E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific deletion mouse strain ( ) and found that is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux.

Plasma Bacterial Metabolites in Crohn's Disease Pathogenesis and Complications.

Background/objectives: Crohn's disease is known for being associated with an abnormal composition of the bacterial flora, dysbiosis and intestinal function disorders. Metabolites produced by gut microbiota play a pivotal role in the pathogenesis of CD, and the presence of unspecific extraintestinal manifestations.

Methods: The aim of this study was a determination of the level of bacterial metabolites in blood plasma in patients with Crohn's disease.

A Role of Inflammation in Charcot-Marie-Tooth Disorders-In a Perspective of Treatment?

Despite the fact that there are published case reports and model work providing evidence of inflammation in Charcot-Marie-Tooth disorders (CMTs), in clinical practice, CMT and inflammatory neuropathies are always classified as two separate groups of disorders. This sharp separation of chronic neuropathies into two groups has serious clinical implications. As a consequence, the patients harboring CMT mutations are practically excluded from pharmacological anti-inflammatory treatments.

Metagenomic exploration and computational prediction of novel enzymes for polyethylene terephthalate degradation.

As a global environmental challenge, plastic pollution raises serious ecological and health concerns owing to the excessive accumulation of plastic waste, which disrupts ecosystems, harms wildlife, and threatens human health. Polyethylene terephthalate (PET), one of the most commonly used plastics, has contributed significantly to this growing crisis. This study offers a solution for plastic pollution by identifying novel PET-degrading enzymes.

Correction: Baláž et al. Mechanochemistry as an Alternative Method of Green Synthesis of Silver Nanoparticles with Antibacterial Activity: A Comparative Study. 2021, , 1139.

In the original publication [...

Deacetylated SNAP47 recruits HOPS to facilitate autophagosome-lysosome fusion independent of STX17.

Autophagy, a conserved catabolic process implicated in a diverse array of human diseases, requires efficient fusion between autophagosomes and lysosomes to function effectively. Recently, SNAP47 has been identified as a key component of the dual-purpose SNARE complex mediating autophagosome-lysosome fusion in both bulk and selective autophagy. However, the spatiotemporal regulatory mechanisms of this SNARE complex remain unknown.

The master male sex determinant Gdf6Y of the turquoise killifish arose through allelic neofunctionalization.

Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development.

Highly sensitive and selective detection of SARS-CoV-2 spike protein S1 using optically-active nanocomposite-coated melt-blown masks.

Detection of viruses, including coronavirus (SARS-CoV-2), via facile, fast, and optical methods is highly important to control pandemics. In this regard, optically-active nanomaterials and nanoparticles (NPs) are a wise choice due to their long-term stability, ease of functionalization, and modifications. In this work, a nanocomposite based on NiFe layered double hydroxide (LDH) and ZIF-67 metal-organic framework (MOF) was designed and synthesized, and decorated on the surface of the melt-blown mask.

High-throughput determination of exchange rates of unmodified and PTM-containing peptides using HX-MS.

Despite the widespread use of MS for hydrogen/deuterium exchange measurements, no systematic, large-scale study has been conducted to compare the observed exchange rates in protein-derived, unstructured peptides measured by MS to the predicted exchange rates calculated from NMR-derived values and how neighboring residues and post-translational modifications influence those exchange rates. In this study, we sought to test the accuracy of predicted values by performing hydrogen exchange measurements on whole cell digests to generate an unbiased dataset of 563 unique peptides derived from naturally-occurring protein sequences. A remarkable 97% of observed exchange rates of peptides are within two-fold of predicted values.

CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading.

Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the selection of immunogenic antigens from a large pool of intracellular peptides. Interactions of chaperoned MHC-I molecules with incoming peptides are transient in nature, and as a result, the precise antigen proofreading mechanism remains elusive.

Decreased expression of hsa-miR-142-3p and hsa-miR-155-5p in common variable immunodeficiency and involvement of their target genes and biological pathways.

Common variable immunodeficiency (CVID) is the most common symptomatic and heterogeneous type of inborn errors of immunity (IEI). However, the pathogenesis process of this disease is often unknown. Epigenetic modifications may be involved in unresolved patients.

25-Hydroxycholesterol modulates synaptic vesicle endocytosis at the mouse neuromuscular junction.

Many synaptic vesicles undergo exocytosis in motor nerve terminals during neuromuscular communication. Endocytosis then recovers the synaptic vesicle pool and presynaptic membrane area. The kinetics of endocytosis may shape neuromuscular transmission, determining its long-term reliability.

H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium.

Plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration.

Satellite DNA shapes dictate pericentromere packaging in female meiosis.

The abundance and sequence of satellite DNA at and around centromeres is evolving rapidly despite the highly conserved and essential process through which the centromere directs chromosome inheritance. The impact of such rapid evolution is unclear. Here we find that sequence-dependent DNA shape dictates packaging of pericentromeric satellites in female meiosis through a conserved DNA-shape-recognizing chromatin architectural protein, high mobility group AT-hook 1 (HMGA1).

AFM observation of protein translocation mediated by one unit of SecYEG-SecA complex.

Protein translocation across cellular membranes is an essential and nano-scale dynamic process. In the bacterial cytoplasmic membrane, the core proteins in this process are a membrane protein complex, SecYEG, corresponding to the eukaryotic Sec61 complex, and a cytoplasmic protein, SecA ATPase. Despite more than three decades of extensive research on Sec proteins, from genetic experiments to cutting-edge single-molecule analyses, no study has visually demonstrated protein translocation.

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.

2-Cyanopyrimidine-Containing Molecules for N-Terminal Selective Cyclization of Phage-Displayed Peptides.

Current methods for the macrocyclization of phage-displayed peptides often rely on small molecule linkers that nonspecifically react with targeted amino acid residues. To expand tool kits for more regioselective macrocyclization of phage-displayed peptides, this study explores the unique condensation reaction between an N-terminal cysteine and nitrile along with the reactivity of an internal cysteine. Five 2-cyanopyrimidine derivatives were synthesized for this purpose and evaluated for their selective macrocyclization of a protein-fused model peptide.

Spectroscopic Properties and Biological Activity of Fluphenazine Conjugates with Gold Nanoparticles.

Fluphenazine (FPZ) is a well-known neuroleptic that has attracted considerable scientific interest due to its biocidal, virucidal, and antitumor properties. Although methods for encapsulating and delivering FPZ to enhance its activity and reduce side effects have been developed, there is still limited knowledge about its conjugates with gold nanoparticles (AuNPs). Therefore, the aim of this research was to develop a preparation method for stable FPZ-AuNP conjugates and to investigate their physicochemical and biological properties.

HROB Is Implicated in DNA Replication.

DNA replication represents a series of precisely regulated events performed by a complex protein machinery that guarantees accurate duplication of the genetic information. Since DNA replication is permanently faced by a variety of exogenous and endogenous stressors, DNA damage response, repair and replication must be closely coordinated to maintain genomic integrity. HROB has been identified recently as a binding partner and activator of the Mcm8/9 helicase involved in DNA interstrand crosslink (ICL) repair.

A Novel Pathogenic Sense Variant in Exon 7 of the HK1 Gene in a Patient with Hexokinase Deficiency and Gilbert Syndrome.

Background: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase deficiency described so far, focusing on the severity of the disease, clinical presentation, treatment applied, and genetic test results.

Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex.

The human mitochondrial proteome comprises approximately 1500 proteins, with only 13 being encoded by mitochondrial DNA. The remainder are encoded by the nuclear genome, translated by cytosolic ribosomes, and subsequently imported into and sorted within mitochondria. The process of mitochondria-destined protein import is mediated by several intricate protein complexes distributed among the four mitochondrial compartments.

Structures of ATP-binding cassette transporter ABCC1 reveal the molecular basis of cyclic dinucleotide cGAMP export.

Cyclic nucleotide GMP-AMP (cGAMP) plays a critical role in mediating the innate immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Recent studies showed that ATP-binding cassette subfamily C member 1 (ABCC1) is a cGAMP exporter. The exported cGAMP can be imported into uninfected cells to stimulate a STING-mediated innate immune response.

Porous Materials for Early Diagnosis of Neurodegenerative Diseases.

Neurodegenerative diseases, particularly Alzheimer's disease and Parkinson's disease, present formidable challenges in modern medicine due to their complex pathologies and the absence of curative treatments. Despite advances in symptomatic management, early diagnosis remains essential for mitigating disease progression and improving patient outcomes. Traditional diagnostic methods, such as MRI, PET, and cerebrospinal fluid biomarker analysis, are often inadequate for the early detection of these diseases.

Fault-Tolerance Study on a Positive-Charged Cleft in 18 rRNA Methyltransferase DIMT1.

Dimethyladenosine transferase 1 (DIMT1) is an RNA -dimethyladenosine (mA) methyltransferase. DIMT1's role in pre-rRNA processing and ribosome biogenesis is critical for cell proliferation. Here, we investigated the minimal number of residues in a positively charged cleft on DIMT1 required for cell proliferation.

Transcription Kinetics in the Coronavirus Life Cycle.

Coronaviruses utilize a positive-sense single-strand RNA, functioning simultaneously as mRNA and the genome. An RNA-dependent RNA polymerase (RdRP) plays a dual role in transcribing genes and replicating the genome, making RdRP a critical target in therapies against coronaviruses. This review explores recent advancements in understanding the coronavirus transcription machinery, discusses it within virus infection context, and incorporates kinetic considerations on RdRP activity.