Tubulin-Binding Region Modulates Cholesterol-Triggered Aggregation of Tau Proteins.

A hallmark of Alzheimer disease (AD) and tauopathies, severe neurodegenerative diseases, is the progressive aggregation of Tau, also known as microtubule-associated Tau protein. Full-length Tau, also known as 2N4R, contains two N-terminal inserts that bind to tubulin. This facilitates the self-assembly of tubulin simultaneously enhancing stability of cell microtubules.

Design and in vitro anticancer assessment of a click chemistry-derived dinuclear copper artificial metallo-nuclease.

Copper compounds with artificial metallo-nuclease (AMN) activity are mechanistically unique compared to established metallodrugs. Here, we describe the development of a new dinuclear copper AMN, Cu2-BPL-C6 (BPL-C6 = bis-1,10-phenanthroline-carbon-6), prepared using click chemistry that demonstrates site-specific DNA recognition with low micromolar cleavage activity. The BPL-C6 ligand was designed to force two redox-active copper centres-central for enhancing AMN activity-to bind DNA, via two phenanthroline ligands separated by an aliphatic linker.

FlbB forms a distinctive ring essential for periplasmic flagellar assembly and motility in Borrelia burgdorferi.

Spirochetes are a widespread group of bacteria with a distinct morphology. Some spirochetes are important human pathogens that utilize periplasmic flagella to achieve motility and host infection. The motors that drive the rotation of periplasmic flagella have a unique spirochete-specific feature, termed the collar, crucial for the flat-wave morphology and motility of the Lyme disease spirochete Borrelia burgdorferi.

Evolutionary Dynamics of RuBisCO: Emergence of the Small Subunit and its Impact Through Time.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is an ancient protein critical for CO2-fixation and global biogeochemistry. Form-I RuBisCO complexes uniquely harbor small subunits that form a hexadecameric complex together with their large subunits. The small subunit protein is thought to have significantly contributed to RuBisCO's response to the atmospheric rise of O2 ∼2.

Bioinformatics analysis of myelin-microbe interactions suggests multiple types of molecular mimicry in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a devastating autoimmune disease that leads to the destruction of the myelin sheath in the human central nervous system (CNS). Infection by viruses and bacteria has been found to be strongly associated with the onset of MS or its severity. We postulated that the immune system's attack on the myelin sheath could be triggered by viruses and bacteria antigens that resemble myelin sheath components.

AlkaPhos: a novel fluorescent probe as a potential point-of-care diagnostic tool to estimate recurrence risk of meningiomas.

Deletion of the short arm of chromosome 1 (1p) increases recurrence rates in meningiomas by up to 33%, regardless of tumor grade, correlating with absence of intracellular alkaline phosphatase enzyme activity. Current screening methods for 1p deletion like fluorescence in situ hybridization (FISH) and loss of heterozygosity (LOH) analysis are resource-intensive. This study evaluated AlkaPhos, a novel fluorescent probe, for detecting alkaline phosphatase in meningioma cells and compared findings with FISH, LOH, and histochemical analysis.

Structural insights into the activation mechanism of the human zinc-activated channel.

The zinc-activated channel (ZAC) is an atypical mammalian cys-loop receptor (CLR) that is activated by zinc ions and protons, allowing cations to pass through. The molecular mechanism that ligands use to activate ZAC remains elusive. Here, we present three cryo-electron microscopy reconstructions of human ZAC (hZAC) under different conditions.

Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer's disease in two independent study cohorts.

A major challenge in the development of more effective therapeutic strategies for Alzheimer's disease (AD) is the identification of molecular mechanisms linked to specific pathophysiological features of the disease. Importantly AD has a two-fold higher incidence in women than men and a protracted prodromal phase characterized by amnestic mild-cognitive impairment (aMCI) suggesting that biological processes occurring early can initiate vulnerability to AD. Here, we used a sample of 125 subjects from two independent study cohorts to determine the levels in plasma (the most accessible specimen) of two essential mitochondrial markers acetyl-L-carnitine (LAC) and its derivative free-carnitine motivated by a mechanistic model in rodents in which targeting mitochondrial metabolism of LAC leads to the amelioration of cognitive function and boosts epigenetic mechanisms of gene expression.

Sphingosine kinase 2 (SphK2) depletion alters redox metabolism and enhances inflammation in a diet-induced MASH mouse model.

Background: Sphingosine-1 phosphate (S1P) is a bioactive lipid molecule that modulates inflammation and hepatic lipid metabolism in MASLD, which affects 1 in 3 people and increases the risk of liver fibrosis and hepatic cancer. S1P can be generated by 2 isoforms of sphingosine kinase (SphK). SphK1 is well-studied in metabolic diseases.

Yerba mate () genome provides new insights into convergent evolution of caffeine biosynthesis.

Yerba mate (YM, ) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here, we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes.

Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels.

Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed to be functionally relevant across mechanosensory organs and vertebrate species. Here, we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line.

Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (M or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 M. TRMT1 installs the ,-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis.

Epistatic hotspots organize antibody fitness landscape and boost evolvability.

The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence-function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype.

Stage-specific modulation of gene expression with muscle GAL4 promoters.

The bipartite GAL4/UAS system is the most widely used method for targeted gene expression in and facilitates rapid genetic experimentation. Defining precise gene expression patterns for tissues and/or cell types under GAL4 control will continue to evolve to suit experimental needs. However, the precise spatial and temporal expression patterns for some commonly used muscle tissue promoters are still unclear.

Toxic Effects of Butanol in the Plane of the Cell Membrane.

Solvent toxicity limits -butanol fermentation titer, increasing the cost and energy consumption for subsequent separation processes and making biobased production more expensive and energy-intensive than petrochemical approaches. Amphiphilic solvents such as -butanol partition into the cell membrane of fermenting microorganisms, thinning the transverse structure, and eventually causing a loss of membrane potential and cell death. In this work, we demonstrate the deleterious effects of -butanol partitioning upon the lateral dimension of the membrane structure, called membrane domains or lipid rafts.

Raubasine-Induced Groove Binding in Salmon Testes DNA: Exploring the Structural Modulation, Antiglycation, and Antioxidant Properties.

As one of nature's most fundamental blueprints and due to its critical role in life processes, DNA has naturally become the cornerstone of numerous research efforts. One particularly intriguing area of study is understanding how small molecules interact with nucleic acids. In this study, we investigated the interaction between the plant-derived indole alkaloid Raubasine (Ajmalicine; AJM) and Salmon Testes (ST) DNA using biophysical and computational techniques.

Adaptive sampling-based structural prediction reveals opening of a GABA receptor through the αβ interface.

γ-Aminobutyric acid type A (GABA) receptors are ligand-gated ion channels in the central nervous system with largely inhibitory function. Despite being a target for drugs including general anesthetics and benzodiazepines, experimental structures have yet to capture an open state of classical synaptic α1β2γ2 GABA receptors. Here, we use a goal-oriented adaptive sampling strategy in molecular dynamics simulations followed by Markov state modeling to capture an energetically stable putative open state of the receptor.

X-Chromosome-Linked miRNAs Regulate Sex Differences in Cardiac Physiology.

Background: Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states.

Methods: We identified microRNA (miRNAs/miR) with sex-differential expression in mouse hearts.

Results: Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males.

Understanding the Interaction of Röntgen Radiation Employed in Computed Tomography/Cone Beam Computed Tomography Investigations of the Oral Cavity by Means of Surface-Enhanced Raman Spectroscopy Analysis of Saliva.

The use of Raman spectroscopy, particularly surface-enhanced Raman spectroscopy (SERS), offers a powerful tool for analyzing biochemical changes in biofluids. This study aims to assess the modifications occurring in saliva collected from patients before and after exposure to cone beam computed tomography (CBCT) and computed tomography (CT) imaging. SERS analysis revealed significantly amplified spectra in post-imaging samples compared to pre-imaging samples, with pronounced intensification of thiocyanate and opiorphin bands, which, together with proteins, dominated the spectra.

Pulsed Electric Field Pretreatment Enhances the Enzyme Hydrolysis of Baker's Yeast.

Baker's yeast is a key starting material for producing extracts with diverse compositions and applications. This study investigates the effect of pulsed electric field (PEF) pretreatment, which induces irreversible electropermeabilization, on the enzymatic hydrolysis of yeast. Cell suspensions were exposed to monopolar rectangular pulses in a continuous flow system followed by 4 h of incubation with Alcalase at concentrations of 0.

5-Substituted Flavones-Another Class of Potent Triplex DNA-Specific Ligands as Antigene Enhancers.

In the field of drug development, the quest for novel compounds that bind to DNA with high affinity and specificity never ends. In the present work, we report the newest development in this field, namely, triplex DNA-specific binding ligands based on the 5-substituted flavone scaffold in our lab. Biophysical studies showed that the newly synthesized flavone derivatives (depending on the side chains) bind to triplex DNA with binding affinities better than or similar to 5-substituted 3,3',4',7-tetramethoxyflavonoids.

In Vitro Anticancer Effects of Aqueous Leaf Extract from L. ssp. .

Despite significant efforts, cancer remains the second leading cause of mortality worldwide. The medicinal plant L. represents a valuable source of biologically active compounds with pharmacological activities including antioxidant, anti-inflammatory, antimicrobial, and antiviral.

The Biomechanics of Fibrillin Microfibrils: Lessons from the Ciliary Zonule.

Marfan syndrome is an inherited connective tissue disorder that affects the cardiovascular, musculoskeletal, and ocular systems. It is caused by pathogenic variants in the fibrillin-1 gene (). Fibrillin is a primary component of microfibrils, which are found throughout the extracellular matrix (ECM) and provide elasticity and resilience to connective tissue.

α-Synuclein Deletion Impairs Platelet Function: A Role for SNARE Complex Assembly.

Granule secretion is an essential platelet function that contributes not only to haemostasis but also to wound healing, inflammation, and atherosclerosis. Granule secretion from platelets is facilitated, at least in part, by Soluble N-ethylmaleimide-Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) complex-mediated granule fusion. Although α-synuclein is a protein known to modulate the assembly of the SNARE complex in other cells, its role in platelet function remains poorly understood.