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Microplastics (MPs) are ubiquitous environmental pollutants with significant ecological risks, particularly due to their potential for bioaccumulation and toxicity. This study examines the effects of virgin spherical MPs and environmentally weathered MPs, specifically polystyrene (PS) and polyethylene (PE), on zebrafish larvae to enhance the environmental relevance of the findings. MP concentrations used were 10 5 -10 6 particles/L for the virgin MP group and 10 4 particles/L for the weathered MP group, reflecting levels commonly observed in natural environments. Weathered MPs were produced through mechanical grinding followed by one month of exposure to water and sunlight to simulate environmental aging. MP characterization was performed using advanced microscopy techniques, including Scanning Electron Microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR). The results indicated significantly higher mortality in the weathered MP group (80%) compared to the virgin MP group (20%). Zebrafish larvae ingested MPs and exhibited disruptions in key molecular pathways, including those involved in oxidative stress response, apoptosis, and DNA damage repair. Notably, this study is among the first to evaluate the impact of MPs on the complete homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways. Our findings highlight the enhanced toxicity of weathered MPs and emphasize the importance of considering MP aging in toxicological assessments. These results contribute to a deeper understanding of MP pollution and provide valuable insights for the development of regulatory measures to protect aquatic ecosystems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Ashutosh Kumar reports financial support was provided by Gujarat Institute of Chemical Technology. Dr. Ashutosh Kumar reports a relationship with Ahmedabad University Biological and Life Sciences Division that includes: employment. 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.)

Breast cancer is the second leading cause of cancer-related deaths in females worldwide. Despite significant advancements in treatment, drug resistance remains a major challenge, limiting the effectiveness of therapies and leading to dismal outcomes. Approximately 50% of HER2+ breast cancer patients develop resistance to trastuzumab, and patients with triple-negative breast cancer often experience resistance to first-line therapies. The drug resistance mechanisms involve altered drug uptake, enhanced DNA repair, and dysregulated apoptosis pathways. MicroRNAs are essential in regulating cellular processes involved in both homeostasis and disease. Recent data suggest that microRNAs can overcome drug resistance by regulating the pathways that confer drug resistance. Combining different conventional anticancer agents with microRNA therapies holds promise for enhancing treatment effectiveness against drug resistant breast cancer. Advancements in nano-drug delivery systems have facilitated the effective delivery of microRNAs by improving their stability, targeting specific cells, and enhancing cellular uptake. This review elucidates the recent advancements in microRNA-based therapies, their effects on gene expression, and their clinical efficacy in overcoming drug resistance in breast cancer., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Inositol-requiring enzyme 1α (IRE1α) is a sensor of endoplasmic reticulum (ER) stress and drives ER stress response pathways. Activated IRE1α exhibits RNase activity and cleaves mRNA encoding X-box binding protein 1, a transcription factor that induces the expression of genes that maintain ER proteostasis for cell survival. Previously, we showed that IRE1α undergoes S -nitrosylation, a post-translational modification induced by nitric oxide (NO), resulting in reduced RNase activity. Therefore, S -nitrosylation of IRE1α compromises the response to ER stress, making cells more vulnerable. We conducted virtual screening and cell-based validation experiments to identify compounds that inhibit the S -nitrosylation of IRE1α by targeting nitrosylated cysteine residues. We ultimately identified a compound (1ACTA) that selectively inhibits the S -nitrosylation of IRE1α and prevents the NO-induced reduction of RNase activity. Furthermore, 1ACTA reduces the rate of NO-induced cell death. Our research identified S -nitrosylation as a novel target for drug development for IRE1α and provides a suitable screening strategy.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Of the 1955 molecules predicted by participants in Round 1 of the challenge, 73 were found to bind to LRRK2 in an SPR assay with a K D lower than 150 μM. These 73 molecules were advanced to the Round 2 hit expansion phase, where computational teams each selected up to 50 analogs. Binding was observed in two orthogonal assays for seven chemically diverse series, with affinities ranging from 18 to 140 μM. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants adopted strikingly diverging screening strategies. Machine learning-accelerated methods achieved similar results to brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

Background: Hypertension affects nearly half of US adults yet remains inadequately controlled in over three-quarters of these cases. This study aimed to assess the association between adherence to antihypertensive medications and total medical costs, health care use, and productivity-related outcomes., Methods and Results: We conducted cross-sectional analyses using MarketScan databases, which included individuals aged 18 to 64 years with noncapitated health insurance plans in 2019. Adherence was defined as ≥80% medication possession ratio for prescribed antihypertensive medications. We used a generalized linear model to estimate total medical costs, a negative binomial model to estimate health care use (emergency department visits and inpatient admissions), an exponential hurdle model to estimate productivity-related outcomes (number of sick absences, short-term disability, long-term disability), and a 2-part model to estimate productivity-related costs in 2019 US dollars. All models were adjusted for age, sex, urbanicity, census region, and comorbidities. We reported average marginal effects for outcomes related to antihypertensive medication adherence. Among 379 503 individuals with hypertension in 2019, 54.4% adhered to antihypertensives. Per person, antihypertensive medication adherence was associated with $1441 lower total medical costs, $11 lower sick absence costs, $291 lower short-term disability costs, and $69 lower long-term disability costs. Per 1000 individuals, medication adherence was associated with lower health care use, including 200 fewer emergency department visits and 90 fewer inpatient admissions, and productivity-related outcomes, including 20 fewer sick absence days and 442 fewer short-term disability days., Conclusions: Adherence to antihypertensives was consistently associated with lower total medical costs, reduced health care use, and improved productivity-related outcomes.

Multimodal cancer therapies are often required for progressive cancers due to the high persistence and mortality of the disease and the negative systemic side effects of traditional therapeutic methods. Thus, the development of less invasive modalities for recurring treatment cycles is of clinical significance. Herein, a light-activatable microparticle system was developed for localized, pulsatile delivery of anticancer drugs with simultaneous thermal ablation by applying controlled ON-OFF thermal cycles using near-infrared laser irradiation. The system is composed of poly(caprolactone) microparticles of 200 μm size containing molybdenum disulfide (MoS 2 ) nanosheets as the photothermal agent and hydrophilic doxorubicin or hydrophobic violacein, as model drugs. Upon irradiation, the nanosheets heat up to ≥50 °C leading to polymer softening and release of the drug. MoS 2 nanosheets exhibit high photothermal conversion efficiency and require low-power laser irradiation. A machine learning algorithm was applied to acquire the optimal laser operation conditions. In a mouse subcutaneous model of 4T1 triple-negative breast cancer, 25 microparticles were intratumorally administered, and after 3-cycle laser treatment, the system conferred synergistic phototherapeutic and chemotherapeutic effects. Our on-demand, pulsatile synergistic treatment resulted in increased median survival up to 39 days post start of treatment compared to untreated mice, with complete eradication of the tumors at the primary site. Such a system is therapeutically relevant for patients in need of recurring cycles of treatment on small tumors, since it provides precise localization and low invasiveness and is not cross-resistant with other treatments.

A series of donor-acceptor (D-π-A) substituted diphenylbutadienes exhibiting solvatochromic emission and a large Stokes shift (100-200 nm) were designed and synthesized for distinctive organelle labelling, enabling real-time monitoring of organelle behaviour such as lysosomal dynamics, mitophagy monitoring, and stress responses. The morpholine-substituted D-A-D diphenylbutadiene (M2) was employed to investigate selective imaging of lysosomes, the uptake of damaged mitochondria through mitophagy, and monitoring lysosomal viscosity or pH changes. Other diphenylbutadiene derivatives (M1, M3, M4) selectively accumulated in lipid droplets. All the synthesized derivatives demonstrated significant uptake in 5-day post-fertilization zebrafish larvae, with M2 showing maximum uptake in the enterocyte-containing heart and intestinal regions, which include the lysosomes., (© 2024 Wiley-VCH GmbH.)

Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction has been reported as one of the key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes like functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide safer and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We have also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy., 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. and Mitochondria Research Society. All rights reserved.)

The human islet amyloid polypeptide (hIAPP) tends to misfold and self-assemble to form amyloid fibrils, which has been associated with the loss of function and viability of pancreatic β-cells in type 2 diabetes mellitus (T2DM). The role of hIAPP in the development of insulin resistance (a hallmark of T2DM) in skeletal muscles - the major sites for glucose utilization - needs further investigation. Even though, insulin-resistant conditions have been known to stimulate hIAPP aggregation, the events that lead to the development of insulin resistance due to hIAPP aggregation in skeletal muscles remain unidentified. Here, we have attempted to identify metabolic perturbations in L6 myotubes that were exposed to increasing concentrations of recombinant hIAPP for different time durations. It was observed that hIAPP exposure was associated with increased mitochondrial and cellular ROS levels, loss in mitochondrial membrane potential and viability of the myotubes. Metabolomic investigations of hIAPP-treated myotubes revealed significant perturbations in o-phosphocholine, sn-glycero-3-phosphocholine and dimethylamine levels (p < 0.05). Therefore, we anticipate that defects in glycerophospholipid metabolism and the associated oxidative stress and membrane damage may play key roles in the development of insulin resistance due to protein misfolding in skeletal muscles. In summary, the perturbed metabolites and their pathways have not only the potential to be used as early biomarkers to predict the onset of insulin resistance and T2DM but also as therapeutic targets for the effective management of the same., Competing Interests: Declaration of Competing Interest The authors declare no financial/personal interest or belief that could affect the objectivity and results of this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There are no recent estimates for hypertension-associated medical expenditures. This study aims to estimate hypertension-associated incremental medical expenditures among privately insured US adults., Methods: We conducted a retrospective cohort study using IQVIA's Ambulatory Electronic Medical Records-US data set linked with PharMetrics Plus claims data. Among privately insured adults aged 18 to 64 years, hypertension was identified as having ≥1 diagnosis code or ≥2 blood pressure measurements of ≥140/90 mm Hg, or ≥1 antihypertensive medication in 2021. Annual total expenditures (in 2021 $US) were estimated using a generalized linear model with gamma distribution and log-link function adjusting for demographic characteristics and cooccurring conditions. Out-of-pocket expenditures were estimated using a 2-part model that included logistic and generalized linear model regression. Overlap propensity score weights from logistic regression were used to obtain a balanced sample on hypertension status., Results: Among the 393 018 adults, 156 556 (40%) were identified with hypertension. Compared with individuals without hypertension, those with hypertension had $2926 (95% CI, $2681-$3170) higher total expenditures and $328 (95% CI, $300-$355) higher out-of-pocket expenditures. Adults with hypertension had higher total inpatient ($3272 [95% CI, $1458-$5086]) and outpatient ($2189 [95% CI, $2009-$2369]) expenditures when compared with those without hypertension. Hypertension-associated incremental total expenditures were higher for women ($3242 [95% CI, $2915-$3569]) than for men ($2521 [95% CI, $2139-$2904])., Conclusions: Among privately insured US adults, hypertension was associated with higher medical expenditures, including higher inpatient and out-of-pocket expenditures. These findings may help assess the economic value of interventions effective in preventing hypertension., Competing Interests: None.

Objective: Diabetic neuropathy is associated with mitochondrial dysfunction and neuroinflammation. Chronic hyperglycemia triggers inflammatory responses and oxidative stress, causing peripheral neuropathy, whereas mitochondrial dysfunction caused by increased ROS generation and reduced bioenergetics maintains the inflammatory cycle. The purpose of this study is to evaluate the pharmacological efficacy of Bay 11-7082 (B11) against diabetic neuropathy in rats., Methods: B11 was administered at doses of 1 and 3 mg/kg to STZ-induced diabetic animals (55 mg/kg, i.p). Behavioral and functional assessments were conducted to assess neuropathy. Molecular protein expressions were evaluated for B11's efficacy against STZ-induced diabetic neuropathic rats and in SHSY5Y cells exposed to 175 mM of d-glucose., Results: Diabetic rats exhibited deficits in nerve functions, altered nociceptive parameters, and increased expression of NLRP3, ASC, Caspase-1, and NF-κB. Additionally, diabetic animals showed reduced levels of PGC1α/Nrf2/HO-1, with an overexpression of PARP1. Compromised mitochondrial function was evident through increased mitochondrial dynamic marker DRP1 and elevated levels of inflammatory cytokines TNF-α, IL-1β, IL-18, and IL-6. However, B11 administration significantly ameliorated these changes, suggesting that B11's NLRP3 inhibition may be attributed to the activation of the mitochondrial biogenesis pathway via PGC1α/Nrf2/HO-1, along with improved mitochondrial health. In high glucose exposed SHSY5Y cells, B11 treatment attenuated neuroinflammation by inhibiting NLRP3 activation and reducing mitochondrial damage., Conclusion: B11, showed a protective effect against diabetic neuropathy by inhibiting oxidative stress, NLRP3 activation, and improving mitochondrial health in experimental diabetic neuropathy. This study provides new mechanistic insights into the neuroprotective role of Bay 11-7082 against diabetic neuropathy., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest. Data availability Data will be made available on request., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sorghum bicolor Glycine-rich RNA-binding protein (SbGRBP), exhibit the ability to bind both single-stranded and double-stranded DNA. The expression of SbGRBP is regulated by heat stress, with the protein localizing to the nucleus and cytosol. The present study delves into the structure and ssDNA binding ability of its truncated version (SbGRBP1-119) which lacks glycine rich domain (GR). This protein has the ability to bind ssDNA Using Nuclear Magnetic Resonance (NMR) spectroscopy, we have revealed the secondary structure of SbGRBP1-119, highlighting the typical configuration of GRBPs with four β-sheets and two α-helices. Notably, we found two additional α-helices at the N-terminal region that seem to interact with ssDNA, a novel observation for GRBPs. Key residues crucial for ssDNA binding were identified, suggesting a specific interaction with the oligonucleotide sequence 5'-TTCTGG-3'. Preliminary assays hinted that SbGRBP1-119 might bolster E. coli resilience to cold stress, indicating a potential chaperone-like role under stress conditions. This study sheds light on the structural basis of SbGRBP1-119's interaction with nucleic acids, deepening our understanding about the role of GRBPs' in RNA metabolism and regulation., Competing Interests: Declaration of competing interest Authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier B.V.)

Breast cancer is a significant global health issue. Tumor-associated macrophages (TAMs) are crucial in influencing the tumor microenvironment and the progression of the disease. TAMs exhibit remarkable plasticity in adopting distinct phenotypes ranging from pro-inflammatory and anti-tumorigenic (M1-like) to immunosuppressive and tumor-promoting (M2-like). This review elucidates the multifaceted roles of TAMs in driving breast tumor growth, angiogenesis, invasion, and metastatic dissemination. Significantly, it highlights the intricate crosstalk between TAMs and non-coding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, as a crucial regulatory mechanism modulating TAM polarization and functional dynamics that present potential therapeutic targets. Nanotechnology-based strategies are explored as a promising approach to reprogramming TAMs toward an anti-tumor phenotype. Various nanoparticle delivery systems have shown potential for modulating TAM polarization and inhibiting tumor-promoting effects. Notably, nanoparticles can deliver ncRNA therapeutics to TAMs, offering unique opportunities to modulate their polarization and activity.

Background: The Delta variant (B.1.617.2) was considered the most dangerous SARS-CoV-2 strain; however, in-depth studies on its impact based on demographic and clinical characteristics of COVID-19 are scarce., Objective: We aimed to investigate the shift in demographic and clinical characteristics of the COVID-19 pandemic with the emergence of the SARS-CoV-2 Delta variant compared with the wild-type (WT) strain (B.1)., Methods: A cross-sectional study of COVID-19 cases in the Indian population caused by the WT strain (B.1) and Delta variant of SARS-CoV-2 was performed. The viral genomic sequence metadata containing demographic, vaccination, and patient status details (N=9500, N Delta =6238, N WT =3262) were statistically analyzed., Results: With the Delta variant, in comparison with the WT strain, a higher proportion of young individuals (<20 years) were infected (0-9 years: Delta: 281/6238, 4.5% vs B.1: 75/3262, 2.3%; 10-19 years: Delta: 562/6238, 9% vs B.1: 229/3262, 7%; P<.001). The proportion of women contracting infection increased (Delta: 2557/6238, 41% vs B.1: 1174/3262, 36%; P<.001). However, it decreased for men (Delta: 3681/6238, 59% vs B.1: 2088/3262, 64%; P<.001). An increased proportion of the young population developed symptomatic illness and were hospitalized (Delta: 27/262, 10.3% vs B.1: 5/130, 3.8%; P=.02). Moreover, an increased proportion of the women (albeit not men) from the young (Delta: 37/262, 14.1% vs B.1: 4/130, 3.1%; P<.001) and adult (Delta: 197/262, 75.2% vs B.1: 72/130, 55.4%; P<.001) groups developed symptomatic illness and were hospitalized. The mean age of men and women who contracted infection (Delta: men=37.9, SD 17.2 years; women=36.6, SD 17.6 years; P<.001; B.1: men=39.6, SD 16.9 years; women=40.1, SD 17.4 years; P<.001) as well as developing symptoms or being hospitalized (Delta: men=39.6, SD 17.4 years; women=35.6, SD 16.9 years, P<.001; B.1: men=47, SD 18 years; women=49.5, SD 20.9 years, P<.001) were considerably lower with the Delta variant than the B.1 strain. The total mortality was about 1.8 times higher with the Delta variant than with the WT strain. With the Delta variant, compared with B.1, mortality decreased for men (Delta: 58/85, 68% vs B.1: 15/20, 75%; P<.001); in contrast, it increased for women (Delta: 27/85, 32% vs B.1: 5/20, 25%; P<.001). The odds of death increased with age, irrespective of sex (odds ratio 3.034, 95% CI 1.7-5.2, P<.001). Frequent postvaccination infections (24/6238) occurred with the Delta variant following complete doses., Conclusions: The increased involvement of young people and women, the lower mean age for illness, higher mortality, and frequent postvaccination infections were significant epidemiological concerns with the Delta variant., (©Ashutosh Kumar, Adil Asghar, Khursheed Raza, Ravi K Narayan, Rakesh K Jha, Abhigyan Satyam, Gopichand Kumar, Prakhar Dwivedi, Chetan Sahni, Chiman Kumari, Maheswari Kulandhasamy, Rohini Motwani, Gurjot Kaur, Hare Krishna, Sujeet Kumar, Kishore Sesham, Sada N Pandey, Rakesh Parashar, Kamla Kant. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 08.10.2024.)

Wound management spans various techniques and materials tailored to address acute and chronic non-healing wounds, with the primary objective of achieving successful wound closure. Chronic wounds pose additional challenges, often necessitating dressings to prepare the wound bed for subsequent surgical procedures like skin grafting. Ideal dressing materials should not only expedite wound healing but also mitigate protein, electrolyte, and fluid loss while minimizing pain and infection risk. Nanotechnology has emerged as a transformative tool in wound care, revolutionizing the landscape of biomedical dressings. Its application offers remarkable efficacy in accelerating wound healing and combating bacterial infections, representing a significant advancement in wound care practices. Integration of nanotechnology into dressings has resulted in enhanced properties, including improved mechanical strength and controlled drug release, facilitating tailored therapeutic interventions. This review article comprehensively explores recent breakthroughs in wound healing therapies, with a focus on innovative medical dressings such as nano-enzymes. Additionally, the utilization of smart materials, like hydrogels and electroactive polymers, in wound dressings offers dynamic functionalities to promote tissue regeneration. Emerging concepts such as bio-fabrication, microfluidic systems, bio-responsive scaffolds, and personalized therapeutics show promise in expediting wound healing and minimizing scarring. Through an in-depth exploration of these advancements, this review aims to catalyze a paradigm shift in wound care strategies, promoting a patient-centric approach to therapeutic interventions., (© 2024. The Author(s).)

Background/objective: Visual impairment affects 55%-80% of medial sphenoid wing meningiomas (mSWMs) patients, making optic nerve decompression a critical surgical goal. Complete resection often leads to better visual outcomes. However, involvement of critical neurovascular structures increases postoperative morbidity and mortality, with vascular injury reported in 18%-20% of cases. This study aims to evaluate the relationship between the extent of resection (EOR), visual outcomes, and the incidence of vascular injury, seeking to identify the optimal surgical approach for mSWMs., Methods: We retrospectively analyzed data from patients undergoing surgery for mSWM at our tertiary care center from January 2001 to December 2021. Inclusion criteria included histopathologically confirmed globoid mSWMs (N = 89). Patients with recurrent tumors (n = 14) or lost to follow-up (n = 9) were excluded. We classified patients into 2 groups based on EOR using Simpson's grade: Group 1 (good-resection,Simpson Grade-I/II,n = 51) and Group 2 (poor-resection,Simpson Grade III/IV, n = 15)., Results: Among 66 (=N) patients, visual impairment was the most common symptom (81.8%), followed by headaches (77.3%) and seizures (27%). T2-hyperintensity on magnetic resonance imaging [(OR:5.4, 95%CI:1.5-18.6) (P-value<0.01)] and cavernous sinus-extension [(OR:3.9, 95%CI:1.1-13.1) (p-value-0.02)] were independent significant predictors of poor resection. Visual status was preserved in 90.3% of Group-1 and 86.6% of Group-2, with no significant difference based on EOR. Vascular involvement was noted in 87.9%, higher than the vessel encasement (>180 0 ) (57.6%, P = 0.04). Vessel injury occurred in 7.8% of Group-1 and 6.6% of Group-2, with no significant impact on EOR., Conclusions: Cavernous sinus-extension and T2-hyperintensity predict poor resection rates in mSWMs. While visual outcomes are not directly affected by EOR, long-term visual status may decline due to tumor recurrence and radiotherapy. Vascular injury incidence is not associated with EOR. Thus, the "maximal safe resection" of mSWMs involves a surgical strategy balancing targeted aggressive and conservative resection for maximal cytoreduction and functional preservation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Platelet shape and volume changes are early mechanical events contributing to platelet activation and thrombosis. Here, we identify single-nucleotide polymorphisms in Leucine-Rich Repeat Containing 8 (LRRC8) protein subunits that form the Volume-Regulated Anion Channel (VRAC) which are independently associated with altered mean platelet volume. LRRC8A is required for functional VRAC in megakaryocytes (MKs) and regulates platelet volume, adhesion, and agonist-stimulated activation, aggregation, ATP secretion and calcium mobilization. MK-specific LRRC8A cKO mice have reduced arteriolar thrombus formation and prolonged arterial thrombosis without affecting bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP/ADP release to amplify agonist-stimulated calcium and PI3K-AKT signaling via P2X1, P2Y 1 and P2Y 12 receptors. Small-molecule LRRC8 channel inhibitors recapitulate defects observed in LRRC8A-null platelets in vitro and in vivo . These studies identify the mechanoresponsive LRRC8 channel complex as an ATP/ADP release channel in platelets which regulates platelet function and thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.

The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show LRRC8A regulates leucine-stimulated mTOR, lysosome size, number, pH, and expression of lysosomal proteins LAMP2, P62, LC3B, suggesting impaired autophagic flux. Mutating a LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signalling and altered lysosomal morphology and pH observed in LRRC8A KO cells. In vivo , LRRC8A-L706A;L707A KI mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance characterized by reduced skeletal muscle glucose-uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8 mediated metabolic signalling function that regulates lysosomal activity, systemic glucose homeostasis and insulin-sensitivity.

Diabetic neuropathy (DN) is one of the major microvascular complications of diabetes mellitus affecting 50% of the diabetic population marred by various unmet clinical needs. There is a need to explore newer pathological mechanisms for designing futuristic regimens for the management of DN. There is a need for post-transcriptional regulation of gene expression by non-coding RNAs (ncRNAs) to finetune different cellular mechanisms with significant biological relevance. MicroRNAs (miRNAs) are a class of small ncRNAs (~ 20 to 24 nucleotide length) that are known to regulate the activity of ~ 50% protein-coding genes through repression of their target mRNAs. Differential expression of these miRNAs is associated with the pathophysiology of diabetic neuropathy via regulating various pathways such as neuronal hyperexcitability, inflammation, axonal growth, regeneration, and oxidative stress. Of note, the circulating and extracellular vesicular miRNAs serve as potential biomarkers underscoring their diagnostic potential. Recent pieces of evidence highlight the potential of miRNAs in modulating the initiation and progression of DN and the possibility of developing miRNAs as treatment options for DN. In this review, we have elaborated on the role of different miRNAs as potential biomarkers and emphasized their druggable aspects for promising future therapies for the clinical management of DN., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation and destruction. Current treatments, such as Methotrexate (MTX), though effective, often face limitations such as high plasma C max and lack of sustained release. This study explores a synergistic approach to RA therapy using folate-liposomal co-delivery of MTX and RELA siRNA (short interfering RNA), targeting RAW264.7 macrophage repolarization via nuclear factor kappa B (NF-κB) pathway inhibition. Extensive in vitro characterizations demonstrate the stability and biocompatibility of this therapy via folate-liposomes. In the collagen-induced arthritis (CIA) rat model, treatment leads to reduced synovial inflammation and improved mobility. The combined MTX and RELA siRNA approach indirectly inhibits inflammatory cytokines, rheumatoid factor (RF), and C-reactive protein (CRP). Targeted macrophage delivery shows marked therapeutic effects in RAW264.7 murine macrophages, potentially modulating M1 to M2 polarization. This research presents a promising avenue for innovative RA therapies by inhibiting the inflammatory cascade and preventing joint damage., (© 2024 Wiley‐VCH GmbH.)

Terminal myelocystocele (TMC) is a rare form of spinal dysraphism which arises due to aberration in the secondary neurulation process involving the caudal cell mass. Terminal myelocystocele has been defined by Pang et al. based on essential and non-essential features. One of the non-essential features includes non dysraphic lipomas which do not tether to the neural placode. We are presenting two cases which meets all the essential criteria outlined by Pang et al. for TMC but also show the presence of a lipomatous component tethering to the neural placode, similar to a dysraphic lipoma. Through this article, we want to showcase a subset which represents "true" terminal lipomyelocystocele (TLMC), bridging the spectrum of spinal dysraphism between TMC and lipomyelomeningocele (LMM)., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Conflict of interest: None, (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Encephalocele represent a group of disorders which is characterised by extracranial herniation of the leptomeninges, brain, and CSF through a structural defect in the cranium. They are usually associated with other intracranial anomalies which may impact the neurological development., Aim: This study aimed to assess the predictors of neurological development of patients undergone surgical excision of occipital encephalocele., Methods: All patients with occipital encephaloceles operated over the last decade (2012-2022). The sac size, presence of hydrocephalous, and associated anomalies were noted. The biopsy of these patients were reviewed and categorised as those which contains mature neural tissue and those without. The neurological outcomes were assessed by social, language, cognitive, and motor milestone and has been stratified into no delay, mild (1 of 4), moderate (2 or 3 of 4), and severe development delay (4 of 4)., Results: Total of 35 patients were included with median age of 10 months (IQR = 5-20 months). Fifteen (42.9%) patients had sac size of ≥ 5 cm, and 23 (65.7%) patients had mature neural tissues on biopsy. The median follow-up period was 6.4 years (IQR = 4.38-10.65) years. Seventeen (49.6%) patients had moderate to severe developmental delay. The sac size of ≥ 5 cm (AOR = 33.5; 95%CI = 3.35-334.8) (p = 0.003) and presence of mature neural content in the sac (AOR = 13.32; 95%CI = 1.1-160.36) (p = 0.041) were associated with significant neurodevelopmental delay., Conclusion: The presence of a large sac of ≥ 5 cm and the presence of mature neural tissues on histopathological specimen of patients with encephalocele point towards the possibility of poor neurological development., Competing Interests: Declarations: I, Dr Pawan Kumar Verma, certify that this manuscript is a unique submission and is not being considered for publication, in part or in full, with any other source in any medium. Ethics approval: This is an observational study. The Institutional Ethics Committee has confirmed that no ethical approval is required. Consent to participate: As this a retrospective study, the patients’ consent to participate were waived off by the Institutional Ethics Committee. Consent for publication: The manuscript does not contain any information from which a patient’s identity could be disclosed. Conflict of interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aneurysms of the distal anterior cerebral artery (DACA) are rare but surgically challenging. Despite a known therapeutic implication of the aneurysm location on the DACA territory, the literature is unclear about its clinical and prognostic significance. Our surgical experience over the last 5 years was reviewed to compare the clinical, operative, and outcome characteristics between aneurysms located below the mid portion of the genu of the corpus callosum (called proximal aneurysms) to those distal to this point (called distal aneurysms). A prognostic factor analysis was done using uni and multivariable analysis. A total of 34 patients were treated (M: F = 1:2.3). The distal group had a higher frequency of poor clinical grade at presentation (n = 9, 47.4%) in contrast to (n = 2, 13.3%) proximal aneurysms (p = 0.039). Despite an overall tendency for a delayed functional improvement in these patients, the results were mainly due to favorable outcomes in the proximal group (favourable functional outcomes at discharge and at last follow-up being 80% and 86.7% respectively). On the multivariable analysis, only WFNS grade (> 2) at presentation (OR = 13.75; 95CI = 1.2-157.7) (p = 0.035) and application of temporary clips (AOR = 34.32; 95CI = 2.59-454.1) (p = 0.007), both of which were more in the distal group, independently predicted a poor long term functional outcome. Thus, the aneurysm location impacts the preoperative clinical grade, the intraoperative aneurysm rupture risk rate as well as the temporary clipping requirement. A combination of these factors leads to worse short and long-term functional outcomes in the distal DACA aneurysms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dopamine is a neurotransmitter in the central nervous system that is essential for many bodily and mental processes, and a lack of it can cause Parkinson's disease. DNA tetrahedral (TD) nanocages are promising in bio-nanotechnology, especially as a nanocarrier. TD is highly programmable, biocompatible, and capable of cell differentiation and proliferation. It also has tissue and blood-brain barrier permeability, making it a powerful tool that could overcome potential barriers in treating neurological disorders. In this study, we used DNA TD as a carrier for dopamine to cells and zebrafish embryos. We investigated the mechanism of complexation between TD and dopamine hydrochloride using gel electrophoresis, fluorescence and circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), and molecular dynamic (MD) simulation tools. Further, we demonstrate that these dopamine-loaded DNA TD nanostructures enhanced cellular uptake and differentiation ability in SH-SY5Y neuroblastoma cells. Furthermore, we extended the study to zebrafish embryos as a model organism to examine survival and uptake. The research provides valuable insights into the complexation mechanism and cellular uptake of dopamine-loaded DNA tetrahedral nanostructures, paving the way for further advancements in nanomedicine for Parkinson's disease and other neurological disorders.

Purpose: Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of patients with acute myeloid leukemia (AML), but the mechanisms by which they contribute to AML are unknown., Experimental Design: To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc gene., Results: Both wild-type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared with their wild-type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML-bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNA profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors., Conclusions: This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies., (©2024 American Association for Cancer Research.)

Rheumatoid arthritis (RA) is a progressive autoimmune disease that mainly affects the inner lining of the synovial joints and leads to chronic inflammation. While RA is not known as lethal, recent research indicates that it may be a silent killer because of its strong association with an increased risk of chronic lung and heart diseases. Patients develop these systemic consequences due to the regular uptake of heavy drugs such as disease-modifying antirheumatic medications (DMARDs), glucocorticoids (GCs), nonsteroidal anti-inflammatory medicines (NSAIDs), etc . Nevertheless, a number of these medications have off-target effects, which might cause adverse toxicity, and have started to become resistant in patients as well. Therefore, alternative and promising therapeutic techniques must be explored and adopted, such as post-translational modification inhibitors (like protein arginine deiminase inhibitors), RNA interference by siRNA, epigenetic drugs, peptide therapy, etc ., specifically in macrophages, neutrophils, Treg cells and dendritic cells (DCs). As the target cells are specific, ensuring targeted delivery is also equally important, which can be achieved with the advent of nanotechnology. Furthermore, these nanocarriers have fewer off-site side effects, enable drug combinations, and allow for lower drug dosages. Among the nanoparticles that can be used for targeting, there are both inorganic and organic nanomaterials such as solid-lipid nanoparticles, liposomes, hydrogels, dendrimers, and biomimetics that have been discussed. This review highlights contemporary therapy options targeting macrophages, neutrophils, Treg cells, and DCs and explores the application of diverse nanotechnological techniques to enhance precision RA therapies.

Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Multidomain proteins with flexible linkers and disordered regions play important roles in many cellular processes, but characterizing their conformational ensembles is difficult. We have previously shown that the coarse-grained model, Martini 3, produces too compact ensembles in solution, that may in part be remedied by strengthening protein-water interactions. Here, we show that decreasing the strength of protein-protein interactions leads to improved agreement with experimental data on a wide set of systems. We show that the 'symmetry' between rescaling protein-water and protein-protein interactions breaks down when studying interactions with or within membranes; rescaling protein-protein interactions better preserves the binding specificity of proteins with lipid membranes, whereas rescaling protein-water interactions preserves oligomerization of transmembrane helices. We conclude that decreasing the strength of protein-protein interactions improves the accuracy of Martini 3 for IDPs and multidomain proteins, both in solution and in the presence of a lipid membrane., (© 2024. The Author(s).)

Introduction: This study seeks to estimate health care expenditures and use associated with hypertension, focusing on differences among racial and ethnic groups., Methods: Data were from the 2019 Medical Expenditure Panel Survey, analyzed in 2023. The study sample included noninstitutionalized U.S. adults aged ≥18 years. Outcome variables were health care expenditures and events. Hypertension was determined by a self-reported diagnosis or diagnosis codes. Race and ethnicity were self-reported. A 2-part model was used to estimate expenditures associated with hypertension. A zero-inflated negative binomial model was used to estimate events associated with hypertension. Sampling designs were applied to generate nationally representative estimates., Results: Hypertension was associated with $2,759 (95% confidence interval [CI]: $2,039, $3,479) in health care expenditures and 10.3 (95% CI: 9.3, 11.3) health care events, including prescriptions filled, in 2019 per person. Compared with non-Hispanic White adults, hypertension-associated health care expenditures were significantly lower among Hispanic adults (difference: -$1,877; 95% CI: -$3,389, -$364) and Asian adults (difference: -$2,452; 95% CI: -$4,093, -$811), and hypertension-associated health care events were significantly lower among Hispanic adults (difference: -3.8; 95% CI: -6.1, -1.6) and non-Hispanic Asian adults (difference: -4.1; 95% CI: -6.9, -1.2). Differences between non-Hispanic White adults and non-Hispanic Black adults were not statistically significant in health care expenditures (difference: -$954; 95% CI: -$2,849, $941) and events (difference: 0.3; 95% CI: -2.1, 2.8)., Conclusions: This study reveals differences in health care expenditures and use associated with hypertension among racial and ethnic groups. Future studies are needed to examine potential drivers of these differences., (Published by Elsevier Inc.)

Cloud computing is an on-demand virtual-based technology to develop, configure, and modify applications online through the internet. It enables the users to handle various operations such as storage, back-up, and recovery of data, data analysis, delivery of software applications, implementation of new services and applications, hosting websites and blogs, and streaming of audio and video files. Thereby, it provides us many benefits although it is backlashed due to problems related to cloud security like data leakage, data loss, cyber attacks, etc. To address the security concerns, researchers have developed a variety of authentication mechanisms. This means that the authentication procedure used in the suggested method is multi-levelled. As a result, a better QKD method is offered to strengthen cloud security against different types of security risks. Key generation for enhanced QKD is based on the ABE public key cryptography approach. Here, an approach named CPABE is used in improved QKD. The Improved QKD scored the reduced KCA attack ratings of 0.3193, this is superior to CMMLA (0.7915), CPABE (0.8916), AES (0.5277), Blowfish (0.6144), and ECC (0.4287), accordingly. Finally, this multi-level authentication using an improved QKD approach is analysed under various measures and validates the enhancement over the state-of-the-art models.

Background:  Surgical resection is the cornerstone of treatment for low-grade tumors, albeit total excision is beneficial. As the thalamus is surrounded by vital neurovascular system, lesions here present a surgical challenge., Method: This article aims to demonstrate the trans-temporal, trans-choroidal fissure approach's effective surgical therapy on patients with thalamic lesions. With this approach, we were able to remove the tumor completely in three patients and almost completely in six more. Here we discuss a few technical details and potential hazards of the procedure with an operative video., Conclusion: This approach  provides excellent access to the deep areas of brain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Vaccination of neonates is crucial for preventing infectious diseases and ensuring public health. However, understanding the attitudes of healthcare providers and parents towards neonatal vaccination and the challenges in implementing vaccination schedules is essential for optimizing vaccination strategies., Materials and Methods: A clinical study was conducted involving healthcare providers and parents of neonates. Surveys were administered to assess attitudes towards neonatal vaccination, perceived barriers, and adherence to vaccination schedules. Data analysis was performed using statistical methods to identify trends and associations., Results: Among healthcare providers (n = 200), 85% expressed strong support for neonatal vaccination, citing its importance in disease prevention. However, concerns regarding vaccine safety (62%) and parental hesitancy (48%) were identified as significant barriers. Among parents (n = 500), 78% reported willingness to vaccinate their neonates, with 60% adhering strictly to vaccination schedules. Common reasons for non-adherence included fear of adverse reactions (42%) and misinformation (28%). Challenges in vaccine administration, such as access issues (20%) and vaccine shortages (15%), were also reported., Conclusion: Healthcare providers generally endorse neonatal vaccination, recognizing its benefits in preventing infectious diseases. However, addressing concerns about vaccine safety and parental hesitancy is crucial for improving vaccination rates. Strategies aimed at enhancing education, promoting vaccine confidence, and addressing logistical challenges are essential for the successful implementation of neonatal vaccination schedules., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Background: Congenital spondylolisthesis is characterized by dysplasia of the facet joint or congenital defect in the pars., Objective: Our study highlights the clinical and radiological profile, various treatment options, and outcomes in patients with pediatric congenital lumbar and lumbosacral spondylolisthesis., Methods: A retrospective analysis and follow-up of 22 patients were conducted presented with radiological diagnosis of congenital lumbar/lumbosacral spondylolisthesis (2018-2021)., Results: Twenty patients (91%) had L5-S1 listhesis and two patients (9%) had L4-L5 listhesis. Six (27.3%) patients had low-grade listhesis (grades 1-2), 16 (72.7%) had high-grade listhesis (grades 3-5). Seventeen (77.3%) had S1, three (13.6%) had L5, and two (9%) had both L4-L5 radiculopathy. All patients had neurogenic claudication. One had an associated spina bifida occulta. Six (27.3%) patients underwent two-level fixation, and 16 (72.7%) underwent three-level fixation. Minimally Invasive Transforaminal Lumbar Interbody Fusion (MIS TLIF) was done in two patients. Revision of at least one screw was done in three patients. After one year of follow-up, all the patients had 75-100% relief in radicular pain and neurogenic claudication. The Oswestry Disability Index (ODI) score in preop for all patients was 41-60% and postoperatively they showed an improvement in ODI score (0-20). The postoperative low back pain score on the Numeric Rating Scale was 0-1 for all patients., Conclusion: Congenital lumbar spondylolisthesis usually presents with high-grade listhesis. Management of such cases is a surgical challenge but posterior decompression resulted in relief of pain in all patients. However, in situ fixation without reduction is also effective in selective cases where attempts to reduce the listhesis result in a decline in intraoperative neuromonitoring parameters., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

In the last decade, extensive research has been performed on developing hand sanitizers that can be used to eradicate the diseases that are caused due to poor hand hygiene. Essential oils possess antibacterial and antifungal properties and thus have great potential to replace the available antibacterial agents. In the present study, sandalwood oil-based nanoemulsion (NE) and sanitizer have been formulated and well characterized for their properties. Antibacterial activity was assessed using growth inhibition studies, agar cup, viability assay, etc. The sandalwood oil NE synthesized had oil to surfactant ratio of 1:0.5 (2.5% sandalwood oil and 0.5% Tween 80) and was observed to have a droplet diameter of 118.3 ± 0.92 nm, the zeta potential of - 18.8 ± 2.01 mV, and stability of 2 months. The antibacterial activity of sandalwood NE and sanitizer was evaluated against microorganisms. The antibacterial activity was assessed using the zone of inhibition value of sanitizer, which was in the range of 19 to 25 mm against all microorganisms. Morphological analysis showed distant changes in membrane shape and size and microorganisms' morphology. The synthesized NE was thermodynamically stable and efficient enough to be used in sanitizer, and the formulated sanitizer showed great antibacterial efficacy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Altering the route of uptake by the cells is an attractive strategy to overcome drug-receptor adaptation problems. Carbon nanoparticles (CNPs) with emission beyond tissue autofluorescence for imaging biological tissues were used to study the phenomenon of uptake by the cells. In this regard, red-emitting carbon nanoparticles (CNPs) were synthesized and incorporated onto lipid microbubbles (MBs). The CNPs showed red emissions in the range of 640 nm upon excitation with 480 nm wavelength of light. Atomic force microscopic and confocal microscopic images showed the successful loading of CNPs onto the MB. Carbon nanoparticle loaded microbubbles (CNP-MBs) were treated with NIH 3 T3 cells at different concentrations. Confocal microscopic imaging studies confirm the presence of CNPs inside the treated cells. Cytotoxicity studies revealed that the CNPs showed minimal toxicity towards cells after loading onto MBs. The CNPs are usually taken up by the cells through the clathrin-mediated (CME) pathway, but when loaded onto MBs, the mechanism of uptake of CNPs is altered, and the uptake by the cells was observed even in the presence of inhibitors for the CME pathway. Loading CNPs onto MBs resulted in the uptake of CNPs by the cell through micropinocytosis and sonophoresis in the presence of ultrasound. The in vivo uptake CNP-MBs were performed in Danio rerio (Zebrafish larvae). This study provides insights into altering the uptake pathway through reformulation by loading nanoparticles onto MBs., 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.)

The existence of a previously unrecognized subarachnoid lymphatic-like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer were reported in some way. A comprehensive search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31 December 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscure names like the epipial, intermediate meningeal, outer pial layers, or intermediate lamella were used to describe it. Its microscopic/ultrastructural details closely resemble the recently reported SLYM. We further examined the counterarguments in current literature that are skeptical of the existence of this layer. The potential physiological and clinical implications of this new meningeal layer are significant, underscoring the urgent need for further exploration of its structural and functional details., (© 2024 American Association for Anatomy.)

One of the crucial requirements of quantum dots for biological applications is their surface modification for very specific and enhanced biological recognition and uptake. Toward this end, we present the green synthesis of bright, red-emitting carbon quantum dots derived from mango leaf extract (mQDs). These mQDs are conjugated electrostatically with dopamine to form mQDs-dopamine (mQDs:DOPA) bioconjugates. Bright-red fluorescence of mQDs was used for bioimaging and uptake in cancerous and noncancerous cell lines, tissues, and in vivo models like zebrafish. mQDs exhibited the highest uptake in brain tissue compared to the heart, kidney, and liver. mQD:DOPA conjugates killed breast cancer cells and increased uptake in epithelial RPE-1 cells and zebrafish. Additionally, mQDs:DOPA promoted neuronal differentiation of SH-SY5Y cells to differentiated neurons. Both mQDs and mQDs:DOPA exhibited the potential for higher collective cell migrations, implicating their future potential as next-generation tools for advanced biological and biomedical applications.

The centromere is epigenetically marked by a histone H3 variant-CENP-A. The budding yeast CENP-A called Cse4, consists of an unusually long N-terminus that is known to be involved in kinetochore assembly. Its disordered chaperone, Scm3 is responsible for the centromeric deposition of Cse4 as well as in the maintenance of a segregation-competent kinetochore. In this study, we show that the Cse4 N-terminus is intrinsically disordered and interacts with Scm3 at multiple sites, and the complex does not gain any substantial structure. Additionally, the complex forms a synergistic association with an essential inner kinetochore component (Ctf19-Mcm21-Okp1-Ame1), and a model has been suggested to this effect. Thus, our study provides mechanistic insights into the Cse4 N-terminus-chaperone interaction and also illustrates how intrinsically disordered proteins mediate assembly of complex multiprotein networks, in general., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Epilepsy is a neurological disorder characterized by the predisposition for recurrent unprovoked seizures. It can broadly be classified as focal, generalized, unclassified, and unknown in its onset. Focal epilepsy originates in and involves networks localized to one region of the brain. Generalized epilepsy engages broader, more diffuse networks. The etiology of epilepsy can be structural, genetic, infectious, metabolic, immune, or unknown. Many generalized epilepsies have presumed genetic etiologies. The aim of this study is to compare the role of genetic testing to brain MRI as diagnostic tools for identifying the underlying causes of idiopathic (genetic) generalized epilepsy (IGE)., Methods:  We evaluated the diagnostic yield of these two categories in children diagnosed with IGE. Data collection was completed using ICD10 codes filtered by TriNetX to select 982 individual electronic medical records (EMRs) of children in the Penn State Children's Hospital who received a diagnosis of IGE. The diagnosis was confirmed after reviewing the clinical history and electroencephalogram (EEG) data for each patient., Results: From this dataset, neuroimaging and genetic testing results were gathered. A retrospective chart review was done on 982 children with epilepsy, of which 143 (14.5%) met the criteria for IGE. Only 18 patients underwent genetic testing. Abnormalities that could be a potential cause for epilepsy were seen in 72.2% (13/18) of patients with IGE and abnormal genetic testing, compared to 30% (37/123) for patients who had a brain MRI with genetic testing., Conclusion: This study suggests that genetic testing may be more useful than neuroimaging for identifying an etiological diagnosis of pediatric patients with IGE., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Heebner et al.)

Background: The ruptured anterior communicating artery aneurysm is the most frequent intra-cranial aneurysm treated at any neurosurgical department. These aneurysms arise from either the A1-A2-Acom artery junction or Acom artery. The surgical outcome depends on the age of the patient, time duration between ictus and surgery, and Hunt and Hess grade at admission. In this article, we intend to analyze the surgical outcome based on our proposed classification with our overall experience of Acom aneurysm., Methods: A retrospective review of our surgical database with 250 patients of ruptured Acom was done, and the location, morphology, and direction of aneurysm, along with other clinical parameters including the demographic profile, radiological findings, and intra-operative details, were studied. We classified the Acom based on both site of origin and morphology (Type I, junctional on the dominant side; Type II, fusiform with an ill-defined neck and branching pattern; Type III, saccular true Acom A) and secondarily as described in the literature on the basis of the direction of fundus (Type A-E). The clinical parameters were compared among the above groups using Fischer-exact and one-way analysis of variance test., Results: A total of 250 patients (M: F =113:137) were included (mean age 52.1 ± 11.5 standard deviation years). 55.2% patients had left A1 dominance. Type I Acom A was commonly found on the left dominant circulation (P = 0.00). The difference in aspect ratio of Type I (2.0 ± 0.8) and Type II (1.8 ± 0.52) aneurysms was insignificant (P = 0.28). However, a significant difference in post-operative vasospasm among different types of aneurysms was found (P < 0.05). The Type I Acom A were anteriorly directed, while Type II and III were posteriorly directed (P = 0.001). The mean follow-up of the study was 44.4 ± 25.7 months, with age (P = 0.007) and Hunt and Hess grade (P = 0.001) at admission correlating with surgical outcome., Conclusion: Classifying the Acom A pre-operatively based on site and morphology, location, and direction of fundus helps in surgical planning and prognosis. The junctional 'Type IA aneurysms' are most common and possess a high intra-operative rupture rate. The anteriorly directed aneurysms have a better prognosis, and visual complaints are usually associated with anterior-inferiorly directed aneurysms., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

While previous reviews found a positive association between pre-existing cancer diagnosis and COVID-19-related death, most early studies did not distinguish long-term cancer survivors from those recently diagnosed/treated, nor adjust for important confounders including age. We aimed to consolidate higher-quality evidence on risk of COVID-19-related death for people with recent/active cancer (compared to people without) in the pre-COVID-19-vaccination period. We searched the WHO COVID-19 Global Research Database (20 December 2021), and Medline and Embase (10 May 2023). We included studies adjusting for age and sex, and providing details of cancer status. Risk-of-bias assessment was based on the Newcastle-Ottawa Scale. Pooled adjusted odds or risk ratios (aORs, aRRs) or hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated using generic inverse-variance random-effects models. Random-effects meta-regressions were used to assess associations between effect estimates and time since cancer diagnosis/treatment. Of 23 773 unique title/abstract records, 39 studies were eligible for inclusion (2 low, 17 moderate, 20 high risk of bias). Risk of COVID-19-related death was higher for people with active or recently diagnosed/treated cancer (general population: aOR = 1.48, 95% CI: 1.36-1.61, I 2  = 0; people with COVID-19: aOR = 1.58, 95% CI: 1.41-1.77, I 2  = 0.58; inpatients with COVID-19: aOR = 1.66, 95% CI: 1.34-2.06, I 2  = 0.98). Risks were more elevated for lung (general population: aOR = 3.4, 95% CI: 2.4-4.7) and hematological cancers (general population: aOR = 2.13, 95% CI: 1.68-2.68, I 2  = 0.43), and for metastatic cancers. Meta-regression suggested risk of COVID-19-related death decreased with time since diagnosis/treatment, for example, for any/solid cancers, fitted aOR = 1.55 (95% CI: 1.37-1.75) at 1 year and aOR = 0.98 (95% CI: 0.80-1.20) at 5 years post-cancer diagnosis/treatment. In conclusion, before COVID-19-vaccination, risk of COVID-19-related death was higher for people with recent cancer, with risk depending on cancer type and time since diagnosis/treatment., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Breast cancer is a global health challenge with staggering statistics underscoring its pervasive impact. The burden of this disease is measured in terms of its prevalence and the challenges it poses to healthcare systems, necessitating a closer look at its epidemiology and impact. Current breast cancer treatments, including surgery, chemotherapy, radiation therapy, and targeted therapies, have made significant strides in improving patient outcomes. However, they are not without limitations, often leading to adverse effects and the development of drug resistance. This comprehensive review delves into the complex landscape of breast cancer, including its incidence, current treatment modalities, and the inherent limitations of existing therapeutic approaches. It also sheds light on the promising role of nanotechnology, encompassing both inorganic and organic nanoparticles equipped with the ability to selectively deliver therapeutic agents to tumor sites, in the battle against breast cancer. The review also addresses the emerging therapies, their associated challenges, and the future prospects of targeted drug delivery in breast cancer management., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This presentation showcases an endoscopic minimally invasive spine surgery (MISS) technique for lumbar interbody fusion. Significantly expanding the scope of Destandau's system within MISS, it serves as a pivotal link to unilateral biportal endoscopy (UBE) for endofusion. The method involves minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) using a 4-mm rigid endoscope through Destandau's system. With the widespread familiarity with Destandau's system and the absence of specialized instrument requirements, this approach is easily adoptable, particularly in resource-limited centers. The favorable clinical and radiological outcomes underscore the effectiveness of this technique, propelling the role of endoscopy in MISS, particularly in endofusion. The video can be found here: https://stream.cadmore.media/r10.3171/2024.1.FOCVID23216., Competing Interests: Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication.The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication., (© 2024, The Authors.)

This research study aimed to explore the mitigating effects of humic acid and clay on the toxicity induced by three different phthalates (DBP, DEP, DEHP) on zebrafish larvae growth. Prolonged exposure to DBP resulted in a concerning 87.33% mortality rate, significantly reduced to 7.3% when co-administered with humic acid. A similar reduction in mortality was observed for the other two phthalates (DEP and DEHP). Additionally, the introduction of phthalates with humic acid, clay, or their combination led to a significant decrease in the malformation rate in larvae. High-Performance Liquid Chromatography (HPLC) analysis of phthalates in treatments revealed a noteworthy decline in their concentration when combined with humic acid and clay. This suggests a reduced bioavailability of phthalates to larvae, aligning with diminished toxicity, lower mortality, fewer malformations, and improved organ development, as well as less oxidative stress. Furthermore, measurements of larval length and morphological scoring affirmed the protective role of humic acid and clay in promoting the normal growth of zebrafish. This study underscores the potential of environment modulators, such as humic acid and clay, as effective bioremediation agents against phthalate toxicity. The generation of reactive oxygen species (ROS), indicative of oxidative stress, was markedly higher in larvae treated solely with phthalates compared to the control. Conversely, larvae treated with a combination of phthalates and humic acid or clay exhibited a significant decrease in ROS generation, signaling a decline in oxidative stress. Histopathological analysis of adult fish subjected to various treatments revealed significant damage to vital organs like the liver and intestine when treated with phthalates alone. However, when phthalates were introduced with humic acid, clay, or both, the morphology closely resembled that of the control, reinforcing the protective role of humic acid and clay in zebrafish development against administered phthalates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Insulin fibrillation poses a significant challenge in the development and treatment of diabetes. Current efforts to unravel its mechanisms have thus far remained incomplete. To shed light on the intricate processes behind insulin fibrillation, we employed mutagenesis techniques to introduce additional positive charge residues into the C-terminal region of the insulin B chain which plays an important role in insulin dimerization. We employed our investigation with various spectroscopic methods, electron microscopy, and molecular dynamics simulations. These methods allowed us to explore the structure and fibrillation behavior of the engineered B chains following their expression in a bacterial host and successful purification. This manipulation had a pronounced impact on the oligomerization behavior of the insulin B chain. It appears that these mutations delay the formation of the dimeric state in the process of transitioning to larger oligomers, consequently, leading to an alteration in the kinetics of fibrillation. Our findings also indicated that the mutant insulin B chains (Di-R, Di-K, and Di-H) displayed resistance to the initiation of fibrillation. This resistance can be attributed to the repulsive forces generated by the introduced positive charges, which disrupt the attractive interactions favoring nucleation. Notably, the mutant B chains formed shorter and less abundant oligomers and fibrils, which can be ascribed to the alterations induced by repulsion. Our engineered mutant B chains exhibited enhanced stability against stress-induced fibrillation, hinting at their potential utility in the development of new insulin analogs. This study underscores the significance of the C-terminal region in the initial stages of insulin B chain fibrillation, providing valuable insights into the intricate mechanisms involved and their potential pharmaceutical applications., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024. Published by Elsevier B.V.)

αB-crystallin, a member of the small heat shock protein (sHSP) family, is expressed in diverse tissues, including the eyes, brain, muscles, and heart. This protein plays a crucial role in maintaining eye lens transparency and exhibits holdase chaperone and anti-apoptotic activities. Therefore, structural and functional changes caused by genetic mutations in this protein may contribute to the development of disorders like cataract and cardiomyopathy. Recently, the substitution of arginine 123 with tryptophan (p.R123W mutation) in human αB-crystallin has been reported to trigger cardiomyopathy. In this study, human αB-crystallin was expressed in Escherichia coli (E. coli), and the missense mutation p.R123W was created using site-directed mutagenesis. Following purification via anion exchange chromatography, the structural and functional properties of both proteins were investigated and compared using a wide range of spectroscopic and microscopic methods. The p.R123W mutation induced significant alterations in the secondary, tertiary, and quaternary structures of human αB-crystallin. This pathogenic mutation resulted in an increased β-sheet structure and formation of protein oligomers with larger sizes compared to the wild-type protein. The mutant protein also exhibited reduced chaperone activity and lower thermal stability. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) demonstrated that the p.R123W mutant protein is more prone to forming amyloid aggregates. The structural and functional changes observed in the p.R123W mutant protein, along with its increased propensity for aggregation, could impact its proper functional interaction with the target proteins in the cardiac muscle, such as calcineurin. Our results provide an explanation for the pathogenic intervention of p.R123W mutant protein in the occurrence of hypertrophic cardiomyopathy (HCM)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Reza Yousefi reports financial support was provided by Iran National Science Foundation. 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.)

Metal-semiconductor nanocomposites have emerged as a viable strategy for concurrently tailoring both thermal and electronic transport properties of established thermoelectric materials, ultimately achieving synergistic performance. In this investigation, a series of nanocomposite thin films were synthesized, embedding metallic cobalt telluride (CoTe 2 ) nanophase within the nanocrystalline ternary skutterudite (Co(Ge 1.22 Sb 0.22 )Te 1.58 or CGST) matrix. Our approach harnessed composition fluctuation-induced phase separation and in situ growth during thermal annealing to seamlessly integrate the metallic phase. The distinctive band structures of both materials have developed an ohmic-type contact characteristic at the interface, which raised carrier density considerably yet negligibly affected the mobility counterpart, leading to a substantial improvement in electrical conductivity. The intricate balance in transport properties is further influenced by the metallic CoTe 2 phase's role in diminishing lattice thermal conductivity. The presence of the metallic phase instigates enhanced phonon scattering at the interface boundaries. Consequently, a 2-fold enhancement in the thermoelectric figure of merit (zT ∼ 1.30) is attained with CGST-7 wt. % CoTe 2 nanocomposite film at 655 K compared to that of pristine CGST.