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Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

This multicenter study aimed to explore whether baseline total immunoglobulin E (IgE) levels could predict omalizumab response in chronic spontaneous urticaria (CSU) patients. Refractory CSU patients, treated with omalizumab after failing second-generation H1-antihistamines, were analyzed retrospectively across seven centers in Brazil. The study assessed total IgE levels at baseline, comparing responders to non-responders and considering complete and partial responses. The results showed a significant reduction in CSU symptoms post-treatment. Non-responders had lower baseline IgE levels. A sensitivity of 67.8% and specificity of 93.3% for predicting a response were found at an IgE level of 59.5 IU/ml. Similar values were observed for complete responders. Notably, a baseline IgE level lower than 59.5 IU/ml may indicate late responders. The study underscores the potential of baseline IgE levels as a predictive biomarker for omalizumab response in CSU patients. Further research, incorporating diverse populations and analyzing response variables, is warranted to validate these findings.

Friction stir spot welding (FSSW) is a prominent solid-state adhesion process. In the recent past, several investigations are performed for the property enhancement of FSSW welded joints especially on the mechanical and metallurgical characterization. In this work, an attempt has been made to analyze the effect of environmental conditions on the output quality characteristics of SiC reinforced Al6061-T6 welded joints, fabricated at optimal parametric setting. For this, welded joints are preserved at sub-zero temperature of −18 ± 2 °C for 90, 180, 270 and 360 days. Output quality characteristics in terms of tensile-shear and micro-hardness test in combination with microstructure analyses using SEM, EDS Mapping, and XRD analysis are emphasized. It is revealed that during sub-zero cooling, weld strength and micro-hardness of weldments increased over time. Additionally, a decrease in crystal size and increase in dislocation density are observed with increase in cooling period of weld joint, which eventually made suitable for extreme applications.

Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL.

In this study, an attempt has been made to evaluate the best management practices (BMPs) in a poorly degraded and economically fragile watershed area in Shivalik hills, Northern India. A scenario-based approach was followed to evaluate the existing BMPs and a few hypothetically implemented BMPs based on SWAT modeling. A regionalization approach was adopted for calibrating the SWAT model for ungauged micro-watersheds within the study area. After successful calibration, soil and water assessment tool (SWAT) model was simulated for several BMPs that are in practice such as Check dams, vegetation and fencing so as to learn about their effectiveness in controlling sediment and nutrient yield. Other hypothetically installed BMPs, such as contouring, terracing, grassed waterways and filter strips were also evaluated in untreated micro and sub-watersheds. The cost–benefit analysis of these hypothetical BMPs revealed that the average reduction in nutrients was maximum for grassed waterways and minimum for terracing. Overall, the scenario-based analysis revealed that conservation practices, in the otherwise degraded watershed, can prove to be beneficial for sustainability of its natural resources. HIGHLIGHTS SWAT model calibration for gauged and ungauged microwatershed using regionalization technique.; Evaluating the effectiveness of in-place best management practices in controlling sediment yield and a few nutrient parameters causing nonpoint pollution during rainfall season.; Cost–benefit analysis of the hypothetically designed and implemented best management practices in conserving nutrient loss using SWAT simulations.;

Natural fibre composites have emerged as a viable alternative to conventional polymer composites, after environmental concerns gain popularity. In recent years, a tremendous growth in the applications of natural fibre composites have been observed, particularly in the field of construction, as well as aerospace and automotive industries. The present study investigates the feasibility of developing a novel tribo-material by reinforcing biopolymer with easily accessible and inexpensive plant fibres from the surroundings. The fibres were treated chemically prior to fabrication. The injection molding process was used to fabricate laminated composites by incorporating three different kinds of fibres (sisal, banana, and bagasse) into Poly-lactic acid (PLA) matrix at 10% and 20% fibre concentrations. Wear properties of fabricated composites were studied on a digital display controlled pin-on-disc test rig. The test parameters under dry sliding conditions were sliding distance (1000–3000 m), sliding speed (2,4 and 6 m/s) and applied load (10 N). The experimental results depict that the incorporation of natural fibres improved tribological properties of neat PLA matrix. The worn surfaces of developed composites were examined using a scanning electron microscope to study the wear mechanism.

Abstract Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

Abstract Background Several complications have been reported in COVID-19 infection. Most of the complications include secondary infection. Case presentation We report an 85-year-old male who presented with cauda equina syndrome 7-months after contracting COVID-19 infection. We excised an extradural mass which on examination proved to be Spinal Aspergillosis. Conclusions Spinal Aspergillosis should be kept in mind in patients who present with local spinal pain with or without neurological deficit after COVID-19 infection.

Cyclin-dependent kinase 5 (Cdk5) is a crucial regulator of neuronal signal transduction. Cdk5 activity is implicated in various neuropsychiatric and neurodegenerative conditions such as stress, anxiety, depression, addiction, Alzheimer’s disease, and Parkinson’s disease. While constitutive Cdk5 knockout is perinatally lethal, conditional knockout mice display resilience to stress-induction, enhanced cognition, neuroprotection from stroke and head trauma, and ameliorated neurodegeneration. Thus, Cdk5 represents a prime target for treatment in a spectrum of neurological and neuropsychiatric conditions. While intracranial infusions or treatment of acutely dissected brain tissue with compounds that inhibit Cdk5 have allowed the study of kinase function and corroborated conditional knockout findings, potent brain-penetrant systemically deliverable Cdk5 inhibitors are extremely limited, and no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases to date. Here, we screened aminopyrazole-based analogs as potential Cdk5 inhibitors and identified a novel analog, 25–106, as a uniquely brain-penetrant anti-Cdk5 drug. We characterize the pharmacokinetic and dynamic responses of 25–106 in mice and functionally validate the effects of Cdk5 inhibition on open field and tail-suspension behaviors. Altogether, 25–106 represents a promising preclinical Cdk5 inhibitor that can be systemically administered with significant potential as a neurological/neuropsychiatric therapeutic.

Purpose: The present study has been carried out to study whether and how different aspects of brand management (brand identity, brand image and brand meaning) are instrumental in maintaining and enhancing attachment strength of students with higher education institutes (HEIs). Further, to understand what brand management aspect channels the impact of what branding driver on attachment strength in most effective manner. Design/methodology/approach: The study analysed combined mediating effects as well as specific mediating effects to test the mediating role of brand management aspects. Findings: The study reveals that brand image plays highest mediating role among all aspects of brand management. HEIs need to enhance service quality because brand image carries the highest influence of service quality on attachment strength. Similarly, brand identity carries the highest influence of heritage on attachment strength. Brand meaning carries the highest influence of competence and reputation on attachment strength. Research limitations/implications: The present study, based on empirical research, has built the framework and mechanism for creating attachment strength utilising the intangible resources of HEIs through brand management. The present study examines how specific intangible resources exhibit varying influences on attachment strength via distinct brand management mediation effects. Practical implications: The present study provides framework for designing branding strategies to build and channelise necessary intangible resources of branding for nourishing and nurturing attachment strength. Originality/value: The present study contributes to scarce branding literature in context of HEIs. The study proposes role of HEI branding in developing students' attachment strength with their HEIs.

Information and communication technology (ICT) has been the backbone of businesses for some time now. ICT adoption has rendered data availability in vertically connected organizations. In recent times, the rise of analytics has paved the way to rethink the structure and working of vertically connected firms within a supply chain. Big data analytics (BDA) for instance, has become a prominent tool to analyse unstructured data. This study explores the application and benefit of various types of analytics such as descriptive analytics, predictive analytics and prescriptive analytics in the process of supply chain management (SCM). Additionally, the study also looks at ways by which analytics could integrally be included within the SCM curriculum in higher education to prepare future supply chain analyst. Notably, the article is positioned for bridging the gap between the use of analytics in SCM, both from academia and the industry perspective. [ABSTRACT FROM AUTHOR]

The banking sector in India plays a crucial role in economic growth. A bank provides an opportunity for investments to encourage economic growth and the potential to yield higher returns. In this study, we develop a bankruptcy prediction model by using machine learning (ML) techniques, namely logistic regression, random forest, and AdaBoost, and compare these models with those developed using deep learning (DL) techniques, namely the artificial neural network (ANN). ANN results in the highest accuracy and the most favourable prediction model for bankruptcy. Data used in this study are collected from survived and failed private and public sector banks from India from March 2001 to March 2018. For bankruptcy prediction, we use the bank's macroeconomic and market structure-related features. The feature selection technique 'Relief algorithm' is used to select useful features for the bankruptcy prediction model. Because failed banks in comparison with survived were less in the dataset, the issue of imbalanced cases may have arisen, in which case most ML and DL techniques do not perform well. Thus, we convert the dataset into a balanced form by using the synthetic minority oversampling technique (SMOTE). The results of this study can help in performing financial analyses of banks and thus have significant implications for their stakeholders. [ABSTRACT FROM AUTHOR]