TAR DNA-binding protein (TDP-43) and Metastasis Associated Lung Adenocarcinoma Transcript (MALAT1) RNA are both abundantly expressed in the human cell nucleus. Increased interaction of TDP-43 and MALAT1, as well as dysregulation of TDP-43 function, was previously identified in brain samples from patients with neurodegenerative disease compared to healthy brain tissues. We hypothesized that TDP-43 function

It has been well established that adenosine plays a key role in the control of inflammation through G protein coupled receptors and recently shown that it can regulate thermogenesis. Here we investigated the specific requirements of the adenosine A2A receptor (A2AR) in mature adipocytes for thermogenic functionality and metabolic homeostasis. We generated fat tissue specific adenosine A2A receptor

Recently, we phenocopied Interleukin (IL-)6 signaling using the dimerized single-chain variable fragment (scFv) derived from the respiratory syncytial virus (RSV) IgG1-antibody Palivizumab (PscFvLHFc) to activate a Palivizumab anti-idiotypic nanobody (AIPVHH)-gp130 receptor fusion protein. Palivizumab was unable to activate STAT3 signaling, so we aimed to create a similar ligand capable of triggering

MicroRNAs are a part of the integral regulatory mechanisms found in eukaryotic cells that help in maintaining cellular homeostasis by modulating the expression of target genes. However, during stress conditions like viral infection, the expression profile of the microRNAs change, thereby directly modulating the expression of viral genes and/or indirectly targeting the virus by regulating the host genes

Melanoma differentiation-associated gene 5 (MDA5) initiates type I interferon (IFN) production by detecting cytosolic viral RNA. Mammalian MDA5 is an IFN-inducible gene and controlled by IFN regulatory factor 1 (IRF1). Teleost MDA5 also induces type I IFN production in response to viruses, yet its regulation remains largely unexplored. This study used the large yellow croaker Larimichthys crocea (Lc)

Selective inhibitors that target cyclin dependent kinases 4 and 6 (CDK4/6i) are FDA approved for treatment of a subset of breast cancers and are being evaluated in numerous clinical trials for other cancers. Despite this advance, a subset of tumors are intrinsically resistant to these drugs and acquired resistance is nearly inevitable. Recent mechanistic evidence suggests that in addition to stalling

The rapid turnover of branched actin networks underlies key in vivo processes such as lamellipodial extension, endocytosis, phagocytosis, and intracellular transport. However, our understanding of the mechanisms used to dissociate, or 'prune', branched filaments has remained limited. Glia maturation factor (GMF) is a cofilin family protein that binds to Arp2/3 complex and catalyzes branch dissociation

Carboplatin resistance in retinoblastoma, an aggressive pediatric intraocular tumor, remains a major clinical challenge in treatment. This study elucidates the role of T-type calcium channels in carboplatin resistance using human retinoblastoma Y79 cells. We generated carboplatin-resistant Y79 (Y79CR) cells and characterized their electrophysiological properties. Patch-clamp recordings revealed a subpopulation

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays a dual role in cancer initiation and progression. Identifying signals that modulate the function of SHP2 can improve current therapeutic approaches for IFN-α/β in HCC. We showed that cAMP-dependent protein kinase A (PKA) suppresses IFN-α/β-induced JAK/STAT signaling by increasing the phosphatase activity of SHP2, promoting the dissociation

Ubiquitination of the proliferating cell nuclear antigen (PCNA) by the budding yeast protein Rad5 have important functions in replication stress responses. Rad5 together with the Ubc13-Mms2 complex attaches Lys63-linked ubiquitin chain to a highly conserved Lys164 residue in PCNA. The reaction requires prior PCNA mono-ubiquitination by the Rad6-Rad18 complex and signals for error-free DNA damage tolerance

Recent success with the use of glucagon-like peptide-1 (GLP-1) receptor analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of patients with diabetes has highlighted the role of the intestine as an endocrine organ. Gut-derived hormones, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, have important roles in the control of energy metabolism and food

Protein arginine methyltransferases (PRMTs) are enzymes that catalyze the methylation of arginine residues in eukaryotic proteins, playing critical roles in modulating diverse cellular processes. The importance of PRMTs in the incidence and progression of a wide range of diseases, particularly cancers, such as breast, liver, lung, colorectal cancer, lymphoma, leukemia, and acute myeloid leukemia (AML)

The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD bound protein that functions as a co-activator of Patatin Like Phospholipase Domain Containing 2 (PNPLA2; also known as Adipose triglyceride lipase, ATGL) the rate-limiting enzyme for TAG hydrolysis

Biomolecular condensates (BMCs) represent a group of organized and programmed systems that participate in gene transcription, chromosome organization, cell division, tumorigenesis, and aging. However, the understanding of BMCs in terms of internal organizations and external regulations remains at an early stage. Recently, novel approaches such as synthetic biology have been used for de novo synthesis

NysL, a cytochrome P450 monooxygenase from the Gram-positive bacterium Streptomyces noursei, catalyzes the C10 hydroxylation of 10-deoxynystain to nystatin A1, a clinically important antifungal. In this study, we present the 2.0 Å resolution crystal structure of NysL bound to nystatin A1. The structure of this complex provides key insights into the structural elements that dictate the regio- and stereo-

Many patients with diabetes use self-measurement devices for blood glucose to understand their blood glucose levels. Most of these devices utilize FAD-dependent glucose dehydrogenase (FAD-GDH) to determine blood glucose levels. For this purpose, FAD-GDHs specifically oxidizing glucose among the sugars present in blood is required. Many FAD-GDHs with high substrate specificity have been reported previously;

Pancreatic islet β-cells express the Cpt1a gene, which encodes the enzyme carnitine palmitoyltransferase 1A (CPT1A), an enzyme that facilitates entry of long chain fatty acids into the mitochondria. Because fatty acids are required for glucose-stimulated insulin secretion, we tested the hypothesis that CPT1A is essential to support islet β-cell function and mass. In this study, we describe genetic

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis, high mortality and limited therapeutic strategy. Autophagy is hyperactivated in PDAC and targeting autophagy are emerging as promising therapeutic strategies. The dysfunction of deubiquitinase USP1 results in tumorigenesis and chemotherapy resistance. However, little is known about how USP1 regulates autophagy and

Tauopathies cover a range of neurodegenerative diseases in which natively unfolded tau protein aggregates and spreads in the brain during disease progression. To gain insights into the mechanism of tau structure and spreading, here, we examined the biochemical and cellular properties of human full-length wild-type and familial mutant tau, ΔK280, with a deletion at lysine 280. Our results showed that

Noncoding small RNAs are essential for modulating bacterial gene expression, especially under carbon and nutrient-limited conditions. In this study, by employing both in silico and molecular hybridization tools, we identified a carbon source responsive small RNA in A. baumannii DS002. Expression of corresponding gene, abcR200, located at the intergenic region of omt (O-methyltransferase) and orf72

Amino acid starvation by the chemotherapy agent asparaginase is a potent activator of the integrated stress response (ISR) in liver and can upregulate autophagy in some cell types. We hypothesized that autophagy related 7 (ATG7), a protein that is essential for autophagy and an ISR target gene, was necessary during exposure to asparaginase to maintain liver health. We knocked down Atg7 systemically

Neurodevelopmental disorders have complex origins that manifest early during embryonic growth and are associated with intricate gene regulation dynamics. A perturbed metabolic environment such as hyperglycemia or dyslipidemia, particularly due to maternal obesity, poses a threat to the optimal development of the embryonic central nervous system. Accumulating evidence suggests that these metabolic irregularities

Miy1 is a highly conserved de-ubiquitinating enzyme in yeast with MINDY1 as its human homolog. Miy1 is known to act on K48-linked polyubiquitin chain, but its biological function is unknown. Miy1 has a putative prenylation site, suggesting it as a membrane-associated protein that may contribute to the regulation of cell signaling. Here, we demonstrate that Miy1 is localized in the plasma membrane and

Lipophagy is a way to degrade lipids; however, the molecular mechanisms are not fully understood. Using the holometabolous lepidopteran insect Helicoverpa armigera, cotton bollworm, as a model, we revealed that the larval fat body undergoes lipophagy during metamorphosis, and lipophagy is essential for metamorphosis. The steroid hormone 20-hydroxyecdysone (20E) induced lipophagy by promoting the expression

Most adhesion GPCRs undergo autoproteolytic cleavage during receptor biosynthesis, resulting in non-covalently bound N- and C-terminal fragments (NTF and CTF) that remain associated during receptor trafficking to the plasma membrane. While substantial evidence supports increased G protein signaling when just the CTF is expressed, there is an ongoing debate about whether NTF removal is required to initiate

FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment

The mTOR (mechanistic target of rapamycin) signaling pathway appears central to the aging process as genetic or pharmacological inhibition of mTOR extends lifespan in most eukaryotes tested. While the regulation of protein synthesis by mTOR has been studied in great detail, its impact on protein misfolding and aggregation during stress and aging is less explored. In this study, we identified the mTOR

Post-translational modification of proteins is a crucial biological reaction that regulates protein functions by altering molecular properties. The specific detection of such modifications in proteins has made significant contributions to molecular biology research and holds potential for future drug development applications. In HIV research, for example, tyrosine sulfation at the N-terminus of C-C

The host-range mutant of rabbitpox virus (RPXV) with a deletion in the gene encoding the serpin serine protease inhibitor 1 (SPI-1) fails to replicate efficiently in restrictive host cells. Depletion of the host cell serine protease FAM111A restores viral replication in these cells, suggesting that SPI-1 targets FAM111A to facilitate infection. However, direct evidence of SPI-1 inhibiting FAM111A has

Coupling interactions between the alpha (α) subunit of the polymerase III core (α-Pol III core) and the tau (τ) subunit of the clamp loader complex (τ-CLC) are vital for efficient and rapid DNA replication in Escherichia coli (E. coli). Specific and targeted mutations in the C-terminal τ-interaction region of the Pol III α-subunit disrupted efficient coupled rolling circle DNA synthesis in vitro and

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. In mammals, there are 16 individual nAChR subunits allowing for numerous possible heteromeric compositions. nAChRs assembled from α7 or α9 subunits will form as homopentamers. In contrast, the structurally related α10 nAChR subunit has historically been thought to require α9 subunits for function. Recently, however

Cervical cancer is the fourth most common malignancy and the fourth leading cause of cancer-related death among women. Advanced stages and resistance to treatment in cervical cancer induce cancer-related deaths. Although epigenetics has been known to plays a vital role in tumor progression and resistance, the function of epigenetic regulators in cervical cancer is an area of investigation. In this

Influenza is a worldwide health problem that causes significant morbidity and mortality among the elderly; therefore, its prevention is important. During influenza virus infection, the cleavage of hemagglutinin (HA) is essential for the virus to enter host cells. Influenza virus-bacteria interactions influence the pathogenicity of infections, and specific bacteria contribute to the severity of the

The translocation of proteins from the cytoplasm to the endoplasmic reticulum occurs via a conserved Sec61 protein channel. Previously, we reported that mutations in histones cause downregulation of a CUP1 copper metallothionein and copper exposure inhibits the activity of Sec61. However, the role of epigenetic dysregulation on the activity of channel is not clear. Identification of cellular factors

Extracellular matrix stiffness is one of the multiple mechanical signals that alters cellular behavior. During studies exploring the effect of matrix rigidity on lung fibroblast survival we discovered that enhanced survival on stiff substrates is dependent on elevated Ras activity, owing to the activation of the GEF, RasGRF1. Mechanistically, we found that the increased Ras activity lead to the activation

Voltage-gated Na+ (Nav) channels are the primary determinants of the action potential in excitable cells. Nav channels rely on a wide and diverse array of intracellular protein-protein interactions (PPIs) to achieve their full function. Glycogen synthase kinase 3 β (GSK3β) has been previously identified as a modulator of Nav1.6-encoded currents and neuronal excitability through PPI formation with Nav1

Protein arginine methyltransferase (PRMT) 5 is an essential arginine methyltransferase responsible for the majority of cellular symmetric dimethyl-arginine (SDMA) marks. PRMT5 uses substrate adaptors such as pICln, RIOK1, and COPR5, to recruit and methylate a wide range of substrates. Although the substrate adaptors play important roles in substrate recognition, how they direct PRMT5 activity towards

Cytochrome P450 (P450) 4A11 is a human P450 family 4 ω-oxidase that selectively catalyzes the hydroxylation of the terminal methyl group of fatty acids. Cytosolic lipids are the substrates for the enzyme but are considered to be primarily bound in cells by liver fatty acid binding protein (FABP1). Lipid binding to recombinant FABP1 with a fluorophore displacement assay showed substantial preference

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors, and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment

Lung cancer is the malignant tumor with the highest morbidity and mortality rate worldwide, of which non-small cell lung cancer (NSCLC) accounts for approximately 85%. KRAS mutations are one of the significant mechanisms underlying the occurrence, development, immune escape, and chemotherapy resistance of NSCLC. Two KRAS inhibitors are approved by FDA for the treatment of NSCLC in the past three years

Bladder cancer (BCa) is a common and lethal disease characterized by high recurrence rates and limited treatment options. Understanding the molecular pathways of BCa progress is crucial for investigating more effective targeted therapies. While ADAMTS12 is known to contribute to cancer progression and treatment resistance, its prognostic significance and underlying mechanisms in BCa remain poorly understood

Bacteria frequently employ carbohydrate-binding proteins, so-called lectins, to colonize and persist in a host. Thus, bacterial lectins are attractive targets for the development of new anti-infectives. To find new potential targets for anti-infectives against pathogenic bacteria, we searched for homologs of Pseudomonas aeruginosa lectins and identified homologs of LecA in Enterobacter species. Here

Abnormalities in the expression of the ubiquitin ligase UBE3A (ubiquitin-protein ligase E3A)/E6AP (human papillomavirus E6-associated protein) are implicated in neurological disorders including Angelman syndrome and autism. Human UBE3A is expressed as three protein isoforms that differ in their abundance and subcellular localization. While previous studies indicate isoform-specific functions, the distinct

Paralogs of the bifunctional nuclease, Ribonuclease J (RNase J), demonstrate varied catalytic efficiencies despite extensive sequence and structural similarity. Of the two Staphylococcus aureus RNase J paralogues, RNase J1 is substantially more active than RNase J2. Mutational analysis of active site residues revealed that only H80 and E166 were critical for nuclease activity. Electronic properties

Genetic studies in Escherichia coli have implicated the unphosphorylated version of PtsN (unphospho-PtsN), the terminal phospho-acceptor of the PtsP-PtsO-PtsN phosphorelay, as a negative regulator of potassium (K+) efflux mediated by YcgO. YcgO is a protein belonging to the CPA1 family of monovalent cation/proton antiporters. Here we show that in vivo, YcgO comprises an approximately 383 amino acid

Hepatocellular carcinoma (HCC) is one of the common malignant tumors. Complement system has become a new focus of cancer research by changing the biological behavior of cancer cells to influence the growth of cancer. Recent studies reported that the complement C5a–C5aR1 axis can promote the malignant phenotype of multiple tumors through various signaling pathways. LukS-PV (Panton–Valentine), the S

We developed a versatile ‘IHC/LCM-Seq’ method for spatial transcriptomics of immunohistochemically detected neurons collected with laser-capture microdissection (LCM). IHC/LCM-Seq uses aluminon and polyvinyl sulfonic acid for inventive RNA-preserving strategies to maintain RNA integrity in free-floating sections of 4% formaldehyde-fixed brains. To validate IHC/LCM-Seq, we first immunostained and harvested

Phosphatase and Tensin Homolog (PTEN) is one of the most frequently lost tumor suppressors in cancer and the predominant negative regulator of the PI3K–AKT signaling axis. A growing body of evidence has highlighted the loss of PTEN with immuno-modulatory functions including the upregulation of the programmed death ligand-1 (PD-L1), an altered tumor-derived secretome that drives an immunosuppressive

Spatial organization of chromatin is essential for cellular functioning. However, the precise mechanisms governing sequence-dependent positioning of nucleosomes on DNA remain unknown in detail. Existing algorithms, considering the sequence-dependent deformability of DNA and its interactions with the histone globular domains, predict rotational setting of only 65% of human nucleosomes mapped in vivo

Mirror-image nucleosides, as potential antiviral drugs, can inhibit virus DNA polymerase to prevent virus replication. Conversely, they may be inserted into the DNA strands during DNA replication or transcription processes, leading to mutations that affect genome stability. Accumulation of significant mutation damage in cells may result in cell aging, apoptosis, and even uncontrolled cell division

Ischemia and hypoxia caused by vascular injury intensify nerve damage. Skin precursor-derived Schwann cells have demonstrated an accelerated in vivo prevascularization of tissue-engineered nerves. Furthermore, extracellular vesicles from skin precursor-derived Schwann cells (SKP-SC-EVs) show the potential in aiding peripheral nerve regeneration. Nonetheless, the capacity of SKP-SC-EVs to facilitate

Endocytosis is a prominent mechanism for SARS-CoV-2 entry into host cells. Upon internalization into early endosomes (EEs), the virus is transported to late endosomes (LEs), where acidic conditions facilitate spike protein processing and viral genome release. Dynein and kinesin motors drive EE transport along microtubules; dynein moves EEs to the perinuclear region, while kinesins direct them towards

The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic sulfate transporter and anti-sigma (STAS) domain and the R domain of cystic fibrosis (CF) transmembrane regulator. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in nonmammals

Familial Alzheimer’s disease (FAD) is frequently associated with mutations in the amyloid precursor protein (APP), which are thought to lead to cognitive deficits by impairing NMDA receptor (NMDAR)-dependent forms of synaptic plasticity. Given the reliance of synaptic plasticity on NMDAR-mediated Ca2+ entry, shaping of NMDAR activity by APP and/or its disease-causing variants could provide a basis

The citrus scent arises from the volatile monoterpene limonene, whose cyclic nature can be viewed as a miniaturized form of the polycyclic sterol triterpenoids. In particular, these rings are all formed from poly-isoprenyl precursors via carbocation cascades. However, the relevant reactions are initiated by distinct mechanisms, either lysis/ionization of an allylic diphosphate ester bond, as in limonene

Alpha-1-antitrypsin (AAT), a circulating serine protease inhibitor, is an acute inflammatory response protein with anti-inflammatory functions. The C-terminal peptides of AAT are found in various tissues and have been proposed as putative bioactive peptides with multiple functions, but its mechanism of action remains unclear. We previously reported that a mouse AAT C-terminal peptide of 35 amino acids

Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) are pluripotent stem cells derived from preimplantation and postimplantation embryos, respectively. These cells are capable of interconversion through manipulation of key transcription factors and signaling pathways. While BRG1/BRM-associated factor (BAF) chromatin remodeling complexes are known to play crucial roles in ESC self-renewal

The remyelination process within the diabetes mellitus (DM) brain is inhibited, and dynamic interactions between DNA methylation and transcription factors are critical for this process. Repressor element-1 silencing transcription factor (REST) is a major regulator of oligodendrocyte differentiation, and the role of REST on DM remyelination remains to be investigated. Here, we investigated the effects