Lipid Specificity of the Fusion of Bacterial Extracellular Vesicles with the Host Membrane.

Bacterial membrane vesicles (MVs) facilitate the long-distance delivery of virulence factors crucial for pathogenicity. The entry and trafficking mechanisms of virulence factors inside host cells are recently emerging; however, whether bacterial MVs can fuse and modulate the physicochemical properties of the host lipid membrane and membrane lipid parameter for fusion remains unknown. In this study, we reconstituted the interaction of bacterial MVs with host cell lipid membranes and quantitatively showed that bacterial MV interaction increases the fluidity, dipole potential, and compressibility of a biologically relevant multicomponent host membrane upon fusion. The presence of cylindrical lipids, such as phosphatidylcholine, and a moderate acyl chain length of C16 help the MV interaction. While significant binding of bacterial MVs to the raft-like lipid membranes with phase-separated regions of the membrane was observed, however, MVs prefer binding to the liquid-disordered regions of the membrane. Furthermore, the elevated levels of cholesterol tend to hinder the interaction of bacterial MVs, as evident from the favorable excess Gibbs free energy of mixing bacterial MVs with host lipid membranes. The findings provide new insights that might have implications for the regulation of host machinery by bacterial pathogens through manipulation of the host membrane properties.

SAGA: Stability-Aware Gait Analysis in constraint-free environments.

BACKGROUND: Gait abnormality detection is a challenging task in clinical practice. The majority of the current frameworks for gait abnormality detection involve the individual processes of segmentation, feature estimation, feature learning, and similarity assessment. Since each component of these modules is fixed and they are mutually independent, their performance under difficult circumstances is not ideal. We combine those processes into a single framework, a gait abnormality detection system with an end-to-end network. METHODS: It is made up of convolutional neural networks and Deep-Q-learning methods: one for coordinate estimation and the other for classification. In a single joint learning technique that may be trained together, the two networks are modeled. This method is significantly more efficient for use in real life since it drastically simplifies the conventional step-by-step approach. RESULTS: The proposed model is experimented on MATLAB R2020a. While considering into consideration the stability factor, our proposed model attained an average case accuracy of 95.3%, a sensitivity of 96.4%, and a specificity of 94.1%. SIGNIFICANCE: Our paradigm for quantifying gait analysis using commodity equipment will improve access to quantitative gait analysis in medical facilities and rehabilitation centers while also allowing academics to conduct large-scale investigations for gait-related disorders. Numerous experimental findings demonstrate the effectiveness of the proposed strategy and its ability to provide cutting-edge outcomes.

Recent Advancements in the Application of Circulating Tumor DNA as Biomarkers for Early Detection of Cancers.

Early detection of cancer is vital for increasing patient survivability chances. The three major techniques used to diagnose cancers are instrumental examination, tissue biopsy, and tumor biomarker detection. Circulating tumor DNA (ctDNA) has gained much attention in recent years due to advantages over traditional technology, such as high sensitivity, high specificity, and noninvasive nature. Through the mechanism of apoptosis, necrosis, and circulating exosome release in tumor cells, ctDNA can spread throughout the circulatory system and carry modifications such as methylations, mutations, gene rearrangements, and microsatellite instability. Traditional gene-detection technology struggles to achieve real-time, low-cost, and portable ctDNA measurement, whereas electrochemical biosensors offer low cost, high specificity alongside sensitivity, and portability for the detection of ctDNA. Therefore, this review focuses on describing the recent advancements in ctDNA biomarkers for various cancer types and biosensor developments for real-time, noninvasive, and rapid ctDNA detection. Further in the review, ctDNA sensors are also discussed in regards to their selections of probes for receptors based on the electrode surface recognition elements.

Minimally Invasive Osteotomy for Correction of Post-Traumatic Tibia Internal Rotation Deformity: A Case Report.

Introduction: Intramedullary nailing is a commonly performed surgery for tibia diaphysis fractures. However, in selected cases, this procedure can get complicated with rotational malalignment if not checked carefully intra-operatively. Case Report: A 29 year-old male sustained polytrauma and was treated with intramedullary nailing for bilateral femur and right-side tibia fractures. Postoperatively, the patient noticed extreme in-toeing suggesting an internal rotation deformity, which caused great difficulty in walking. The patient was planned for a revision surgery to correct the internal rotation deformity, 6 months after the index surgery. A minimally invasive metaphyseal osteotomy was performed, away from his fracture site by drilling multiple holes. The distal locking bolts of the interlocking nail were removed, and two K wires used to achieve the desired correction angle. After rotating the distal fragment, locking bolts were reinserted in new holes. We kept the patient on our regular follow-up till he achieved sound union at the osteotomy site, after which we allowed him unrestricted activities. Conclusion: The presence of an intramedullary nail can hence help the surgeon in correcting such isolated rotational deformities without getting into the hassle of implant removal to achieve the same.

Role of Inhibin B, AMH, GnRHa Test and HCG Stimulation Test to Distinguish Isolated Hypogonadotropic Hypogonadism (IHH) from Constitutional Delay in Growth and Puberty (CDGP).

Introduction: This study aimed to distinguish isolated hypogonadotropic hypogonadism (IHH) from constitutional delay in growth and puberty (CDGP) by various hormonal tests in both sexes. Methods: Boys with testicular volume (TV) <4 ml (14-18 years) and girls with breast B1 stage (13-18 years) were enrolled in this study. A detailed history, clinical examination and hormonal analysis including basal luteinising hormone (LH), follicle-stimulating hormone (FSH), inhibin B, anti-Mullerian hormone (AMH), testosterone (boys), oestradiol (girls), triptorelin stimulation test and 3-day human chorionic gonadotropin (HCG) stimulation test (boys) were performed. All patients were followed for 1.5 years or till 18 years of age. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-offs with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for various hormones to distinguish IHH from CDGP. Results: Of 34 children (male: 22 and female: 12), CDGP and IHH were diagnosed in 21 and 13 children, respectively. 4 hours post-triptorelin LH had the highest sensitivity (100%) and specificity (100%) for identifying IHH in both sexes. Basal inhibin B had good sensitivity (male: 85.7% and female: 83.8%) and specificity (male: 93.3% and female: 100%) for diagnosing IHH. 24 hours post-triptorelin testosterone (<34.5 ng/dl), day 4 post-HCG testosterone (<99.7 ng/dl) and 24 hours post-triptorelin oestradiol (<31.63 pg/ml) had reasonable sensitivity and specificity for identifying IHH. Basal LH, FSH and AMH were poor discriminators for IHH in both sexes. Conclusion: The best indicator was post-triptorelin 4-hour LH followed by inhibin B, which had a reasonable diagnostic utility to distinguish IHH from CDGP in both boys and girls.

Digital phenotyping correlates of mobile cognitive measures in schizophrenia: A multisite global mental health feasibility trial.

Traditional cognitive assessments in schizophrenia are time-consuming and necessitate specialized training, making routine evaluation challenging. To overcome these limitations, this study investigates the feasibility and advantages of utilizing smartphone-based assessments to capture both cognitive functioning and digital phenotyping data and compare these results to gold standard measures. We conducted a secondary analysis of data from 76 individuals with schizophrenia, who were recruited across three sites (one in Boston, two in India) was conducted. The open-source mindLAMP smartphone app captured digital phenotyping data and Trails A/B assessments of attention / memory for up to 12 months. The smartphone-cognitive tasks exhibited potential for normal distribution and these scores showed small but significant correlations with the results from the Brief Assessment of Cognition in Schizophrenia, especially the digital span and symbol coding tasks (r2 = 0.21). A small but significant correlation (r2 = 0.29) between smartphone-derived cognitive scores and health-related behaviors such as sleep duration patterns was observed. Smartphone-based cognitive assessments show promise as cross-cultural tools that can capture relevant data on momentary states among individuals with schizophrenia. Cognitive results related to sleep suggest functional applications to digital phenotyping data, and the potential of this multimodal data approach in research.

Facile synthesis and in silico studies of benzothiazole-linked hydroxypyrazolones targeting α-amylase and α-glucosidase.

Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t, were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.

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Melphalan-associated encephalopathy following autologous stem cell transplant: a transplanter's nightmare!

Melphalan-induced encephalopathy is a rare complication observed in patients undergoing autologous stem cell transplantation (ASCT) and is characterized by symptoms ranging from drowsiness to seizures. Previous reports have described similar cases, including a review of a large cohort of patients in whom melphalan-associated encephalopathy was identified in 2% of the patients undergoing ASCT. We describe the case of a 63-year-old male with Multiple Myeloma and underlying chronic kidney disease (CKD) who underwent ASCT with a reduced dose of melphalan due to renal dysfunction in complete remission following induction therapy and subsequent neurological deterioration, which necessitated an extensive evaluation of several neurological and infective etiologies. In this report, we highlight that melphalan-associated encephalopathy is a distinct entity complicating ASCT in patients with myeloma, especially in those with preexisting renal insufficiency, and consider its management.

Neglected Dorsal Proximal Interphalangeal Joint Dislocation Treated by Volar Plate Arthroplasty: A Case Series.

Chronic unreduced dislocations of the proximal interphalangeal joint are uncommon, and management principles for these injuries have not been defined. The dislocation can be volar or dorsal and closed reduction is rarely successful owing to soft tissue contractures. Treatment options in literature reviews for such rare injuries included open reduction of pip joint with volar plate arthroplasty, extension block pinning, hemi hamate arthroplasty, pip joint arthrodesis, Suzuki dynamic frame fixation, open reduction and repair of capsule and collateral ligaments with suture anchors. Few cases of amputation following treatment were even reported in literature emphasizing the role of meticulous soft tissue handling in such neglected cases of hand. We report six cases of neglected (more than three months old) dorsal dislocation of the PIP joint of the hand, treated with volar plate arthroplasty and extension block pinning. A functional range of motion with a stable joint can be achieved in such injuries with volar plate arthroplasty, as long as the articular cartilage is relatively preserved and bone loss is <30%.

Protective Role of Nanoceria-Infused Nanofibrous Scaffold toward Bone Tissue Regeneration with Senescent Cells.

The presence of oxidative stress in bone defects leads to delayed regeneration, especially in the aged population and patients receiving cancer treatment. This delay is attributed to the increased levels of reactive oxygen species (ROS) in these populations due to the accumulation of senescent cells. Tissue-engineered scaffolds are emerging as an alternative method to treat bone defects. In this study, we engineered tissue scaffolds tailored to modulate the adverse effects of oxidative stress and promote bone regeneration. We used polycaprolactone to fabricate nanofibrous mats by using electrospinning. We exploited the ROS-scavenging properties of cerium oxide nanoparticles to alleviate the high oxidative stress microenvironment caused by the presence of senescent cells. We characterized the nanofibers for their physical and mechanical properties and utilized an ionization-radiation-based model to induce senescence in bone cells. We demonstrate that the presence of ceria can modulate ROS levels, thereby reducing the level of senescence and promoting osteogenesis. Overall, this study demonstrates that ceria-infused nanofibrous scaffolds can be used for augmenting the osteogenic activity of senescent progenitor cells, which has important implications for engineering bone tissue scaffolds for patients with low regeneration capabilities.

Lipo-polymeric nano-complexes for dermal delivery of a model protein.

Delivering macromolecules across the skin poses challenges due to the barrier properties of stratum corneum. Different strategies have been reported to cross this barrier, such as chemical penetration enhancers and physical methods like microneedles, sonophoresis, electroporation, laser ablation, etc. Herein, we explored a cationic lipo-polymeric nanocarrier to deliver a model protein across the skin. A cationic amphiphilic lipo-polymer was used to prepare blank nanoplexes, which were subsequently complexed with anionic fluorescein-tagged bovine serum albumin (FITC-BSA). Blank nanoplexes and FITC-BSA complexed nanoplexes showed sizes of 93.72 ± 5.8 (PDI-0.250) and 145.9 ± 3.2 nm (PDI-0.258), respectively, and zeta potentials of 25.6 ± 7.0 mV and 9.17 ± 1.20 mV. In vitro cell culture, and toxicity studies showed optimal use of these nanocarriers, with hemocompatibility data indicating non-toxicity. Ex vivo skin permeation analysis showed a skin permeation rate of 33% after 24 h. The optimized formulation was loaded in a carbopol-based gel that exhibits non-Newtonian flow characteristics with shear-thinning behavior and variable thixotropy. The nanoplexes delivered via gel demonstrated skin permeation of 57% after 24 h in mice skin ex vivo. In vivo skin toxicity testing confirmed the low toxicity profile of these nanocarriers. These results are promising for the transdermal/dermal delivery of macromolecules, such as protein therapeutics, using nanoplexes.

Development in the Synthesis of Bioactive Thiazole-Based Heterocyclic Hybrids Utilizing Phenacyl Bromide.

Heterocyclic hybrid frameworks represent a burgeoning domain within the realms of drug discovery and medicinal chemistry, attracting considerable attention in recent years. Thiazole pharmacophore fragments, inherent in natural products such as peptide alkaloids, metabolites, and cyclopeptides, have demonstrated a broad spectrum of pharmacological potentials. Given their profound biological significance, a plethora of thiazole-based hybrids have been synthesized through the conjugation of thiazole moieties with bioactive pyrazole and pyrazoline fragments. This review systematically presents a compendium of robust methodologies for the synthesis of thiazole-linked hybrids, employing the (3 + 2) heterocyclization reaction, specifically the Hantzsch-thiazole synthesis, utilizing phenacyl bromide as the substrate. The strategic approach of molecular hybridization has markedly enhanced drug efficacy, mitigated resistance to multiple drugs, and minimized toxicity concerns. The resultant thiazole-linked hybrids exhibit a myriad of medicinal properties viz. anticancer, antibacterial, anticonvulsant, antifungal, antiviral, and antioxidant activities. This compilation of methodologies and insights serves as a valuable resource for medicinal chemists and researchers engaged in the design of novel thiazole-linked hybrids endowed with therapeutic attribute.

cRGD-modified hybrid lipopolymeric nanoplexes for gene editing in the posterior segment of the eye.

Eye-related diseases, specifically retinal dystrophy (RD) conditions, are the leading cause of blindness worldwide. Gene addition, regulation, or editing could potentially treat such diseases through gene expression regulation. CRISPR/Cas9 gene editing is one of the most prominent and precise gene editing tools which could be employed to edit genes related to the dystrophic condition. However, CRISPR/Cas9 faces in vivo delivery challenges due to its high molecular weight, negative charge, prone to degradation in the presence of nucleases and proteases, poor cellular degradation, etc., which makes it challenging to adopt for therapeutic applications. We developed cRGD-modified lipopolymeric nanoplexes loaded with Cas9 RNPs with a particle size and zeta potential of 175 ±â€¯20 nm and 2.15 ±â€¯0.9 mV, respectively. The cRGD-modified lipopolymeric nanoplexes were stable for 194 h and able to transfect >70 % ARPE-19 and NIH3T3 cells with an Indel frequency of ~40 % for the VEGF-A gene. The cRGD-modified lipopolymeric nanoplexes found good vitreous mobility and could transfection retinal cells in vivo after 48 h of intravitreal injection in Wistar Rats. Moreover, in vivo VEGFA gene editing was ~10 % with minimal toxicities. Collectively, the cRGD-modified lipopolymeric nanoplexes were found to have extreme potential in delivering CRISPR/Cas9 RNPs payload to the retinal tissues for therapeutic applications.

Use of cost-effective software for lesion localization in brain surgery: Technical note.

Lesion localization has been an important aspect of neurosurgery and has advanced significantly with technological evolution. The journey started from the localization of lesion based on clinical findings to the current era where neuronavigation and virtual reality are being used for the purpose. However, the financial implications of these advanced equipments have made them inaccessible for patients in the majority of low- and middle-income countries. The authors describe techniques to use software, which are cost effective and can be used effectively for the localization of a lesion of the brain.

Mechanism and potentialities of photothermal and photodynamic therapy of transition metal dichalcogenides (TMDCs) against cancer.

The ultimate goal of nanoparticle-based phototherapy is to suppress tumor growth. Photothermal therapy (PTT) and photothermal photodynamic therapy (PDT) are two types of physicochemical therapy that use light radiation with multiple wavelength ranges in the near-infrared to treat cancer. When a laser is pointed at tissue, photons are taken in the intercellular and intracellular regions, converting photon energy to heat. It has attracted much interest and research in recent years. The advent of transition materials dichalcogenides (TMDCs) is a revolutionary step in PDT/PTT-based cancer therapy. The TMDCs is a multilayer 2D nano-composite. TMDCs contain three atomic layers in which two chalcogens squash in the transition metal. The chalcogen atoms are highly reactive, and the surface characteristics of TMDCs help them to target deep cancer cells. They absorb Near Infrared (NIR), which kills deep cancer cells. In this review, we have discussed the history and mechanism of PDT/PTT and the use of TMDCs and nanoparticle-based systems, which have been practiced for theranostics purposes. We have also discussed PDT/PTT combined with immunotherapy, in which the cancer cell apoptosis is done by activating the immune cells, such as CD8+.

Uracil as a biomarker for spatial pyrimidine metabolism in the development of gingivobuccal oral squamous cell carcinoma.

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.

Molecular insight into the structural and functional aspects of arene Ru(II) complexes bearing bulky thiourea ligands.

Herein we report four new arene ruthenium(II) complexes [RuII(η6-p-cymene)(L1)к1(S)Cl2] (C1), [RuII(η6-benzene)(L1)к1(S)Cl2] (C2) where L1 is N-((2,6-dimethylphenyl)carbamothioyl)benzamide (L1), and [RuII(η6-p-cymene)(L2)к1(S)Cl2] (C3), [RuII(η6-benzene)(L2)к1(S)Cl2] (C4) where L2 is N-((2,6-diisopropylphenyl)carbamothioyl)benzamide (L2) which were synthesized and evaluated for biological activity. The monodentate coordination of thione sulphur (S) to ruthenium ion along with two terminal chloride was confirmed by X-Ray diffraction analysis thus revealing a typical "piano-stool" pseudo tetrahedral geometry. DPPH radical scavenging activity showed that ligands were less efficient however on complex formation it showed significant efficacy with C4 showing the highest activity. The ligands and ruthenium complexes exhibited minimal to no cytotoxic effects on HEK cells within the concentration range of 10-300 µM. Evaluating the cytotoxicity against prostate cancer cells (DU145) L1, L2 and C1 displayed more pronounced cytotoxic activity with C1 showing high cytotoxicity against the cancer cells, in comparison to cisplatin indicating its potential for further investigation and analysis. Considering this, compound C1 was used to further study its interaction with BSA using fluorescence spectroscopy and it was found to be 2.64 × 106 M-1. Findings from CD spectroscopy indicate the binding in the helix region which was further confirmed with the molecular docking studies.

Influence of climatic factors on the life stages of Aedes mosquitoes and vectorial transmission: A review.

BACKGROUND OBJECTIVES: Aedes aegypti and Aedes albopictus are two sympatric mosquito species that compete with each other for resources when their breeding habitats overlap. This study examines what happens when sympatric Aedes aegypti and Aedes albopictus mosquitoes' mate with each other and other species by looking at insemination rates, fecundity, and hatchability rate. METHODS: We performed controlled mating experiments in laboratory setting, assessing both conspecific and interspecific crosses. We measured insemination rates, egg numbers, and hatching success to examine the reproductive interference dynamics between these two distinct mosquito species. RESULTS: In the context of conspecific mating, it was observed that both female Ae. aegypti and Ae. albopictus exhibited high insemination rates, with percentages of 98% and 94%, respectively. However, interspecific mating exhibited interesting asymmetries: Ae. albopictus males achieved a notable insemination success rate of 28% when mating with Ae. aegypti females, while Ae. aegypti males achieved only 8% insemination success with Ae. albopictus females. Additionally, females that mated with interspecific males had reduced production of viable eggs compared to conspecific mating. Most notably, interspecific mating resulted in the production of infertile eggs, while conspecific mating led to successful hatching. INTERPRETATION CONCLUSION: The study reveals that, Ae. aegypti and Ae. albopictus can asymmetrically interfere with each other's reproduction, causing a 'satyr' effect. This understanding of interspecific competition and reproductive interference in these mosquito species could impact their coexistence in shared breeding habitats.