Association between situs inversus and maternal SARS-CoV-2 infection at gestational age 4-6.

BACKGROUND: A dramatic increase in fetal situs inversus diagnoses by ultrasound in the months following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surge of December 2022 in China led us to investigate whether maternal SARS-CoV-2 exposure could be associated with elevated risk of fetal situs inversus. METHODS: In this multi-institutional, hospital-based, matched case-control study, we investigated pregnant women who underwent ultrasonographic fetal biometric assessment at gestational weeks 20-24 at our hospitals. Each pregnant woman carrying a situs inversus fetus was randomly matched with four controls based on the date of confinement. Relevant information, including SARS-CoV-2 infection, and other potential risk factors were collected. Conditional logistic regression was used to test possible associations between fetal situs inversus and SARS-CoV-2 infection at different gestational weeks as well as individual risk factors. FINDINGS: A total of 52 pregnant women diagnosed with fetal situs inversus between January 1 and October 31, 2023 and 208 matched controls with normal fetuses were enrolled. We found no association between an increased risk of fetal situs inversus with gestational SARS-CoV-2 infection or with other risk factors. However, fetal situs inversus was significantly associated with SARS-CoV-2 infection specifically in gestational weeks 4-6 (adjusted odds ratio [aOR] 6.54 [95% confidence interval 1.76-24.34]), but not with infection at other gestational ages, after adjusting for covariates. CONCLUSIONS: Increased risk of fetal situs inversus is significantly associated with maternal SARS-CoV-2 infection at gestational weeks 4-6, corresponding to the fetal developmental window for visceral lateralization in humans. FUNDING: National Key R&D Program of China, etc.

Tracking the extensive three-dimensional motion of single ions by an engineered point-spread function.

Three-dimensional (3D) imaging of individual atoms is a critical tool for discovering new physical phenomena and developing new technologies in microscopic systems. However, the current single-atom-resolved 3D imaging methods are limited to static circumstances or a shallow detection range. Here, we demonstrate a generic dynamic 3D imaging method to track the extensive motion of single ions by exploiting the engineered point-spread function (PSF). We show that the image of a single ion can be engineered into a helical PSF, thus enabling single-snapshot acquisition of the position information of the ion in the trap. A preliminary application of this technique is demonstrated by recording the 3D motion trajectory of a single trapped ion and reconstructing the 3D dynamical configuration transition between the zig and zag structures of a 5-ion crystal. This work opens the path for studies on single-atom-resolved dynamics in both trapped-ion and neutral-atom systems.

Doctor simulator: Delta-Age-Sex-AdaIn enhancing bone age assessment through AdaIn style transfer.

BACKGROUND: Bone age assessment assists physicians in evaluating the growth and development of children. However, deep learning methods for bone age estimation do not currently incorporate differential features obtained through comparisons with other bone atlases. OBJECTIVE: To propose a more accurate method, Delta-Age-Sex-AdaIn (DASA-net), for bone age assessment, this paper combines age and sex distribution through adaptive instance normalization (AdaIN) and style transfer, simulating the process of visually comparing hand images with a standard bone atlas to determine bone age. MATERIALS AND METHODS: The proposed Delta-Age-Sex-AdaIn (DASA-net) consists of four modules: BoneEncoder, Binary code distribution, Delta-Age-Sex-AdaIn, and AgeDecoder. It is compared with state-of-the-art methods on both a public Radiological Society of North America (RSNA) pediatric bone age prediction dataset (14,236 hand radiographs, ranging from 1 to 228 months) and a private bone age prediction dataset from Zigong Fourth People's Hospital (474 hand radiographs, ranging from 12 to 218 months, 268 male). Ablation experiments were designed to demonstrate the necessity of incorporating age distribution and sex distribution. RESULTS: The DASA-net model achieved a lower mean absolute deviation (MAD) of 3.52 months on the RSNA dataset, outperforming other methods such as BoneXpert, Deeplasia, BoNet, and other deep learning based methods. On the private dataset, the DASA-net model obtained a MAD of 3.82 months, which is also superior to other methods. CONCLUSION: The proposed DASA-net model aided the model's learning of the distinctive characteristics of hand bones of various ages and both sexes by integrating age and sex distribution into style transfer.

Efficacy of linaclotide in combination with polyethylene glycol for bowel preparation in Chinese patients undergoing colonoscopy polypectomy: protocol for a randomised controlled trial.

BACKGROUND: Adequate bowel preparation is essential for successful colonoscopy and polypectomy procedures. However, a significant proportion of patients still exhibit suboptimal bowel preparation, ranging from 18% to 35%. The effectiveness of bowel preparation agents can be hampered by volume and taste, adversely affecting patient compliance and tolerance. Therefore, exploring strategies to minimise laxative volume and improve patient tolerance and adherence is imperative to ensure optimal bowel preparation quality. METHODS AND ANALYSIS: This study is a two-arm, single-blinded, parallel-group randomised controlled trial designed to compare the efficacy of 2 L polyethylene glycol (PEG) combined with linaclotide with 4 L PEG in bowel cleansing. A total of 422 participants will be randomly assigned in a 1:1 ratio to either the intervention group (2 L PEG combined with 580 µg linaclotide) or the control group (4 L PEG). The primary outcome measure is bowel cleansing efficacy, which is assessed using the Boston Bowel Preparation Scale. Secondary outcomes include evaluating the tolerability and safety of the bowel preparation regimens, bowel diary assessments, postpolypectomy complications (such as bleeding and perforation) and the size and number of removed polyps. ETHICS AND DISSEMINATION: The study has received approval from the Clinical Research Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine. The findings of this trial will serve as a valuable resource for clinicians and patients undergoing colonoscopy polypectomy by guiding the selection of appropriate bowel preparation regimens. Study findings will be disseminated to participants, presented at professional society meetings, and published in peer-reviewed journals. This trial was registered on the Chinese Clinical Trial Registry with registration number ChiCTR2300075410.

Enhancing interfacial electron transfer and photoelectrochemical kinetics for efficient water-treatment strategy through N-doped carbon dots modified PhC2Cu.

To improve the water environment quality, the development of an effective photocatalyst for pollutant removal was considered a promising strategy. The aim of the development of a novel photocatalyst PNC is pursued by modifying copper-phenylacetylide (PhC2Cu) with nitrogen-doped carbon quantum dots (N-CDs). Leading to a remarkable improvement in its light absorption capability, electron transfer efficiency and photoelectrochemical properties. Importantly, PNC possesses the characteristic of straightforward synthesis and demonstrates remarkable performance in the photodegradation of 99.87% sulfamethoxazole (SMX) within just 15 min, with a 3.95-fold increase in the photocatalytic rate. Analysis of the active substances revealed that 1O2, O2·-, and h+ are the generated active species by PNC. Active sites and degradation pathways of SMX were explored through density functional theory (DFT) calculations and intermediate analysis. Key evidence regarding the direction of electron transfer within the system was obtained through in-situ irradiated X-ray (ISI-XPS) techniques. This study deepened our understanding of the electron transfer characteristics of phenylacetylene copper and provided new insights for the modification of photocatalysts.

Relationship between pelvic floor muscle function and insulin resistance among non-diabetic females: a 3d ultrasound evaluation.

BACKGROUND: To use the three-dimensional (3D) ultrasound for assessment of pelvic floor muscle function in non-diabetic females with insulin resistance (IR), and to evaluate its functional relationship with insulin levels. METHODS: From October 2022 to November 2023, 216 non-diabetic females with insulin-resistant (IR group) and 118 normal females (control group) were sequentially recruited from our hospital for our study. The 3D ultrasound was used to assess the levator hiatus in resting state for all females regarding diameter lines, perimeters and areas; as well as the Valsalva manoeuvre (VM). The t-test and linear regression model were used to analyse the collected data. RESULTS: The analysis indicates that there were significant differences in the resting state of the levator hiatus between the IR and the control groups (14.8 ± 5.8 cm2 and 11.6 ± 2.7 cm2, p < 0.05); and in the VM (18.2 ± 6.3 cm2 and 13.4 ± 3. 4 cm2, p < 0.05). In addition, the anterior-posterior (AP) diameters of the hiatus on VM were significantly increased in the IR group (40.0 ± 4.7 mm and 33.0 ± 4.4 mm, p < 0.05). With insulin levels as the dependent variable, multivariate regression analysis shows that insulin levels were significantly correlated with the levator hiatus area on VM (p < 0.05) and waist circumference (p < 0.05). The pelvic organ descent on VM in the IR group was significant (p < 0.05). CONCLUSIONS: The areas of resting state levator hiatus and on VM were significantly larger in the IR than that in the control groups. In addition, the position of the pelvic organ on VM in the IR group was significantly descended. The insulin levels were correlated with the pelvic floor muscle function.

With regard to insulin resistance and pelvic floor function, previous studies focused on the role of polycystic ovaries, metabolic syndrome, and pelvic prolapse. The use of ultrasound can improve understanding of the static, dynamic and organ prolapse conditions. This study aimed to assess pelvic floor muscle function in non-diabetic women with insulin resistance, a condition where the body uses insulin less effectively. A total of 216 women with insulin resistance and 118 without it were examined using 3D ultrasound during rest and while performing the Valsalva manoeuvre. Our results show that the pelvic floor muscles had extra space between them and moved differently in women with insulin resistance than in those without the condition. This suggests that insulin resistance may affect function of pelvic floor muscles to cause adverse consequences.

Ethnic-specific genetic susceptibility loci for endometriosis in Taiwanese-Han population: a genome-wide association study.

Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies.

Uncovering the Shuixian tea grades hierarchy in Chinese national standard: From sensory evaluation to microstructure and volatile compounds analysis.

Basic standard samples are integral for ensuring consistency and quality control of tea. Understanding the real reasons behind the hierarchical system of Shuixian tea grades in the Chinese national standard is crucial to the scientific development of tea standardization. In this investigation, different grade samples of Shuixian tea strictly conformed to the Chinese national standard, serving as the research objects. Sensory evaluation, SEM and HS-SPME-GC-MS were employed to comprehensively analyze the aroma characteristics. The odor profiles of special grade samples predominantly featured floral and fruity aromas, which attributed to compounds such as geraniol, indole, phenylethyl alcohol. Additionally, hexanal, (E)-3-hexen-1-ol and other compounds contributed to fruity and sweet aroma in first grade. Notably, the predominant roasted and sweet aromas of second grade were attributed to compounds including pyridine, 2,5-dimethyl-pyrazine. This study lays a solid foundation for the scientific development of Chinese national standards and international standard system.

Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Identification of PgRg1-3 Gene for Ginsenoside Rg1 Biosynthesis as Revealed by Combining Genome-Wide Association Study and Gene Co-Expression Network Analysis of Jilin Ginseng Core Collection.

Ginseng, an important medicinal plant, is characterized by its main active component, ginsenosides. Among more than 40 ginsenosides, Rg1 is one of the ginsenosides used for measuring the quality of ginseng. Therefore, the identification and characterization of genes for Rg1 biosynthesis are important to elucidate the molecular basis of Rg1 biosynthesis. In this study, we utilized 39,327 SNPs and the corresponding Rg1 content from 344 core ginseng cultivars from Jilin Province. We conducted a genome-wide association study (GWAS) combining weighted gene co-expression network analysis (WGCNA), SNP-Rg1 content association analysis, and gene co-expression network analysis; three candidate Rg1 genes (PgRg1-1, PgRg1-2, and PgRg1-3) and one crucial candidate gene (PgRg1-3) were identified. Functional validation of PgRg1-3 was performed using methyl jasmonate (MeJA) regulation and RNAi, confirming that this gene regulates Rg1 biosynthesis. The spatial-temporal expression patterns of the PgRg1-3 gene and known key enzyme genes involved in ginsenoside biosynthesis differ. Furthermore, variations in their networks have a significant impact on Rg1 biosynthesis. This study established an accurate and efficient method for identifying candidate genes, cloned a novel gene controlling Rg1 biosynthesis, and identified 73 SNPs significantly associated with Rg1 content. This provides genetic resources and effective tools for further exploring the molecular mechanisms of Rg1 biosynthesis and molecular breeding.

A comparative metabolomic analysis reveals the metabolic variations among cartilage of Kashin-Beck disease and osteoarthritis.

Aims: The metabolic variations between the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) remain largely unknown. Our study aimed to address this by conducting a comparative analysis of the metabolic profiles present in the cartilage of KBD and OA. Methods: Cartilage samples from patients with KBD (n = 10) and patients with OA (n = 10) were collected during total knee arthroplasty surgery. An untargeted metabolomics approach using liquid chromatography coupled with mass spectrometry (LC-MS) was conducted to investigate the metabolomics profiles of KBD and OA. LC-MS raw data files were converted into mzXML format and then processed by the XCMS, CAMERA, and metaX toolbox implemented with R software. The online Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to annotate the metabolites by matching the exact molecular mass data of samples with those from the database. Results: A total of 807 ion features were identified for KBD and OA, including 577 positive (240 for upregulated and 337 for downregulated) and 230 negative (107 for upregulated and 123 for downregulated) ions. After annotation, LC-MS identified significant expressions of ten upregulated and eight downregulated second-level metabolites, and 183 upregulated and 162 downregulated first-level metabolites between KBD and OA. We identified differentially expressed second-level metabolites that are highly associated with cartilage damage, including dimethyl sulfoxide, uric acid, and betaine. These metabolites exist in sulphur metabolism, purine metabolism, and glycine, serine, and threonine metabolism. Conclusion: This comprehensive comparative analysis of metabolism in OA and KBD cartilage provides new evidence of differences in the pathogenetic mechanisms underlying cartilage damage in these two conditions.

Evolutionary history of adenomas to colorectal cancer in FAP families.

Objective: Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC). In this study, we present a comprehensive analysis of the evolutionary history of FAP-CRC from precancerous adenoma to carcinoma. Design: Tissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families. Phylogenetic trees were reconstructed, and evolutionary analysis was conducted to reveal the temporal sequence of events leading to CRC. Results: Inherited germline mutation sites in APC gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs*19), FAP04 (p.E1538*, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs*3). Notably, p.V677Sfs*3 mutation was recognized as a novel germline mutation in APC, supported by evidence of genotype-phenotype correlation in pedigree analysis. Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability. Furthermore, a progressive increase in the HRD score (a measure of "genomic scars") was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. Clonal evolution demonstrated that liver metastases can originate from the same cancer-primed cell present in a primary cancerous lesion. Conclusion: We identified a novel pathogenic variant in APC, namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN. Subsequently, additional mutations occur in other putative CIN genes (e.g., DNA repair, chromatin remodeling), ultimately leading to the development of microsatellite stable (MSS) tumors. Our study provides a comprehensive understanding of the genomic landscapes that underlie the transition from adenoma to carcinoma.

Toward AI-driven neuroepigenetic imaging biomarker for alcohol use disorder: A proof-of-concept study.

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

[Retracted] MicroRNA­30e inhibits adhesion, migration, invasion and cell cycle progression of prostate cancer cells via inhibition of the activation of the MAPK signaling pathway by downregulating CHRM3.

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the Transwell invasion assay data shown in Fig. 7B on p. 451 were strikingly similar to data that had appeared in Fig. 3D in a previously published paper written by different authors at a different research institute, which had been received at the journal Cancer Letters at around the same time, and which has subsequently been retracted [Gu J, Wang Y, Wang X, Zhou D, Shao C, Zhou M and He Z: Downregulation of lncRNA GAS5 confers tamoxifen resistance by activating miR­222 in breast cancer. Cancer Lett 434: 1­10, 2018]. In addition, there were potentially anomalous features associated with the western blot and cell cycle data in this paper.  In view of the fact that certain of the data in the above article were also submitted to a different journal within the space of a few days, the Editor of International Journal of Oncology has decided that this paper should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 54: 443­454, 2019; DOI: 10.3892/ijo.2018.4647].

Factors related to accurate clinicians' prediction of survival: an international multicenter study in East Asia.

PURPOSE: Recent guidelines for prognostic evaluation recommend clinicians' prediction of survival (CPS) for survival prediction in patients with advanced cancer. However, CPS is often inaccurate and optimistic. Studies on factors associated with overestimation or underestimation of CPS are limited. We aimed to investigate the factors associated with the overestimation and underestimation of CPS in patients with far-advanced cancer. METHODS: The current study was a secondary analysis of an international multicenter prospective cohort study, which enrolled newly admitted patients with advanced cancer in palliative care units (PCUs) in Japan, Korea, and Taiwan from 2017 to 2018. We obtained the temporal CPS at enrollment and performed multivariate logistic regression analysis to identify the factors associated with "underestimation (less than 33% of actual survival)" and "overestimation (more than 33% of actual survival)." RESULTS: A total of 2571 patients were assessed and admitted in 37 PCUs between January 2017 and September 2018. Older age (adjusted odds ratio [aOR] 1.01; 95% confidence interval [CI] 1.01-1.02; P < 0.01) and reduced oral intake (aOR 0.68; 95% CI 0.51-0.89; P < 0.01) were identified as significant factors associated with underestimation. Dyspnea (aOR 1.28; 95% CI 1.06-1.54; P = 0.01) and hyperactive delirium (aOR 1.34; 95% CI 1.05-1.72; P = 0.02) were identified as significant factors associated with overestimation. CONCLUSION: Older age was related to underestimation, while dyspnea and hyperactive delirium were related to overestimation of CPS for patients with weeks of survival. However, reduced oral intake was less likely to lead to underestimation.

Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and independent desensitization mechanisms.

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin (TK) signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their post-translational modifications were observed in extracts of CNS ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (TKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C-termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

Phytochemistry and Biological Profile of the Chinese Endemic Herb Genus Notopterygium.

Notopterygium, a plant genus belonging to the Apiaceae family, is utilized in traditional Chinese medicine for its medicinal properties. Specifically, the roots and rhizomes of these plants are employed in phytotherapy to alleviate inflammatory conditions and headaches. This review provides a concise overview of the existing information regarding the botanical description, phytochemistry, pharmacology, and molecular mechanisms of the two Notopterygium species: Notopterygium incisum and N. franchetii. More than 500 distinct compounds have been derived from these plants, with the root being the primary source. These components include volatile oils, coumarins, enynes, sesquiterpenes, organic acids and esters, flavonoids, and various other compounds. Research suggests that Notopterygium incisum and N. franchetii exhibit a diverse array of pharmacological effects, encompassing antipyretic, analgesic, anti-inflammatory, antiarrhythmic, anticoagulant, antibacterial, antioxidant, and anticancer properties on various organs such as the brain, heart, digestive system, and respiratory system. Building activity screening models based on the pharmacological effects of Notopterygium species, as well as discovering and studying the pharmacological mechanisms of novel active ingredients, will constitute the primary development focus of Notopterygium medicinal research in the future.

Revealing Differential RNA Editing Specificity of Human ADAR1 and ADAR2 in Schizosaccharomyces pombe.

Adenosine-to-inosine (A-to-I) RNA editing is an important post-transcriptional modification mediated by the adenosine deaminases acting on RNA (ADAR) family of enzymes, expanding the transcriptome by altering selected nucleotides A to I in RNA molecules. Recently, A-to-I editing has been explored for correcting disease-causing mutations in RNA using therapeutic guide oligonucleotides to direct ADAR editing at specific sites. Humans have two active ADARs whose preferences and specificities are not well understood. To investigate their substrate specificity, we introduced hADAR1 and hADAR2, respectively, into Schizosaccharomyces pombe (S. pombe), which lacks endogenous ADARs, and evaluated their editing activities in vivo. Using transcriptome sequencing of S. pombe cultured at optimal growth temperature (30 °C), we identified 483 A-to-I high-confident editing sites for hADAR1 and 404 for hADAR2, compared with the non-editing wild-type control strain. However, these sites were mostly divergent between hADAR1 and hADAR2-expressing strains, sharing 33 common sites that are less than 9% for each strain. Their differential specificity for substrates was attributed to their differential preference for neighboring sequences of editing sites. We found that at the -3-position relative to the editing site, hADAR1 exhibits a tendency toward T, whereas hADAR2 leans toward A. Additionally, when varying the growth temperature for hADAR1- and hADAR2-expressing strains, we observed increased editing sites for them at both 20 and 35 °C, compared with them growing at 30 °C. However, we did not observe a significant shift in hADAR1 and hADAR2's preference for neighboring sequences across three temperatures. The vast changes in RNA editing sites at lower and higher temperatures were also observed for hADAR2 previously in budding yeast, which was likely due to the influence of RNA folding at these different temperatures, among many other factors. We noticed examples of longer lengths of dsRNA around the editing sites that induced editing at 20 or 35 °C but were absent at the other two temperature conditions. We found genes' functions can be greatly affected by editing of their transcripts, for which over 50% of RNA editing sites for both hADAR1 and hADAR2 in S. pombe were in coding sequences (CDS), with more than 60% of them resulting in amino acid changes in protein products. This study revealed the extensive differences in substrate selectivity between the two active human ADARS, i.e., ADAR1 and ADAR2, and provided novel insight when utilizing the two different enzymes for in vivo treatment of human genetic diseases using the RNA editing approach.