Insights into the regulation of CHIP E3 ligase-mediated ubiquitination of neuronal protein BNIP-H.

BCL2/adenovirus E1B 19-kDa protein-interacting protein 2 homolog (BNIP-H or Caytaxin), a pivotal adaptor protein that facilitates cerebellar cortex growth and synaptic transmission, is posttranslationally modified to regulate neuronal function. This study reports the ubiquitination of BNIP-H by Carboxyl terminus of Hsc70-Interacting Protein (CHIP), a U-box containing E3 ligase that is also regulated autoubiquitination. Specifically, it was observed that CHIP autoubiquitinated itself primarily at Lys23 and Lys31 .

Structural transitions in kinesin minus-end directed microtubule motility.

Kinesin motor proteins hydrolyze ATP to produce force for spindle assembly and vesicle transport, performing essential functions in cell division and motility, but the structural changes required for force generation are uncertain. We now report high-resolution structures showing new transitions in the kinesin mechanochemical cycle, including power stroke fluctuations upon ATP binding and a post-hydrolysis state with bound ADP + free phosphate. We find that rate-limiting ADP release occurs upon microtubule binding, accompanied by central β-sheet twisting, which triggers the power stroke - stalk rotation and neck mimic docking - upon ATP binding.

Structural basis for the distinct roles of non-conserved Pro116 and conserved Tyr124 of BCH domain of yeast p50RhoGAP.

p50RhoGAP is a key protein that interacts with and downregulates the small GTPase RhoA. p50RhoGAP is a multifunctional protein containing the BNIP-2 and Cdc42GAP Homology (BCH) domain that facilitates protein-protein interactions and lipid binding and the GAP domain that regulates active RhoA population. We recently solved the structure of the BCH domain from yeast p50RhoGAP (BCH) and showed that it maintains the adjacent GAP domain in an auto-inhibited state through the β5 strand.

A Q-transform-based deep learning model for the classification of atrial fibrillation types.

According to the World Health Organization (WHO), Atrial Fibrillation (AF) is emerging as a global epidemic, which has resulted in a need for techniques to accurately diagnose AF and its various subtypes. While the classification of cardiac arrhythmias with AF is common, distinguishing between AF subtypes is not. Accurate classification of AF subtypes is important for making better clinical decisions and for timely management of the disease.

Recognition of Mosquito Saliva Protein LTRIN by the Human Receptor LTβR for Controlling the Immune Response.

Salivary proteins from mosquitoes have received significant attention lately due to their potential to develop therapeutic treatments or vaccines for mosquito-borne diseases. Here, we report the characterization of LTRIN (lymphotoxin beta receptor inhibitor), a salivary protein known to enhance the pathogenicity of ZIKV by interrupting the LTβR-initiated NF-κB signaling pathway and, therefore, diminish the immune responses. We demonstrated that the truncated C-terminal LTRIN (ΔLTRIN) is a dimeric protein with a stable alpha helix-dominant secondary structure, which possibly aids in withstanding the temperature fluctuations during blood-feeding events.

Sensing for survival: specialised regulatory mechanisms of Type III secretion systems in Gram-negative pathogens.

For centuries, Gram-negative pathogens have infected the human population and been responsible for numerous diseases in animals and plants. Despite advancements in therapeutics, Gram-negative pathogens continue to evolve, with some having developed multi-drug resistant phenotypes. For the successful control of infections caused by these bacteria, we need to widen our understanding of the mechanisms of host-pathogen interactions.

Assessment of factors related to poly cystic ovarian syndrome - A comparative and correlational study.

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder that primarily affects women of reproductive age. It is particularly prevalent among adolescent females who receive an insufficient diagnosis despite having potentially adverse consequences. The use of PCOS screening questionnaires has the potential to aid in the early detection of symptoms.

Exploring the potential of machine learning to design antidiabetic molecules: a comprehensive study with experimental validation.

Recent advances in hardware and software algorithms have led to the rise of data-driven approaches for designing therapeutic modalities. One of the major causes of human mortality is diabetes. Thus, there is a tremendous opportunity for research into effective antidiabetic designs.

Investigating anti-inflammatory and apoptotic actions of fucoidan concentrating on computational and therapeutic applications.

Fucoidan is linked to a variety of biological processes. Differences in algae species, extraction, seasons, and locations generate structural variability in fucoidan, affecting its bioactivities. Nothing is known about fucoidan from the brown alga , its anti-inflammatory properties, or its inherent mechanism.

Investigating anti-inflammatory actions of marine algal compound against lipoxygenase concentrating on therapeutic applications through computational approach.

Inflammation is the preliminary response given to any possible harmful stimuli including infections, injury or stress by immune system where neutrophils and macrophages gets activated and produces mediators, such as nitric oxide and cytokines that serves as biomarkers of inflammation. Lipoxygenases are enzymes that peroxidises lipids and are involved in the pathogenesis of several diseases including inflammatory diseases. These are oxidative enzymes comprising a non-heme iron atom in active site and are convoluted in inflammatory reactions.

Structural and functional characterization of Aedes aegypti pupal cuticle protein that controls dengue virus infection.

The pupal cuticle protein from Aedes aegypti (AaPC) inhibits dengue virus (DENV) infection; however, the underlying mechanism of this inhibition remains unknown. Here, we report that AaPC is an intrinsically disordered protein and interacts with domain I/II of the DENV envelope protein via residues Asp59, Asp61, Glu71, Asp73, Ser75, and Asp80. AaPC can directly bind to and cause the aggregation of DENV, which in turn blocks virus infection during the virus-cell fusion stage.

Structural Basis for the Enzymatic Activity of the HACE1 HECT-Type E3 Ligase Through N-Terminal Helix Dimerization.

HACE1 is an ankyrin repeat (AKR) containing HECT-type E3 ubiquitin ligase that interacts with and ubiquitinates multiple substrates. While HACE1 is a well-known tumor suppressor, its structure and mode of ubiquitination are not understood. The authors present the cryo-EM structures of human HACE1 along with in vitro functional studies that provide insights into how the enzymatic activity of HACE1 is regulated.

Bacterioferritin nanocage structures uncover the biomineralization process in ferritins.

Iron is an essential element involved in various metabolic processes. The ferritin family of proteins forms nanocage assembly and is involved in iron oxidation, storage, and mineralization. Although several structures of human ferritins and bacterioferritins have been solved, there is still no complete structure that shows both the trapped Fe-biomineral cluster and the nanocage.

CatBoost-based improved detection of P-wave changes in sinus rhythm and tachycardia conditions: a lead selection study.

Examining P-wave morphological changes in Electrocardiogram (ECG) is essential for characterizing atrial arrhythmias. However, standard 12-lead ECGsuffer from diagnostic redundancy due to low signal-to-noise ratio of P-waves. To address this issue, various optimal leads have been proposed for improved atrial activity recording, but the right selection among these leads is crucial for enhancing diagnostic efficacy.

Large-scale computational screening of Indian medicinal plants reveals to be a potentially anti-diabetic.

Researchers are investigating the medicinal properties of herbal plants throughout the world, which often leads to the discovery of novel plants and their chemicals for prophylactic needs of humans. Natural phytochemicals continue to be sought as alternative treatments for various diseases because of their non-toxic and therapeutic properties. In recent years, computational phytochemistry has enabled large-scale screening of phytochemicals, enabling researchers to pursue a wide range of therapeutic research alternatives to traditional ethnopharmacology.

Structures of apo Cas12a and its complex with crRNA and DNA reveal the dynamics of ternary complex formation and target DNA cleavage.

Cas12a is a programmable nuclease for adaptive immunity against invading nucleic acids in CRISPR-Cas systems. Here, we report the crystal structures of apo Cas12a from Lachnospiraceae bacterium MA2020 (Lb2) and the Lb2Cas12a+crRNA complex, as well as the cryo-EM structure and functional studies of the Lb2Cas12a+crRNA+DNA complex. We demonstrate that apo Lb2Cas12a assumes a unique, elongated conformation, whereas the Lb2Cas12a+crRNA binary complex exhibits a compact conformation that subsequently rearranges to a semi-open conformation in the Lb2Cas12a+crRNA+DNA ternary complex.

A novel allosteric site employs a conserved inhibition mechanism in human kidney-type glutaminase.

Glutaminase catalyses the metabolic process called glutaminolysis. Cancer cells harness glutaminolysis to increase energy reserves under stressful conditions for rapid proliferation. Glutaminases are upregulated in many tumours.

Gun violence among young adults with a juvenile crime record in North Carolina: Implications for firearm restrictions based on age and risk.

Youth who acquire a juvenile crime record may be at increased risk of perpetrating gun violence as adults. North Carolina and 22 other states permit young adults who were adjudicated by a juvenile court - even for some felony-equivalent offenses - to legally access firearms. Effectiveness of gun restrictions for adults with juvenile crime histories has not been systematically studied.

Identification of Aedes aegypti salivary gland proteins interacting with human immune receptor proteins.

Mosquito saliva proteins modulate the human immune and hemostatic systems and control mosquito-borne pathogenic infections. One mechanism through which mosquito proteins may influence host immunity and hemostasis is their interactions with key human receptor proteins that may act as receptors for or coordinate attacks against invading pathogens. Here, using pull-down assays and proteomics-based mass spectrometry, we identified 11 Ae.

Scaffold stability and P14' residue steric hindrance in the differential inhibition of FXIIa by Aedes aegypti trypsin inhibitor versus Infestin-4.

Kazal-type protease inhibitors strictly regulate Factor XIIa (FXIIa), a blood-clotting serine protease. However, when negatively charged surface of prosthetic device come into contact with FXII, it undergoes conformational change and auto-activation, leading to thrombus formation. Some research suggests that Kazal-type protease inhibitor specificity against FXIIa is governed solely by the reactive-site loop sequence, as this sequence makes most-if not all-of the direct contacts with FXIIa.

Mapping of molecular interactions between human E3 ligase TRIM69 and Dengue virus NS3 protease using hydrogen-deuterium exchange mass spectrometry.

Tripartite motif (TRIM) E3 ligases target specific substrates, including viral proteins, for proteasomal degradation, and are thus essential regulators of the innate antiviral response. TRIM69 ubiquitinates the non-structural NS3 protein of Dengue virus for its degradation by the host machinery. This antiviral strategy abrogates the immunosuppression mediated by the NS2B-NS3 protease complex.

Identification of putative binding interface of PI(3,5)P lipid on rice black-streaked dwarf virus (RBSDV) P10 protein.

Rice black-streaked dwarf virus (RBSDV) is an important reovirus that infects both plants and its transmission vector small brown planthopper, causing severe crop loss. High affinity binding between RBSDV P10 and PI(3,5)P lipid layer was measured using biolayer interferometry (BLI). Subcellular co-localization of PI(3,5)P and RBSDV P10 was observed on membranous structures in insect cells with stochastic optical reconstruction microscopy (STORM) imaging.

Sequence preference and scaffolding requirement for the inhibition of human neutrophil elastase by ecotin peptide.

Human neutrophil elastase (hNE) is an abundant serine protease that is a major constituent of lung elastolytic activity. However, when secreted in excess, if not properly attenuated by selective inhibitor proteins, it can have detrimental effects on host tissues, leading to chronic lung inflammation and non-small cell lung cancer. To improve upon the design of inhibitors against hNE for therapeutic applications, here, we report the crystal structure of hNE in complex with an ecotin (ET)-derived peptide inhibitor.

Bacterial antagonism of Chromobacterium haemolyticum and characterization of its putative type VI secretion system.

This study reports the isolation of a new Chromobacterium haemolyticum strain named WI5 from a hydroponic farming facility. WI5 exhibited remarkable bacterial antagonistic properties, eliminating Salmonella, Escherichia coli, Listeria monocytogenes and Staphylococcus aureus (initial inoculum load ∼10 CFU/ml) in dual-species co-culture biofilms. Antagonism was strictly contact-dependent and highly influenced by nutrient availability.

Crystal structure of Aedes aegypti trypsin inhibitor in complex with μ-plasmin reveals role for scaffold stability in Kazal-type serine protease inhibitor.

Kazal-type protease inhibitor specificity is believed to be determined by sequence of the reactive-site loop that make most, if not all, contacts with the serine protease. Here, we determined the complex crystal structure of Aedes aegypti trypsin inhibitor (AaTI) with μ-plasmin, and compared its reactivities with other Kazal-type inhibitors, infestin-1 and infestin-4. We show that the shortened 99-loop of plasmin creates an S2 pocket, which is filled by phenylalanine at the P2 position of the reactive-site loop of infestin-4.