Analytical code sharing practices in biomedical research.

Data-driven computational analysis is becoming increasingly important in biomedical research, as the amount of data being generated continues to grow. However, the lack of practices of sharing research outputs, such as data, source code and methods, affects transparency and reproducibility of studies, which are critical to the advancement of science. Many published studies are not reproducible due to insufficient documentation, code, and data being shared. We conducted a comprehensive analysis of 453 manuscripts published between 2016-2021 and found that 50.1% of them fail to share the analytical code. Even among those that did disclose their code, a vast majority failed to offer additional research outputs, such as data. Furthermore, only one in ten articles organized their code in a structured and reproducible manner. We discovered a significant association between the presence of code availability statements and increased code availability. Additionally, a greater proportion of studies conducting secondary analyses were inclined to share their code compared to those conducting primary analyses. In light of our findings, we propose raising awareness of code sharing practices and taking immediate steps to enhance code availability to improve reproducibility in biomedical research. By increasing transparency and reproducibility, we can promote scientific rigor, encourage collaboration, and accelerate scientific discoveries. We must prioritize open science practices, including sharing code, data, and other research products, to ensure that biomedical research can be replicated and built upon by others in the scientific community.

Delineation of the role of G6PD in Alzheimer's disease and potential enhancement through microfluidic and nanoparticle approaches.

Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aß deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements.

Comparative Vision of Nonlinear Thermo-Optical Features and Third-Order Susceptibility of Mechanically Flexible Metallosupramolecular Self-Repairing Networks with Isomeric Organic Acids.

Two self-healing-type supramolecular Ni(II)-metallogels are achieved. The choice of proper low-molecular-weight organic gelators such as trans-butenedioic acid (i.e., trans-BDA) and cis-butenedioic acid (i.e., cis-BDA) and triethylamine in N,N'-dimethylformamide solvent facilitates the metallogelation process. Through rheological investigations the mechanical robustness and viscoelastic properties of synthesized metallogels are explored. An in-depth exploration of thixotropic behavior also supports their self-healing features. Notably, distinct variations in morphologies of metallogels are also ascertained through field emission scanning electron microscopy studies. Furthermore, the existence of versatile noncovalent supramolecular interactions operating throughout the metallogel network is clearly revealed via Fourier transform infrared spectroscopy. Electrospray ionization-mass studies also explore the construction protocol of individual Ni(II)-metallogels. The Z-scan measurements with a 532 nm continuous wave laser were employed to unveil the nonlinear thermo-optical response of two synthesized self-healing metallogels, i.e., trans-BDA-TEA@Ni(II) and cis-BDA-TEA@Ni(II). Crucial parameters like the nonlinear refractive index, nonlinear absorption coefficient, thermo-optical coefficient, and third-order susceptibility of these metallogels are obtained. Metallogels show negative signs for the nonlinear refractive index and the nonlinear absorption coefficient. The real parts of the third-order susceptibility for these metallogels are much greater than the imaginary parts (i.e., χR(3) > χI(3)), making such metallogels very promising for all optical-switching applications.

Insights into the dynamic interactions of RNase a and osmolytes through computational approaches.

Osmolytes are small organic molecules that are known to stabilize proteins and other biological macromolecules under various stressful conditions. They belong to various categories such as amino acids, methylamines, and polyols. These substances are commonly known as 'compatible solutes' because they do not disrupt cellular processes and help regulate the osmotic balance within cells. In the case of ribonuclease A (RNase A), which is prone to aggregation, the presence of osmolytes can help to maintain its structural stability and prevent unwanted interactions leading to protein aggregation. In this study, we investigated the interaction between RNase A and several osmolytes using molecular docking and molecular dynamics (MD) simulations. We performed molecular docking to predict the binding mode and binding affinity of each osmolyte with RNase A. MD simulations were then carried out to investigate the dynamics and stability of the RNase A-osmolyte complexes. Our results show that two osmolytes, glucosylglycerol and sucrose have favorable binding affinities with RNase A. The possible role of these osmolytes in stabilizing the RNase A and prevention of aggregation is also explored. By providing computational insights into the interaction between RNase A and osmolytes, the study offers valuable information that could aid in comprehending the mechanisms by which osmolytes protect proteins and help in designing therapeutics for protein-related disorders based on osmolytes. These findings may have significant implications for the development of novel strategies aimed at preventing protein misfolding and aggregation in diverse disease conditions.Communicated by Ramaswamy H. Sarma.

Role of Urinary Biomarkers (Transforming Growth Factor ß1, Neutrophil Gelatinase-Associated Lipocalin, and Cystatin C) as a Prognostic Factor of Renal Outcome in the Posterior Urethral Valve.

Background: The urinary biomarker response precedes the appearance of any renal structural or functional derangement. Transforming growth factor-ß1 (TGF-ß1), neutrophil gelatinase associated lipocalin (NGAL), and Cystatin C (CysC) can act as the early prognostic markers in posterior urethral valve (PUV) patients. Aim: To compare the urinary levels of TGF-ß1, NGAL, and CysC between PUV cases and age matched controls and to correlate these with renal structural and functional parameters. Materials and Methods: This prospective study included children with PUV diagnosed using the standard investigations and an equal number of age-matched controls with nonurological problems. For the study subjects, the urinary samples were collected at three different time points (pre- and postoperatively at 3 and 6 months), whereas for controls, only single-voided samples were studied. The urinary levels of TGF-ß1, NGAL, and CysC were estimated by the standardized techniques using the ELISA kits. Statistical methods were used to drive the comparisons between cases and controls. Results: Fifteen children with a median age of 10 (5-48) months were enrolled in each of the two groups. The mean uTGF-ß1 in the case group was significantly higher at all three time points (43.20 ± 6.13 pg/ml, 43.33 ± 11.89 pg/ml and 40.71 ± 9.01 pg/ml) as compared to the control group (29.12 ± 8.31 pg/ml) (P ≤ 0.001). The median uNGAL in the case group was also higher (17.78 ng/ml, 2.35 ng/ml and 2.536 ng/ml) as compared to the control group (1.31 ng/ml). However, the difference was significant only preoperatively (P = 0.02). The median uCysC in case group was similarly higher (0.347 µg/ml, 0.439 µg/ml, and 0.382 µg/ml) than the control group (0.243 µg/ml) (P > 0.05). Serum creatinine in the case group (0.49 mg/dl) showed no significant rise above that of control (0.24 mg/dl). A cutoff value of uTGF-ß1 = 36.55 pg/ml (P < 0.001), uNGAL = 0.879 ng/ml (P = 0.02), and uCysC = 0.25 µg/ml (P = 0.22) was found to be associated with renal damage in PUV. A significant correlation was found between uNGAL and S. creatinine at 3 months (r = 0.43, P = 0.017) and 6 months (r = 0.47, P = 0.08). Conclusion: The elevated uTGF-ß1, a decline in uNGAL and an increase in uCysC suggests ongoing inflammation, improvement in hydronephrosis and a prolonged proximal tubular dysfunction in PUV patients, respectively.

Characterization of Bioactive Metabolites and Antioxidant Activities in Solid and Liquid Fractions of Fresh Duckweed (Wolffia globosa) Subjected to Different Cell Wall Rupture Methods.

Fresh Wolffia globosa, the smallest flowering plant well-known for its favorable nutrient composition and rich content of bioactive compounds, was subjected to boiling, freeze-thawing, and mechanical crushing to reduce its excessive (95-96%) moisture level and consequent drying time. The resultant three wolffia matrixes were filtered through a plankton net to fractionate into the residue and the filtrate. The proximate composition, bioactive metabolites, antioxidant activity, and characterization of bioactive metabolites by LC-ESI-QTOF-MS/MS and Fourier transform infrared spectroscopy were made from oven-dried residues and filtrates. Among residues, crude protein (29.84%), crude lipid (5.77%), total carotenoids (TCC; 722.8 µg/g), and vitamin C (70.02 mg/100 g) were the highest (p < 0.05) for freeze-thawing against higher ash (7.99%), total phenolic content (TPC; 191.47 mg GAE g-1 dry weight), total flavonoid content (TFC; 91.54 mg QE g-1 dry weight), DPPH activity (47.46%), and ferric reducing antioxidant power (FRAP) activity (570.19 µmol FeSO4 equiv/mg) for the crushed counterpart and Chl-b in residues from boiling. No significant variation was evident in the total tannin content (TTC). Among filtrates, higher total phenolic content (773.29 mg GAE g-1 dry weight), TFC (392.77 mg QE g-1 dry weight), TTC (22.51 mg TAE g-1), and antioxidant activity as DPPH activity (66.46%) and FRAP (891.62 µmol FeSO4 equiv/mg) were evident for boiling, while that from crushing exhibited the highest TCC (1997.38 µg/g DM). LC-ESI-QTOF-MS/MS analysis identified 72 phenolic compounds with the maximum in residue (33) and filtrate (33) from freeze-thawing, followed by crushing (18 and 19) and boiling (14 and 13) in order, respectively. The results indicated that the predrying cell rupturing method significantly impacted quantitative, as well as qualitative compositions of residues and filtrates from fresh wolffia.

Structural Basis of Aquaporin-4 Autoantibody Binding in Neuromyelitis Optica.

Neuromyelitis Optica (NMO) is an autoimmune disease of the central nervous system where pathogenic autoantibodies target the human astrocyte water channel aquaporin-4 causing neurological impairment. Autoantibody binding leads to complement dependent and complement independent cytotoxicity, ultimately resulting in astrocyte death, demyelination, and neuronal loss. Aquaporin-4 assembles in astrocyte plasma membranes as symmetric tetramers or as arrays of tetramers. We report molecular structures of aquaporin-4 alone and bound to Fab fragments from patient-derived NMO autoantibodies using cryogenic electron microscopy. Each antibody binds to epitopes comprised of three extracellular loops of aquaporin-4 with contributions from multiple molecules in the assembly. The structures distinguish between antibodies that bind to the tetrameric form of aquaporin-4, and those targeting higher order orthogonal arrays of tetramers that provide more diverse bridging epitopes.

Validation and Estimation of Obesity-Induced Intervertebral Disc Degeneration through Subject-Specific Finite Element Modelling of Functional Spinal Units.

(1) Background: Intervertebral disc degeneration has been linked to obesity; its potential mechanical effects on the intervertebral disc remain unknown. This study aimed to develop and validate a patient-specific model of L3-L4 vertebrae and then use the model to estimate the impact of increasing body weight on disc degeneration. (2) Methods: A three-dimensional model of the functional spinal unit of L3-L4 vertebrae and its components were developed and validated. Validation was achieved by comparing the range of motions (RoM) and intradiscal pressures with the previous literature. Subsequently, the validated model was loaded according to the body mass index and estimated stress, deformation, and RoM to assess disc degeneration. (3) Results: During validation, L3-L4 RoM and intradiscal pressures: flexion 5.17° and 1.04 MPa, extension 1.54° and 0.22 MPa, lateral bending 3.36° and 0.54 MPa, axial rotation 1.14° and 0.52 MPa, respectively. When investigating the impact of weight on disc degeneration, escalating from normal weight to obesity reveals an increased RoM, by 3.44% during flexion, 22.7% during extension, 29.71% during lateral bending, and 33.2% during axial rotation, respectively. Also, stress and disc deformation elevated with increasing weight across all RoM. (4) Conclusions: The predicted mechanical responses of the developed model closely matched the validation dataset. The validated model predicts disc degeneration under increased weight and could lay the foundation for future recommendations aimed at identifying predictors of lower back pain due to disc degeneration.

Management of Ipsilateral Terrible Triad Injury of Elbow and Concomitant Proximal Humerus Fracture: A Case Report and Literature Review.

Introduction: A difficult pattern of injuries is Hotchkiss's terrible triad, which includes elbow dislocations with fracture of the coronoid and head of radius. It is uncommon to have a concurrent proximal humerus fracture, which makes clinical care even more difficult. Case Report: An injured worker, 33 years old, claimed to have fallen from a height and received several injuries when he arrived at our emergency center. On physical examination, the patient showed signs of deformity and had an open injury over his left elbow. The radiographic evaluation showed that the patient had a posterior elbow dislocation along with a fracture of the left coronoid, head of radius, and proximal humerus. Following the reduction in a closed manner, computed tomography of the left elbow was carried out for additional assessment. The patient had both the proximal humerus and elbow fixed, and then the elbow was immobilized for 2 weeks. Conclusion: Complex musculoskeletal injuries resulting from high-energy trauma require a thorough, multidisciplinary strategy to address since long-term results and any consequences will require ongoing monitoring and rehabilitation.

HAT and HDAC: Enzyme with Contradictory Action in Neurodegenerative Diseases.

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors.

Climate change effects on aquaculture production and its sustainable management through climate-resilient adaptation strategies: a review.

Aquaculture witnessed a remarkable growth as one of the fastest-expanding sector in the food production industry; however, it faces serious threat from the unavoidable impacts of climate change. Understanding this threat, the present review explores the consequences of climate change on aquaculture production and provides need based strategies for its sustainable management, with a particular emphasis on climate-resilient approaches. The study examines the multi-dimensional impacts of climate change on aquaculture which includes the shifts in water temperature, sea-level rise, ocean acidification, harmful algal blooms, extreme weather events, and alterations in ecological dynamics. The review subsequently investigates innovative scientific interventions and climate-resilient aquaculture strategies aimed at strengthening the adaptive capacity of aquaculture practices. Some widely established solutions include selective breeding, species diversification, incorporation of ecosystem-based management practices, and the implementation of sustainable and advanced aquaculture systems (aquaponics and recirculating aquaculture systems (RAS). These strategies work towards fortifying aquaculture systems against climate-induced disturbances, thereby mitigating risks and ensuring sustained production. This review provides a detailed insight to the ongoing discourse on climate-resilient aquaculture, emphasizing an immediate need for prudent measures to secure the future sustainability of fish food production sector.

Implication of calcium supplementations in health and diseases with special focus on colorectal cancer.

Calcium is a fundamental and integrative element and helps to ensure optimal health by regulating various physiological and pathological processes. While there is substantiated evidence confirming the beneficial effects of calcium in the treatment, management, and prevention of various health conditions, including cancer, conflicting studies are imperative to acknowledge the potential negative role of calcium supplementation. The studies on calcium supplementation showed that a specific dose can help in the maintenance of good human health, and in the control of different types of diseases, including cancer. Calcium alone and when combined with vitamin D, emerges as a promising therapeutic option for efficiently managing cancer growth, when used with chemotherapy. Combination therapy is considered a more effective approach for treating advanced types of colorectal cancer. Nevertheless, several challenges drastically influence the treatment of cancer, such as individual discrepancy, drug resistance, and stage of cancer, among others. Henceforth, novel preventive, reliable therapeutic modalities are essential to control and reduce the incidence and mortality of colorectal cancer (CRC). The calcium-sensing receptor (CaSR) plays a pivotal role in calcium homeostasis, metabolism, and regulation of oncogenesis. Numerous studies have underscored the potential of CaSR, a G protein-coupled receptor, as a potential biomarker and target for colorectal cancer prevention and treatment. The multifaceted involvement of CaSR in anti-inflammatory and anti-carcinogenic processes paves the way for its utilization in the diagnosis and management of colorectal cancer. The current review highlights the important role of supplemental calcium in overall health and disease, along with the exploration of intricate mechanisms of CaSR pathways in the management and prevention of colorectal cancer.

Structural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1.

Yeast Cadmium Factor 1 (Ycf1) sequesters glutathione and glutathione-heavy metal conjugates into yeast vacuoles as a cellular detoxification mechanism. Ycf1 belongs to the C subfamily of ATP Binding Cassette (ABC) transporters characterized by long flexible linkers, notably the regulatory domain (R-domain). R-domain phosphorylation is necessary for activity, whereas dephosphorylation induces autoinhibition through an undefined mechanism. Because of its transient and dynamic nature, no structure of the dephosphorylated Ycf1 exists, limiting understanding of this R-domain regulation. Here, we capture the dephosphorylated Ycf1 using cryo-EM and show that the unphosphorylated R-domain indeed forms an ordered structure with an unexpected hairpin topology bound within the Ycf1 substrate cavity. This architecture and binding mode resemble that of a viral peptide inhibitor of an ABC transporter and the secreted bacterial WXG peptide toxins. We further reveal the subset of phosphorylation sites within the hairpin turn that drive the reorganization of the R-domain conformation, suggesting a mechanism for Ycf1 activation by phosphorylation-dependent release of R-domain mediated autoinhibition.

Maximum outcome with minimal resources: report of a multiligamentous knee injury managed with 'modified confluent tunnel technique'.

Multiligamentous knee injuries (MLKIs) are rare and challenging to manage in many aspects. The injury requires prompt diagnosis, reconstruction of multiple ligaments, and management of associated neurovascular injuries. Another important aspect that surgeons should consider is resource availability. Successful management of a case of MLKI using the cost-effective 'modified confluent tunnel technique' is described in this case report. We used confluent tunnels for intra- and extra-articular ligament reconstructions at the femoral side. We incorporated the weave technique for medial collateral ligament (MCL) reconstruction, and Larson's technique for posterolateral corner (PLC) reconstruction in this construct, and augmented the anterior cruciate ligament (ACL) and posterior cruciate ligament reconstruction with the remaining PLC and MCL grafts, respectively. This was cost-effective and resulted in good functional outcomes. The technique also helped us to avoid tunnel convergence which is an expected complication in MLKI surgeries.

Structural Basis for Oxidized Glutathione Recognition by the Yeast Cadmium Factor 1.

Transporters from the ABCC family have an essential role in detoxifying electrophilic compounds including metals, drugs, and lipids, often through conjugation with glutathione complexes. The Yeast Cadmium Factor 1 (Ycf1) transports glutathione alone as well as glutathione conjugated to toxic heavy metals including Cd2+, Hg2+, and As3+. To understand the complicated selectivity and promiscuity of heavy metal substrate binding, we determined the cryo-EM structure of Ycf1 bound to the substrate, oxidized glutathione. We systematically tested binding determinants with cellular survival assays against cadmium to determine how the substrate site accommodates different-sized metal complexes. We identify a "flex-pocket" for substrate binding that binds glutathione complexes asymmetrically and flexes to accommodate different size complexes.

Nonlinear study of indolamines: A hidden property that might have possible implications in neurodegeneration.

Indolamines (e.g., serotonin and melatonin) are tryptophan-derived class of neurotransmitters and neuromodulators that play crucial roles in mood regulation, sleep-wake cycles, and gastrointestinal functions. These biogenic amines exert their effects by binding to specific receptors in the central nervous system, influencing neuronal activity and signalling cascades. Indolamines are vital in maintaining homeostasis, and imbalances in their levels have been implicated in various neurological and psychiatric disorders. Hence, in the present study, we have investigated the nonlinear properties of indolamines under a continuous wave (CW) and pulsed laser excitation using the closed-aperture (CA) Z-scan technique. The CA Z-scan is a cost-effective and sensitive analytical tool for investigating nonlinear properties. It is observed that indolamines show negative refractive and positive absorptive nonlinearity under in vitro physiological conditions. The origin of nonlinearity is ascribed to the thermo-optical effect governed by the saturated atomic absorption and molecular orientation mechanisms under CW and pulsed laser excitation, respectively. The strength of nonlinearity is found to vary linearly with the concentration of indolamines. Overall, serotonin possesses stronger nonlinearity than melatonin. The maximum nonlinearity (refractive index (n2) & absorption coefficient (ß)) for melatonin under CW and pulsed laser excitations are (-1.266 × 10-12 m2W-1 and -1.883 × 10-17 m2W-1) & (8.046 × 10-8 mW-1 and 1.516 × 10-13 mW-1), respectively. Meanwhile, the maximum n2 and ß under pulsed laser excitation for serotonin are obtained as -3.195 × 10-17 m2W-1 and 6.149 × 10-12 mW-1, respectively. The outcome of the results may be utilized in understanding processes mediated by indolamines and designing therapeutic interventions.

Hematin anhydride (ß-hematin): An analogue to malaria pigment hemozoin possesses nonlinearity.

Hematin anhydride (ß-hematin), the synthetic analogue of the malaria pigment, "hemozoin", is a heme dimer produced by reciprocal covalent bonds among carboxylic acid groups on the protoporphyrin-IX ring and the iron atom present in the two adjacent heme molecules. Hemozoin is a disposal product formed from the digestion of hemoglobin present in the red blood cells infected with hematophagous malaria parasites. Besides, as the parasites invade red blood cells, hemozoin crystals are eventually released into the bloodstream, where they accumulate over time in tissues. Severe malaria infection leads to significant dysfunction in vital organs such as the liver, spleen, and brain in part due to the autoimmune response to the excessive accumulation of hemozoin in these tissues. Also, the amount of these crystals in the vasculature correlates with disease progression. Thus, hemozoin is a unique indicator of infection used as a malaria biomarker and hence, used as a target for the development of antimalarial drugs. Hence, exploring various properties of hemozoin is extremely useful in the direction of diagnosis and cure. The present study focuses on finding one of the unknown properties of ß-hematin in physiological conditions by using the Z-scan technique, which is simple, sensitive, and economical. It is observed that hemozoin possesses one of the unique material properties, i.e., nonlinearity with a detection limit of âˆ¼ 15 µM. The self-defocusing action causes ß-hematin to exhibit negative refractive nonlinearity. The observed data is analyzed with a thermal lensing model. We strongly believe that our simple and reliable approach to probing the nonlinearity of ß-hematin will provide fresh opportunities for malaria diagnostics & cure in the near future.

Dual targeting of mitochondrial Lon peptidase 1 and chymotrypsin-like protease by small molecule BT317, as potential therapeutics in malignant astrocytoma.

Malignant astrocytomas are aggressive glioma tumors characterized by extensive hypoxia-induced, mito-chondria-dependent changes such as altered respiration, increased chymotrypsin-like (CT-L) proteasome activity, decreased apoptosis, drug resistance, stemness and increased invasiveness. Mitochondrial Lon Peptidase I (LonP1) overexpression and increased CT-L proteasome inhibitors activity are the biomarkers of aggressive high grade glioma phenotype, poor prognosis and found to be associated with recurrence and poor patient survival, and drugs targeting either LonP1 or the CT-L activity have anti-glioma activity in pre-clinical models. We here for the first time introduced and evaluated a novel small molecule, BT317, derived from coumarinic compound 4 (CC4) using structure-activity modeling which we found to inhibit both LonP1 and CT-L proteasome activity. Using gain-of-function and loss-of-function genetic models, we dis-covered that BT317 is more effective than the individual LonP1 or CT-L inhibition in increasing reactive oxy-gen species (ROS) generation and inducing apoptosis in high-grade astrocytoma lines. In vitro, BT317 had activity as a single agent but, more importantly, enhanced synergy with the standard of care commonly used chemotherapeutic temozolomide (TMZ). In orthotopic xenograft, patient derived glioma models, BT317 was able to cross the blood-brain barrier, to show selective activity at the tumor site and to demonstrate therapeutic efficacy both as a single agent and in combination with TMZ. BT317 defines an emerging class of dual LonP1, and CT-L proteasome inhibitors exhibited promising anti-tumor activity and could be a promising candidate for clinical translation in the space of malignant astrocytoma therapeutics.

An enhanced estimator of finite population variance using two auxiliary variables under simple random sampling.

In this article, we have suggested a new improved estimator for estimation of finite population variance under simple random sampling. We use two auxiliary variables to improve the efficiency of estimator. The numerical expressions for the bias and mean square error are derived up to the first order approximation. To evaluate the efficiency of the new estimator, we conduct a numerical study using four real data sets and a simulation study. The result shows that the suggested estimator has a minimum mean square error and higher percentage relative efficiency as compared to all the existing estimators. These findings demonstrate the significance of our suggested estimator and highlight its potential applications in various fields. Theoretical and numerical analyses show that our suggested estimator outperforms all existing estimators in terms of efficiency. This demonstrates the practical value of incorporating auxiliary variables into the estimation process and the potential for future research in this area.