Somatic GNA11/GNAQ variants in a cohort of Chinese children with phakomatosis pigmentovascularis.

Importance: Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G-protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective: To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods: We performed whole-exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep-targeted sequencing was conducted to validate the somatic mutations. A genotype-phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results: Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype-phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation: Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

Targeting TYK2 for Fighting Diseases: Recent Advance of TYK2 Inhibitors.

TYK2 (tyrosine-protein kinase 2) is a non-receptor protein kinase belonging to the JAK family and is closely associated with various diseases, such as psoriasis, inflammatory bowel disease, systemic lupus erythematosus. TYK2 activates the downstream proteins STAT1-5 by participating in the signal transduction of immune factors such as IL-12, IL-23, and IL-10, resulting in immune expression. The activity of the inhibitor TYK2 can effectively block the transduction of excessive immune signals and treat diseases. TYK2 inhibitors are divided into two types of inhibitors according to the different binding sites. One is a TYK2 inhibitor that binds to JH2 and inhibits its activity through an allosteric mechanism. The representative inhibitor is BMS-986165, developed by Bristol-Myers Squibb. The other class binds to the JH1 adenosine triphosphate (ATP) site and prevents the catalytic activity of the kinase by blocking ATP and downstream phosphorylation. This paper mainly introduces the protein structure, signaling pathway, synthesis, structure-activity relationship and clinical research of TYK2 inhibitors.

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

Current status of drugs targeting PDGF/PDGFR.

As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.

Pre-service teachers' altruistic motivation for choosing teaching as a career: where does it come from?

This study aims to examine the factors influencing pre-service teachers' altruistic motivation for selecting their profession within a Chinese educational setting. Drawing on existing research, a three-element (social-cognitive, emotional, and realistic) model is integrated to explore how pre-service teachers' altruistic motivations are formed and evolved. Utilizing this model, interview data from 18 students enrolled in the Chinese Free Teacher Education program were collected and analyzed by thematic analysis. The findings indicate that social-cognitive factors impact altruistic motivation through engagement with social issues and reflections on practical educational challenges. The emotional factor is manifested through the participants' positive and negative emotions. The realistic factor comprises familial influences and personal career preferences, which play a role in the decision to pursue teaching as a lifelong vocation. This study proposes a structured and functional model that can serve as a foundation for future research into the development of altruistic motivation. It also offers insights into nurturing altruistic motivation among both pre-service and practicing teachers in their career decision-making process.

Interventional embolisation for patients with cirrhosis and recurrent or persistent hepatic encephalopathy related to spontaneous portosystemic shunts: protocol for a prospective, non-randomised controlled study.

INTRODUCTION: The presence of spontaneous portosystemic shunts (SPSS) has been identified to be associated with hepatic encephalopathy (HE) in patients with cirrhosis. Nevertheless, the role of interventional embolisation in managing such patients remains poorly defined. Consequently, this prospective controlled study aims to assess the efficacy and safety of interventional embolisation as a therapeutic approach for patients with cirrhosis and recurrent or persistent HE related to SPSS. METHODS AND ANALYSIS: Cirrhotic patients diagnosed with recurrent or persistent HE associated with SPSS will be recruited for this study, and assigned to either the interventional embolisation group or the standard medical treatment group. The efficacy endpoints encompass the evaluation of postoperative alleviation of HE symptoms and the incidence of overt HE recurrence during the follow-up period, as well as the duration and frequency of hospitalisations for HE, alterations in liver function and volume, and overall survival. The safety endpoints encompass both immediate and long-term postoperative complications. ETHICS AND DISSEMINATION: This study will be conducted in strict adherence to the principles of good clinical practice and the guidelines outlined in the Declaration of Helsinki. Ethical approval for the trial has been obtained from the Ethics Committee of Mengchao Hepatobiliary Hospital of Fujian Medical University (2023_013_02). Written informed consent will be obtained from all the participants by the treating physician for each patient prior to their enrolment. The documented informed consent forms will be retained as part of the clinical trial records for future reference. The study findings will be disseminated through publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300072189.

Exclusive and Switchable Superoxide Radical Generation by O2-Capture-Based Electron Transfer and Supramolecular Assembly.

Type-I photosensitizers (PSs) can generate free radical anions with a broad diffusion range and powerful damage effect, rendering them highly desirable in various areas. However, it still remains a recognized challenge to develop pure Type-I PSs due to the inefficiency in producing oxygen radical anions through the collision of PSs with nearby substrates. In addition, regulating the generation of oxygen radical anions is also of great importance toward the control of photosensitizer (PS) activities on demand. Herein, a piperazine-based cationic Type-I PS (PPE-DPI) that exhibits efficient intersystem crossing and subsequently captures oxygen molecules through binding O2 to the lone pair of nitrogen in piperazine is reported. The close spatial vicinity between O2 and PPE-DPI strongly promotes the electron transfer reaction, ensuring the exclusive superoxide radical (O2 •-) generation via Type-I process. Particularly, PPE-DPI with cationic pyridine groups is able to associate with cucurbit[7]uril (CB[7]) through host-guest interactions. Thus, supramolecular assembly and disassembly are easily utilized to realize switchable O2 •- generation. This switchable Type-I PS is successfully employed in photodynamic antibacterial control.

Summary and future of medicine for hereditary angioedema.

Hereditary angioedema (HAE) is a rare autosomal genetic disease for which there are currently nine FDA-approved drugs. This review summarizes drug treatments for HAE based on four therapeutic pathways: inhibiting the contact system, inhibiting bradykinin binding to B2 receptors, supplying missing C1 inhibitors, and inhibiting plasminogen conversion. The review generalizes the clinical use, pharmacological effects and mechanisms of HAE drugs, and it also discusses possible development directions and targets to enhance understanding of HAE and help researchers.

A pilot study on the expression of circadian clock genes in the alveolar bone of mice with periodontitis.

This study aimed to investigate the expression of circadian clock genes in mouse alveolar bone, and the possible reasons for these changes. Fifty C57 mice were orally inoculated with P. gingivalis, establishing a model of periodontitis using healthy mice as controls. The alveolar bone of both groups was taken for micro-computed tomography scanning to measure the amount of attachment loss, and the relative expression of mRNA in each clock gene and periodontitis related inflammatory factor was detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). After the establishment of the mouse model, the height of alveolar bone in the periodontitis group was significantly lower than that in the normal group (p < 0.05). The relative transcriptional level of Bmal1, Per2, and Cry1 mRNA was in the circadian rhythm in the normal group (p ≤ 0.05), while in the periodontitis group, its circadian rhythm disappeared and the transcriptional level characteristics were changed. Interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and interferon (IFN-γ) mRNA transcriptional level were elevated in the periodontitis group compared to the normal group. In conclusion, the mRNA transcriptional level of Bmal1, Per2, and Cry1 in alveolar bone of normal mice has circadian rhythm, but the rhythm disappears under the condition of periodontitis, and the cause of its occurrence may be related to inflammatory cytokines.

Chemical synthesis of a 28 kDa full-length PET degrading enzyme ICCG by the removable backbone modification strategy.

Chemical protein synthesis offers a powerful way to access otherwise-difficult-to-obtain proteins such as mirror-image proteins. Although a large number of proteins have been chemically synthesized to date, the acquisition to proteins containing hydrophobic peptide fragments has proven challenging. Here, we describe an approach that combines the removable backbone modification strategy and the peptide hydrazide-based native chemical ligation for the chemical synthesis of a 28 kDa full-length PET degrading enzyme IGGC (a higher depolymerization efficiency of variant leaf-branch compost cutinase (LCC)) containing hydrophobic peptide segments. The synthetic ICCG exhibits the enzymatic activity and will be useful in establishing the corresponding mirror-image version of ICCG.

A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C).

K-Ras is a frequently mutated oncogene in human malignancies, and the development of inhibitors targeting various oncogenic K-Ras mutant proteins is a major challenge in targeted cancer therapy, especially K-Ras(G12C) is the most common mutant, which occurs in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other highly prevalent malignancies. In recent years, significant progress has been made in developing small molecule covalent inhibitors targeting K-Ras(G12C), thanks to the production of nucleophilic cysteine by the G12C mutant, breaking the "spell" that K-Ras protein cannot be used as a drug target. With the successful launch of sotorasib and adagrasib, the development of small molecule inhibitors targeting various K-Ras mutants has continued to gain momentum. In recent years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology, fragment-based drug design strategies have shown great potential in the development of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually become the focus of this field, indirectly indicating that such small molecule inhibitors still the potential for the development of these small molecule inhibitors are also indirectly indicated. This paper traces the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, as well as their common problems and general solutions, in order to provide inspiration and help to the subsequent researchers.

Diagnostic performance of renal cortical elasticity by supersonic shear wave imaging in pediatric glomerular disease.

PURPOSE: To explore the diagnostic performance of renal cortical elasticity expressed by Young's modulus (YM) using the supersonic shear wave imaging (SSI) technique in pediatric glomerular disease. MATERIALS AND METHODS: Seventy-one children with glomerular disease confirmed by renal biopsy and sixty healthy volunteers were enrolled in this study. Conventional and SSI ultrasound examinations were performed in all individuals for both kidneys. We measured renal length, renal width, renal thickness, parenchyma thickness, interlobar arterial resistive index (RI) and the YM of the middle and lower pole. RESULTS: Regardless of which pole and which side of the kidney, the YM in the disease group was significantly higher than that in the control group (P < 0.001). The YM of the middle pole in the left kidney demonstrated the largest AUC (0.936, P < 0.001), and the corresponding cut-off value was 15.48 kPa with a sensitivity of 87.3% and a specificity of 86.7%. There was no significant difference in the YM among different pathological types of pediatric glomerular disease in the disease group, and the same in different grades of patients with Immunoglobulin A (IgA) nephropathy by Lee classification and the Oxford Classification as well as Henoch-Schonlein purpura nephritis (HSPN) by International Study of Kidney Disease in Children (ISKDC) classification (P > 0.05). We found positive but weak correlations between the YM and renal length (r = 0.299, P = 0.001), renal width (r = 0.408, P < 0.001), renal thickness (r = 0.299, P = 0.001), and parenchyma thickness (r = 0.212, P = 0.015), whereas the YM had no significant correlations with age, sex, BMI, interlobar arterial RI, and laboratory findings (P > 0.05). CONCLUSIONS: SSI technology is a non-invasive and feasible method for the diagnosis of pediatric glomerular disease. However, SSI did not show good performance in distinguishing different pathological types and disease grades in our study.

Digital intervention in improving the outcomes of mental health among LGBTQ+ youth: a systematic review.

LGBTQ+ youth experience mental health disparities and higher rates of mental disorders due to barriers to accessing care, including insufficient services and the anticipated stigma of revealing their identities. This systematic review incorporated 15 empirical studies on digital interventions' impact on LGBTQ+ youth mental health, examining their potential to address these inequities. This study innovatively categorized existing digital interventions into four streams: Structured Formal (telehealth, online programs), Structured Informal (serious games), Unstructured Formal (mobile applications), and Unstructured Informal (social media). We found that S&F and U&F effectively reduced symptoms. U&F showed potential but required enhancement, while U&I fostered resilience but posed risks. Further integration of emerging technologies like virtual reality may strengthen these interventions. This review identifies the characteristics of effective digital health interventions and evaluates the overall potential of digital technologies in improving LGBTQ+ youth mental health, uniquely contributing insights on digital solutions advancing LGBTQ+ youth mental healthcare.

Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.

BACKGROUND: Somatic mutations of cancer driver genes are found to be responsible for vascular malformations with clinical manifestations ranging from cutaneous birthmarks to life-threatening systemic anomalies. Till now, only a limited number of cases and mutations were reported in Chinese population. The purpose of this study was to describe the somatic mutation spectrum of a cohort of Chinese pediatrics with vascular malformations. METHODS: Pediatrics diagnosed with various vascular malformations were collected between May 2019 and October 2020 from Beijing Children's Hospital. Genomic DNA of skin lesion of each patient was extracted and sequenced by whole-exome sequencing to identify pathogenic somatic mutations. Mutations with variant allele frequency less than 5% were validated by ultra-deep sequencing. RESULTS: A total of 67 pediatrics (33 males, 34 females, age range: 0.1-14.8 years) were analyzed. Exome sequencing identified somatic mutations of corresponding genes in 53 patients, yielding a molecular diagnosis rate of 79.1%. Among 29 PIK3CA mutations, 17 were well-known hotspot p.E542K, p.E545K and p.H1047R/L. Non-hotspot mutations were prevalent in patients with PIK3CA-related overgrowth spectrum, accounting for 50.0% (11/22) of detected mutations. The hotspot GNAQ p.R183Q and TEK p.L914F mutations were responsible for the majority of port-wine stain/Sturge-Weber syndrome and venous malformation, respectively. In addition, we identified a novel AKT1 p.Q79K mutation in Proteus syndrome and MAP3K3 p.E387D mutation in verrucous venous malformation. CONCLUSIONS: The somatic mutation spectrum of vascular malformations in Chinese population is similar to that reported in other populations, but non-hotspot PIK3CA mutations may also be prevalent. Molecular diagnosis may help the clinical diagnosis, treatment and management of these pediatric patients with vascular malformations.

Data evaluation algorithm for compensation litigation for ecotope pollution damage in the Yellow River valley caused by industrial wastewater from the perspective of green development.

Since the reform and opening up, China's economy has achieved amazing growth. At the same time of industrialization transformation, the traditional high-energy consumption and external growth model has brought serious environmental problems, and the pollution control situation is facing many difficulties. The Yellow River Valley gives birth to the Chinese civilization. With the formulation of the national strategy for ecological protection and high-quality development in the Yellow River Basin and the demand for green development, the control of industrial pollution has become the main task of environmental protection in the Yellow River Basin. However, the research on the ecotope pollution in the Yellow River Valley mainly stays in the theory and strategy. In response to the above problems, this paper would carry out scientific data analysis and high-dimensional research on the ecotope pollution in the Yellow River Valley from the perspective of green development and data analysis algorithms. The research results showed that the reconstruction probability of the Threshold-based Sparsity Adaptive Matching Pursuit (TSAMP) algorithm remained 100% when K was less than 50.

Cyclodextrin-induced phase transformation of cesium copper bromide perovskite.

Phase transformation represents a fascinating way to tune the structural and optical properties of metal halide perovskites. Macrocyclic cyclodextrin could trigger transformation of cesium copper bromide, driven by strong interactions of the macrocyclic hydroxyl groups with the perovskite cesium and bromide ions.

Pathophysiological consequences and treatment strategy of obstructive jaundice.

Obstructive jaundice (OJ) is a common problem in daily clinical practice. However, completely understanding the pathophysiological changes in OJ remains a challenge for planning current and future management. The effects of OJ are widespread, affecting the biliary tree, hepatic cells, liver function, and causing systemic complications. The lack of bile in the intestine, destruction of the intestinal mucosal barrier, and increased absorption of endotoxins can lead to endotoxemia, production of proinflammatory cytokines, and induce systemic inflammatory response syndrome, ultimately leading to multiple organ dysfunction syndrome. Proper management of OJ includes adequate water supply and electrolyte replacement, nutritional support, preventive antibiotics, pain relief, and itching relief. The surgical treatment of OJ depends on the cause, location, and severity of the obstruction. Biliary drainage, surgery, and endoscopic intervention are potential treatment options depending on the patient's condition. In addition to modern medical treatments, Traditional Chinese medicine may offer therapeutic benefits for OJ. A comprehensive search was conducted on PubMed for relevant articles published up to August 1970. This review discusses in detail the pathophysiological changes associated with OJ and presents effective strategies for managing the condition.

Rational Design of Esterase-Insensitive Fluorogenic Probes for In Vivo Imaging.

Small-molecule fluorogenic probes are indispensable tools for performing research in biomedical fields and chemical biology. Although numerous cleavable fluorogenic probes have been developed to investigate various bioanalytes, few of them meet the baseline requirements for in vivo biosensing for disease diagnosis due to their insufficient specificity resulted from the remarkable esterase interferences. To address this critical issue, we developed a general approach called fragment-based fluorogenic probe discovery (FBFPD) to design esterase-insensitive probes for in vitro and in vivo applications. With the designed esterase-insensitive fluorogenic probe, we successfully achieved light-up in vivo imaging and quantitative analysis of cysteine. This strategy was further extended to design highly specific fluorogenic probes for other representative targets, sulfites, and chymotrypsin. The present study expands the bioanalytical toolboxes available and offers a promising platform to develop esterase-insensitive cleavable fluorogenic probes for in vivo biosensing and bioimaging for the early diagnosis of diseases.