Diverse Pathways Research Articles

A chromosome-level genome reveals genome evolution and molecular basis of anthraquinone biosynthesis in Rheum palmatum

BackgroundRhubarb is one of common traditional Chinese medicine with a diverse array of therapeutic efficacies. Despite its widespread use, molecular research into rhubarb remains limited, constraining our comprehension of the geoherbalism.ResultsWe assembled the genome of Rheum palmatum L., one of the source plants of rhubarb, to elucidate its genome evolution and unpack the biosynthetic pathways of its bioactive compounds using a combination of PacBio HiFi, Oxford Nanopore, Illumina, and Hi-C scaffolding approaches. Around 2.8 Gb genome was obtained after assembly with more than 99.9% sequences anchored to 11 pseudochromosomes (scaffold N50 = 259.19 Mb). Transposable elements (TE) with a continuous expansion of long terminal repeat retrotransposons (LTRs) is predominant in genome size, contributing to the genome expansion of R. palmatum. Totally 30,480 genes were predicted to be protein-coding genes with 473 significantly expanded gene families enriched in diverse pathways associated with high-altitude adaptation for this species. Two successive rounds of whole genome duplication event (WGD) shared by Fagopyrum tataricum and R. palmatum were confirmed. We also identified 54 genes involved in anthraquinone biosynthesis and other 97 genes entangled in flavonoid biosynthesis. Notably, RpALS emerged as a compelling candidate gene for the octaketide biosynthesis after the key residual screening.ConclusionOverall, our findings offer not only an enhanced understanding of this remarkable medicinal plant but also pave the way for future innovations in its genetic breeding, molecular design, and functional genomic studies.

STAM2 negatively regulates the MyD88-mediated NF-κB signaling pathway in miiuy croaker, Miichthys miiuy

Signal transducing adapter molecule 2 (STAM2), a member of the Signal Transducing Adapter Molecule (STAM) family, is a protein with significant implications in diverse signaling pathways and endocytic membrane trafficking. However, the role of the STAM2, especially in fish, remains largely unknown. In this study, we discovered that STAM2 negatively regulates the NF-κB signaling pathway, and its inhibitory effect is enhanced upon LPS induction. Our study confirmed that STAM2 can enhance the degradation of myeloid differentiation primary-response protein 88 (MyD88), an upstream regulator of NF-κB pathway. Furthermore, the UIM domain of STAM2 is important for the inhibition of MyD88. Mechanistically, STAM2 inhibits the NF-κB signaling pathway by targeting the MyD88 autophagy pathway. In addition, we showed that STAM2 promotes the proliferation of Vibrio harveyi. In summary, our study reveals that STAM2 inhibits NF-κB signaling activation and mediates innate immunity in teleost via the autophagy pathway.

Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. MethodsHepatic SHP knockout mice (SHPΔhep) and their wild-type littermates (SHPfl/fl) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHPΔhep mice were reconstituted with bone marrow lacking interferon γ (IFNγ−/−) to suppress inflammation. ResultsHepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake, including UCP1, CPT1α, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80+ cells and mRNA levels of inflammatory cytokines (IL-12, IL-6, Ccl2, and IFNγ) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHPΔhep mice. The increased inflammation and fibrosis in SHPΔhep mice were corrected with bone marrow-derived IFNγ−/− myeloid cell transplantation. ConclusionHepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNγ specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation during fructose diet feeding but, in doing so, prevents pro-MASH pathways. The IFNγ-mediated inflammation in myeloid cells appears to be a potential therapeutic target to suppress MASH.

Modulation of atherosclerosis-related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives.

Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), NF-E2-related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator-activated receptor (PPAR), nucleotide oligo-structural domain-like receptor thermoprotein structural domain-associated protein 3 (NLRP3), silencing information regulator 2-associated enzyme 1 (Sirt1), nuclear transcription factor-κB (NF-κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor-β (TGF-β), and Janus kinase-signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high-intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.

Sulfate Availability and Hormonal Signaling in the Coordination of Plant Growth and Development.

Sulfur (S), one of the crucial macronutrients, plays a pivotal role in fundamental plant processes and the regulation of diverse metabolic pathways. Additionally, it has a major function in plant protection against adverse conditions by enhancing tolerance, often interacting with other molecules to counteract stresses. Despite its significance, a thorough comprehension of how plants regulate S nutrition and particularly the involvement of phytohormones in this process remains elusive. Phytohormone signaling pathways crosstalk to modulate growth and developmental programs in a multifactorial manner. Additionally, S availability regulates the growth and development of plants through molecular mechanisms intertwined with phytohormone signaling pathways. Conversely, many phytohormones influence or alter S metabolism within interconnected pathways. S metabolism is closely associated with phytohormones such as abscisic acid (ABA), auxin (AUX), brassinosteroids (BR), cytokinins (CK), ethylene (ET), gibberellic acid (GA), jasmonic acid (JA), salicylic acid (SA), and strigolactones (SL). This review provides a summary of the research concerning the impact of phytohormones on S metabolism and, conversely, how S availability affects hormonal signaling. Although numerous molecular details are yet to be fully understood, several core signaling components have been identified at the crossroads of S and major phytohormonal pathways.

LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD-fed mice.

LDL receptor-related protein-1 (LRP1) is a cell-surface receptor that functions in diverse physiological pathways. We previously demonstrated that hepatocyte-specific LRP1 deficiency (hLRP1KO) promotes diet-induced insulin resistance and increases hepatic gluconeogenesis in mice. However, it remains unclear whether LRP1 regulates hepatic glycogenesis. Insulin signaling, glycogenic gene expression, and glycogen content were assessed in mice and HepG2 cells. The pcDNA 3.1 plasmid and adeno-associated virus serotype 8 vector (AAV8) were used to overexpress the truncated β-chain (β∆) of LRP1 both invitro and invivo. On a normal chow diet, hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content. Moreover, LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose- and time-dependent manner. Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3β, increased levels of phosphorylated glycogen synthase (GYS), and diminished glycogen synthesis in insulin-stimulated HepG2 cells, which was restored by exogenous expression of the β∆-chain. By contrast, AAV8-mediated hepatic β∆-chain overexpression significantly improved the insulin signaling pathway, thus activating glycogenesis and enhancing glycogen storage in the livers of high-fat diet (HFD)-fed mice. Our data revealed that LRP1, especially its β-chain, facilitates hepatic glycogenesis by improving the insulin signaling pathway, suggesting a new therapeutic strategy for hepatic insulin resistance-related diseases.

MAP3K4 kinase action and dual role in cancer.

It is commonly known that the MAPK pathway is involved in translating environmental inputs, regulating downstream reactions, and maintaining the intrinsic dynamic balance. Numerous essential elements and regulatory processes are included in this pathway, which are essential to its functionality. Among these, MAP3K4, a member of the serine/threonine kinases family, plays vital roles throughout the organism's life cycle, including the regulation of apoptosis and autophagy. Moreover, MAP3K4 can interact with key partners like GADD45, which affects organism's growth and development. Notably, MAP3K4 functions as both a tumor promotor and suppressor, being activated by a variety of factors and triggering diverse downstream pathways that differently influence cancer progression. The aim of this study is to provide a brief overview of physiological functions of MAP3K4 and shed light on its contradictory roles in tumorigenesis.

The role of income inequality as an ecological determinant of mental health: A nation-wide multilevel analysis on an Italian sample.

Income inequality, a pivotal determinant of general and mental health, operates through intricate mechanisms at various geographical scales. While established at country or region levels, the impact of lower-level (municipal or neighborhood) inequality remains inconsistent. This study explores the influence of regional- and municipal-level income inequality on individual psychological distress during the COVID-19 pandemic in Italy, employing a multilevel data analysis. In a post hoc analysis of data from the first wave of the pandemic (March to April 2020), three hierarchical levels were considered: individual participants, municipalities, and regions. Depressive and anxiety symptoms were measured using the PHQ-9 and GAD-7 scales, while the Gini coefficient gauged income inequality at municipal and regional levels. The analysis incorporated demographic variables as potential confounders. The study encompassed 21 regions, 3,900 municipalities, and 21,477 subjects. Income inequality at both regional and municipal levels exhibited associations with distress scores, suggesting independent effects. Notably, higher distress scores were identified in southern regions with elevated inequality, despite a more substantial COVID-19 impact in the north. Findings contribute to existing literature by emphasizing the independent impact of lower-level (municipal) and higher-level (regional) income inequality on population psychopathology. The study supports theories suggesting diverse pathways through which inequality at different levels influences health, such as potential associations with healthcare system dysfunction at the regional level and welfare dysfunction at the municipal level. The observed north-south gradient in distress scores highlights the need for psychosocial interventions to alleviate income inequality, especially in historically disadvantaged southern regions. Future research should explore the nuanced interplay between income inequality and various ecological variables to provide a comprehensive understanding of its health impact.

Photo‐promoted rapid reconstruction induced alterations in active site of Ag@amorphous NiFe hydroxides for enhanced oxygen evolution reaction

AbstractThe dynamic surface self‐reconstruction behavior in local structure correlates with oxygen evolution reaction (OER) performance, which has become an effective strategy for constructing the catalytic active phase. However, it remains a challenge to understand the mechanisms of reconstruction and to accomplish it fast and deeply. Here, we reported a photo‐promoted rapid reconstruction (PRR) process on Ag nanoparticle‐loaded amorphous Ni‐Fe hydroxide nanosheets on carbon cloth for enhanced OER. The photogenerated holes generated by Ag in conjunction with the anodic potential contributed to a thorough reconstruction of the amorphous substrate. The valence state of unsaturated coordinated Fe atoms, which serve as active sites, is significantly increased, while the corresponding crystalline substrate shows little change. The different structural evolutions of amorphous and crystalline substrates during reconstruction lead to diverse pathways of OER. This PRR utilizing loaded noble metal nanoparticles can accelerate the generation of active species in the substrate and increase the electrical conductivity, which provides a new inspiration to develop efficient catalysts via reconstruction strategies.

Physical interpretation on development and validation of the reaction routes of complex chemical kinetic model

Simulating the complexity in its entirety proves highly challenging, to examine both the local and global stability of the model, as well as its positivity, recognizing the overall instability. To address this challenge, a strategy of splitting down the multi-route complex reactions into its independent sub-routes is employed. For the validation of sub-routes, the stability and positivity of each individual route were comprehensively analyzed. In addition, we employ techniques to simplify our models by considering factors such as reaction speed and thermodynamic properties, ensuring their accuracy. Furthermore, we integrate the Spectral Quasi-Equilibrium Manifold to obtain a deeper understanding of the sequential advancement of reactions, focusing on the slowest eigenvector. A comprehensive examination of the mathematical underpinnings of these reaction steps and diverse pathways is conducted. We also investigate the temporal behavior of these pathways, yielding fresh perspectives. Our findings suggest the feasibility of independently evaluating each pathway rather than treating the entire mechanism as a singular entity. To enhance our analysis, we conduct a local sensitivity assessment using the SimBiology toolbox in MATLAB of each route and compare calculation periods for TRM (Total Relative Motion). Furthermore, we employ the short-time Fourier transform graph to capture time–frequency information regarding the steady state of compounds in various routes, revealing spectral variations over time.

Diverse pathways from adolescence to early adulthood among China's rural youth: A new perspective

Past studies examining the transition to adulthood within the Chinese context often implicitly or explicitly assume that the rural population is a homogeneous group and suggest that rural individuals tend to enter the workforce and marry at younger ages than their urban peers. This assumption overlooks the distinct challenges faced by rural youth, who often confront higher poverty risks and greater uncertainties compared to urban counterparts, yet empirical research on these unique challenges is limited. Using both a national survey and a unique longitudinal sample of rural youth in one of the poorest regions of China, this study demonstrates that rural youth experience a greater diversity of pathways from adolescence to early adulthood than do urban youth, which contradicts many earlier studies in Western contexts. In addition, this study identifies a variety of childhood environment factors that structure the transition pathways of rural youth. This study highlights the growing rural–urban disparity in China and has important implications for research on social stratification and rural youth development.

Exploring multifaceted pathways: understanding behavioral formation in green tourism selection through fsQCA

ABSTRACT Rather than confining the investigation solely to intentions, as typically done within the unifinality paradigm (e.g. Structural Equation Modeling with prespecified hypotheses), this paper extends the traditional approach by delving into the actual behaviors of tourists through diverse pathways. Employing mixed methods, we aim to uncover potential explanations for the formation of green behavioral patterns among tourists. While our findings reveal a limited variance in behavior explained solely by intention, it is imperative to recognize the critical role of intention as a significant determinant of behavior, as supported by our empirical data.

Dietary Supplementation with Nervonic Acid Ameliorates Cerebral Ischemia-Reperfusion Injury by Modulating of Gut Microbiota Composition-Fecal Metabolites Interaction.

Cerebral ischemia-reperfusion (IR) injury stands as a prominent global contributor to disability and mortality. Nervonic acid (NA), a bioactive elongated monounsaturated fatty acid, holds pivotal significance in human physiological well-being. This research aims to explore the prophylactic effects and fundamental mechanisms of NA in a rat model of cerebral IR injury. Through the induction of middle cerebral artery occlusion, this study establishes a rat model of cerebral IR injury and comprehensively assesses the pharmacodynamic impacts of NA pretreatment. This evaluation involves behavioral analyses, histopathological examinations, and quantification of serum markers. Detailed mechanisms of nervonic acid's prophylactic effects are revealed through fecal metabolomics and 16S rRNA sequencing analyses. Our findings robustly support nervonic acid's capacity to ameliorate neurological impairments in rats afflicted with cerebral IR injury. Beyond its neurological benefits, NA demonstrates its potential by rectifying metabolic perturbations across diverse pathways, particularly those pertinent to unsaturated fatty acid metabolism. Additionally, NA emerges as a modulator of gut microbiota composition, notably by selectively enhancing vital genera like Lactobacillus. These comprehensive findings highlight the potential of incorporating NA as a functional component in dietary interventions aimed at targeting cerebral IR injury.

A Review of Current and Future Pharmacologic Treatments for Narcolepsy

IntroductionNarcolepsy is a rare but disabling neurological disorder involving disruption of the sleep-wake cycle that is often under- or misdiagnosed (Barateau L, et al. J Sleep Res. 2022;31(4):e13631). It is characterized by a classical tetrad of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Narcolepsy is divided into 3 types: Narcolepsy Type 1 (NT1); Narcolepsy Type 2 (NT2); and Secondary Narcolepsy. The pathophysiology remains unclear but is primarily associated with loss of hypocretin (orexin) neurons involving autoimmune and genetic risk factors, particularly for NT1.ObjectivesTo review the currently available therapies for the treatment of narcolepsy.MethodsThe extant literature was reviewed and discussed in the context of clinical relevance.ResultsTreatment historically has included medications developed for the treatment of other conditions such as psychostimulants (methylphenidate, modafinil/armodafinil, pemoline) and antidepressants (SSRIs,TCAs). These agents are also associated with limiting side effects in practice. In more recent years a variety of specific treatments have been approved that act on diverse pathways. Pitolisant, a histamine H3 receptor inverse agonist, is approved for the treatment of EDS or cataplexy in adult patients with narcolepsy (and children> 6 years in European Union) (Keam SJ.Paediatr Drugs. 2023;25(4):483-488). Solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI) is indicated to improve wakefulness in adult patients with EDS associated with narcolepsy or obstructive sleep apnea (OSA) (Winter Y, et al. Sleep Med. 2023;103:138-143). Sodium oxybate (SXB), a GABAB receptor agonist, is approved for the treatment of cataplexy associated with narcolepsy and (EDS) in patients 7 years or older (Bogan RK, et al. CNS Drugs. 2023;37(4):323-335). Current research focuses on on-peptide hypocretin receptor-2 agonists (Saitoh T, Sakurai T. Peptides. 2023;167:171051).ConclusionsDespite limited understanding of the pathophysiology of narcolepsy there have been substantial advances in the pharmacotherapy, including medications now approved for children. Early diagnosis and treatment are associated with better outcomes. In view of the chronic and disabling morbidity associated with narcolepsy further research and better access to appopriate medications is necessary.Disclosure of InterestNone Declared

Exploring the role of histone deacetylase inhibitors in cancer development and therapeutic potential.

The process of acetylation and deacetylation of histones within the nucleus operates within a dynamic equilibrium. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) collaboratively and precisely regulate normal gene transcription and expression. Any disorder in the activity of HATs/HDACs can lead to uncontrolled gene expression, consequently resulting in tumorigenesis. Histone deacetylase inhibitors (HDACIs) have the capacity to block the cell cycle, thereby restraining tumor cell proliferation and tumor growth. Also, HDACIs exhibit a significant capability to diminish the expression of apoptosis protein inhibitors such as Bcl-2 and B-cell lymphoma-extra-large (Bcl-xL), while concurrently up-regulating pro-apoptotic proteins such as Bax, Bad, and Bim. Also, HDACIs demonstrate the ability to inhibit tumor cell angiogenesis. Representing a new category of targeted anti-cancer therapeutics, HDACIs possess the capability to restore the expression of tumor suppressor genes, induce apoptosis, and stimulate cell differentiation. Additionally, they exert anti-cancer effects through diverse pathways both in vivo and in vitro, thereby presenting promising prospects in tumor therapy. This review delves into the involvement of HDACs in cancer pathology and the therapeutic potential of HDACIs as emerging drugs in cancer treatment.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part2: Modulation of hypoxia, redox status, and mitochondrial protection ina neuroblastoma cell line, SH-SY5Y.

To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis. Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity. Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells. Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity. Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.

A Stepwise Multivariate Granger Causality Method for Constructing Hierarchical Directed Brain Functional Network.

The directed brain functional network construction gives us the new insights into the relationships between brain regions from the causality point of view. The Granger causality analysis is one of the powerful methods to model the directed network. The complex brain network is also hierarchically constructed, which is particularly suited to facilitate segregated functions and the global integration of the segregated functions. Therefore, it is of great interest to explore new approach to model the hierarchical architecture of the directed network. In the present study, we proposed a new approach, namely, stepwise multivariate Granger causality (SMGC), considering both the directed and hierarchical features of brain functional network to explore the stepwise causal relationship in the network. The simulation study demonstrated that the diverse and complex hierarchical organization could be embedded in the apparently simple directed network. The proposed SMGC method could capture the multiple hierarchy of the directed network. When applying to the real functional magnetic resonance imaging (fMRI) datasets, the core triple resting-state networks in human brain showed within-network directed connections in the first-level directed network and rich and diverse between-network pathways in the second-level hierarchical network. The default mode network (DMN) had a prominent role in the resting-state acting as both the causal source and the important relay station. Further exploratory research on the adaption of directed hierarchical network in athletes suggested the enhanced bidirectional communication between the DMN and the central executive network (CEN) and the enhanced directed connections from the salience network (SN) to the CEN in the athlete group. The SMGC approach is capable of capturing the hierarchical architecture of the brain directed functional network, which refreshes the new stepwise causal relationship in the directed network. This might shed light on the potential application for exploring the altered hierarchical organization of brain directed network in neuropsychiatric disorders.

Cell viability and cytotoxicity assays: Biochemical elements and cellular compartments.

Cell viability and cytotoxicity assays play a crucial role in drug screening and evaluating the cytotoxic effects of various chemicals. The quantification of cell viability and proliferation serves as the cornerstone for numerous in vitro assays that assess cellular responses to external factors. In the last decade, several studies have developed guidelines for defining and interpreting cell viability and cytotoxicity based on morphological, biochemical, and functional perspectives. As this domain continues to experience ongoing growth, revealing new mechanisms orchestrating diverse cell cytotoxicity pathways, we suggest a revised classification for multiple assays employed in evaluating cell viability and cell death. This classification is rooted in the cellular compartment and/or biochemical element involved, with a specific focus on mechanistic and essential aspects of the process. The assays are founded on diverse cell functions, encompassing metabolic activity, enzyme activity, cell membrane permeability and integrity, adenosine 5'-triphosphate content, cell adherence, reduction equivalents, dye inclusion or exclusion, constitutive protease activity, colony formation, DNA fragmentation and nuclear splitting. These assays present straightforward, reliable, sensitive, reproducible, cost-effective, and high-throughput approaches for appraising the effects of newly formulated chemotherapeutic biomolecules on the cell survival during the drug development process.

RACK1A promotes hypocotyl elongation by scaffolding light signaling components in Arabidopsis.

Plants deploy versatile scaffold proteins to intricately modulate complex cell signaling. Among these, RACK1A (Receptors for Activated C Kinase 1A) stands out as a multifaceted scaffold protein functioning as a central integrative hub for diverse signaling pathways. However, the precise mechanisms by which RACK1A orchestrates signal transduction to optimize seedling development remain largely unclear. Here, we demonstrate that RACK1A facilitates hypocotyl elongation by functioning as a flexible platform that connects multiple key components of light signaling pathways. RACK1A interacts with PHYTOCHROME INTERACTING FACTOR (PIF)3, enhances PIF3 binding to the promoter of BBX11 and down-regulates its transcription. Furthermore, RACK1A associates with ELONGATED HYPOCOTYL 5 (HY5) to repress HY5 biochemical activity toward target genes, ultimately contributing to hypocotyl elongation. In darkness, RACK1A is targeted by CONSTITUTIVELY PHOTOMORPHOGENIC (COP)1 upon phosphorylation and subjected to COP1-mediated degradation via the 26 S proteasome system. Our findings provide new insights into how plants utilize scaffold proteins to regulate hypocotyl elongation, ensuring proper skoto- and photo-morphogenic development.

Antiarrhythmic Effect of SGLT-2 Inhibitors in high-degree AV Block Caused by Heart Failure: A Case Report

Highlights: 1. The antiarrhythmic effect of SGLT-2 inhibitors, particularly empagliflozin, is a very interesting topic to discuss further. 2. In patients with high degree AV block due to HF in rural areas, the use of SGLT-2 inhibitors is quite rare in Indonesia. - Background: According to WHO's Top 10 Global Health Threats, non-communicable diseases such as heart failure contribute to more than 70% of all deaths worldwide. Several studies have shown that SGLT-2 inhibitors can considerably reduce HF. As research progresses, SGLT-2 inhibitors may lessen the risk of arrhythmias in HF patients. Case Summary: A 57-year-old female with uncontrolled hypertension came to the ED after collapsing at home. The vital signs and physical examination are normal. The preliminary ECG showed a high degree AV Block with multiple multifocal PVC. Early laboratory revealed mild hypokalemia. The patient experienced a seizure the next day, and an ECG showed total AV block with a non-sustained VT episode with PVC R on T. Following critical cardiac care and stabilization, the patient underwent echocardiography, which showed mild MR and AR with a reduced ejection fraction (47.7%). Once the patient's condition has stabilized, the patient is given 1x10mg Empagliflozin PO. Discussion: SGLT-2 inhibitors are beneficial in the treatment of heart failure and arrhythmia. SGLT-2 inhibitors have antiarrhythmic effects through a variety of pathways, such as lowering preload and afterload, inhibition of sodium-hydrogen exchange in myocardial cells, and suppression of the sympathetic nervous system.