq in indicine cattle breeds. The study shall help in conservation and leveraging genetic improvements in Gir and Tharparkar cattle.

Visceral leishmaniasis (VL) is a vector-borne neglected tropical protozoan disease with high fatality and no certified vaccine. Conventional vaccine preparation is challenging and tedious. Here in this work, we created a global multiepitope subunit vaccination against VL utilizing innovative immunoinformatics technique based on the extensively conserved epitopic regions of the PrimPol protein of Leishmania donovani consisting of four subunits which were analyzed and studied, out of which DNA primase large subunit and DNA polymerase α subunit B were evaluated as antigens by Vaxijen 2.0. The multiepitope vaccine design includes a single adjuvant β-defensins, eight CTL epitopes, eight HTL epitopes, seven linear BCL epitopes and one discontinuous BCL epitope to induce innate, cellular and humoral immune responses against VL. The Expasy ProtParam tool characterized the physiochemical parameters of the vaccine. At the same time, SOLpro evaluated our vaccine constructs to be soluble upon expression. We also modeled the stable tertiary structure of our vaccine construct through Robetta modeling for molecular docking studies with toll-like receptor proteins through HADDOCK 2.4. Simulations based on molecular dynamics revealed an intact vaccine and TLR8 complex, supporting our vaccine design's immunogenicity. Also, the immune simulation of our vaccine by the C-ImmSim server demonstrated the potency of the multiepitope vaccine construct to induce proper immune response for host defense. Codon optimization and in silico cloning of our vaccine further assured high expression. The outcomes of our study on multiepitope vaccine design significantly produced a potential candidate against VL and can potentially eradicate the disease in the future after clinical investigations.Communicated by Ramaswamy H. Sarma.

Neurofibromin (NF1) is a negative regulator of RAS signaling, frequently mutated in cancer. NF1-mutant melanoma is a highly malignant tumor for which targeted therapies are lacking. Here, we use biochemical and pharmacological assays on patient-derived models and isogenic cell lines to identify potential pharmacologic targets, revealing that NF1-null melanomas are dependent on RAS activation and that MEK inhibition relieves ERK-dependent negative feedback, increasing RAS signaling. MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited. However, concurrent inhibition of MEK and SOS1 abrogates ERK activation, induces cell death, and suppresses tumor growth. In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells., Competing Interests: Declaration of interests M.H.H., D.G., and F.S. are employees of Boehringer Ingelheim. T.M. is a consultant for Immunos Therapeutics, Daiichi Sankyo Co, TigaTX, Normunity, and Pfizer; is a cofounder of and equity holder in IMVAQ Therapeutics; has received research grants funding from Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics; currently receives research funding from Bristol Myers Squibb, Enterome SA, and ReAlta Life Sciences; and is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, BeiGene, Bicara Therapeutics, Bristol Myers Squibb, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Takeda, Tizona, Trishula Therapeutics, Immunocore (on their data safety board), and Scancell; received grant/research support from Bristol Myers Squibb and Enterome; has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and XenImmune; and is an inventor on the following patents: Xenogeneic DNA Vaccines, Newcastle Disease Viruses for Cancer Therapy, Myeloid-Derived Suppressor Cell Assay, Prediction of Responsiveness to Treatment with Immunomodulatory Therapeutics and Method of Monitoring Abscopal Effects During Such Treatment, Anti-PD1 Antibody, Anti-CTLA4 Antibodies, and Anti-GITR Antibodies and Methods of Use Thereof. Z.Y. is a past scientific advisory board (SAB) member of MapKure and currently an employee of Loxo Oncology at Lilly. D.S. reports personal fees from Pfizer, Vividion Therapeutics, BridgeBio, FogPharma, FORE Therapeutics, Scorpion Therapeutics, and Rain Therapeutics outside the submitted work. S.M. reports grants from Boehringer Ingelheim and Daiichi Sankyo outside the submitted work and is a SAB member of Bionseek. N.R. is on the SAB and owns equity in BeiGene, Zai Labs, MapKure, Ribon, and Effector; is also on the SAB of AstraZeneca and Chugai and a past SAB member of Novartis, Millennium-Takeda, Kura, and Araxes; and is a consultant to Revolution Medicines, Tarveda, Array-Pfizer, Boehringer Ingelheim, and Eli Lilly. He receives research funding from Revolution Medicines, AstraZeneca, Array Pfizer, and Boehringer Ingelheim and owns equity in Kura Oncology and Fortress., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ganoderma lucidum, known as the "mushroom of immortality," is a white rot fungus renowned for its medicinal properties, attributed to its bioactive compounds. Although species with similar morphological traits to G. lucidum are found across the globe, precise identification is made possible through DNA barcoding and molecular phylogenetic analysis. Global cultivation and wild harvesting of G. lucidum are both done in response to the growing market needs. Artificial cultivation is typically performed on sawdust, but other woody substrates and the wood log method are also employed. This cultivation leverages the fungus's ecological role in converting industrial and agricultural solid wastes into biomass, thereby producing functional food and potential pharmaceutical sources. The review consolidates research on various aspects of, including cultivation methods (sawdust, agricultural waste, wood logs, and submerged fermentation), and the current global market conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Recently, there has been a surge in research focusing on triazolone-based energetic materials, propelled by their remarkable properties such as good detonation performance as well as acceptable thermal and physical stability. In this work, a novel combination of the triazolone framework with dinitropyrazoles has been attained using the N -methylene-C-linked approach. Different substituents (NH 2 , NO 2 , N 3 , OH) were utilized on the dinitropyrazole moiety to obtain neutral energetic compounds 3-5 and 8. Furthermore, the hydroxy derivative (compound 8) facilitates the formation of energetic salts 9-13 to fine-tune the overall properties further. All the novel compounds 3-13 were thoroughly characterized by IR, multinuclear NMR spectroscopy, high-resolution mass spectrometry (HRMS), and elemental analysis. Compounds 3, 4, 8, and 10 were further confirmed via 15 N NMR spectroscopy. The structure of compounds 3 and 8 was also confirmed through single-crystal X-ray diffraction studies. The majority of synthesized compounds showed good thermal stability as well as insensitivity toward external stimuli. Computational studies, including analyses such as Hirshfeld surface, non-covalent interaction, electrostatic potential surface, and HOMO-LUMO analysis, were conducted to examine the influence of substitution at the 4th position on the overall stability of compounds 3, 4, and 8.

Hypoxia inducible factors (HIFs) are heterodimeric proteins that belong to a small group of transcription factors, which mainly regulates transcription of genes under hypoxic conditions. Particularly, oxygen sensing subunit of HIF-1α is a predominant subtype that heterodimerizes with oxygen-independent HIF-1β subunit, to trigger the transcription of hypoxia responsive genes. Due to poor supply of blood and rapid division of cancerous cells, tumor microenvironment exhibits low oxygen condition and therefore increased levels of HIF-1α. One of the promising therapeutic strategies to cancer is modulation of HIF-1α signaling pathway. Small interfering RNA (siRNA) mediated downregulation of HIF-1α has been reported to prevent growth and progression of various types of cancer and holds great promise in the cancer treatment. In this study, computational approaches were used to design potential siRNAs targeting HIF-1α and investigate their interaction with the human argonaute-2 (hAgo2). Molecular dynamic simulation of HIF-1α siRNAs-hAgo2 complexes revealed key interactions required for the efficient binding of guide strand to hAgo2 protein. Two siRNAs (S2 and S5) exhibiting strong binding with hAgo2 were further considered. Subsequently, we transfected the MCF-7 cell line with both standard HIF-1α and our designed siRNAs (S2 and S5). Following transfection, translation changes in the MCF-7 cells were assessed through western blotting. S2 and S5 efficiently reduced the expression of HIF-1α in hypoxic conditions. The aim of the present study is to understand the siRNA-hAgo2 interaction. It is also focused on the desiging of effective siRNA against HIF-1α., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Prior research has shown the effectiveness of dalbergin (DL), dalbergin nanoformulation (DLF), and dalbergin-loaded PLGA-galactose-modified nanoparticles (DLMF) in treating hepatocellular carcinoma (HCC) cells. The present investigation constructs upon our previous research and delves into the molecular mechanisms contributing to the anticancer effects of DLF and DLMF. This study examined the anti-cancer effects of DL, DLF, and DLMF by diethyl nitrosamine (DEN)-induced HCC model in albino Wistar rats. In addition, we performed biochemical, antioxidant, lipid profile tests, and histological studies of liver tissue. The anticancer efficacy of DLMF is equivalent to that of 5-fluorouracil, a commercially available therapy for HCC. Immunoblotting studies revealed a reduction in the expression of many apoptotic markers, such as p53, BAX, and Cyt-C, in HCC. Conversely, the expression of Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3 was elevated. Nevertheless, the administration of DL, DLF, and DLMF effectively controlled the levels of these apoptotic markers, resulting in a considerable decrease in the expression of Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3. Specifically, the activation of TNF-alpha and STAT-3 triggers the signalling pathways that include the Bcl-2 family of proteins, Cyt-C, caspase 3, and 9. This ultimately leads to apoptosis and the suppression of cell growth. Furthermore, metabolomic analysis using 1 H NMR indicated that the metabolites of animals reverted to normal levels after the treatment., 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.)

Background: Conventional MR acceleration techniques, such as compressed sensing, parallel imaging, and half Fourier often face limitations, including noise amplification, reduced signal-to-noise ratio (SNR) and increased susceptibility to artifacts, which can compromise image quality, especially in high-speed acquisitions. Artificial intelligence (AI)-assisted compressed sensing (ACS) has emerged as a novel approach that combines the conventional techniques with advanced AI algorithms. The objective of this study was to examine the imaging quality of the ACS approach by qualitative and quantitative analysis for brain, spine, kidney, liver, and knee MR imaging, as well as compare the performance of this method with conventional (non-ACS) MR imaging., Methods: This study included 50 subjects. Three radiologists independently assessed the quality of MR images based on artefacts, image sharpness, overall image quality and diagnostic efficacy. SNR, contrast-to-noise ratio (CNR), edge content (EC), enhancement measure (EME), scanning time were used for quantitative evaluation. The Cohen's kappa correlation coefficient (k) was employed to measure radiologists' inter-observer agreement, and the Mann Whitney U-test used for comparison between non-ACS and ACS., Results: The qualitative analysis of three radiologists demonstrated that ACS images showed superior clinical information than non-ACS images with a mean k of ~ 0.70. The images acquired with ACS approach showed statistically higher values (p < 0.05) for SNR, CNR, EC, and EME compared to the non-ACS images. Furthermore, the study's findings indicated that ACS-enabled images reduced scan time by more than 50% while maintaining high imaging quality., Conclusion: Integrating ACS technology into routine clinical settings has the potential to speed up image acquisition, improve image quality, and enhance diagnostic procedures and patient throughput., (© 2024. The Author(s).)

Neuromorphic computing (NC) architecture has shown its suitability for energy-efficient computation. Amongst several systems, spin-orbit torque (SOT) based domain wall (DW) devices are one of the most energy-efficient contenders for NC. To realize spin-based NC architecture, the computing elements such as synthetic neurons and synapses need to be developed. However, there are very few experimental investigations on DW neurons and synapses. The present study demonstrates the energy-efficient operations of neurons and synapses by using novel reading and writing strategies. We have used a W/CoFeB-based energy-efficient SOT mechanism to drive the DWs at low current densities. We have used the concept of meander devices for achieving synaptic functions. By doing this, we have achieved 9 different resistive states in experiments. We have experimentally demonstrated the functional spike and step neurons. Additionally, we have engineered the anomalous Hall bars by incorporating several pairs, in comparison to conventional Hall crosses, to increase the sensitivity as well as signal-to-noise ratio (SNR). We have performed micromagnetic simulations and transport measurements to demonstrate the above-mentioned functionalities.

Cellulosic materials, such as cellulose nanocrystals (CNCs), are biocompatible, biodegradable and have unique and fascinating biomedical applications. Calxinin (CXN), a potent multistage antimalarial compound was functionalised with CNCs to improve biocompatibility and enhance the bioactivity of the resulting CNC-CXN nano-conjugate. Elemental analysis, powder X-ray, SEM, AFM, Infrared, and solid-state NMR spectroscopic techniques confirmed the composition of novel CNC-CXN nano-conjugate. Next, CNC-CXN nano-conjugate did not exhibit apparent cytotoxic effects on the sensitive Vero E6 cell line up to a concentration of 4.66 μg/μl. The CNC-CXN nano-conjugate was also evaluated for its preliminary efficacy on Plasmodium falciparum (3D7) malaria parasite and showed a 50 % inhibitory concentration value of 0.02 μg/μl. Overall, the selectivity index (SI) of the CNC-CXN nano-conjugate significantly improved to 233, indicating its suitability for further validation studies in animal models., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The first search for the Z boson decay to ττμμ at the CERN LHC is presented, based on data collected by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 138  fb^{-1}. The data are compatible with the predicted background. For the first time, an upper limit at the 95% confidence level of 6.9 times the standard model expectation is placed on the ratio of the Z→ττμμ to Z→4μ branching fractions. Limits are also placed on the six flavor-conserving four-lepton effective-field-theory operators involving two muons and two tau leptons, for the first time testing all such operators.

The widespread use of pesticides poses significant threats to both environmental and human health, primarily due to their potential toxic effects. The study investigated the cardiovascular toxicity of selected pesticides, focusing on their interactions with Toll-like receptor 4 (TLR4), an important part of the innate immune system. Using computational tools such as molecular docking, molecular dynamics (MD) simulations, principal component analysis (PCA), density functional theory (DFT) calculations, and ADME analysis, this study identified C160 as having the lowest binding affinity (-8.2 kcal/mol), followed by C107 and C165 (-8.0 kcal/mol). RMSD, RMSF, Rg, and hydrogen bond metrics indicated the formation of stable complexes between specific pesticides and TLR4. PCA revealed significant structural changes upon ligand binding, affecting stability and flexibility, while DFT calculations provided information about the stability, reactivity, and polarity of the compounds. ADME studies highlighted the solubility, permeability, and metabolic stability of C107, C160, and C165, suggesting their potential for bioavailability and impact on cardiovascular toxicity. C107 and C165 exhibit higher bioactivity scores, indicating favourable absorption, metabolism, and distribution properties. C165 also violated rule where molecular weight is greater than 500 g/mol. Further, DFT and NCI analysis of post MD conformations confirmed the binding of ligands at the binding pocket. The analysis shed light on the molecular mechanisms of pesticide-induced cardiovascular toxicity, aiding in the development of strategies to mitigate their harmful effects on human health., (© 2024. The Author(s).)

The use of CO 2 and CO 2 -derived chemicals offers society sustainable and biocompatible chemistry for a variety of applications, ranging from materials to medicines. In this context, dimethyl carbonate (DMC) stands out owing to its low toxicity, high biodegradability, tunable reactivity, and sustainable production. Further, the ability of DMC to act as an ambient electrophile at varied temperatures and reaction conditions in order to produce methoxycarbonylated (via B AC 2) and methylated products (via B AL 2) is very promising. While the methylation of hetero-H (N-, O-, and S-methylation) with DMC is established and well-reviewed, the C-H methylation reaction with DMC is limited, and there is no specific literature detailing the C-methylation reaction using DMC, creating new opportunities as well as challenges in the same domain. In this context, the present perspective focuses on the new breakthroughs, recent advances, and trends in C-H methylation reactions employing DMC. A critical analysis of the mechanistic course of reactions under each category was undertaken. We believe this timely perspective will offer an in-depth analysis of existing literature with critical remarks, which will certainly inspire fellow researchers across disciplines to understand and pursue cutting-edge research in the area of C-H methylation (alkylation) using DMC and related organic carbonates.

Purpose: Following treatment for localized prostate cancer, a subset of men will develop recurrent disease in the abdominopelvic nodes. For radiation therapy (RT), the optimal treatment volume, fractionation schedule, and dose remain unanswered questions. We report early outcomes for patients treated with involved-field stereotactic body radiation therapy (SBRT) (IF-SBRT) for nodal oligo-recurrent (NOR) prostate cancer., Methods: Between January 2018 and October 2023, 67 patients with a median age of 75 with NOR prostate cancer treated with 74 courses of IF-SBRT at Georgetown were eligible for this analysis. NOR was defined as any volume of disease that could be safely treated within an IF. All patients were treated with five-fraction IF-SBRT (27.5-35 Gy). The IF treatment volume was defined as the nodal basin containing the gross disease as well as the immediately adjacent basins. Disease progression was defined as a prostate-specific antigen (PSA) rise above the pretreatment baseline or initiation of a second treatment. Local control and progression-free survival were calculated using the Kaplan-Meier method., Results: Detection of pre-SBRT NOR was ascertained by prostate-specific membrane antigen (PSMA) (38%), fluciclovine (50%), or MRI/CT (12%). Median follow-up was 50 months (1-262). The median pre-salvage PSA was 6.5 ng/mL (range, 0.1-335). The median number of involved nodes was 3 (range, 1-16). The local control at 1 and 2 years was 98% and 93%, respectively. The 1- and 2-year progression-free survival was 78% and 50%, respectively. Twenty percent of treatment courses were followed by acute Grade 2 gastrointestinal (GI) toxicity: diarrhea (9%) and/or nausea (14%). Two patients (3%) experienced late Grade 2 nausea. On univariate analysis, measures of disease volume such as hormone sensitivity ( p = 0.03), increasing involved node number ( p = 0.008), and abdominal treatment ( p = 0.03) were significantly associated with GI toxicity., Conclusions: With the widespread adoption of PSMA agents, NORs are likely to increase. The optimal combination of local and systemic therapy in this population is unknown. With a favorable toxicity profile, IF-SBRT represents a safe and convenient local therapy treatment option for an elderly patient population. Patient- and treatment-related factors such as a large number of involved nodes and/or abdominal treatment may be associated with an increased risk of GI toxicity., Competing Interests: SC serves as a clinical consultant to Accuray, Inc., Blue Earth Diagnostics, Pfizer, and Sumitomo Pharma America, Inc. The Department of Radiation Medicine at Georgetown University Hospital receives a grant from Accuray to support a research coordinator. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Koh, Pilkington, Koh, Lawlor, Creswell, O’Connor, Zwart, Danner, Kumar, Suy, Carrasquilla and Collins.)

Optical tweezers use strongly focused light for trapping, characterizing, and manipulating objects in the microscopic and nanoscopic regimes. However, fully understanding optical trapping at the nanoscale remains a significant challenge. This holds importance because the nanoscale is the frontier for numerous promising advancements, ranging from enhancing single-molecule investigations in biology to developing hybrid devices for nanoelectronics and photonics and exploring fundamental quantum phenomena in opto-mechanics. We report an experimental and theoretical study of nanoparticles of various sizes, showing the advantages of the immense peak power of ultrashort laser pulses over conventional optical tweezers. We also demonstrate highly stable trapping of nanoparticles for extended durations at low average laser power using femtosecond lasers.

Background: This review investigates the efficacy of deutetrabenazine in the management of chorea related to HD. Motor, psychological, and cognitive symptoms characterize HD, a neurodegenerative disease. One prominent movement disorder associated with HD is chorea, which results in uncontrollably jerky movements of the muscles. HD has no known cure; instead, symptom management with a variety of medication options is the main goal. Effective management is essential because chorea has a significant impact on patients' quality of life. Dutetrabenazine is the first deuterated medication to receive approval from the US Food and Drug Administration (FDA) for the therapeutic treatment of chorea in Huntington's disease (HD)., Objectives: Treating chorea associated with HD may benefit from the use of deutetrabenazine. The novel compound deutetrabenazine contains deuterium. It inhibits CYP2D6 metabolism, prolongs the half-lives of active metabolites, and may cause persistent systemic exposure while maintaining significant pharmacological action. Deutetrabenazine decreases the release of monoamines, including dopamine, in the synaptic cleft by inhibiting the VMAT2 vesicular monoamine transporter. For chorea, this mechanism has a therapeutic effect. For the treatment of choreiform movement and tardive dyskinesia in HD, the FDA approved deutetrabenazine in 2017., Conclusion: Here we highlight, Deutetrabenazine as a promising new treatment for Huntington's disease chorea, for patients with chorea, deutetrabenazine offers hope for an enhanced quality of life. To completely understand its effectiveness and potential advantages, additional research is necessary, including direct comparison studies, as a result of the mixed study results., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We demonstrate the role of signaling via the glucocorticoid receptor, NR3C1, in differentiation of CD8+ T cell memory. Pharmacological inhibition as well as the short hairpin RNA-mediated knockdown of the receptor hindered memory transition and limited the homeostatic turnover of the activated CD8+ T cells. Dexamethasone exposure of CD8+ T cells expanded during a resolving infection with influenza A virus or a γ-herpesvirus promoted conversion of effector cells into memory cells by modulating cellular metabolism and lowering the accumulation of reactive oxygen species. Reduced reactive oxygen species levels in the responding effector cells upregulated Bcl2 and enhanced survival. The generated virus-specific memory CD8+ T cells were efficiently recalled following challenge of animals with a secondary infection to control it better. The memory-enhancing effect was predominantly evident at low doses of dexamethasone. Therefore, controlled glucocorticoid signaling within the effector CD8+ T cells is crucial for optimal memory differentiation., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Artificial intelligence (AI) encompasses a broad spectrum of techniques that have been utilized by pharmaceutical companies for decades, including machine learning, deep learning, and other advanced computational methods. These innovations have unlocked unprecedented opportunities for the acceleration of drug discovery and delivery, the optimization of treatment regimens, and the improvement of patient outcomes. AI is swiftly transforming the pharmaceutical industry, revolutionizing everything from drug development and discovery to personalized medicine, including target identification and validation, selection of excipients, prediction of the synthetic route, supply chain optimization, monitoring during continuous manufacturing processes, or predictive maintenance, among others. While the integration of AI promises to enhance efficiency, reduce costs, and improve both medicines and patient health, it also raises important questions from a regulatory point of view. In this review article, we will present a comprehensive overview of AI's applications in the pharmaceutical industry, covering areas such as drug discovery, target optimization, personalized medicine, drug safety, and more. By analyzing current research trends and case studies, we aim to shed light on AI's transformative impact on the pharmaceutical industry and its broader implications for healthcare.

Background: Adherence to chemotherapy regimens is crucial for achieving optimal treatment outcomes in cancer patients. However, measuring adherence remains a significant challenge. This study aimed to develop and validate a comprehensive self-report tool for assessing chemotherapy adherence., Methods: The Chemotherapy Adherence Assessment Scale (CAAS) was developed through a multi-stage process involving literature review, expert input, and pilot testing. Face validation was conducted with 23 subject experts, and content validity was assessed using the Content Validity Index (CVI). The CAAS was pilot-tested on 28 cancer patients undergoing chemotherapy. Psychometric properties were evaluated through internal consistency analysis (Cronbach's alpha) and Exploratory Factor Analysis (EFA)., Results: Face validation revealed 85% agreement among experts regarding grammar, clarity, and content. The CVI was 0.81 for individual items and 0.83 for the overall scale, indicating good content validity. Cronbach's alpha was 0.789, demonstrating strong internal consistency. The EFA yielded a robust five-factor structure, explaining 94.63% of the total variance. Most items exhibited strong factor loadings (>0.7) and high communalities (>0.7), supporting the construct validity of the CAAS., Conclusions: The CAAS demonstrated robust psychometric properties, including good content validity, high internal consistency, and a well-defined factor structure capturing key dimensions of chemotherapy adherence. The CAAS represents a valuable contribution to adherence assessment in oncology settings, with potential applications in clinical practice and adherence interventions., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Tissue cytokines in chronic hand eczema (CHE) can predict targeted therapy with novel drugs including JAK inhibitors. Our primary objective was to assess the tissue expression of cytokines of Th1 and Th2 cell lines in CHE patients and to study the efficacy of oral tofacitinib. We recruited patients presenting with recalcitrant CHE. Lesional and non-lesional tissue samples were assessed for Th1(IFN-γ, TNF-α) and Th2 related cytokines (IL-4, IL-13, IL-2,) using real time PCR. Tofacitinib 5 mg twice daily was initiated with 4 weekly assessment and we also noted relapses post therapy.Of 21 refractory hyperkeratotic CHE patients, cytokine analysis was performed in 11 patients which showed upregulation of IL-4 [n = 5/11, 1.87-fold increase], TNF-α (n = 5/11, 5.13-fold) and IFN-γ (n = 6/11, 1.98-fold) as compared to uninvolved skin. All patients (100%) had used topical corticosteroids (TCS) and 4/21 (19%) had failed methotrexate and 2/21 (9.5%) had failed acitretin. Tofacitinib 5 mg twice daily was given in 15/21 patients. The mean time to achieve hand eczema severity index 90 (HECSI 90) was 4 weeks (mean duration of treatment:5.8 months, n = 12). Side effects were observed in 4/12 (33.3%) patients and relapse was noted in 3/12 (25%) patients after a mean duration of 7 months after discontinuation of tofacitinib. Tofacitinib (pan-JAK inhibitor) showed an excellent response in refractory CHE patients with predominant tissue Th1/Th2 cells related cytokine expression., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Poultry manure is widely used as organic fertilizer in agriculture during the cultivation of crops, but the persistent high-level use of antibiotics in poultry production has raised concerns about the selection for reservoirs of antimicrobial resistance genes (ARGs). Previous studies have shown that the addition of poultry manure can increase the abundance of genes associated with resistance to tetracyclines, aminoglycosides, fluoroquinolones, sulfonamides, bacitracin, chloramphenicol, and macrolide-lincosamide-streptogramin in soil and plants. Understanding the microbial populations that harbor these ARGs is important to identify microorganisms that could enter the human food chain. Here, we test the hypothesis that environmental exposure to poultry manure increases the occurrence of antimicrobial resistance (AMR) in plant endophytes using selective culture, phenotypic Antibiotic Susceptibility Testing (AST), phylogenetic analysis, and whole genome sequencing (WGS). Endophytes from poultry manure treated Sorghum bicolor (L.) Moench plant root and stem samples showed increased phenotypic and genotypic resistance against multiple antibiotics compared to untreated controls. Comparison of AMR phenotype-to-genotype relationships highlighted the detection of multi-drug resistant (MDR) plant endophytes, demonstrating the value of genomic surveillance for emerging drug-resistant pathogens. The increased occurrence of ARGs in poultry manure-exposed endophytes highlights the need for responsible antibiotic use in poultry and animal farming to reduce contamination of ecological niches and transgression into endophytic plant microbiome compartments. It also emphasizes the requirement for proper manure management practices and vigilance in monitoring and surveillance efforts to tackle the growing problem of antibiotic resistance and preserve the efficacy of antibiotics for human and veterinary medicine., 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.)

For the first time, we present the detailed synthesis, photophysical, electrochemical, host-guest and charge transport properties of spiro[fluorene-9,9'-xanthene] (SFX) and carbazole macrocycle SPS-NR-02. The electron and hole transport values measured using the space charge limited current (SCLC) method resulted in ambipolar charge transport with an electron to hole mobility ratio of 0.39.

Background: Viral mediated diseases are continuously posing potent threat to human health. Nutraceuticals are being employed as novel therapeutics during viral outbreaks. MAM granules consist of Curcuma longa, Withania somnifera, and Piper nigrum, is one such patented Siddha nutraceutical supplement that has been proposed to be a therapeutic agent against viral diseases., Objective: We characterised MAM for their phytochemical and physicochemical properties and evaluated its cytotoxicity via in vivo acute toxicity studies using Wistar rats and by cell-based MTT assays., Materials and Methods: The antiviral properties of the aqueous extract of MAM were investigated against SARS-CoV-2 and chikungunya virus (CHIKV). Further, using ABTS radical scavenging, SOD enzymatic assays and measurement of intracellular ROS, we investigated the antioxidant potential of MAM extract and its ingredients in RAW264.7 cells. Additionally, production of inflammatory mediators was evaluated via NO release, PGE2 production and release of pro-inflammatory cytokines (IL-1β and TNFα)., Results: The MAM granules and aqueous extracts demonstrated no significant toxicity and demonstrated potent antiviral activity during co-incubation assay with SARS-CoV-2 and CHIKV. Moreover, we observed potent antioxidant and anti-inflammatory activity of MAM extract in a dose dependent manner. Further investigations on the individual ingredients with respect to their antioxidant and anti-inflammatory activities showed that all ingredients contributed synergistically and Withania somnifera showed most potent anti-oxidant activity., Conclusion: The overall in vitro, and in vivo analysis demonstrated that MAM granules were non-toxic and possessed potent antiviral activity. Additionally, observed significant anti-oxidant and anti-inflammatory properties of MAM suggested the modulation of innate immune response in the host validating its use as an effective nutraceutical during viral outbreaks., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent interest in quantum nonlinearity has spurred the development of rectifiers for harvesting energy from ambient radiofrequency waves. However, these rectifiers face efficiency and bandwidth limitations at room temperature. We address these challenges by exploring Bi 2 Te 3 , a time-reversal symmetric topological quantum material. Bi 2 Te 3 exhibits robust room temperature second-order voltage generation in both the longitudinal and transverse directions. We harness these coexisting nonlinearities to design a multidirectional quantum rectifier that can simultaneously extract energy from various components of an input signal. We demonstrate the efficacy of Bi 2 Te 3 -based rectifiers across a broad frequency range, spanning from existing Wi-Fi bands (2.45 GHz) to frequencies relevant to next-generation 5G technology (27.4 GHz). Our Bi 2 Te 3 -based rectifier surpasses previous limitations by achieving a high rectification efficiency and operational frequency, alongside a low operational threshold and broadband functionality. These findings enable practical topological quantum rectifiers for high-frequency electronics and energy conversion, advancing wireless energy harvesting for next-generation communication.

We report herein a transition-metal-free two-fold reductive coupling between prenal (allyl) tosylhydrazone and boronic acids/1,3-borotropic shift cascade to furnish 1,4-skipped dienes. In this work, a single batch operation produces ( E , E )-1,4-skipped dienes by undergoing a second reductive coupling of the transient boronic acid, which developed in situ following the first reductive allylation and a cascade 1,3-boron migration. Remarkably, the protocol is compatible with various aryl- and alkyl-substituted boronic acids, is scalable and has demonstrated on 61 substrates with yields up to 98%.

Computational methods such as molecular dynamics (MD) have illuminated how single-atom ions permeate membrane channels and how selectivity among them is achieved. Much less is understood about molecular permeation through eukaryotic channels that mediate the flux of small molecules (e.g. connexins, pannexins, LRRC8s, CALHMs). Here we describe computational methods that have been profitably employed to explore the movements of molecules through wide pores, revealing mechanistic insights, guiding experiments, and suggesting testable hypotheses. This review illustrates MD techniques such as voltage-driven flux, potential of mean force, and mean first-passage-time calculations, as applied to molecular permeation through wide pores. These techniques have enabled detailed and quantitative modeling of molecular interactions and movement of permeants at the atomic level. We highlight novel contributors to the transit of molecules through these wide pathways. In particular, the flexibility and anisotropic nature of permeant molecules, coupled with the dynamics of pore-lining residues, lead to bespoke permeation dynamics. As more eukaryotic large-pore channel structures and functional data become available, these insights and approaches will be important for understanding the physical principles underlying molecular permeation and as guides for experimental design., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8-35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1-43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8-51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease., (© 2024 Tsimberidou et al.)

A search for collective effects inside jets produced in proton-proton collisions is performed via correlation measurements of charged particles using the CMS detector at the CERN LHC. The analysis uses data collected at a center-of-mass energy of sqrt[s]=13  TeV, corresponding to an integrated luminosity of 138  fb^{-1}. Jets are reconstructed with the anti-k&#95;{T} algorithm with a distance parameter of 0.8 and are required to have transverse momentum greater than 550 GeV and pseudorapidity |η^{jet}|<1.6. Two-particle correlations among the charged particles within the jets are studied as functions of the particles' azimuthal angle and pseudorapidity separations (Δϕ^{*} and Δη^{*}) in a jet coordinate basis, where particles' η^{*}, ϕ^{*} are defined relative to the direction of the jet. The correlation functions are studied in classes of in-jet charged-particle multiplicity up to N&#95;{ch}^{j}≈100. Fourier harmonics are extracted from long-range azimuthal correlation functions to characterize azimuthal anisotropy for |Δη^{*}|>2. For low-N&#95;{ch}^{j} jets, the long-range elliptic anisotropic harmonic, v&#95;{2}^{*}, is observed to decrease with N&#95;{ch}^{j}. This trend is well described by Monte Carlo event generators. However, a rising trend for v&#95;{2}^{*} emerges at N&#95;{ch}^{j}≳80, hinting at a possible onset of collective behavior, which is not reproduced by the models tested. This observation yields new insights into the dynamics of jet evolution in the vacuum.

Background Breast cancer is the most frequently diagnosed cancer in women worldwide, accounting for more than one in ten new cancer cases each year. It ranks as the second leading cause of cancer-related mortality among women. The majority of patients present with palpable breast lumps. Effective surgical management of breast cancer largely depends on accurate preoperative pathological diagnosis. This study evaluates the diagnostic accuracy and prognostic implications of fine-needle aspiration cytology (FNAC) compared with core needle biopsy (CNB) in breast carcinoma. Objectives The objectives of this study are to assess the sensitivity and specificity of FNAC and CNB, to compare the diagnostic accuracy of FNAC and CNB against histopathological findings from gross specimens in the evaluation of breast lumps, and to identify and examine the limitations associated with both FNAC and CNB procedures. Materials and methods This study included female patients presenting with clinically suspicious palpable breast lumps at the General Surgery OPD of Bankura Sammilani Medical College and Hospital, Bankura. All patients underwent FNAC followed by CNB. The cytological and CNB diagnoses were compared with the final pathological diagnosis obtained from excisional biopsy. Results The study included 44 female patients aged 20 to 70 years. The most common age group for breast carcinoma was 50-59 years (36.36%). Malignancy was diagnosed in 75% of cases (33/44), with right breast involvement (65%) being more common than the left. The upper outer quadrant (59%) was the most frequently affected area. Among the 33 confirmed malignant cases, 69.70% had lesions larger than 5 cm. FNAC demonstrated a sensitivity of 93.93%, specificity of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 84.61%, and diagnostic accuracy of 95.45%. CNB showed a sensitivity of 96.97%, specificity of 100%, PPV of 100%, NPV of 91.67%, and diagnostic accuracy of 97.73%. Both methods correlated significantly with the final histopathology results (p < 0.05). FNAC identified ductal carcinoma in 93.55% of cases, while CNB identified it in 96.77%. Conclusion CNB provides additional information on receptor status but is more resource-intensive. FNAC remains a cost-effective and time-efficient first-line diagnostic tool, especially in resource-constrained settings like rural India. FNAC should be employed for initial diagnosis, with CNB reserved for cases requiring further clarification., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee of Bankura Sammilani Medical College issued approval 185. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Pradhan et al.)

Objective: The biomechanics of upper airway collapse in obstructive sleep apnea (OSA) remains poorly understood. The goal of this study is to compare the area-pressure relationship (tube law) of the velopharynx at peak inspiration and peak expiration., Study Design: Cross-sectional., Setting: Academic tertiary medical center., Methods: The velopharyngeal tube law was quantified in a convenience sample of 20 OSA patients via step reductions in nasal mask pressure during drug induced sleep endoscopy (DISE). The velopharyngeal airspace cross-sectional area was estimated from endoscopy while luminal pressure was recorded with a catheter. The tube law was quantified for nasal mask pressures from 14 to 0 cmH 2 O at peak inspiration and at peak expiration in all patients. The tube law was also quantified during the breathing cycle at a constant nasal mask pressure of 4 cmH 2 O in 3 patients representing different phenotypes., Results: Velopharyngeal compliance (the slope of the tube law) was not statistically different in the peak inspiration versus peak expiration tube laws. Three phenotypes were observed, namely inspiratory collapse (phenotype 1), expiratory collapse (phenotype 2 = palatal prolapse), and a mostly stable airway during inspiration and expiration that collapsed as CPAP was reduced (phenotype 3)., Conclusion: Velopharyngeal compliance is not significantly different at peak inspiration and peak expiration, which suggests that muscle tone is low when luminal pressure is above the closing pressure. Additional studies are needed to investigate how different phenotypes of velopharyngeal collapse may affect therapeutic outcomes., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objective: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a common cause of ventilator-associated pneumonia (VAP). Some in vitro data favour various combination antibiotic therapy. However, there is a need for more in vivo studies for the management of VAP caused by CRAB. This retrospective study was done to evaluate the effectiveness of various combination antibiotic therapy including sulbactam on outcomes of VAP caused by CRAB., Methods: Adult patients (age ≥18 years) diagnosed with VAP caused by CRAB were included. Patients with polymicrobial infections were excluded from the study. Patients with CRAB associated VAP who were given sulbactam based antibiotic combinations were observed for outcomes. The primary outcome was 28-day mortality after diagnosis of VAP caused by CRAB. Reduction in serum HsCRP (High sensitivity C-reactive protein) during treatment and requirement of inotropes were the secondary outcomes. Outcomes were compared between various sulbactam based antibiotic combination therapies., Results: A total of 103 patients were included. A total of 44 (42.7 %) patients received sulbactam and minocycline or sulbactam and polymyxin B dual antibiotic combination, and 59 (57.3 %) patients received sulbactam, polymyxin B and minocycline triple antibiotic combination. The percentage difference in 28 days mortality was 27.51 % (95 % CI 8.03 %-44.06 %; p = 0.005) in dual vs triple sulbactam based antibiotic combination therapy. The percentage difference in requirement of inotropes during therapy and HsCRP reduction after 7 days of therapy was 23.65 % (95 % CI 6.43 %-38.3 %; p = 0.007) and 25.1 % (95%CI 10.1 %-38.2 %; p < 0.001) respectively when compared between dual vs triple sulbactam based antibiotic combination therapy., Conclusion: Treatment with sulbactam, polymyxin B and minocycline combination antibiotic therapy was associated with significantly lower 28-day mortality. Moreover, the lower requirement of inotropes during treatment and a significant reduction in HsCRP level favours this combination antibiotic therapy in VAP caused by CRAB., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Deepak Kumar reports financial support was provided by Indian Council of Medical 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 © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

In the quest for early cancer diagnosis, early identification and treatment are paramount. Recently, ctDNA detection has emerged as a viable avenue for early screening of cancer. The examination of ctDNA in fluid biopsies has gained substantial attention in tumor diagnosis and therapy. Both the scientific community and industry are actively exploring this field. However, developing cost-effective, portable, and real-time ctDNA measurement methods using conventional gene detection equipment poses a significant challenge. This challenge has led to the exploration of alternative approaches. Electrochemical biosensors, distinguished by their heightened sensitivity, remarkable specificity, affordability, and excellent portability, have emerged as a promising avenue for ctDNA detection. This review is dedicated to the specific focus on ctDNA detection, highlighting recent advancements in this evolving detection technology. We aimed to reference previous studies related to ctDNA-targeted cancer detection using electrochemical biosensors to advocate the utilization of electrochemical biosensors in healthcare diagnostics. Further research is imperative for the effective integration of ctDNA analysis into point-of-care cancer testing. Innovative approaches utilizing multiple markers need to be explored to advance this technology and make substantial contributions to societal well-being., (© 2024. The Author(s).)

In this study, we demonstrated that arranging positive and negative capacitance materials in series, based on isomeric polythiophene, led to a notable increase in total capacitance. Furthermore, the application of negative capacitance (NC) technology in supercapacitor (SC) construction offers the potential for energy storage capabilities surpassing fundamental limits. Our findings suggest the feasibility of developing all-organic based energy storage devices with high capacitance.