Exploring the multifaceted role of RASGRP1 in disease: immune, neural, metabolic, and oncogenic perspectives.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Factor B inhibitor iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with a variety of manifestations. Currently, the methods for treating PNH include anti-C5 treatments (eculizumab and ravulizumab) and pegcetacoplan (a targeted C3 inhibitor). On December 5, 2023, the US FDA approved a factor B inhibitor called Fabhalta® (iptacopan), previously known as LNP023, for the treatment of adult patients with PNH, including those who have previously received anti-C5 therapy. The main objective of this review was to elucidate the clinical efficacy and safety of the newly approved factor B inhibitor, iptacopan. Iptacopan plays a proximal role in the alternative complement pathway to control extravascular hemolysis mediated by C3b and intravascular hemolysis mediated by terminal complement. The recommended dosage is 200 mg orally twice daily. The 24-week results of the pivotal phase III open-label trial, APPLY-PNH, demonstrated that among PNH patients who had previously received anti-C5 therapy, 51/60 (estimated percentages 82%) of patients in the iptacopan group showed an increase in hemoglobin of ≥2 g/dL compared to 0/35 (estimated percentages 2%) in the standard treatment group, also, 69% of iptacopan-treated patients achieved hemoglobin levels ≥12 g/dL, while no patients in the standard treatment group reached this level (both p < 0.001). The 48-week results were similar to those observed at 24 weeks. The most common adverse events were headache, infection and diarrhea. There were almost no clinical breakthrough hemolysis. Trials evaluating the long-term safety and efficacy of iptacopan are currently recruiting.

A Precise and Stable Space-Based Time System for Navigation in Smart Cities.

The high-accuracy and high-stability space-based time system is necessary for satellite navigation systems to achieve high quality of service (QoS) on navigation and positioning in smart city applications. This paper proposes a precise and high-stability space-based time system established under the autonomous time scale of navigation satellites. The generation, maintenance, and transfer of high-precision space-based time references are researched. A centralized time comparison method based on the ALGOS algorithm conducts the two-way time comparison of the inter-satellite link. Specifically, using the relative clock difference observations of all links between satellites for a certain period of time, the clock difference, clock speed, and clock drift parameters of n-1 stars in a constellation of n stars relative to the same reference can be estimated simultaneously. Simulations are conducted on real collected data from the Beidou navigation systems when providing services to smart cities around the world. The simulation results show the high accuracy and stability of the proposed space-based time system under the autonomous time scale reference. Moreover, the clock offset monitoring arc coverage is much higher than the satellite clock offset obtained by the direct observation of the satellite and the anchor station. It proves the efficiency of the proposed space-based time system to be used for satellite clock offset modeling and prediction.

Role of SLC5A2 polymorphisms and effects of genetic polymorphism on sodium glucose cotransporter 2 inhibitorsinhibitor response.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by hyperglycaemia. T2DM is a highly heterogeneous polygenic disease. Due to genetic variation, variations in lifestyle and other environmental exposures, there are certain variations in the phenotype of T2DM patients. Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel hypoglycaemic agents that increase urinary glucose excretion by inhibiting glucose reabsorption in the proximal tubules of the kidney. For glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, studies have confirmed a variety of gene variants that may modify their effects. For SGLT2 inhibitors, research has focused on the SLC5A2 gene encoding SGLT2 and UGT1A9 gene polymorphisms affecting SGLT2 inhibitor metabolism. The SLC5A2 polymorphism rs9934336 have been associated with decreased HbA1c during the oral glucose tolerance test. Common variants of the SLC5A2 gene are related to blood glucose and insulin concentrations, but not glucagon concentrations. SLC5A2 rs9934336 and rs3116150 are related to a lower risk of heart failure. SGLT2 inhibitor exposure of UGT1A9*3 carriers is commonly higher than that of noncarriers, while these effects commonly have no obvious clinical significance on SGLT2 inhibitor pharmacokinetics. In terms of efficacy, general SLC5A2 variants show no significant effect on the response to the SGLT2 inhibitor empagliflozin. At present, research on the relationship between genetic polymorphisms and the efficacy of SGLT2 inhibitors is limited. The main purpose of this review is to elucidate the general effects of SGLT2 polymorphisms and the association between polymorphisms and the treatment response to SGLT2 inhibitors.

Effects of single-nucleotide polymorphism on the pharmacokinetics and pharmacodynamics of metformin.

INTRODUCTION: Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin. AREAS COVERED: Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins. EXPERT OPINION: The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms.

CD25-targeted antibody-drug conjugate camidanlumab tesirine for relapsed or refractory classical Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) accounts for more than 90% of HL in developed countries. Although the current combined modality therapy make it have a high cure rate, the prognosis for heavily pretreated patients with relapsed or refractory (R/R) cHL remains poor. A novel antibody-drug conjugate (ADC), named camidanlumab tesirine (ADCT-301, Cami), is currently being evaluated for its efficacy and safety in R/R cHL. The primary objective of this review is to examine the current pharmacological properties of camidanlumab tesirine as well as its clinical antitumor activity and safety. Camidanlumab tesirine comprises a human IgG1 anti-CD25 monoclonal antibody HuMax®-TAC, conjugated to a pyrrolobenzodiazepine dimer toxin. Once it bound to CD25-expressing cells, camidanlumab tesirine is internalized by cells and delivers SG3199, then SG3199 irreversibly binds to DNA and forms DNA interstrand crosslinks, ultimately leading to cell death. In the phase 1 study, patients with R/R cHL who received camidanlumab tesirine had an overall response rate (ORR) of 71% and a complete response rate (CRR) of 42%. Additionally, the recommended doses provided in R/R cHL were determined to be 30 and 45 µg/kg. The pivotal phase 2 trial showed significant antitumor activity of camidanlumab tesirine in heavily pretreated R/R cHL patients who failed brentuximab vedotin and programmed death-1 blockade: ORR was 70.1% and CRR was 33.3%, and the median duration of response was 13.7 months. Adverse events such as fatigue, maculopapular rash, and anemia were frequently observed following administration of camidanlumab tesirine. Moreover, camidanlumab tesirine may cause Guillain-Barré syndrome or polyradiculopathy.

The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management.

Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve ß-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.

Genome-wide identification of PEBP gene family members in potato, their phylogenetic relationships, and expression patterns under heat stress.

BACKGROUND: The phosphatidylethanolamine-binding protein (PEBP) gene family is involved in regulating many plant traits. Genome-wide identification of PEPB members and knowledge of their responses to heat stress may assist genetic improvement of potato (Solanum tuberosum). METHODS AND RESULTS: We identified PEBP gene family members from both the recently-updated, long-reads-based reference genome (DM v6.1) and the previous short-reads-based annotation (PGSC DM v3.4) of the potato reference genome and characterized their heat-induced gene expression using RT-PCR and RNA-Seq. Fifteen PEBP family genes were identified from DM v6.1 and named as StPEBP1 to StPEBP15 based on their locations on 6 chromosomes and were classified into FT, TFL, MFT, and PEBP-like subfamilies. Most of the StPEBP genes were found to have conserved motifs 1 to 5. Tandem or segmental duplications were found between StPEBP genes in seven pairs. Heat stress induced opposite expression patterns of certain FT and TFL members but involving different members in leaves, roots and tubers. CONCLUSION: The long-reads-based genome assembly and annotation provides a better genomic resource for identification of PEBP family genes. Heat stress tends to decrease FT gene activities but increases TFL gene activities, but this opposite expression involves different FT/TFL pairs in leaves, roots, and tubers. This tissue-specific expression pattern of PEBP members may partly explain why different potato organs differ in their sensitivities to heat stress. Our study provides candidate PEBP family genes and relevant information for genetic improvement of heat tolerance in potato and may help understand heat-induced responses in other plants.

Study on Multiple Fractal Analysis and Response Characteristics of Acoustic Emission Signals from Goaf Rock Bodies.

Based on the actual monitoring data of the acoustic emission (AE) ground pressure monitoring and positioning system, this paper introduces fractal theory and the multifractal detrended fluctuation analysis (MF-DFA) method to estimate the waveform multifractal spectrum of goaf rock acoustic emission signals and investigate multifractal time-varying response characteristics. The research results show that the wavelet hard thresholding method has the best noise reduction effect on the original signal, and the box counting dimension has a strong waveform identification effect. Before deformation damage occurs, fractal spectral width Δα shows an increase and then decrease and the fluctuation scale factor Δf(α) decreases and then increases. When damage occurs, fractal spectral width Δα decreases and then stabilizes and concentrates. Simultaneously, the fluctuation scale factor Δf(α) keeps decreasing until the lowest point, and then shows an increasing trend until it reaches a stable state. This study is of great significance to the stability evaluation and disaster early warning of mine goaf.

Gbps terahertz external modulator based on a composite metamaterial with a double-channel heterostructure.

The past few decades have witnessed a substantial increase in terahertz (THz) research. Utilizing THz waves to transmit communication and imaging data has created a high demand for phase and amplitude modulation. However, current active THz devices, including modulators and switches, still cannot meet THz system demands. Double-channel heterostructures, an alternative semiconductor system, can support nanoscale two-dimensional electron gases (2DEGs) with high carrier concentration and mobility and provide a new way to develop active THz devices. In this Letter, we present a composite metamaterial structure that combines an equivalent collective dipolar array with a double-channel heterostructure to obtain an effective, ultrafast, and all-electronic grid-controlled THz modulator. Electrical control allows for resonant mode conversion between two different dipolar resonances in the active device, which significantly improves the modulation speed and depth. This THz modulator is the first to achieve a 1 GHz modulation speed and 85% modulation depth during real-time dynamic tests. Moreover, a 1.19 rad phase shift was realized. A wireless free-space-modulation THz communication system based on this external THz modulator was tested using 0.2 Gbps eye patterns. Therefore, this active composite metamaterial modulator provides a basis for the development of effective and ultrafast dynamic devices for THz wireless communication and imaging systems.