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Domains rich in alternating arginine and serine residues (RS domains) are frequently found in metazoan proteins involved in pre-mRNA splicing. The RS domains of splicing factors associate with each other and are important for the formation of protein-protein interactions required for both constitutive and regulated splicing. The prevalence of the RS domain in splicing factors suggests that it might serve as a useful signature for the identification of new proteins that function in pre-mRNA processing, although it remains to be determined whether RS domains also participate in other cellular functions. Using database search and sequence clustering methods, we have identified and categorized RS domain proteins encoded within the entire genomes of Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae. This genome-wide survey revealed a surprising complexity of RS domain proteins in metazoans with functions associated with chromatin structure, transcription by RNA polymerase II, cell cycle, and cell structure, as well as pre-mRNA processing. Also identified were RS domain proteins in S. cerevisiae with functions associated with cell structure, osmotic regulation, and cell cycle progression. The results thus demonstrate an effective strategy for the genomic mining of RS domain proteins. The identification of many new proteins using this strategy has provided a database of factors that are candidates for forming RS domain-mediated interactions associated with different steps in pre-mRNA processing, in addition to other cellular functions.

The Internet, especially the World Wide Web has transformed how today's researchers communicate, share information, and analyze their data. Unfortunately, the vast number of online databases, information resources and analytical tools, some of them masked by unfamiliar titles and Internet addresses, has hindered their universal and effective use by the research community. To overcome these hurdles, subject- and function-specific compendiums are now available which organize information and online tolls in a manner familiar to the biological researcher. The Protein Kinase Resource and the CMS Molecular Biology Resource are two excellent examples of web compendia.

Summary: Subclass III sucrose nonfermenting1‐related protein kinase 2s (SnRK2s) are positive regulators of abscisic acid (ABA) signaling and abiotic stress responses. However, the underlying activation mechanisms of osmotic stress/ABA‐activated protein kinase 8/9/10 (SAPK8/9/10) of rice (Oryza sativa) subclass III SnRK2s in ABA signaling remain to be elucidated.In this study, we employed biochemical, molecular biology, cell biology, and genetic approaches to identify the molecular mechanism by which OsPP47, a type one protein phosphatase in rice, regulates SAPK8/9/10 activity in ABA signaling.We found that OsPP47 not only physically interacted with SAPK8/9/10 but also interacted with ABA receptors PYLs. OsPP47 negatively regulated ABA sensitivity in seed germination and root growth. In the absence of ABA, OsPP47 directly inactivated SAPK8/9/10 by dephosphorylation. In the presence of ABA, ABA‐bound OsPYL2 formed complexes with OsPP47 and inhibited its phosphatase activity, partially releasing the inhibition of SAPK8/9/10. SAPK8/9/10‐mediated H2O2 production inhibited OsPP47 activity by oxidizing Cys‐116 and Cys‐256 to form OsPP47 oligomers, resulting in not only preventing the OsPP47‐SAPK8/9/10 interaction but also blocking the inhibition of SAPK8/9/10 activity by OsPP47.Our results reveal novel pathways for the inhibition of SAPK8/9/10 in the basal state and for the activation of SAPK8/9/10 induced by ABA in rice. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer stem cells (BCSCs) are a small population of cells in breast cancer tumors, playing a putative role in the cancer's progression. BCSC biomarkers are associated with cells' enhanced growth, adhesion, migration, and invasion potential and are responsible for poor outcomes. Due to the vast heterogeneity of breast cancer signaling pathways and associated therapeutic targets, treatment strategies vary and depend on the molecular subtype of BC. Nevertheless, drugs affecting the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways have been effectively applied in BCSC elimination strategies. The complexity of the characteristics of each molecular subtype of breast cancer, with an emphasis on the involvement of breast cancer stem cells in the development, metastasis, and recurrence of the tumor, requires greater understanding. Continuous updating of knowledge and the development of new therapies will allow the effective elimination of cancer cells and the rapid recovery of patients. Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, all breast cancers are organized in a hierarchy of heterogeneous cell populations, with a small proportion of cancer stem cells (breast cancer stem cells (BCSCs)) playing a putative role in cancer progression, and they are responsible for therapeutic failure. In different molecular subtypes of breast cancer, they present different characteristics, with specific marker profiles, prognoses, and treatments. Recent efforts have focused on tackling the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways. Developing diagnostics and therapeutic strategies enables more efficient elimination of the tumor mass together with the stem cell population. Thus, the knowledge about appropriate therapeutic methods targeting both "normal" breast cancer cells and breast cancer stem cell subpopulations is crucial for success in cancer elimination. [ABSTRACT FROM AUTHOR]

Introduction: Phosphorylation reactions highlight the essential role of protein kinases in sperm motility. TSSK6 protein is thought to play a crucial role in this process. Indeed, sperm obtained from mice with the Tssk6-/-genotype are unable to carry out fertilization and exhibit decreased motility. This leads us to investigate the causes of asthenozoospermia by searching for polymorphisms in the TSSK6 gene. Therefore, the objective of this study is to identify polymorphisms in the TSSK6 gene in men affected by asthenozoospermia. Material & Methods: The methodology involved direct sequencing of spermatozoa DNA. Thirty ejaculates were analyzed, including 20 from asthenozoospermic men and 10 from normozoospermic men. Spermograms were performed according to WHO procedures. DNA extraction was carried out using the phenol/chloroform method followed by conventional PCR. The amplicons were sequenced using the Sanger method, and the sequences were analyzed with BioEdit software. The data were analyzed using Fisher and Mann-Whitney tests. Results: The results revealed mutations in the TSSK6 gene in both normospermic and asthenozoospermic ejaculates. The synonymous mutations c.690T>C (p.Tyr230Tyr) and c.372C>A (p.Arg124Arg) were the most frequent, occurring at rates of 50% and 33.33%, respectively. Analysis of the mutations using PolyPhen-2 indicated that all mutations observed in normozoospermic samples are benign and would not affect sperm quality. However, only the mutations described in asthenozoospermic samples are predicted to be damaging to the protein. Conclusion: In conclusion, mutations in the TSSK6 gene were observed in infertile men. Deleterious mutations in the TSSK6 protein are associated with asthenozoospermia. [ABSTRACT FROM AUTHOR]

Introduction: Human T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection. Material and Methods: The study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3β), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software. Results: While there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3β, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs. Conclusion: HTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries. [ABSTRACT FROM AUTHOR]

Background: Paediatric low-grade gliomas (pLGGs) are the most common primary brain tumour in children. Though considered benign, slow-growing lesions with excellent overall survival, their long-term morbidity can be significant, both from the tumour and secondary to treatment. Vast progress has been made in recent years to better understand the molecular biology underlying pLGGs, with promising implications for new targeted therapeutic strategies. Summary: A multi-layered classification system of biologic subgroups, integrating distinct molecular and histological features has evolved to further our clinical understanding of these heterogeneous tumours. Though surgery and chemotherapy are the mainstays of treatment for pLGGs, many tumours are not amenable to surgery and/or progress after conventional chemotherapy. Therapies targeting common genetic aberrations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway have been the focus of many recent studies and offer new therapeutic possibilities. Here, we summarise the updated molecular classification of pLGGs and provide a review of current treatment strategies, novel agents, and open trials. Key Messages: (1) There is a need for treatment strategies in pLGG that provide lasting tumour control and better quality of survival through minimising toxicity and protecting against neurological, cognitive, and endocrine deficits. (2) The latest World Health Organisation classification of pLGG incorporates a growing wealth of molecular genetic information by grouping tumours into more biologically and molecularly defined entities that may enable better risk stratification of patients, and consideration for targeted therapies in the future. (3) Novel agents and molecular-targeted therapies offer new therapeutic possibilities in pLGG and have been the subject of many recent and currently open clinical studies. (4) Adequate molecular characterisation of pLGG is therefore imperative in today's clinical trials, and treatment responses should not only be evaluated radiologically but also using neurological, visual, and quality of life outcomes to truly understand treatment benefits. [ABSTRACT FROM AUTHOR]

Background and objective The biological and molecular characteristics of spread through air spaces (STAS), a newly recognized invasive mode of lung cancer, remain controversial. The aim of this study was to investigate the clinicopathological features and molecular characteristics of STAS in patients with pulmonary adenocar-cinoma. Methods A total of 694 resected invasive non-mucinous lung adenocarcinomas diagnosed by clinicopathology from July 2019 to March 2021 in the First Affiliated Hospital of Guangzhou Medical University were collected, and the relationship between STAS and clinicopathological factors was analyzed. The state of protein expression of anaplastic lymphoma kinase (ALK) was detected by immunohistochemical method. Epidermal growth factor receptor (EGFR) was detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). ROS proto-onco-gene 1-receptor (ROS1) was detected by reverse transcription-PCR (RT-PCR). Results A total of 344 STAS positive cases and 350 STAS negative cases were collected. By univariate analysis, STAS positivity was statistically associated with tumor maximum diameter (P<0.001), pleural invasion (P<0.001), lymphovascular invasion (P<0.001), nerve invasion (P=0.013), lymph node metastasis (P<0.001), clinical stage (P<0.001) and histological type (P<0.001). There was a statistical correlation between STAS and ALK protein expression (P=0.001). Multivariate analysis showed that STAS positive was correlated with pleural invasion (P=0.001), vascular invasion (P<0.001), lymph node metastasis (P=0.005)and ALK protein expression (P=0.032). Conclusion STAS is associated with highly aggressive biological behavior of lung adenocarcinoma, suggesting a poor prognosis. [ABSTRACT FROM AUTHOR]

Microtubule-Associated Serine/Threonine (MAST) kinases represent an evolutionary conserved branch of the AGC protein kinase superfamily in the kinome. Since the discovery of the founding member, MAST2, in 1993, three additional family members have been identified in mammals and found to be broadly expressed across various tissues, including the brain, heart, lung, liver, intestine and kidney. The study of MAST kinases is highly relevant for unraveling the molecular basis of a wide range of different human diseases, including breast and liver cancer, myeloma, inflammatory bowel disease, cystic fibrosis and various neuronal disorders. Despite several reports on potential substrates and binding partners of MAST kinases, the molecular mechanisms that would explain their involvement in human diseases remain rather obscure. This review will summarize data on the structure, biochemistry and cell and molecular biology of MAST kinases in the context of biomedical research as well as organismal model systems in order to provide a current profile of this field. [ABSTRACT FROM AUTHOR]

This document discusses the emerging roles of ADP-dependent glucokinase (ADPGK) in prostate cancer (PCa). The standard clinical practice for treating advanced PCa is androgen deprivation therapy, but there is a need for novel therapeutic targets to improve treatment efficacy and patient survival. Glucose metabolism, particularly the Warburg effect, plays a key role in tumor progression. The study by Xu et al. identifies ADPGK as a crucial participant in PCa, with its upregulation correlating with adverse prognosis. ADPGK regulates PCa metabolic adaptability by interacting with aldolase C and activating AMP-activated protein kinase (AMPK) signaling. Targeting ADPGK shows potential for future drug development and clinical trials. ADPGK also promotes PCa cell migration and metastasis, making it a significant risk factor and promoter for PCa. The study provides unique perspectives on the involvement of ADPGK in PCa and may facilitate the development of innovative therapeutic approaches. ADPGK has also been reported to play essential roles in the regulation of immune cell activity, which could impact the comprehensive management of PCa. The complex of ADPGK and aldolase C promotes the phosphorylation of AMPK, suggesting a noncanonical kinase function of ADPGK. Overall, this research contributes to our understanding of PCa tumorigenesis and development and provides promising therapeutic targets for future treatment. [Extracted from the article]

Background: Trace amines, such as tyramine, are endogenous amino acid metabolites that have been hypothesized to promote headache. However, the underlying cellular and molecular mechanisms remain unknown. Methods: Using patch-clamp recording, immunostaining, molecular biological approaches and behaviour tests, we elucidated a critically functional role of tyramine in regulating membrane excitability and pain sensitivity by manipulating Kv1.4 channels in trigeminal ganglion (TG) neurons. Results: Application of tyramine to TG neurons decreased the A-type K+ current (IA) in a manner dependent on trace amine-associated receptor 1 (TAAR1). Either siRNA knockdown of Gαo or chemical inhibition of βγ subunit (Gβγ) signaling abrogated the response to tyramine. Antagonism of protein kinase C (PKC) prevented the tyramine-induced IA response, while inhibition of conventional PKC isoforms or protein kinase A elicited no such effect. Tyramine increased the membrane abundance of PKCθ in TG neurons, and either pharmacological or genetic inhibition of PKCθ blocked the TAAR1-mediated IA decrease. Furthermore, PKCθ-dependent IA suppression was mediated by Kv1.4 channels. Knockdown of Kv1.4 abrogated the TAAR1-induced IA decrease, neuronal hyperexcitability, and pain hypersensitivity. In a mouse model of migraine induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus, blockade of TAAR1 signaling attenuated mechanical allodynia; this effect was occluded by lentiviral overexpression of Kv1.4 in TG neurons. Conclusion: These results suggest that tyramine induces Kv1.4-mediated IA suppression through stimulation of TAAR1 coupled to the Gβγ-dependent PKCθ signaling cascade, thereby enhancing TG neuronal excitability and mechanical pain sensitivity. Insight into TAAR1 signaling in sensory neurons provides attractive targets for the treatment of headache disorders such as migraine. [ABSTRACT FROM AUTHOR]

Being one of the most extensively researched and widely used thermostable DNA polymerases, Taq DNA polymerase derived from Thermus aquaticus has played pivotal roles in numerous molecular biology applications. The accurate and convenient determination of enzymatic activity is a fundamental prerequisite for both academic research and the industrial application of Taq DNA polymerase. To address the limitations of traditional methods for polymerase activity determination, such as low accuracy, complicated operation, and radioactive hazards, we have devised an absolute-quantitation method for Taq DNA polymerase based on chemiluminescence detection of the consumption of dATP (CDC-dATP). The CDC-dATP method offers several advantages, including simplicity suitable for routine laboratory use, high sensitivity (detecting as low as 0.0025 U/μL), excellent reproducibility, a broad linear range for Taq DNA polymerase (0.0025–0.1 U/μL) with a strong linear relationship (R2 > 0.99), and, significantly, absolute activity quantitation without the associated radioactive hazards. We delved into the molecular behavior of Taq DNA polymerase in the CDC-dATP method. Furthermore, we explored the extensive application potential of the CDC-dATP methodology for measuring the activity of various other enzymes involved in dATP/ATP generation or consumption, encompassing other DNA polymerases, reverse transcriptases, RNA polymerases, hydrolases, and protein kinases, covering all seven major categories of enzymes. • Absolute quantification method for the detection of Taq DNA polymerase by chemiluminescence based on dATP depletion. • It has the advantages of high sensitivity, no radioactive hazard, and absolute viability quantification. • Addresses the current lack of useful and approachable quantification methods for Taq DNA polymerase. • It can be used to measure the activity of various other enzymes related to dATP/ATP production or consumption. [ABSTRACT FROM AUTHOR]

Myocardial ischemia–reperfusion injury(MIRI) is one of the common complications after myocardial infarction surgery, Oxidative stress is among the main mechanisms of myocardial ischemia–reperfusion injury. Plantamajoside (PMS), the main effective ingredient in the genus Plantain, has been reported to possess an antioxidation, anti-inflammatory and anti-apoptosis role. However, whether PMS can attenuate myocardial ischemia–reperfusion injury is not yet known. Herein, we explored the effects of PMS on hypoxia-reoxygenation (H/R) injury in H9c2 cardiomyocytes and the underling molecular mechanisms of the treatment. Network pharmacological analysis screened the top 31 key genes in the treatment of MIRI disease treated with PMS, and the result of molecular docking further illustrated the roles that the PMS play in the treatment of MIRI through its interference with integrin-linked kinase (ILK) target protein. PMS was not cytotoxic in the concentration range of 5–40 μM and increased cell survival after H/R injury in a concentration-dependent manner without affecting proliferation or growth. PMS significantly reduced the levels of lactate dehydrogenase, malonic dialdehyde, reactive oxygen species and cell apoptosis, and increased soperoxide dismutase activity compared with those of the H/R injury group. PMS promoted the protein and mRNA expression of ILK and Bcl-2, the protein expression of p-Akt, and reduced the protein and mRNA expression of Bax, Caspase-3, and Cytochrome c, the protein expression of p–c-Src. PMS has protective effects against H/R injury in H9c2 cells, and its protective mechanism may be related to reactive oxygen species clearance, activation of the ILK/c-Src/Akt pathway and inhibition of the mitochondrial apoptosis. Highlights: • It's the first time to explore the protective effect of PMS on H9c2 cardiomyocyte hypoxia-reoxygenation injury, and to reveal its potential mechanism at the cellular level, which provides a new perspective for the prevention and treatment of MIRI in clinical practice. • The protective effect of PMS on H9c2 cardiomyocytes injured by H/R is related to stimulating the ILK/c-Src/Akt signaling pathway and inhibiting the mitochondrial apoptosis pathway. • PMS could be further developed as a drug to treat MIRI. • The result of this work will facilitate further studies on the pathophysiological mechanism of MIRI. [ABSTRACT FROM AUTHOR]

Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology. [ABSTRACT FROM AUTHOR]

Objective To analyse pro-survival mechanisms elicited in RA synovial fibroblasts (RASFs) upon detachment from their extracellular matrix dependent on the disintegrin metalloproteinase ADAM15 and Yes-associated protein kinase 1 (YAP1). Methods Detachment-induced apoptosis was determined by caspase 3/7 assays. Immunofluorescent stainings, cell surface biotinylation and immunoblotting were applied to analyse phosphorylated kinases and subcellular localization of YAP1 and connective tissue growth factor (CTGF). Caspase and transwell transmigration assays served to study CTGF function. Results Silencing of ADAM15 or YAP1 in RASFs leads to significantly increased levels of detachment-induced caspase activity. In non-silenced RASFs detachment causes simultaneous ADAM15-enhanced phosphorylation of YAP1 at S127, known for promoting its cytoplasmic localization, and Src-dependent phosphorylation at tyrosine Y357. The majority of nuclear YAP1 leaves the nucleus shortly after cell detachment, but prolonged detachment causes a marked nuclear re-entry of YAP1, resulting in significantly increased synthesis of CTGF. The newly synthesized CTGF, however, is not detectable in the supernatant, but is bound to the outside of the plasma membrane. In vitro studies demonstrated autocrine binding of CTGF to the EGF receptor and β1 integrin, with concomitant triggering of survival kinases, AKT1, ERK1/2, Src and focal adhesion kinase. Functional studies revealed anti-apoptotic effects of CTGF on detached RASFs and an enhancement of their potential for endothelial transmigration using HUVEC-coated transwells. Conclusion The elucidation of a new molecular mechanism that protects RASFs in the highly pro-apoptotic environment of inflamed RA joints by promoting anoikis-resistance and transendothelial migration via ADAM15/YAP1-mediated CTGF upregulation uncovers potentially new targets for future therapeutic intervention. [ABSTRACT FROM AUTHOR]

Despite the fact that sorafenib is recommended for the treatment of oncological diseases of the liver, kidneys, and thyroid gland, and recently it has been used for combination therapy of brain cancer of various genesis, there are still significant problems for its widespread and effective use. Among these problems, the presence of the blood–brain barrier of the brain and the need to use high doses of sorafenib, the existence of mechanisms for the redistribution of sorafenib and its release in the brain tissue, as well as the high resistance of gliomas and glioblastomas to therapy should be considered the main ones. Therefore, there is a need to create new methods for delivering sorafenib to brain tumors, enhancing the therapeutic potential of sorafenib and reducing the cytotoxic effects of active compounds on the healthy environment of tumors, and ideally, increasing the survival of healthy cells during therapy. Using vitality tests, fluorescence microscopy, and molecular biology methods, we showed that the selenium-sorafenib (SeSo) nanocomplex, at relatively low concentrations, is able to bypass the mechanisms of glioblastoma cell chemoresistance and to induce apoptosis through Ca2+-dependent induction of endoplasmic reticulum stress, changes in the expression of selenoproteins and selenium-containing proteins, as well as key kinases-regulators of oncogenicity and cell death. Selenium nanoparticles (SeNPs) also have a high anticancer efficacy in glioblastomas, but are less selective, since SeSo in cortical astrocytes causes a more pronounced activation of the cytoprotective pathways. [ABSTRACT FROM AUTHOR]

Protein kinases and phosphatases catalyze the phosphorylation and dephosphorylation of their protein substrates, respectively, and these are important mechanisms in cellular signal transduction. The rice blast fungus Magnaporthe oryzae possesses 6 protein phosphatases of type 2C class, including MoPtc1, 2, 5, 6, 7 and 8. However, only very little is known about the roles of these phosphatases in filamentous fungi. Here in, we deployed genetics and molecular biology techniques to identify, characterize and establish the roles of MoPtc5 and MoPtc7 in M. oryzae development and pathogenicity. We found that during pathogen-host interaction, MoPTC7 is differentially expressed. Double deletion of MoPTC7 and MoPTC5 suppressed the fungal vegetative growth, altered its cell wall integrity and reduced its virulence. The two genes were found indispensable for stress tolerance in the phytopathogen. We also demonstrated that disruption of any of the two genes highly affected appressorium turgor generation and Mps1 and Osm1 phosphorylation levels. Lastly, we demonstrated that both MoPtc5 and MoPtc7 are localized to mitochondria of different cellular compartments in the blast fungus. Taken together, our study revealed synergistic coordination of M. oryzae development and pathogenesis by the type 2C protein phosphatases. [ABSTRACT FROM AUTHOR]

Objective: Ferroptosis is a newly discovered form of programmed cell death; however, the specific mechanisms that regulate ferroptosis have yet to be fully elucidated in gastric carcinoma. In this study, we aimed to investigate how microsomal glutathione S-transferase 1 (MGST1) regulates ferroptosis in gastric carcinoma cells. Methods: Gastric adenocarcinoma (SGC7901) cells that overexpressed MGST1 or expressed only low levels of MGST1, were treated with specific compounds (erastin, sorafenib, RSL3, MK-2206 and SC79). Then, we detected the levels of malondialdehyde (MDA), glutathione (GSH), iron and reactive oxygen species (ROS). Protein expression levels of the non-classical autophagy and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathways were determined by western blotting and cell viability was analyzed by Cell Counting Kit-8 (CCK-8) assays. The expressions of target genes were detected using qRT-PCR. Results: We evaluated a range of ferroptosis-inducing compounds and found that MGST1 expression was down-regulated during ferroptosis in SGC7901 cells. The ferroptosis inducer RSL3 played a role in classical ferroptotic events while the overexpression of MGST1 impaired these effects. Interestingly, the overexpression of MGST1 resulted in the inactivation of autophagy by repressing the expression of ATG16L1 and the conversion of LC3-I to LC3-II. The upregulation of ATG16L1 eliminated the inhibitory action of MGST1 on ferroptosis. Notably, the overexpression of MGST1 induced the activation of the Akt/GSK-3β pathway. An Akt inhibitor antagonized the inhibitory effects of MGST1 on autophagy and ferroptosis. Conclusion: Collectively, our findings demonstrate a novel molecular mechanism and signaling pathway for ferroptosis. We also characterized that the overexpression of MGST1 induces gastric carcinoma cell proliferation by activating the Akt/GSK-3β signaling pathway. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background. Adrenocortical carcinoma (ACC) is a rare and poor prognosis malignancy. Necroptosis is a special type of cell apoptosis, which is regulated in caspase-independent pathways and mainly induced through the activation of receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like pseudokinase. A precise predictive tool based on necroptosis is needed to improve the level of diagnosis and treatment. Method. Four ACC cohorts were enrolled in this study. The Cancer Genome Atlas ACC (TCGA-ACC) cohort was used as the training cohort; three datasets (GSE19750, GSE33371, and GSE49278) from Gene Expression Omnibus (GEO) platform were combined as the GEO testing cohort after removing of batch effect. Forty-nine necroptosis-associated genes were obtained from a prior study and further filtered by least absolute shrinkage and selection operator Cox regression analysis; corresponding coefficients were used to calculate the necroptosis-associated gene score (NAGs). Patients in the TCGA-ACC cohort were equally divided into two groups with the mean value of NAGs. We investigated the associations between NAGs groups and clinicopathological feature distribution and overall survival (OS) in ACC, the molecular mechanisms, and the value of NAGs in therapy prediction. A nomogram risk model was established to quantify risk stratification for ACC patients. Finally, the results were confirmed in the GEO-combined cohort. Result. Patients in the TCGA-ACC cohort were divided into high and low NAGs groups. The high NAGs group had more fatal cases and advanced stage patients than the low NAGs group (P < 0.001 , hazard ratio HR = 13.97 , 95% confidence interval (95% CI): 4.168–46.844; survival rate: low NAGs, 7.69% vs. high NAGs, 61.53%). NAGs were validated to be negatively correlated with OS (R = − 0.48 , P < 0.001) and act as an independent factor in ACC with high discriminative efficacy (P < 0.001 , HR = 11.76 , 95% CI: 2.86–48.42). In addition, a high predictive efficacy nomogram risk model was established combining NAGs with tumor stage. Higher mutation rates were observed in the high NAGs group, and the mutation of TP53 may lead to a high T cell infiltration level among the NAGs groups. Patients belonged to the high NAGs are more sensitive to the chemotherapy of cisplatin, gemcitabine, paclitaxel, and etoposide (all P < 0.05). Ultimately, the same statistical algorithms were conducted in the GEO-combined cohort, and the crucial role of NAGs prediction value was further validated. Conclusion. We constructed a necroptosis-associated gene signature, revealed the prognostic value between ACC and it, systematically explored the molecular alterations among patients with different NAGs, and manifested the value of drug sensitivity prediction in ACC. [ABSTRACT FROM AUTHOR]

Purpose: The molecular mechanisms by which physical exercise produces beneficial effects on pathologic features and behavioral symptoms of Alzheimer's disease (AD) are not well understood. Herein, we examined whether regular moderate exercise could improve cognitive function and produce transcriptomic responses in the brain. Methods: Four groups of mice were studied: nontransgenic control, mice expressing the human presenilin-2 wild type, mice expressing the human presenilin-2 with the N141I mutation (Tg-PS2m), and Tg-PS2m that were subjected to treadmill exercise (TE) at a speed of 10 m·min−1 for 50 min·d−1, 5 d·wk−1, for 6 wk (Tg-PS2m/Ex). Results: Tg-PS2m/Ex mice exhibited increased preference in exploring a novel object than Tg-PS2m in the novel object recognition test, whereas differences observed in the water maze test and passive avoidance test were not significant. Western blot and histological analyses using amyloid oligomer (A11) and β-amyloid (6E10) antibody indicated that amyloid oligomer-reactive bands and plaque deposition in the hippocampus were reduced, although not significantly, after TE. Transcriptomic (RNA-sequencing) analysis and subsequent protein analysis revealed that the cell cycle regulatory gene, Cdc28 protein kinase regulatory subunit 2 (Cks2), was decreased, and the cell cycle– and apoptotic cell death–related factors, including cyclin D1, proliferating cell nuclear antigen, and cleaved caspase-3, were increased in the hippocampus of Tg-PS2m, whereas TE reversed their altered expression. Conclusions: The results support the hypothesis that the pathologic features and behavioral symptoms of AD caused by accumulation of amyloid β-peptide in hippocampus, causing aberrant cell cycle reentry and apoptosis, can be reversed by regular exercise. [ABSTRACT FROM AUTHOR]

Migration of keratinocytes plays a crucial role in the re‐epithelialization phase during wound healing. Circular RNA (circRNA) protein kinase, DNA‐activated, catalytic subunit (circ_PRKDC, hsa_circ_0084443) has been identified as a regulator of keratinocyte migration. However, the molecular basis governing it remains unclear. The levels of circ_PRKDC, microRNA (miR)‐20a‐3p, and RAS p21 protein activator 1 (RASA1) were assessed by quantitative real‐time PCR (qRT‐PCR) or western blot. Subcellular localization, Actinomycin D, and Ribonuclease (RNase) R assays were performed to characterise circ_PRKDC. Cell migration was gauged by transwell and wound‐healing assays. A direct relationship between miR‐20a‐3p and circ_PRKDC or RASA1 was verified by dual‐luciferase reporter and RNA pull‐down assays. Circ_PRKDC expression was reduced in wound skin during wound healing. Circ_PRKDC modulated migration of HaCaT keratinocytes. Mechanistically, circ_PRKDC directly targeted miR‐20a‐3p. The regulation of circ_PRKDC on HaCaT keratinocyte migration was mediated by miR‐20a‐3p. RASA1 was identified as a direct and functional target of miR‐20a‐3p, and miR‐20a‐3p‐mediated inhibition of RASA1 impacted HaCaT keratinocyte migration. Circ_PRKDC acted as a post‐transcriptional modulator of RASA1 expression through miR‐20a‐3p. Moreover, circ_PRKDC modulated migration of HaCaT keratinocytes by RASA1. Our findings demonstrated a novel molecular basis, the miR‐20a‐3p/RASA1 axis, for the regulation of circ_PRKDC on HaCaT keratinocyte migration. [ABSTRACT FROM AUTHOR]

Background: Our previous study indicated that Ginkgo biloba leaf extract (EGb) could protect against cisplatin-induced acute kidney injury in rabbits. The present study aimed to determine the effects and potential molecular mechanisms of EGb on chronic renal interstitial fibrosis induced by cisplatin using in vivo and in vitro models. Methods: Rats received a single dose of cisplatin on Day 1, and a subset of rats was intraperitoneally injected with EGb daily between Days 22–40. In vitro, HK-2 cells were treated with cisplatin, and a subset of cells was cultivated with EGb or SIS3 (Smad3 inhibitor) for 48 h. Renal function of rats was assessed by detecting the levels of serum creatinine (Scr), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG). Hematoxylin and eosin staining and Masson's trichrome staining were used to evaluate the damage and fibrosis of renal tissue. Western blotting, immunohistochemistry and immunofluorescence were used to detect the protein levels of fibrosis-associated proteins and signaling pathway-related proteins. RT–qPCR analysis was used to examine the mRNA levels of related indicators. Results: EGb significantly decreased the increased levels of Scr, BUN and urinary NAG and attenuated renal damage and the relative area of renal interstitial fibrosis induced by cisplatin. Additionally, EGb decreased the protein levels of α-SMA, Col I, TGF-β1, smad2/3, phosphorylated (p)-smad2/3, p38 MAPK, and p-p38 MAPK; the ratio of p-p38 MAPK/p38 MAPK; and the mRNA level of p38 MAPK in renal tissues induced by cisplatin. In agreement with in vivo studies, EGb significantly reduced the increased protein levels of these indicators. Additionally, EGb significantly reduced the increased protein levels of vimentin, TIMP-1, and CTGF, as well as the mRNA levels of α-SMA, vimentin, and TGF-β1, while it significantly increased the reduced E-cadherin protein level and the MMP-1/TIMP-1 ratio in HK-2 cells induced by cisplatin. It's worth noting that the effects of SIS3 in changing the above indicators were similar to those of EGb. Conclusion: Our study demonstrated that EGb improved cisplatin-induced chronic renal interstitial fibrosis, and its mechanisms were associated with inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells via the Smad3/TGF-β1 and Smad3/p38 MAPK pathways. [ABSTRACT FROM AUTHOR]

Aims: Diabetic population have a twofold to threefold increased risk of developing liver cancer, and hyperglycaemia is a prime causative factor that propends the tumour cells to undergo aggressive metabolic growth. In this study, we aimed to examine the molecular mechanism by which lutein inhibits hyperglycaemia‐induced human hepatocarcinoma (HepG2) cell proliferation. Methods: The effect of lutein on high glucose‐induced proliferation was measured using the WST‐1 reagent. Its effect on intracellular reactive oxygen species (ROS) levels was measured by DCF assay. The effect on the expression of antioxidant enzymes, cell cycle regulatory proteins and intracellular protein kinases was analysed by western blotting. The modulatory effect of lutein on different phases of the cell cycle was analysed by flow cytometry. Results: The data showed that lutein at 5 µM concentration significantly blocked glucose‐promoted HepG2 cell proliferation. Suppression of high glucose‐induced cell proliferation by lutein was not associated with apoptosis induction, but it was linked with inhibition of hyperglycaemia‐mediated elevated ROS and upregulated expression of high glucose‐mediated repressed heme oxygenase 1 (HO1). Furthermore, G2/M phase cell cycle arrest and associated phosphorylation of Cdk1 and P53 were found to be linked with suppressed hyperglycaemia‐mediated cell proliferation by lutein. In addition, lutein inhibited hyperglycaemia‐induced activation of P38 which relates to high glucose‐induced ROS‐mediated growth suppression and modulated the phosphorylation of Erk, JNK and Akt in hyperglycaemic HepG2 cells. Conclusion: Our findings portray that sufficient intake of lutein may offer a negative impact on diabetes‐associated tumour growth. [ABSTRACT FROM AUTHOR]

Biological regulatory networks are dynamic, intertwined, and complex systems making them challenging to study. While quantitative measurements of transcripts and proteins are key to investigate the state of a biological system, they do not inform the "active" state of regulatory networks. In consideration of that fact, "functional" proteomics assessments are needed to decipher active regulatory processes. Phosphorylation, a key post-translation modification, is a reversible regulatory mechanism that controls the functional state of proteins. Recent advancements of high-throughput protein kinase activity profiling platforms allow for a broad assessment of protein kinase networks in complex biological systems. In conjunction with sophisticated computational modeling techniques, these profiling platforms provide datasets that inform the active state of regulatory systems in disease models and highlight potential drug targets. Taken together, system-wide profiling of protein kinase activity has become a critical component of modern molecular biology research and presents a promising avenue for drug discovery. [ABSTRACT FROM AUTHOR]

Rationale: Δ9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood. Objectives: The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours. Methods: We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats. Results: We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states. Conclusions: These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions. [ABSTRACT FROM AUTHOR]

Molecular mechanisms underlying the nephrotoxicity associated with bevacizumab are unclear. Endothelin-1 (ET-1) is involved in podocyte injury and proteinuria, and its level increases in most cases of kidney disorders. Forkhead box protein O1 (FoxO1), a transcription factor, is a major determinant of ET-1 promoter activation and is regulated by protein kinase B (Akt) phosphorylation-dependent nuclear exclusion. We evaluated the effect of bevacizumab on ET-1 production in human glomerular microvascular endothelial cells (hGECs). We analyzed the changes in the mRNA and protein levels of ET-1 in hGECs treated with bevacizumab using real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Changes in the protein levels and phosphorylation status of Akt and FoxO1 in hGECs treated with bevacizumab were analyzed by western blotting. After cell lysis, FoxO1 protein was isolated from the cytoplasmic and nuclear fractions. We also investigated the effects of AS1842856 (a FoxO1 inhibitor) on bevacizumab-induced ET-1 production. Bevacizumab significantly and dose-dependently increased the mRNA and protein levels of ET-1 in hGECs (p < 0.05). Bevacizumab treatment also led to a decrease in phosphorylated Akt protein levels. Inhibition of Akt activity by LY294002 promoted ET-1 production. Bevacizumab also induced an increase in FoxO1 protein levels in the nucleus. Inhibition of FoxO1 activity by AS1842856 resulted in decreased ET-1 levels in bevacizumab-treated hGECs. ET-1 axis activation, Akt inactivation, and FoxO1 nuclear localization are the molecular mechanisms underlying bevacizumab-induced nephrotoxicity. Therefore, inhibition of renal ET-1 production could be a promising approach to protect against or treat bevacizumab-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Ixeris sonchifolia alias Kudiezi, it was named Ixeris sonchifolia (Bunge) Hance , a synonym for Crepidiastrum sonchifolium (Bunge) Pak & Kawano in the https://www.iplant.cn/. And it was first published in J. Linn. Soc., Bot. 13: 108 (1873), which was named Ixeris sonchifolia (Maxim.) Hance in the MPNS (http://mpns.kew.org). As a widely distributed medicinal and edible wild plant, it possesses unique bitter-cold characteristics and constituents with various pharmacological activities. Its main antitumor substances, same as artemisinin and paclitaxel, are classified as terpenoids and have become research foci in recent years. However, its specific biological activity and role in antitumor treatment remain largely unclear. This study aimed to elucidate the molecular targets and potential mechanisms of hepatocellular carcinoma apoptosis induced by Ixeris sonchifolia. We used network pharmacology methods to analyze and screen the active ingredients and possible underlying mechanisms of Ixeris sonchifolia in treating liver cancer and employed integrative time- and dose-dependent toxicity, transcriptomics, and molecular biology approaches to comprehensively verify the function of Ixeris sonchifolia extract (IsE) in human hepatoblastoma cell (HepG2) apoptosis and its potential mechanism. A total of 169 common targets were screened by network pharmacology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that IsE inhibited HepG2 cell activity in a time- and dose-dependent manner. Western blot analysis confirmed that IsE promoted HepG2 cell apoptosis by inhibiting the PI3K/AKT signaling pathway and that the PI3K/AKT inhibitor LY294002 also substantially enhanced IsE-induced apoptosis. The PI3K/AKT signaling pathway exhibited significant differences compared to that in the control group. Combining network pharmacology with experimental verification, IsE inhibited mitochondrial function and the PI3K/AKT pathway while inducing hepatoma cell apoptosis. IsE may have promising potential for liver cancer treatment and chemoprevention. [Display omitted] • Ixeris sonchifolia , Its main antitumor substances, same as artemisinin and paclitaxel, are classified as terpenoids. • The antitumor activity of terpenoids has become a research hotspot in recent years. • We predicted the anti-liver cancer components of Ixeris sonchifolia and their possible mechanisms, and verified them. • Ixeris sonchifolia inhibited mitochondrial function and the PI3K/AKT pathway while inducing hepatoma cell apoptosis. [ABSTRACT FROM AUTHOR]

Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a deadly malignant brain tumor that is resistant to most clinical treatments. Novel therapeutic agents that are effective against GBM are required. Antrodia cinnamomea has shown antiproliferative effects in GBM cells. However, the exact mechanisms and bioactive components remain unclear. Thus, the present study aimed to investigate the effect and mechanism of 4-acetylantrocamol LT3 (4AALT3), a new ubiquinone from Antrodia cinnamomeamycelium, in vitro. U87 and U251 cell lines were treated with the indicated concentration of 4AALT3. Cell viability, cell colony-forming ability, migration, and the expression of proteins in well-known signaling pathways involved in the malignant properties of glioblastoma were then analyzed by CCK-8, colony formation, wound healing, and western blotting assays, respectively. We found that 4AALT3 significantly decreased cell viability, colony formation, and cell migration in both in vitro models. The epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Hippo/yes-associated protein (YAP), and cAMP-response element binding protein (CREB) pathways were suppressed by 4AALT3. Moreover, 4AALT3 decreased the level of DNA repair enzyme O6-methylguanine-DNA methyltransferase and showed a synergistic effect with temozolomide. Our findings provide the basis for exploring the beneficial effect of 4AALT3 on GBM in vivo. [ABSTRACT FROM AUTHOR]

Background: The Hippo pathway is a developmental pathway recently discovered in Drosophila melanogaster; in mammals it normally controls organ development and wound healing. Hippo signaling is deregulated in breast cancer (BC). MST1/2 and LATS1/2 kinases are the upstream molecular elements of Hippo signaling which phosphorylate and regulate the two effectors of Hippo signaling, YAP1 and TAZ cotranscriptional activators. The two molecular effectors of the Hippo pathway facilitate their activity through TEAD transcription factors. Several molecular pathways with known oncogenic functions cross-talk with the Hippo pathway. Methods: A systematic review studying the correlation of the Hippo pathway with BC tumorigenesis, prognosis, and treatment was performed. Results: Recent literature highlights the critical role of Hippo signaling in a wide spectrum of biological mechanisms in BC. Discussion: The Hippo pathway has a crucial position in BC molecular biology, cellular behavior, and response to treatment. Targeting the Hippo pathway could potentially improve the prognosis and outcome of BC patients. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is the etiologic agent of COVID-19. There is currently no effective means of preventing infections by SARS-CoV-2, except through restriction of population movement and contact. An understanding of the origin, evolution and biochemistry (molecular biology) of SARS-CoV-2 is a prerequisite to its control. Mutations in the phosphorylation sites of SARS-CoV-2 encoded nucleocapsid protein isolated from various populations and locations, are described. Mutations occurred in the phosphorylation sites, all located within a stretch which forms a phosphorylation dependent interaction site, including C-TAK1 phosphorylation sites for 14-3-3. The consequences of these mutations are discussed and a structure-based model for the role of protein 14-3-3 in the sequestration and inhibition of SARS-CoV-2 nucleocapsid protein's function is presented. It is proposed that the phosphorylation of SARS-CoV-2 nucleocapsid protein and its sequestration by Protein 14-3-3 is a cellular response mechanism for the control and inhibition of the replication, transcription and packaging of the SARS-CoV-2 genome. • Mutations in the phosphorylation sites of SARS-CoV-2 encoded nucleocapsid protein. • Phosphorylation dependent binding and sequestration sites for protein 14-3-3. • Structure-model of the phosphorylation dependent binding and sequestration. • Proposal that sequestration by Protein 14-3-3 is a cellular response mechanism. • Sequestration inhibits replication, transcription and packaging of NCp genome. [ABSTRACT FROM AUTHOR]

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species. [ABSTRACT FROM AUTHOR]

A short biographical sketch of Professor David Shugar, the "father of the IPK conferences," is presented, focusing on the growing interest of this eminent scientist for protein kinases and his farsighted perception of the extraordinary therapeutic potential of protein kinase inhibitors, after his discovery in 1986 that 5,6‐dichloro‐1‐(beta‐D‐ribofuranosyl)benzimidazole effects are mediated by inhibition of protein kinase CK2. This led David Shugar to conceive the idea of organizing a periodic international conference on protein kinase inhibitors ("IPK conference"). The first conference was held in 1998 and the 10th one under the auspices of International Union of Biochemistry and Molecular Biology in September 2019. David Shugar died at the age of 100 in 2015, shortly after having organized the eight IPK conference. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Protein kinase A-mediated phosphorylation of the broad-complex transcription factor in silkworm suppresses its transcriptional activity." The correction addresses an error in the immunoblot images in figure 3 of the original article. The images were mistakenly replaced with duplicates from another panel, but this does not affect the scientific conclusions of the study. The authors provide the correct images and assure readers that the veracity of their conclusions remains intact. [Extracted from the article]