Comprehensive profiling of the catalytic conformations of human Guanylate kinase.

Human guanylate kinase (GMPK) as the sole enzyme for GDP biosynthesis plays pivotal roles in antiviral prodrug activation and tumorigenesis. Despite its biological significance, the catalytic mechanism remains poorly understood. Here, we resolve crystal structures of GMPK in free and GMP-bound form, revealing the interdomain motions of GMPBD and LID relative to the CORE domain.

Structural insights into ZBTB20 action at the AFP promoter.

ZBTB20, a C2H2 zinc finger and broad-complex, tramtrack and bric-à-brac (BTB) domain-containing protein, is crucial for organ development and metabolic homeostasis. Its functionality is dependent on its DNA-binding zinc fingers, and heterozygous mutations within these regions are linked to Primrose syndrome, which is characterized by various physical and developmental abnormalities. However, the molecular basis underlying ZBTB20 zinc finger recognition of DNA remains largely unknown.

Enhanced Optoelectronic Response of TiO Photodetector Sensitized via CuInSe Quantum Dots.

Colloidal copper-based chalcogenide quantum dots (QDs), particularly lead-free CuInSe systems, have emerged as promising photosensitizers for optoelectronic de-vices due to their high extinction coefficients and solution processability. In this work, we demonstrate a TiO photodetector enhanced through interfacial engineering with the size of 9.88 ± 2.

Human tripartite motif-containing protein 71 NCL-1/HT2A/LIN-41 domain crystal structure and its potential natural inhibitors.

TRIM71 NHL Domain is a critical driver of various cellular process and is dysregulated in several medical conditions like non-small cell lung cancer, hepatocellular carcinoma and congenital hydrocephalus. However, its pathways and binding with CDKN1A has not been well studied. To investigate its interaction with CDKN1A, we expressed TRIM71 NHL domain in SF9 (Spodoptera frugiperda) insect cells using the pFastBacTM HT B plasmid, was purified by size exclusion chromatography and its crystal structure was determined successfully (PDB ID: 9JUR).

Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies.

Cancer remains the leading cause of mortality worldwide, and the emergence of drug resistance has made the identification of new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct of glycolysis with limited ATP-producing capacity, has recently gained recognition as a critical signaling molecule. It plays a key role not only in cancer cell metabolism but also in shaping the tumor microenvironment (TME).

NSUN6 inhibitor discovery guided by its mRNA substrate bound crystal structure.

NSUN6 preferentially catalyzes the methylation of cytosine nucleotides in mRNA substrates, which enhances transcription. Dysregulation of NSUN6 catalysis drives the oncogenesis of certain cancers. In this study, we determined the crystal structure of human NSUN6 in complex with its S-adenosyl-L-methionine analog and a bound NECT-2 3'-UTR RNA substrate at 2.

Early weaning damages the intestinal epithelial barrier of squabs through toll-like receptor signaling pathways.

Stress damage caused by early weaning and its possible mechanism have been studied mainly in young mammals, but rarely in altrices, especially in squabs. The study aimed to investigate the possible molecular mechanism of intestinal epithelial barrier damage caused by early weaning in squabs through determining the intestinal permeability, the ultrastructure of villous epithelium, the contents of ileal cytokines, and the protein relative expression of tight-junction proteins, TLRs and their mediated key factors in inflammatory signaling pathways. A total of 192 newly hatched squabs were randomly divided into 2 groups, 1 group was weaned and fed artificial pigeon milk from d 7, and the other group continued to be fed by the parent pigeons.

Nonlinear Optical Response of Au/CsPbI Quantum Dots and Its Laser Modulation Characteristics at 2.7 μm.

A passively Q-switched Er:YAP laser of 2.7 µm, utilizing Au-doped CsPbI quantum dots (QDs) as a saturable absorber (SA), was realized. It was operated stably with a minimum pulse width of 185 ns and a maximum repetition rate of 480 kHz.

Structural basis for TNIP1 binding to FIP200 during mitophagy.

TNIP1 has been increasingly recognized as a security check to finely adjust the rate of mitophagy by disrupting the recycling of the Unc-51-like kinase complex during autophagosome formation. Through tank-binding kinase 1-mediated phosphorylation of the TNIP1 FIP200 interacting region (FIR) motif, the binding affinity of TNIP1 for FIP200, a component of the Unc-51-like kinase complex, is enhanced, allowing TNIP1 to outcompete autophagy receptors. Consequently, FIP200 is released from the autophagosome, facilitating further autophagosome expansion.

Causal relationships between modifiable risk factors and polycystic ovary syndrome: a comprehensive Mendelian randomization study.

Background: Polycystic Ovary Syndrome (PCOS) is a heritable condition with an as yet unclear etiology. Various factors, such as genetics, lifestyle, environment, inflammation, insulin resistance, hyperandrogenism, iron metabolism, and gut microbiota, have been proposed as potential contributors to PCOS. Nevertheless, a systematic assessment of modifiable risk factors and their causal effects on PCOS is lacking.

Structural basis of pri-let-7 recognition by human pseudouridine synthase TruB1.

Let-7 was one of the first microRNAs (miRNAs) to be discovered and its expression promotes differentiation during development and function as tumor suppressors in various cancers. The maturation process of let-7 miRNA is tightly regulated by multiple RNA-binding proteins. For example, LIN28 binds to the terminal loops of the precursors of let-7 family and block their processing into mature miRNAs.

Structural insights into the recognition of the A/T-rich motif in target gene promoters by the LMX1a homeobox domain.

LIM homeodomain transcription factor 1-alpha (LMX1a) is a neuronal lineage-specific transcription activator that plays an essential role during the development of midbrain dopaminergic (mDA) neurons. LMX1a induces the expression of multiple key genes, which ultimately determine the morphology, physiology, and functional identity of mDA neurons. This function of LMX1a is dependent on its homeobox domain.

Structural insights into the specific recognition of mitochondrial ribosome-binding factor hsRBFA and 12 S rRNA by methyltransferase METTL15.

Mitochondrial rRNA modifications are essential for mitoribosome assembly and its proper function. The mC methyltransferase METTL15 maintains mitochondrial homeostasis by catalyzing mC839 located in 12 S rRNA helix 44 (h44). This modification is essential to fine-tuning the ribosomal decoding center and increasing decoding fidelity according to studies of a conserved site in Escherichia coli.

Imaging the Self-Healing Dynamics of Single-Nanoparticle Electron Transfer Event Regulated by Local Electron Insertion.

The self-healing properties of nanomaterials to resist electron beam damage are of great concern, which is inspiring to improve the stability and electron transfer efficiency of nanoelectronic devices especially in an abnormal environment. However, the influence of electron beam insertion on the electron transfer efficiency of single nanoentities at a heterogeneous electrochemical interface is still in debate, which is a concern for the development of liquid cell transmission electron microscopy of the next generation. Herein, we employ an electro-optical imaging technique and directly visualize the controllable recovery of electron transfer ability for single Prussian blue nanoparticle (PBNP) after electron beam insertion with different electron doses.

Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells.

Melanoma differentiation-associated gene 9 (MDA-9) is a small adaptor protein with tandem PDZ domains that promotes tumor progression and metastasis in various human cancers. However, it is difficult to develop drug-like small molecules with high affinity due to the narrow groove of the PDZ domains of MDA-9. Herein, we identified four novel hits targeting the PDZ1 and PDZ2 domains of MDA-9, namely PI1A, PI1B, PI2A, and PI2B, using a protein-observed nuclear magnetic resonance (NMR) fragment screening method.

Structural insights into the recognition of telomeric variant repeat TTGGGG by broad-complex, tramtrack and bric-à-brac - zinc finger protein ZBTB10.

Multiple proteins bind to telomeric DNA and are important for the role of telomeres in genome stability. A recent study established a broad-complex, tramtrack and bric-à-brac - zinc finger (BTB-ZF) protein, ZBTB10 (zinc finger and BTB domain-containing protein 10), as a telomeric variant repeat-binding protein at telomeres that use an alternative method for lengthening telomeres). ZBTB10 specifically interacts with the double-stranded telomeric variant repeat sequence TTGGGG by employing its tandem C2H2 zinc fingers (ZF1-2).

The recognition mode between hsRBFA and mitoribosome 12S rRNA during mitoribosomal biogenesis.

Eukaryotes contain two sets of genomes: the nuclear genome and the mitochondrial genome. The mitochondrial genome transcripts 13 mRNAs that encode 13 essential proteins for the oxidative phosphorylation complex, 2 rRNAs (12s rRNA and 16s rRNA), and 22 tRNAs. The proper assembly and maturation of the mitochondrial ribosome (mitoribosome) are critical for the translation of the 13 key proteins and the function of the mitochondrion.

Molecular mechanism underlying the di-uridylation activity of Arabidopsis TUTase URT1.

In Arabidopsis, HESO1 and URT1 act cooperatively on unmethylated miRNA and mRNA uridylation to induce their degradation. Their collaboration significantly impacts RNA metabolism in plants. However, the molecular mechanism determining the functional difference and complementarity of these two enzymes remains unclear.

Structural basis for Gemin5 decamer-mediated mRNA binding.

Gemin5 in the Survival Motor Neuron (SMN) complex serves as the RNA-binding protein to deliver small nuclear RNAs (snRNAs) to the small nuclear ribonucleoprotein Sm complex via its N-terminal WD40 domain. Additionally, the C-terminal region plays an important role in regulating RNA translation by directly binding to viral RNAs and cellular mRNAs. Here, we present the three-dimensional structure of the Gemin5 C-terminal region, which adopts a homodecamer architecture comprised of a dimer of pentamers.

Directly Imaging Dynamic Electronic Coupling during Electrochemical Oxidation of Single Silver Nanoparticles.

The electronic coupling between a metal electrode and single nano-entities is of unfading significance which impacts the heterogeneous electron transfer. Herein, we demonstrated a simple optical technique for directly imaging the transient interfacial electronic coupling events during electrochemical oxidation of single Ag nanoparticles on Au electrode. The electronic coupling brings out a dramatic dip behavior of bright field imaging traces, and is conductive to cross the energy barrier of oxidation for single silver nanoparticles.

Analysis of World-Scale Mitochondrial DNA Reveals the Origin and Migration Route of East Asia Goats.

Despite much attention on the history of goat evolution, information on origin, demographic history, and expansion route remains controversial. To address these questions, we collected 4,189 published goat DNA sequences including 1,228 sequences from 57 breeds in China and 2,961 sequences including 193 goat breeds from 71 other countries and carried out an integrated analysis. We found goat breeds from South China had the highest genetic diversity of lineage B, and subclades B2 only were found in Southwest China, suggesting that lineage B (particularly, subclade B2) probably originated from Southwest China and its surrounding areas.

Structural insights reveal the specific recognition of meiRNA by the Mei2 protein.

In the fission yeast Schizosaccharomyces pombe, Mei2, an RNA-binding protein essential for entry into meiosis, regulates meiosis initiation. Mei2 binds to a specific non-coding RNA species, meiRNA, and accumulates at the sme2 gene locus, which encodes meiRNA. Previous research has shown that the Mei2 C-terminal RNA recognition motif (RRM3) physically interacts with the meiRNA 5' region in vitro and stimulates meiosis in vivo.

Determining the depth of surface charging layer of single Prussian blue nanoparticles with pseudocapacitive behaviors.

Understanding the hybrid charge-storage mechanisms of pseudocapacitive nanomaterials holds promising keys to further improve the performance of energy storage devices. Based on the dependence of the light scattering intensity of single Prussian blue nanoparticles (PBNPs) on their oxidation state during sinusoidal potential modulation at varying frequencies, we present an electro-optical microscopic imaging approach to optically acquire the Faradaic electrochemical impedance spectroscopy (oEIS) of single PBNPs. Here we reveal typical pseudocapacitive behavior with hybrid charge-storage mechanisms depending on the modulation frequency.