[Genetic analysis of a fetus with with 45,X/46,X,idic(Y)(q11.2) mosaicism].

OBJECTIVE: To explore the genetic characteristics of a fetus with sex chromosome abnormality indicated by non-invasive prenatal testing (NIPT) at 25+ gestational weeks. METHODS: A pregnant woman who was admitted to the Taizhou Hospital for abnormal NIPT result on January 6, 2023 was selected as the study subject. Relevant clinical data was collected. The fetus was subjected to chromosomal karyotyping analysis, copy number variation sequencing (CNV-seq), fluorescence in situ hybridization (FISH), and multiplex PCR assays. RESULTS: NIPT had suggested monosomy of X chromosome. The fetus was found to have a chromosomal karyotype of 45,X[59]/46,X,del(Y)(q11.2)[17] at 30+ weeks of gestational age. CNV-seq suggested the presence a 7.98 Mb deletion at Yq11.222q12 and a mosaicism 16.92 Mb deletion. FISH suggested that the fetus harbored two SRY genes and a mosaicism sex chromosomal abnormality, and multiplex PCR revealed that its AZF b+c region was completely deleted. C-banded karyotyping showed darkly stained dense mitotic granules at both ends of the Y chromosome. The fetus was ultimately determined as a 45,X/46,X,idic(Y)(q11.2) mosaicism. Following elected abortion, testing of the fetal tissue confirmed the presence of 45,X/46,XY mosaicism, and CNV-seq result of the placental tissue was compatible with that of NIPT. CNV-seq analysis of the couple revealed no obvious abnormality. CONCLUSION: With combined NIPT, karyotyping, CNV-seq, FISH and multiplex PCR assays, the fetus was diagnosed as a 45,X/46,X,idic(Y)(q11.2) mosaicism with deletion of the AZF b+c region. Above finding has enabled prenatal diagnosis for the fetus.

Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .

Cell-recruited microspheres for OA treatment by dual-modulating inflammatory and chondrocyte metabolism.

Osteoarthritis (OA) is a degenerative disease potentially exacerbated due to inflammation, cartilage degeneration, and increased friction. Both mesenchymal stem cells (MSCs) and pro-inflammatory macrophages play important roles in OA. A promising approach to treating OA is to modify multi-functional hydrogel microspheres to target the OA microenvironment and structure. Arginyl-glycyl-aspartic acid (RGD) is a peptide widely used in bioengineering owing to its cell adhesion properties, which can recruit BMSCs and macrophages. We developed TLC-R, a microsphere loaded with TGF-ß1-containing liposomes. The recruitment effect of TLC-R on macrophages and BMSCs was verified by in vitro experiments, along with its function of promoting chondrogenic differentiation of BMSCs. And we evaluated the effect of TLC-R in balancing OA metabolism in vitro and in vivo. When TLC-R was co-cultured with BMSCs and lipopolysaccharide (LPS)-treated macrophages, it showed the ability to recruit both cells in substantial numbers. As the microspheres degraded, TGF-ß1 and chondroitin sulfate (ChS) were released to promote chondrogenic differentiation of the recruited BMSCs, modulate chondrocyte metabolism and inhibit inflammation induced by the macrophages. Furthermore, in vivo analysis showed that TLC-R restored the narrowed space, reduced osteophyte volume, and improved cartilage metabolic homeostasis in OA rats. Altogether, TLC-R provides a comprehensive and novel solution for OA treatment by dual-modulating inflammatory and chondrocyte metabolism.

Genomic and biological insights of bacteriophages JNUWH1 and JNUWD in the arms race against bacterial resistance.

The coevolution of bacteria and bacteriophages has created a great diversity of mechanisms by which bacteria fight phage infection, and an equivalent diversity of mechanisms by which phages subvert bacterial immunity. Effective and continuous evolution by phages is necessary to deal with coevolving bacteria. In this study, to better understand the connection between phage genes and host range, we examine the isolation and genomic characterization of two bacteriophages, JNUWH1 and JNUWD, capable of infecting Escherichia coli. Sourced from factory fermentation pollutants, these phages were classified within the Siphoviridae family through TEM and comparative genomic analysis. Notably, the phages exhibited a viral burst size of 500 and 1,000 PFU/cell, with latent periods of 15 and 20 min, respectively. They displayed stability over a pH range of 5 to 10, with optimal activity at 37°C. The complete genomes of JNUWH1 and JNUWD were 44,785 bp and 43,818 bp, respectively. Phylogenetic analysis revealed their close genetic relationship to each other. Antibacterial assays demonstrated the phages' ability to inhibit E. coli growth for up to 24 h. Finally, through laboratory-driven adaptive evolution, we successfully identified strains for both JNUWH1 and JNUWD with mutations in receptors specifically targeting lipopolysaccharides (LPS) and the lptD gene. Overall, these phages hold promise as additives in fermentation products to counter E. coli, offering potential solutions in the context of evolving bacterial resistance.

The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and aurora kinases.

Despite the development of several Fms-like tyrosine kinase 3 (FLT3) inhibitors that have improved outcomes in patients with FLT3-mutant acute myeloid leukemia (AML), drug resistance is frequently observed, which may be associated with the activation of additional pro-survival pathways, such as those regulated by BTK, aurora kinases (AuroK), and potentially others, in addition to acquired tyrosine kinase domain (TKD) mutations of FLT3 gene. FLT3 may not always be a driver mutation. We evaluated the anti-leukemia efficacy of the novel multi-kinase inhibitor CG-806, which targets FLT3 and other kinases, to circumvent drug resistance and target FLT3 wild-type (WT) cells. The anti-leukemia activity of CG-806 was investigated by measuring apoptosis induction and analyzing the cell cycle using flow cytometry in vitro. CG-806 demonstrated superior anti-leukemia efficacy compared to commercially available FLT3 inhibitors, both in vitro and in vivo, regardless of FLT3 mutational status. The mechanism of action of CG-806 may involve its broad inhibitory profile against FLT3, BTK, and AuroK. In FLT3 mutant cells, CG-806 induced G1 phase blockage, whereas in FLT3 WT cells, it resulted in G2/M phase arrest. Targeting FLT3 and Bcl-2 and/or Mcl-1 simultaneously results in a synergistic pro-apoptotic effect in FLT3 mutant leukemia cells. The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemic efficacy regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).Key pointsThe multi-kinase inhibitor CG-806 exerts superior anti-leukemic activity in AML, regardless of its FLT3 status.CG-806 triggered G1 arrest in FLT3 mutated cells and G2/M arrest in FLT3 WT cells through the suppression of FLT3/BTK and aurora kinases.Concomitantly targeting FLT3 and Bcl-2 and/or Mcl-1 exerted synergistic pro-apoptotic effects on both FLT3 WT and mutated AML cells.

Expression of circRNA-0036474 in esophageal cancer and its clinical significance.

Circular RNAs are considered to play important roles in the progression of different cancers such as esophageal squamous cell carcinoma. However, the functions of circular RNAs in esophageal squamous cell carcinoma are still not clear. This study aimed to investigate the role and mechanism of circRNA-0036474 in the progression of esophageal squamous cell carcinoma. The hsa_circ_0036474 expression levels were found to be elevated in both EC109 cells and esophageal squamous cell carcinoma tissue samples. Moreover, knockdown of circRNA-0036474 expression in the EC109 cells induced migration and invasion, characterized by the down-regulation of E-cadherin, and up-regulation of N-cadherin and vimentin. In addition, the over-expressed hsa_circ_0036474 significantly decreased the activity of EC109 cells, elevated E-cadherin expression but declined N-cadherin and vimentin expression. Moreover, over-expressed mir-223-3p levels and interfered RERG expression verified the role of hsa_circ_0036474 in inhibiting the invasion and migration of EC109 cells, reducing the expression of N-cadherin and vimentin, and promoting the expression of E-cadherin. In conclusion, circRNA-0036474 mitigated the progression of esophageal squamous cell carcinoma through regulating mir-223-3p/RERG axis, presenting a potential therapeutic target for the treatment.

Bibliometric analysis of the acetabular labrum.

The acetabular labrum (AL) plays a crucial role in the normal physiological functioning of the hip joint. This study aims to present an overview of the current status and research hotspots concerning the AL and to explore the field from a bibliometric perspective. A total of 1918 AL-related records published between January 1, 2000 and November 8, 2023 were gathered from the Web of Science Core Collection database. By utilizing tools such as HisCite, CiteSpace, VOSviewer, and the R package "bibliometrix," the regions, institutions, journals, authors, and keywords were analyzed to predict the latest trends in AL research. Global research interest and publication output related to this topic continues to escalate. The United States leads in international collaborations, number of publications, and citation frequency, underscoring its preeminent position in this field. The American Hip Institute emerged as the most prolific institution, making the greatest contribution to publications. Notably, Arthroscopy and the American Journal of Sports Medicine are the 2 most popular journals in this domain, accounting for 13.29% and 10.1% of publications, respectively, and were also found to be the most co-cited journals. Amongst authors, Benjamin G. Domb leads with 160 articles (8.35%), while Marc J. Philippon is the most frequently cited author. The keyword co-occurrence network showed 3 hot clusters, including "AL," "femoral acetabular impingement (FAI)," and "osteoarthritis." In addition, "survivorship," "FAI," and "patient-reported outcomes" were identified as trending topics for future exploration. This study represents the first comprehensive bibliometric analysis, summarizing the present state and future trends in AL research. The findings serve as a valuable resource for scholars, offering practical insights into key information within the field and identifying potential research frontiers and emerging directions in the near future.

Artificial intelligence iterative reconstruction in abdominal CT of patients with irregular arm positioning: a case-by-case evaluation.

BACKGROUND: Streak artifacts induced by irregular arm positioning have been an issue in diagnosing the abdomen. PURPOSE: To illustrate the risk of misdiagnosis in abdominal computed tomography (CT) of patients with irregular arm positioning through a case-by-case evaluation and to test if it can be solved by the artificial intelligence iterative reconstruction (AIIR) algorithm. MATERIAL AND METHODS: By reviewing 5220 cases of chest and thoracoabdominal CT, 64 patients with irregular arm positioning were enrolled, whose image data were reconstructed using AIIR in addition to routine hybrid iterative reconstruction (HIR). Lesion detection for livers, spleens, kidneys, gallbladders, and pancreas on AIIR images, performed by two radiologists, was compared with those on HIR images. Discrepancies arising from AIIR images included both cases with additional abnormalities and those with corrections made on previous detections. For cases with discrepancies, artifact scores for organs where discrepancies were found, and contrast-to-noise ratios (CNRs) of cysts with discrepancies were compared between two image sets. RESULTS: Additional abnormalities were detected for 15 cases: additional liver cirrhosis (n=2); additional gallbladder stone (n=1); additional cholecystitis (n=1), additional spleen nodule (n=1); additional kidney cysts (n=8); additional liver cysts (3); and additional spleen cyst (n=1). A spleen contusion was corrected for one case. All involved artifact scores were improved on AIIR images. CNRs of involved liver, kidney, and spleen cysts were improved by up to 539.7%, 538.5%, and 245.5%, respectively. CONCLUSION: Irregular arm positioning may induce a variety of misdiagnoses in abdominal CT, which is almost totally avoidable by the AIIR algorithm.

Overexpression of NDNF Improves the Cytoprotective Effects of Aged Human Bone Marrow Mesenchymal Stem Cells by Modulating Oxidative Stress and Apoptosis.

The therapeutic potential of autologous stem cell transplantation for heart repair diminishes in the elderly due to stem cell aging. Rejuvenating aged stem cells to enhance their protective effects on injured cardiomyocytes is crucial for aging patients with heart failure. In this study, we aimed to investigate whether neuron-derived neurotrophic factor (NDNF) over-expression improves the protective effect of aged stem cells for injured cardiomyocytes and explore the underlying mechanism. Human bone marrow was collected from both young and old patients, and bone marrow mesenchymal stem cells (BMSCs) were cultured. Lentivirus expression vectors carrying NDNF genes were used to transfect aged BMSCs. Fatal hypoxia-induced injury in H9C2 cells served as an in vitro ischemia model. The conditioned medium from different BMSC groups was applied to assess the beneficial effects on hypoxia-induced damage in myocardial H9C2 cells. Results revealed that the conditioned medium of NDNF over-expressed old BMSCs increased H9C2 cell viability and reduced oxidative stress and apoptosis levels under fatal hypoxia. NDNF over-expressed old BMSCs exhibited an antiapoptotic role by upregulating the antiapoptotic gene Bcl-2 and downregulating the proapoptotic genes Bax. Additionally, the protective effects were mediated through the elevation of phosphorylated AKT. Our data support the promise of NDNF as a potential target to enhance the protective effects of autologous aged BMSCs on ischemic cardiomyocytes and then improve the curative effects of stem cell for ischemic heart injury in aged patients.

[Advances in study of surgical approaches and MRI evaluation of total hip arthroplasty].

Objective: To review the research on different surgical approaches and MRI evaluation of total hip arthroplasty (THA), to clarify the possible muscle damage caused by different approaches, and to help clinicians avoid intraoperative muscle damage and identify the causes of certain muscle-related complications after operation. Methods: The research literature on different surgical approaches and MRI evaluation of THA at home and abroad was extensively reviewed to summarize the MRI performance of the posterior approach, modified direct lateral approach, direct anterior approach, and minimally invasive anterolateral approach (also called Orthopadische Chirurgie Munchen approach). Results: The traditional posterior approach mainly damages the short external rotator muscle group and increases the incidence of postoperative dislocation; the piriformis-keeping posterior approach significantly improves the quality of the pyriformis tendon in the postoperative period, but it may lead to damage to the intrapelvic portion of the piriformis muscle. The modified direct lateral approach mainly damages the gluteus medius muscle, which increases the risk of postoperative claudication. The direct anterior approach mainly damages the vastus tensoris muscle and may result in damage to the short external rotator muscle group and the muscles around the incision. The minimally invasive anterolateral approach primarily damages the superior gluteal nerve, which subsequently leads to denervation of the broad fascial tensor fasciae latae, and this approach may also result in injury to the gluteus medius and gluteus minimus muscles. The muscle damage status significantly affects prognosis, and the minimally invasive approach is more suitable for elderly patients. Conclusion: MRI can clarify the different types of muscle damage caused by different surgical approaches. Minimally invasive approaches can reduce muscle damage and improve postoperative function compared with traditional approaches, and can benefit elderly patients more, but due to the small field, forcing to expand the surgical field will lead to unintended muscle damage and reduce postoperative function.

Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Diversity of returnee executives' foreign experience and corporate social responsibility performance.

Top managers' past experiences (e.g., foreign experience) significantly impact their decision-making behavior, which may influence firms' sustainable development. The available literature, focusing on the role of the increase in the number of top executives with foreign experience in corporate social responsibility (CSR), yields mixed results. In order to clarify the ambiguous relationship between executive foreign experience and CSR, we empirically examine the effect of the geographic diversity of top executives' foreign experience on CSR. Based on a hand-collected dataset of the top management team's (TMT's) foreign experience, we demonstrate the positive impact of the geographic diversity of returnee executives' foreign experience on firms' CSR using Chinese A-share listed firms from 2009 to 2018. Moreover, this impact is stronger in firms with political connections with the central government and in regions with good market development. Furthermore, the mechanism analysis shows that returnee executives drive firms' CSR by promoting corporate donations and green innovation. This paper offers clear policy implications by suggesting that hiring returnees with a broad geographic scope of foreign experience as corporate executives is an efficient way to enhance firms' CSR.

CircPRMT5 promotes progression of osteosarcoma by recruiting CNBP to regulate the translation and stability of CDK6 mRNA.

Research has demonstrated that circular RNAs (circRNAs) exert critical functions in the occurrence and progression of numerous malignant tumors. CircPRMT5 was recently reported to be involved in the pathogenesis of cancers. However, the potential role of circPRMT5 in osteosarcoma needs further investigation. In present study, our results suggested that circPRMT5 was highly upregulated in osteosarcoma cells and mainly localizes in the cytoplasm. CircPRMT5 promoted the proliferation, migration and invasion capacities of osteosarcoma cells, and suppressed cell apoptosis. Knockdown of circPRMT5 exerted the opposite effects. Mechanically, circPRMT5 promoted the binding of CNBP to CDK6 mRNA, which enhanced the stability of CDK6 mRNA and facilitated its translation, thereby promoting the progression of osteosarcoma. Knockdown of CDK6 reversed the promoting effect of circPRMT5 on osteosarcoma cells. These findings suggest that circPRMT5 promotes osteosarcoma cell malignant activity by recruiting CNBP to regulate the translation and stability of CDK6 mRNA. Thus, circPRMT5 may represent a promising therapeutic target for osteosarcoma.

Clear cell hepatocellular carcinoma: Gd-EOB-DTPA-enhanced MR imaging features and prognosis.

PURPOSE: To investigate imaging findings on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) and prognosis of clear cell hepatocellular carcinoma (CCHCC) comparing with non-otherwise specified hepatocellular carcinoma (NOS-HCC). METHODS: The clinical, pathological and MR imaging features of 42 patients with CCHCC and 84 age-matched patients with NOS-HCC were retrospectively analyzed from January 2015 to October 2021. Univariate and multivariate logistic regression and Cox regression analyses were performed to identify independent diagnostic and prognostic factors for CCHCC. Disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier analysis. RESULTS: CCHCC showed fat content more frequently (P < 0.001) and relatively higher Edmondson tumor grade (P = 0.001) compared with NOS-HCC. The lesion-to-muscle ratio (LMR) and lesion-to-liver ratio (LLR) of CCHCC on pre-enhancement T1-weighted imaging (pre-T1WI) (P = 0.001, P = 0.003) and hepatobiliary phase (HBP) (P = 0.007, P = 0.048) were significantly higher than those of NOS-HCC. The area under the curve (AUC) for fat content, LLR on pre-T1WI and their combination with better diagnostic performance in predicting CCHCC were 0.678, 0.666, and 0.750, respectively. There was no statistically significant difference in clinical outcomes between CCHCC and NOS-HCC. Multivariate Cox analysis confirmed that tumor size > 2 cm and enhancing capsule were independent prognostic factors for DFS and OS among CCHCC patients. CONCLUSION: Fat content and adjusted lesion signal intensity on pre-T1WI and HBP could be used to differentiate CCHCC from NOS-HCC. CCHCC had similar prognosis with NOS-HCC.

[Analysis of X chromosome inactivation and prenatal diagnosis for a Chinese pedigree with loss of heterozygosity at Xq22.1q22.3].

OBJECTIVE: To explore the correlation between skewed X chromosome inactivation (XCI) and clinical phenotype of a Chinese pedigree with loss of heterozygosity at Xq22.1q22.3. METHODS: A pedigree diagnosed at Taizhou Hospital on November 10, 2021 was selected as the study subject. G-banded chromosomal karyotyping and copy number variation sequencing (CNV-seq) were carried out to analyze the amniotic fluid and peripheral blood samples from the couple. XCI was detected by PCR amplification of CAG repeats in exon 1 of androgen receptor gene before and after the digestion with methylation-sensitive restriction enzyme Hpa II. Correlation between the genotype and clinical phenotype was analyzed. RESULTS: The karyotypes of the pregnant woman and the fetus were both determined as 46,X,del(X)(q22), and the result of CNV-seq was seq[hg19]del(X)(q22.1q22.3) chrX: g.10046000_105740000del, suggesting that both had harbored a 5.28 Mb deletion on the X chromosome. No obvious abnormality was found in the husband. XCI analysis showed that the activity ratio of the two X chromosomes of the pregnant woman and her fetus was 0 : 100. The X chromosome harboring the q22.1q22.3 deletion was completely inactivated, and the inactivated X chromosome of the fetus was derived from its mother. CONCLUSION: The fetus has harbored a maternally derived inactivated X chromosome del(X)(q22) , and its phenotype is closely associated with the activity of the abnormal X chromosome. Pedigree XCI analysis combined with the clinical phenotype has facilitated recognition of the maternal phenotype and prognosis of female fetus with loss of heterozygosity at Xq22.1q22.3.

Immunogenicity and effectiveness of an mRNA therapeutic vaccine for HPV-related malignancies.

Human papillomavirus (HPV) infections account for several human cancers. There is an urgent need to develop therapeutic vaccines for targeting preexisting high-risk HPV (such as HPV 16 and 18) infections and lesions, which are insensitive to preventative vaccines. In this study, we developed a lipid nanoparticle-formulated mRNA-based HPV therapeutic vaccine (mHTV), mHTV-02, targeting the E6/E7 of HPV16 and HPV-18. mHTV-02 dramatically induced antigen-specific cellular immune response and robust memory T-cell immunity in mice, besides significant CD8+ T-cell infiltration and cytotoxicity in TC-1 tumors expressing HPV E6/E7, resulting in tumor regression and prolonged survival in mice. Moreover, evaluation of routes of administration found that intramuscular or intratumoral injection of mHTV-02 displayed significant therapeutic effects. In contrast, intravenous delivery of the vaccine barely showed any benefit in reducing tumor size or improving animal survival. These data together support mHTV-02 as a candidate therapeutic mRNA vaccine via specific administration routes for treating malignancies caused by HPV16 or HPV18 infections.

Requirements for essential micronutrients during caloric restriction and fasting.

Caloric restriction (CR) or energy restriction, when carefully designed, monitored, and implemented in self-motivated and compliant individuals, proves to be a viable non-pharmacologic strategy for human weight control and obesity management. Beyond its role in weight management, CR has the potential to impede responses involved not only in the pathogenesis of various diseases but also in the aging process in adults, thereby being proposed to promote a healthier and longer life. The core objective of implementing caloric restriction is to establish a balance between energy intake and expenditure, typically involving a reduction in intake and an increase in expenditure-a negative balance at least initially. It may transition toward and maintain a more desired equilibrium over time. However, it is essential to note that CR may lead to a proportional reduction in micronutrient intake unless corresponding supplementation is provided. Historical human case reports on CR have consistently maintained adequate intakes (AI) or recommended dietary allowances (RDA) for essential micronutrients, including vitamins and minerals. Similarly, longevity studies involving non-human primates have upheld micronutrient consumption levels comparable to control groups or baseline measures. Recent randomized controlled trials (RCTs) have also endorsed daily supplementation of multivitamins and minerals to meet micronutrient needs. However, aside from these human case reports, limited human trials, and primate experiments, there remains a notable gap in human research specifically addressing precise micronutrient requirements during CR. While adhering to AI or RDA for minerals and vitamins appears sensible in the current practice, it's important to recognize that these guidelines are formulated for generally healthy populations under standard circumstances. The adequacy of these guidelines in the setting of prolonged and profound negative energy balance remains unclear. From perspectives of evidence-based medicine and precision nutrition, this field necessitates comprehensive exploration to uncover the intricacies of absorption, utilization, and metabolism and the requirement of each hydrophilic and lipophilic vitamin and mineral during these special periods. Such investigations are crucial to determine whether existing daily dietary recommendations for micronutrients are quantitatively inadequate, excessive, or appropriate when energy balance remains negative over extended durations.

Improving Wear Resistance and Corrosive Resistance of Cemented Carbide for Mud Pulser Rotor by Deep Cryogenic Treatment.

Cemented carbide used in the rotor of a mud pulser is subjected to the scouring action of solid particles and corrosive mud media for a long time, which causes abrasive wear and electrochemical corrosion. To improve the wear and corrosive resistance of cemented carbide, samples with different cobalt content (WC-5Co, WC-8Co, and WC-10Co) receive deep cryogenic treatment (DCT) at -196 °C for 2.5 h. An optical metalloscope (OM) and X-ray diffractometer (XRD) are used to observe the phase changes of cemented carbides, and the XRD is also used to observe the change in residual stress on the cemented carbide's surface. A scanning electron microscope (SEM) is used to characterize the wear and electrochemical corrosion surface microstructure of cemented carbides (untreated and DCT). The results show that the DCT promotes the precipitation of the η phase, and the diffraction peak of ε-Co tends to intensify. Compared with the untreated, the wear rates of WC-5Co, WC-8Co, and WC-10Co can be reduced by 14.71%, 37.25%, and 41.01% by DCT, respectively. The wear form of the cemented carbides is mainly the extrusion deformation of Co and WC shedding. The precipitation of the η phase and the increase in WC residual compressive stress by DCT are the main reasons for the improvement of wear resistance. The electrochemical corrosion characteristic is the dissolution of the Co phase. DCT causes the corrosion potential of cemented carbide to shift forward and the corrosion current density to decrease. The enhancement of the corrosion resistance of cemented carbide caused by DCT is due to the Co phase transition, η phase precipitation, and the increase in the compressive stress of cemented carbide.

HyCas9-12aGEP: an efficient genome editing platform for Corynebacterium glutamicum.

Corynebacterium glutamicum plays a crucial role as a significant industrial producer of metabolites. Despite the successful development of CRISPR-Cas9 and CRISPR-Cas12a-assisted genome editing technologies in C. glutamicum, their editing resolution and efficiency are hampered by the diverse on-target activities of guide RNAs (gRNAs). To address this problem, a hybrid CRISPR-Cas9-Cas12a genome editing platform (HyCas9-12aGEP) was developed in C. glutamicum in this study to co-express sgRNA (corresponding to SpCas9 guide RNA), crRNA (corresponding to FnCas12a guide RNA), or hfgRNA (formed by the fusion of sgRNA and crRNA). HyCas9-12aGEP improves the efficiency of mapping active gRNAs and outperforms both CRISPR-Cas9 and CRISPR-Cas12a in genome editing resolution and efficiency. In the experiment involving the deletion of the cg0697-0740 gene segment, an unexpected phenotype was observed, and HyCas9-12aGEP efficiently identified the responsible genotype from more than 40 genes. Here, HyCas9-12aGEP greatly improve our capability in terms of genome reprogramming in C. glutamicum.