Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks.

The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress.

Habitat Mapping of in Parsa National Park, Nepal: Ensemble Modeling Approach.

, a globally vulnerable and protected priority species in Nepal, has experienced habitat loss and fragmentation, poaching, and diseases. Consequently, their population is isolated significantly in Parsa National Park and Chitwan National Park in Nepal. However, their distribution even in these protected areas is limited to topographical features.

Workflow for E3 Ligase Ligand Validation for PROTAC Development.

Proteolysis targeting chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. The development of PROTACs has been mainly focused on using CRBN (Cereblon) and VHL (Von Hippel-Lindau ligase) E3 ligase ligands. However, the considerable size of the human E3 ligase family, newly developed E3 ligase ligands, and the favorable druggability of some E3 ligase families hold the promise that novel degraders with unique pharmacological properties will be designed in the future using this large E3 ligase space.

Gall bladder duplication: A rare biliary malformation.

Gallbladder duplication is a rare anatomical variation with an incidence of approximately 1 in 3800 to 4000 live births, resulting from aberrant biliary organogenesis. This case report discusses a 35-year-old female who presented with intermittent lower abdominal pain, with initial imaging revealing a complex left adnexal cyst. Follow-up CT and ultrasound examinations revealed 2 distinct gallbladder-like structures in the gallbladder fossa, each with a cystic duct draining into the common bile duct.

Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε.

Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules.

Identification of suitable target/E3 ligase pairs for PROTAC development using a rapamycin-induced proximity assay (RiPA).

The development of proteolysis targeting chimeras (PROTACs), which induce the degradation of target proteins by bringing them into proximity with cellular E3 ubiquitin ligases, has revolutionized drug development. While the human genome encodes more than 600 different E3 ligases, current PROTACs use only a handful of them, drastically limiting their full potential. Furthermore, many PROTAC development campaigns fail because the selected E3 ligase candidates are unable to induce degradation of the particular target of interest.

Development of 2-Aminoadenine-Based Proteolysis-Targeting Chimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle 1 and Aurora Kinases.

Monopolar spindle 1 (Mps1, also known as TTK) and Aurora kinase (AURK) A and B are critical regulators of mitosis and have been linked to the progression of various cancers. Here, we report the design, synthesis, and biological evaluation of a series of PROTACs (proteolysis-targeting chimeras) targeting TTK and AURKs. We synthesized various degrader molecules based on four different 2-aminoadenine-based ligands, recruiting either cereblon or VHL as the E3-ligase.

Cardioprotective effects of sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase 4 inhibitor in type 2 diabetes: A meta-analysis of comparative safety and efficacy.

Background: Sodium glucose cotransporter 2 inhibitors are recommended for the treatment of heart failure due to their cardioprotective effects, despite primarily being used as antidiabetic medications. However, the comparative profile of two antidiabetic drugs, sodium glucose cotransporter 2 inhibitors with dipeptidyl peptidase 4 inhibitor remains unclear.

Study Hypothesis: This study aims to compare the safety and efficacy profiles of sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitor drugs.

Pontine tubercular abscess: A rare presentation of CNS tuberculosis masquerading as glioma in a child.

Tuberculous brain abscess (TBA) in a child was initially misdiagnosed as glioma. Two craniotomies, abscess drainage, and anti-tubercular therapy led to recovery. Pontine TBA, though rare and atypical, can have better outcome with timely intervention.

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.

Objective: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC).

Evaluating aortomesenteric parameters in a tertiary center of Nepal for superior mesenteric artery syndrome diagnosis and risk factors: cross-sectional study.

Background And Objectives: This study examines aortomesenteric angle (AMA) and distance (AMD), which are critical in superior mesenteric artery (SMA) syndrome. Addressing the scarcity of SMA cases, the research explores potential links with lower BMI and aims to establish normative data for diagnostic and predictive purposes, using contrast-enhanced computed tomography (CT) scans across various BMI and sex categories.

Methodology: A retrospective quantitative cross-sectional study was conducted on 189 patients undergoing abdominal contrast-enhanced CT scans between December 2019 and December 2020.

Carbon footprint of Nepalese healthcare system: A study of Dhulikhel Hospital.

Background: Though direct greenhouse gas emissions cannot be observed in health care sectors, there can exist indirect emissions contributing to global climate change. This study addresses the concept of the carbon footprint and its significance in understanding the environmental impact of human activities, with a specific emphasis on the healthcare sector through gate-to-gate (GtoG) life cycle assessment. Transportation, energy consumption, and solid waste generated by hospitals are the primary sources of carbon emissions.

Implications of irregular shelterwood system on regeneration and species diversity of Sal ( Gaertn. f.) forest in Nepal.

Silvicultural systems are essential for effective forest management and utilize the resources by conserving biodiversity, health, and valuable services forests offer to society. However, Nepal faces a significant knowledge gap due to the limited data on the effect of silvicultural systems and forest management practices on tree diversity and regeneration. Therefore, this study was conducted to assess the effects of canopy opening on natural regeneration and species diversity of Sal ( Gaertn.

Innovations and adaptations in neonatal and pediatric respiratory care for resource constrained settings.

Respiratory disease is a leading cause of death in children under 5 years of age worldwide, and most of these deaths occur in low- to middle-income countries (LMICs) where advanced respiratory care technology is often limited. Much of the equipment required to provide advanced respiratory care is unavailable in these areas due to high costs, the need for specialty trained personnel, and myriad other resource constraints that limit uptake and sustainable use of these devices, including reliable access to electricity, sensitive equipment needing frequent maintenance, single-patient-use supplies, and lack of access to sterilization equipment. Compounding the problem, pediatrics is uniquely challenging in that one size does not fit all, or even most patients.

Growth and Photosynthetic Responses of Cowpea Genotypes under Waterlogging at the Reproductive Stage.

Waterlogging is an important environmental stress limiting the productivity of crops worldwide. Cowpea ( L.) is particularly sensitive to waterlogging stress during the reproductive stage, with a consequent decline in pod formation and yield.

Short waterlogging events differently affect morphology and photosynthesis of two cucumber ( L.) cultivars.

Waterlogging induces growth and developmental changes in sensitive crops such as cucumber ( L.) during early plant development. However, information on the physiological mechanisms underpinning the response of cucumber plants to waterlogging conditions is limited.

Enhanced seedling growth by 3--pentadecylphenolethanolamide is mediated by fatty acid amide hydrolases in upland cotton ( L.).

Fatty acid amide hydrolase (FAAH) is a conserved amidase that is known to modulate the levels of endogenous -acylethanolamines (NAEs) in both plants and animals. The activity of FAAH is enhanced by synthetic phenoxyacylethanolamides resulting in greater hydrolysis of NAEs. Previously, 3--pentadecylphenolethanolamide (PDP-EA) was shown to exert positive effects on the development of Arabidopsis seedlings by enhancing Arabidopsis FAAH (AtFAAH) activity.

Evaluation of Breast Mass by Mammography and Ultrasonography with Histopathological Correlation.

Background: Mammography, ultrasound and Magnetic Resonance Imaging are the available modalities for the evaluation of breast masses. Advances and ongoing improvements in imaging technologies have improved the sensitivity of breast cancer detection and diagnosis, but each modality is most beneficial when utilized according to individual traits such as age, risk factors, and breast density. However, pathological diagnosis is most crucial for the treatment of breast masses.

Screening of cowpea (Vigna unguiculata (L.) Walp.) genotypes for waterlogging tolerance using morpho-physiological traits at early growth stage.

The majority of cowpea (Vigna unguiculata (L.) Walp.) produced in the U.

Generation of auxin inducible degron (AID) knock-in cell lines for targeted protein degradation in mammalian cells.

Targeted protein degradation using degrons, such as the mini-Auxin-inducible degron (mAID), has an advantage over genetic silencing/knockout. However, the efficiency of sgRNA, homologous recombination, tedious expansion, and screening single clones makes the process of tagging endogenous proteins long and laborious. This protocol describes a practical and economical way to obtain AID-tagged endogenous proteins using CRISPR/Cas9-mediated homology-directed repair (HDR).

LC-HRMS Profiling and Antidiabetic, Antioxidant, and Antibacterial Activities of (L.f.) Willd.

(L.f.) Willd is a profoundly used traditional medicinal plant in Asia.

Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination.

SPT6 is a histone chaperone that tightly binds RNA polymerase II (RNAPII) during transcription elongation. However, its primary role in transcription is uncertain. We used targeted protein degradation to rapidly deplete SPT6 in human cells and analyzed defects in RNAPII behavior by a multi-omics approach and mathematical modeling.

Antidiabetic, Antimicrobial, and Molecular Profiling of Selected Medicinal Plants.

Natural products have been the center of attraction ever since they were discovered. Among them, plant-based natural products were popular as analgesics, anti-inflammatory, antidiabetic, and cosmetics and possess widespread biotechnological applications. The use of plant products as cosmetics and therapeutics is deep-rooted in Nepalese society.