Mesoporous Cubic Nanocages Assembled by Coupled Monolayers With 100% Theoretical Capacity and Robust Cycling.

High capacity and long cycling often conflict with each other in electrode materials. Despite extensive efforts in structural design, it remains challenging to simultaneously achieve dual high electrochemical properties. In this study, we prepared brand-new completely uniform mesoporous cubic-cages assembled by large d-spacing Ni(OH)2 coupled monolayers intercalated with VO4 3- (NiCMCs) using a biomimetic approach. Such unique mesoporous structural configuration results in an almost full atomic exposure with an amazing specific surface area of 505 m2/g and atomic utilization efficiency close to the theoretical limit, which is the highest value and far surpasses all of the reported Ni(OH)2. Thus, a breakthrough in simultaneously attaining high capacity approaching the 100% theoretical value and robust cycling of 10,000 cycles is achieved, setting a new precedent in achieving double-high attributes. When combined with high-performance Bi2O3 hexagonal nanotubes, the resulting aqueous battery exhibits an ultrahigh energy density of 115 Wh/kg and an outstanding power density of 9.5 kW/kg among the same kind. Characterizations and simulations reveal the important role of large interlayer spacing intercalation units and mesoporous cages for excellent electrochemical thermodynamics and kinetics. This work represents a milestone in developing "double-high" electrode materials, pointing in the direction for related research and paving the way for their practical application.

Maintenance therapy with anlotinib after induction therapy with platinum-based chemotherapy for advanced non-small-cell lung cancer: A pooled analysis of 2 single-arm trials.

BACKGROUND: Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. METHODS: This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. RESULTS: The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. CONCLUSION: Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.

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.

Glycerol Metabolism Contributes to Competition by Oral Streptococci through Production of Hydrogen Peroxide.

As a biological byproduct from both humans and microbes, glycerol's contribution to microbial homeostasis in the oral cavity remains understudied. Here we examined glycerol metabolism by Streptococcus sanguinis, a commensal associated with oral health. Genetic mutants of glucose-PTS enzyme II ( manL ), glycerol metabolism ( glp and dha pathways), and transcriptional regulators were characterized with regard to glycerol catabolism, growth, production of hydrogen peroxide (H 2 O 2 ), transcription, and competition with Streptococcus mutans . Biochemical assays identified the glp pathway as a novel source of H 2 O 2 production by S. sanguinis that is independent of pyruvate oxidase (SpxB). Genetic analysis indicated that the glp pathway requires glycerol and a transcriptional regulator, GlpR, for expression and is negatively regulated by PTS, but not the catabolite control protein, CcpA. Conversely, deletion of either manL or ccpA increased expression of spxB and a second, H 2 O 2 -non-producing glycerol metabolic pathway ( dha ), indicative of a mode of regulation consistent with conventional carbon catabolite repression (CCR). In a plate-based antagonism assay and competition assays performed with planktonic and biofilm-grown cells, glycerol greatly benefited the competitive fitness of S. sanguinis against S. mutans. The glp pathway appears to be conserved in several commensal streptococci and actively expressed in caries-free plaque samples. Our study suggests that glycerol metabolism plays a more significant role in the ecology of the oral cavity than previously understood. Commensal streptococci, though not able to use glycerol as a sole carbohydrate for growth, benefit from catabolism of glycerol through production of both ATP and H 2 O 2 . Importance: Glycerol is an abundant carbohydrate found in oral cavity, both due to biological activities of humans and microbes, and as a common ingredient of foods and health care products. However, very little is understood regarding the metabolism of glycerol by some of the most abundant oral bacteria, commensal streptococci. This was in part because most streptococci cannot grow on glycerol as the sole carbon source. Here we show that Streptococcus sanguinis , an oral commensal associated with dental health, can degrade glycerol for persistence and competition through two independent pathways, one of which generates hydrogen peroxide at levels capable of inhibiting a dental pathobiont, Streptococcus mutans . Preliminary studies suggest that several other commensal streptococci are also able to catabolize glycerol, and glycerol-related genes are being actively expressed in human dental plaque samples. Our findings reveal the potential of glycerol to significantly impact microbial homeostasis which warrants further exploration.

Matrix protein of vesicular stomatitis virus targets the mitochondria, reprograms glucose metabolism，and sensitizes to 2-deoxyglucose in glioblastoma.

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism towards glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog, was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP effects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mTOR signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells, however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment, and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.

Enhanced water decontamination via photogenerated electron delocalization of π → π* and D-π-A synergistically.

Mixed-dimensional van der Waals heterojunctions (MD-vdWhs), known for exceptional electron transfer and charge separation capabilities, remain underexplored in photocatalysis. In this study, we leveraged the synergistic effect of intermolecular π â†’ π* and D-π-A dual channels to fabricate novel MD-vdWhs. Owing to the synergistic effect, it exhibits superior electron transfer and delocalization ability, thereby enhancing its photocatalytic performance. The Optimal photocatalyst can degrade 98.78 % of 20 mg/L tetracycline (TC) within 15 min. Additionally, we introduced a novel proof strategy for investigating the photoelectron transfer path, creatively demonstrating the synergistic dual channels effect, which can be attributed to the carbonyl density and light-excitation degree. Notably, even under low-power light sources, it achieved complete inactivation of Escherichia coli within just 7 mins, far surpassing current cutting-edge research. This theoretical framework holds promise for broader applications within related studies.

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.

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.

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.

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.

Mechanism investigation of Forsythoside A against esophageal squamous cell carcinoma in vitro and in vivo.

CONTEXT: Forsythoside A (FSA) was extracted from Forsythia suspensa, a traditional Chinese medicine, which has been demonstrated to exert anti-inflammatory, antibacterial, and other pharmacological effects. However, the anticancer effect of FSA in esophageal squamous cell carcinoma (ESCC) has not been documented. OBJECTIVE: The present study aimed to elucidate the mechanism of FSA against ESCC. MATERIALS AND METHODS: Network pharmacology and molecular docking were employed to predict the mechanism. FSA was utilized to treat ESCC cell lines KYSE450 and KYSE30, followed by CCK-8 assay, cell cloning formation assay, flow cytometry, Western blot, RNA-seq analysis, and subsequent in vivo experiments. RESULTS: Network pharmacology and molecular docking predicted that the therapeutic effect of FSA in ESCC is mediated through proteins such as BCL2 and BAX, influencing KEGG pathways associated with apoptosis. In vitro experiments showed that FSA inhibited cell proliferation and plate clone formation, promoted cell apoptosis and impacted the cell cycle distribution of G2/M phase by regulating BCL2, BAX, and p21. Further RNA-seq in KYSE450 cells showed that FSA regulated the expression of 223 genes, specifically affecting the biological process of epidermal development. In vivo experiments showed that gastric administration of FSA resulted in notable reductions in both tumor volume and weight by regulating BCL2, BAX, and p21. 16S rRNA sequencing showed that FSA led to significant changes of beta diversity. Abundance of 11 specific bacterial taxa were considerably changed following administration of FSA. CONCLUSIONS: This study presents a novel candidate drug against ESCC and establishes a foundation for future clinical application.

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.

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.

[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].

The efficacy of early office hysteroscopy in preventing intrauterine adhesions after abortion: a randomized controlled trial.

BACKGROUND: Intrauterine adhesions (IUA) are a challenging clinical problem in reproductive infertility. The most common causes are intrauterine surgery and abortions. We aimed to investigate whether early second-look office hysteroscopy can prevent IUA. METHODS: A single-center, prospective, two-armed, randomized controlled trial was designed to explore the efficacy of early office hysteroscopy after first-trimester induced abortion (suction dilatation and curettage [D&C]) and to further analyze fertility outcomes. Women aged 20-45 years undergoing suction D&C and desiring to conceive were recruited. Between October 2019 and September 2022, 66 women were enrolled, of whom 33 were allocated to group A (early hysteroscopy intervention). The women in intervention group A were planned to receive 2 times of hysteroscopies (early and late). In group B, women only underwent late (6 months post suction D&C) hysteroscopy. RESULTS: The primary outcome was the IUA rate assessed using office hysteroscopy 6 months after artificial abortion. Secondary outcomes included menstrual amount/durations and fertility outcomes. In intervention group A, 31 women underwent the first hysteroscopy examination, and 15 completed the second. In group B (late hysteroscopy intervention, 33 patients), 16 completed the hysteroscopic exam 6 months after an artificial abortion. Twenty-one women did not receive late hysteroscopy due to pregnancy. The IUA rate was 16.1% (5/31) at the first hysteroscopy in group A, and no IUA was detected during late hysteroscopy. Neither group showed statistically significant differences in the follow-up pregnancy and live birth rates. CONCLUSIONS: Early hysteroscopy following suction D&C can detect intrauterine lesions. IUA detected early by hysteroscopy can disappear on late examination and become insignificant for future pregnancies. Notably, the pregnancy outcomes showed a favorable trend in the early hysteroscopy group, but there were no statistically significant differences. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04166500. Registered on 2019-11-10. https://clinicaltrials.gov/ct2/show/NCT04166500 .

A high stable sample loading for analysis of adult alpha-thalassemia via the improved microarray isoelectric focusing of Hb species.

The isoelectric focusing has realized various improvements, including the protocols and creation of mIEF (microcolumn isoelectric focusing) instruments with excellent sensitivity for screening of diabetes and beta thalassemia. However, the problem of manual sample loading and hydration for the mIEF limits the operational capacity for stably detecting and quantitating most abnormal hemoglobin (Hb). Herein, we provided a high stable sample loading protocol for analysis of alpha thalassemia and Hb variants. In contrast to the previous volume of 20 µl, a 100 µl blood sample solution in this protocol was optimized with mixture of 6.4-7.5 and 3-10 pH carrier ampholytes, pI markers and loaded for 30 mins IPG microcolumn hydration. The hydrated microcolumn was then automatically loaded onto the mIEF chip array to which CH3COOH and NH4OH act as anodic and cathodic solutions. Lastly, the IEF was run for 9 mins. Hb H, Barts, A1c, F, A2 and CS were simultaneously separated and focused with higher resolution and sensitivity in quantifying H and Barts as low as 0.6 and 0.5 % respectively. Accordingly, there was an enhanced stability and linearity with a rapid assay time of 45 secs per sample. Moreover, analysis showed a fitting linear relationship with conventional technology at R2 = 0.9803 for H and R2 = 0.9728 for Barts thereby indicating greater accuracy confirmed by the AUC. Hence, the developed protocol could simply be employed for high stable and throughput batch sample loading of hydration, and accurate separation and quantitation of Hb variants for alpha and beta thalassemia.

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.

Effects of N levels on land productivity and N2O emissions in maize-soybean relay intercropping.

BACKGROUND: Relay intercropping of maize and soybean can improve land productivity. However, the mechanism behind N2O emissions in this practice remains unclear. A two-factor randomized block field trial was conducted to reveal the mechanism of N2O emissions in a full additive maize-soybean relay intercropping. Factor A was three cropping systems - that is, monoculture maize (Zea mays L.), monoculture soybean (Glycine max L. Merr.) and maize-soybean relay intercropping. Factor B was different N supply, containing no N, reduced N and conventional N. Differences in N2O emissions, soil properties, rhizosphere bacterial communities and yield advantage were evaluated. RESULTS: The land equivalent ratio was 1.55-2.44, and the cumulative N2O emission ( C E N 2 O $$ \mathrm{C}{\mathrm{E}}_{{\mathrm{N}}_2\mathrm{O}} $$ ) was notably lower by 60.2% in intercropping than in monoculture, respectively. Reduced N declined C E N 2 O $$ \mathrm{C}{\mathrm{E}}_{{\mathrm{N}}_2\mathrm{O}} $$ without penalty on the yield advantages. The relay intercropping shifted soil properties - for example, soil organic matter, total N, NH 4 + $$ {\mathrm{NH}}_4^{+} $$ and protease activity - and improved the soil microorganism community - for example, Proteobacteria and Acidobacteria. Intercropping reduced C E N 2 O $$ \mathrm{C}{\mathrm{E}}_{{\mathrm{N}}_2\mathrm{O}} $$ by directly suppressing nirS- and amoA-regulated N2O generation during soil N cycling, or nirS- and amoA-mediated soil properties shifted to reduce C E N 2 O $$ \mathrm{C}{\mathrm{E}}_{{\mathrm{N}}_2\mathrm{O}} $$ indirectly. Reduced N directly reduced C E N 2 O $$ \mathrm{C}{\mathrm{E}}_{{\mathrm{N}}_2\mathrm{O}} $$ by decreasing soil N content and reducing soil microorganism activities to alleviate N2O produced in soil N cycling. CONCLUSION: Conducting a full additive maize-soybean relay intercropping with reduced nitrogen supply provides a way to alleviate N2O emissions without the penalty on the yield advantage by changing rhizosphere bacterial communities and soil N cycling. © 2024 Society of Chemical Industry.