TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation.

It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here, we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate-limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C. elegans subjected to proteotoxic stress. TRP14 can also reduce cysteinyl moieties on proteins, rescuing their activities as here shown with cysteinylated peroxiredoxin 2. Txndc17 knockout mice were, surprisingly, protected in an acute pancreatitis model, concomitant with activation of Nrf2-driven antioxidant pathways and upregulation of transsulfuration. We conclude that TRP14 is the evolutionarily conserved enzyme principally responsible for intracellular cystine reduction in C. elegans, mice, and humans.

MIB2 Functions in Oocyte Meiosis by Modulating Chromatin Configuration.

Chromatin configuration serves as a principal indicator of GV (germinal vesicle)-stage oocyte quality. However, the underlying mechanisms governing the chromatin configuration transition from NSN (non-surrounded nucleolus) to SN (surrounded nucleolus) remain unclear. In this study, by conducting a quantitative proteomic analysis, we identified an increased expression of the MIB2 (MIB E3 ubiquitin protein ligase 2) protein in SN oocytes. Specific depletion of MIB2 in SN oocytes not only leads to severe disruption of the meiotic apparatus and a higher incidence of aneuploidy but also adversely affects meiotic maturation and early embryo development. Notably, overexpression of MIB2 in NSN oocytes facilitates the chromatin configuration transition. Meantime, we observed that forced expression of MIB2 in NSN oocytes significantly mitigates spindle/chromosome disorganization and aneuploidy. In summary, our results suggest that chromatin configuration transition regulated by MIB2 is crucial for oocytes to acquire developmental competence.

MI-DenseCFNet: deep learning-based multimodal diagnosis models for Aureus and Aspergillus pneumonia.

OBJECTIVE: To build and merge a diagnostic model called multi-input DenseNet fused with clinical features (MI-DenseCFNet) for discriminating between Staphylococcus aureus pneumonia (SAP) and Aspergillus pneumonia (ASP) and to evaluate the significant correlation of each clinical feature in determining these two types of pneumonia using a random forest dichotomous diagnosis model. This will enhance diagnostic accuracy and efficiency in distinguishing between SAP and ASP. METHODS: In this study, 60 patients with clinically confirmed SAP and ASP, who were admitted to four large tertiary hospitals in Kunming, China, were included. Thoracic high-resolution CT lung windows of all patients were extracted from the picture archiving and communication system, and the corresponding clinical data of each patient were collected. RESULTS: The MI-DenseCFNet diagnosis model demonstrates an internal validation set with an area under the curve (AUC) of 0.92. Its external validation set demonstrates an AUC of 0.83. The model requires only 10.24s to generate a categorical diagnosis and produce results from 20 cases of data. Compared with high-, mid-, and low-ranking radiologists, the model achieves accuracies of 78% vs. 75% vs. 60% vs. 40%. Eleven significant clinical features were screened by the random forest dichotomous diagnosis model. CONCLUSION: The MI-DenseCFNet multimodal diagnosis model can effectively diagnose SAP and ASP, and its diagnostic performance significantly exceeds that of junior radiologists. The 11 important clinical features were screened in the constructed random forest dichotomous diagnostic model, providing a reference for clinicians. CLINICAL RELEVANCE STATEMENT: MI-DenseCFNet could provide diagnostic assistance for primary hospitals that do not have advanced radiologists, enabling patients with suspected infections like Staphylococcus aureus pneumonia or Aspergillus pneumonia to receive a quicker diagnosis and cut down on the abuse of antibiotics. KEY POINTS: • MI-DenseCFNet combines deep learning neural networks with crucial clinical features to discern between Staphylococcus aureus pneumonia and Aspergillus pneumonia. • The comprehensive group had an area under the curve of 0.92, surpassing the proficiency of junior radiologists. • This model can enhance a primary radiologist's diagnostic capacity.

Oncofetal protein glypican-3 is a biomarker and critical regulator of function for neuroendocrine cells in prostate cancer.

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland.

Single-cell RNA-seq analysis hearts in patients with fetal tetralogy of Fallot.

INTRODUCTION: To explore the cytological characteristics of tetralogy of Fallot (TOF), we collected samples and studied the differences in cytological classification between normal fetal hearts and fetuses with TOF, and then we searched for possible differential genes of disease markers through single-cell sequencing analysis. METHODS: In this study, we analyzed the right ventricle of a TOF and a healthy human fetal heart sample by single-cell sequencing. Utilizing Cellranger to perform data quality control filtering, comparison, quantification, and identification of recovered cells on the raw data, ultimately obtaining gene expression matrices for each cell. Subsequently, Seurat was used for further cell filtration, standardization, cell subgroup classification, differential expression gene analysis of each subgroup, and Marker gene screening. RESULTS: Bioinformatic analysis identified 9979 and 15224 cells derived from the healthy and disease samples, respectively, with an average read depth of 25000/cell. The cardiomyocyte cell populations derived from the abnormal samples identified by the first-level graph-based analysis were separated into six distinct cell clusters. CONCLUSIONS: Our study reveals some information on TOF in a fetus, which can provide a new reference for early detection and treatment of TOF by comparing it with normal heart cells.

Neuroimaging Insights: Structural Changes and Classification in Ménière's Disease.

OBJECTIVES: This study aimed to comprehensively investigate the neuroanatomical alterations associated with idiopathic Ménière's disease (MD) using voxel-based morphometry and surface-based morphometry techniques. The primary objective was to explore nuanced changes in gray matter volume, cortical thickness, fractal dimension, gyrification index, and sulcal depth in MD patients compared with healthy controls (HC). Additionally, we sought to develop a machine learning classification model utilizing these neuroimaging features to effectively discriminate between MD patients and HC. DESIGN: A total of 55 patients diagnosed with unilateral MD and 70 HC were enrolled in this study. Voxel-based morphometry and surface-based morphometry were employed to analyze neuroimaging data and identify structural differences between the two groups. The selected neuroimaging features were used to build a machine learning classification model for distinguishing MD patients from HC. RESULTS: Our analysis revealed significant reductions in gray matter volume in MD patients, particularly in frontal and cingulate gyri. Distinctive patterns of alterations in cortical thickness were observed in brain regions associated with emotional processing and sensory integration. Notably, the machine learning classification model achieved an impressive accuracy of 84% in distinguishing MD patients from HC. The model's precision and recall for MD and HC demonstrated robust performance, resulting in balanced F1-scores. Receiver operating characteristic curve analysis further confirmed the discriminative power of the model, supported by an area under the curve value of 0.92. CONCLUSIONS: This comprehensive investigation sheds light on the intricate neuroanatomical alterations in MD. The observed gray matter volume reductions and distinct cortical thickness patterns emphasize the disease's impact on neural structure. The high accuracy of our machine learning classification model underscores its diagnostic potential, providing a promising avenue for identifying MD patients. These findings contribute to our understanding of MD's neural underpinnings and offer insights for further research exploring the functional implications of structural changes.

Effectiveness and pregnancy outcomes of ultrasound-indicated and physical examination-indicated cervical cerclage: a retrospective study from a single centre.

OBJECTIVE: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide, and cervical incompetence (CIC) is a significant contribution. Cervical cerclage (CC) is an effective obstetric intervention. However, many clinical factors affect the success rate of surgery. The objective was to investigate and compare the pregnancy and neonatal outcomes of patients who underwent ultrasound- and physical examination-indicated cervical cerclage and to explore the influencing factors of preterm delivery before 34 weeks. METHODS: The sociodemographic characteristics and clinical data of patients with a diagnosis of cervical incompetence who underwent ultrasound- and physical examination-indicated transvaginal cervical cerclage at Nanjing Maternal and Child Health Hospital from January 2020 to December 2022 were retrospectively analyzed. The pregnancy and neonatal outcomes of the patients were evaluated. Continuous variables were compared using Student's t test (for normally distributed data) or the Mann-Whitney U test (for nonnormally distributed data). Categorical variables were analysed using the chi-square test or Fisher's exact test. Additionally, logistic regression analyses and receiver operating characteristic curves were used to evaluate the associations of inflammatory markers with maternal and neonatal outcomes. RESULTS: This study included 141 participants who underwent cervical cerclage, including 71 with ultrasound-indicated cerclage and 70 with physical examination-indicated cerclage. Compared to those in the ultrasound-indicated cerclage group, the duration from cerclage to delivery, birth weight, and APGAR score in the physical examination-indicated cerclage group were significantly lower, and the rates of delivery at < 28 weeks, < 32 weeks, < 34 weeks, and < 37 weeks of gestation and neonatal mortality were significantly higher (all P < 0.05). Compared to those in the physical ultrasound-indicated cerclage group, in the physical examination-indicated cerclage group, maternal blood inflammatory markers, such as C-reactive protein (CRP), the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI) were significantly higher (P < 0.05). Additionally, maternal blood inflammatory markers, such as the CRP, white blood cell count, platelet to lymphocyte ratio (PLR), SII, and SIRI were significantly higher in the group with delivery before 34 weeks of gestation. Furthermore, the results demonstrated that twin pregnancy had the highest OR for preterm delivery before 34 weeks of gestation (OR = 3.829; 95% CI 1.413-10.373; P = 0.008), as well as the following: the SII level (OR = 1.001; 95% CI 1.000-1.002; P = 0.003) and CRP level (OR = 1.083; 95% CI 1.038-1.131; P = 0.022). The risk factors for preterm delivery before 34 weeks of gestation were twin gestation, an increased SII level and an increased CRP level, which had good combined predictive value. CONCLUSION: In patients with cervical insufficiency, ultrasound-indicated cervical cerclage appears to lead to better pregnancy outcomes than physical examination-indicated cerclage. Twin pregnancy and maternal blood inflammatory markers, such as the CRP level and the SII, are associated with preterm delivery before 34 weeks of gestation.

Early result of percutaneous full-endoscopic transforaminal lumbar interbody fusion in the treatment of single-level lumbar degenerative diseases: a retrospective study.

OBJECTIVE: The study aimed to evaluate the short-term clinical efficacy of percutaneous full-endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) for lumbar degenerative diseases (LDD). METHODS: From July 2020 to July 2021, 93 patients who underwent single-level lumbar fusion procedure were retrospective analysis. The patients were divided into Endo-TLIF group and transforaminal lumbar interbody fusion (TLIF) group. General demographic and perioperative data were recorded, the clinical outcomes were evaluated using visual analogue scale (VAS) and oswestry disability index (ODI). The disk height (DH) was compared between the two groups. RESULTS: All of the surgical procedures were successfully completed, and the patients were followed for a minimum of 2 years. Intraoperative blood loss, drainage volume, time to independent ambulation and hospital length of stay in the Endo-TLIF group were significantly decreased in comparison with the open TLIF group (p < 0.05). The VAS for back pain on postoperative 7 day and ODI on postoperative 1 month were lower in the Endo-TLIF group than in the open TLIF group (P < 0.05), but no significant difference at 1 year and 2 years postoperatively (P > 0.05). The VAS score of leg pain had no demographic statistically significant differences between the groups (P > 0.05). The DH were significantly heightened after surgery compared to the preoperative height (p < 0.05). CONCLUSION: Endo-TLIF is a minimally invasive, safety surgery which can achieve comparable short-term effects as open TLIF. It may be a promising option for the treatment of LDD.

Characterization of near-field temporal and spatial variations of pesticide residues using honeybee specimens as bio-sensing matrices.

This study was prompted by recent reports of the ubiquity of neonicotinoids (neonics) in environment and the likelihood of exposures and health hazards to non-target organisms. We aimed to quantify neonics levels in time- and location-match pollen and nectar samples foraged by honeybees (Apis mellifera) and characterized the temporal and spatial variations using a relative potency factor method to determine the total neonic levels, expressed as the imidacloprid-adjusted total neonics, IMIRPF (ng/g). Six pairs of pollen and nectar samples, a total of twelve samples, were collected from each of the thirty-two experimental hives during the active foraging months of March, April, and June and analyzed for eight neonics. We found 59% and 64% of pollen and nectar contained at least one neonic, respectively. Among those neonic-detected pollen and nectar samples, 45% and 77% of them contained more than one neonic, respectively. Imidacloprid and acetamiprid in pollen and clothianidin and thiamethoxam in nectar accounted for 60% and 83% detection, respectively. The highest 3-month average of IMIRPF in pollen (6.56 ng/g) and nectar (11.19 ng/g) were detected in a location with the predominant production of citrus fruit. The temporal and spatial variations of IMIRPF levels demonstrated the robustness of using paired pollen and nectar data as the bio-sensing matrices to facilitate the assessment of near-field exposure to total neonics and the delineation of risks.

Progress in the treatment of Osteoarthritis with avocado-soybean unsaponifiable.

Osteoarthritis (OA) is one of the leading causes of joint dysfunction and disability in the elderly, posing serious social problems and a huge socio-economic burden. Existing pharmacological treatments have significant drawbacks, and searching for an effective pharmacological intervention is an urgent priority. Recent studies have demonstrated the chondroprotective, anabolic, and anti-catabolic properties of avocado-soybean unsaponifiable (ASU), a natural plant extract made from avocado and soybean oils, consisting of the remainder of the saponified portion of the product that cannot be made into soap. The main components of ASU are phytosterols, beta-sitosterol, canola stanols, and soya stanols, which are rapidly incorporated into cells. Studies have confirmed the anti-inflammatory, antioxidant, and analgesic properties of phytosterols. ASU slows down the progression of OA primarily by inhibiting pathways involved in the development of OA disease. ASU prevents cartilage degradation by inhibiting the release and activity of matrix metalloproteinases and by increasing the tissue inhibition of these catabolic enzymes; ASU is also involved in the inhibition of the activation of nuclear factor κB (NF-κB) which is a transcriptional inhibitor that regulates the inflammatory response of chondrocytes. NF-κB is a transcription factor that regulates the inflammatory response of chondrocytes, and inhibition of the transfer of the transcription factor NF-κB from the cytoplasm to the nucleus regulates the transcription of many pro-inflammatory factors. By appealing to the mechanism of action and thus achieving anti-inflammatory, anti-catabolic, and pro-synthetic effects on cartilage tissues, AUS is clinically responsive to the reduction of acute pain and OA symptom progression. This paper aims to summarize the studies on the use of avocado-soybean unsaponifiable in the pharmacological treatment of osteoarticular.

Rheumatoid arthritis is a protective factor against Alzheimer's disease: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Epidemiological evidence suggests that there is an association between rheumatoid arthritis (RA) and Alzheimer's disease (AD). However, the causal relationship between RA and AD remains unclear. Therefore, this study aimed to investigate the causal relationship between RA and AD. METHODS: Using publicly available genome-wide association study datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using the inverse-variance weighted (IVW), weighted median, MR‒Egger regression, simple mode, and weighted mode methods. RESULTS: The results of MR for the causal effect of RA on AD (IVW, odds ratio [OR] = 0.959, 95% confidence interval [CI]: 0.941-0.978, P = 2.752E-05; weighted median, OR = 0.960, 95% CI: 0.937-0.984, P = 0.001) revealed a causal association between genetic susceptibility to RA and an increased risk of AD. The results of MR for the causal effect of AD on RA (IVW, OR = 0.978, 95% CI: 0.906-1.056, P = 0.576; weighted median, OR = 0.966, 95% CI: 0.894-1.043, P = 0.382) indicated that there was no causal association between genetic susceptibility to AD and an increased risk of RA. CONCLUSIONS: The results of this two-way two-sample Mendelian randomization analysis revealed a causal association between genetic susceptibility to RA and a reduced risk of AD but did not reveal a causal association between genetic susceptibility to AD and an increased or reduced risk of RA.

Using autogenous tooth sticky bone graft repair mandibular third molar dentigerous cyst osseous defects.

BACKGROUND: Dentigerous cyst are most common odontogenic cyst and they frequently occur at the mandibular third molar. Their asymptomatic long medical history always resulted in severe bone resorption at the distal aspect of the adjacent second molar. BonMaker® ATB demonstrate an excellent autogenous bone graft candidacy. The aim of this study is to share a single team's experience of dentigerous cyst osseous defect repairing by applying autogenous tooth sticky bone graft. METHOD: In total, 18 patients with dentigerous cyst, which was arised from mandibular third molar unilaterally, were enrolled in this study. Enucleation of dentigerous cyst was performed extracting with involving teeth under general anesthesia. Autogenous tooth sticky bone graft was prepared using extracted tooth and autogenous fibrin glue. Subsequently, grafting was performed above covering with concentrate growth factors. Patients were followed up at sixth months. RESULTS: They were eleven male and seven female patients. Their ages ranged from 20 to 40 years, with a mean of 31 years. Primary wound healing of all sites was achieved in all the patients. Sixth months postoperative radiographic assessment show that dentigerous cysts osseous defects of seventeen patients were good bone filling and ossification. One patient occurred slight bone resorption at the distal aspect of the adjacent second molar. CONCLUSION: Within the limitation of sample size and retrospective nature of the present study, autogenous tooth sticky bone graft demonstrates one of the best alternative alveolar bones repairing graft.

Ultralight Ultrafast Enzymes.

Inorganic materials depleted of heavy stable isotopes are known to deviate strongly in some physicochemical properties from their isotopically natural counterparts. Here we explored for the first time the effect of simultaneous depletion of the heavy carbon, hydrogen, oxygen and nitrogen isotopes on the bacterium E. coli and the enzymes expressed in it. Bacteria showed faster growth, with most proteins exhibiting higher thermal stability, while for recombinant enzymes expressed in depleted media, faster kinetics was discovered. At room temperature, luciferase, thioredoxin and dihydrofolate reductase and Pfu DNA polymerase showed up to a 250 % increase in activity compared to the native counterparts, with an additional ∼50 % increase at 10 °C. Diminished conformational and vibrational entropy is hypothesized to be the cause of the accelerated kinetics. Ultralight enzymes may find an application where extreme reaction rates are required.

MR-Corr2: a two-sample Mendelian randomization method that accounts for correlated horizontal pleiotropy using correlated instrumental variants.

MOTIVATION: Mendelian randomization (MR) is a valuable tool to examine the causal relationships between health risk factors and outcomes from observational studies. Along with the proliferation of genome-wide association studies, a variety of two-sample MR methods for summary data have been developed to account for horizontal pleiotropy (HP), primarily based on the assumption that the effects of variants on exposure (γ) and HP (α) are independent. In practice, this assumption is too strict and can be easily violated because of the correlated HP. RESULTS: To account for this correlated HP, we propose a Bayesian approach, MR-Corr2, that uses the orthogonal projection to reparameterize the bivariate normal distribution for γ and α, and a spike-slab prior to mitigate the impact of correlated HP. We have also developed an efficient algorithm with paralleled Gibbs sampling. To demonstrate the advantages of MR-Corr2 over existing methods, we conducted comprehensive simulation studies to compare for both type-I error control and point estimates in various scenarios. By applying MR-Corr2 to study the relationships between exposure-outcome pairs in complex traits, we did not identify the contradictory causal relationship between HDL-c and CAD. Moreover, the results provide a new perspective of the causal network among complex traits. AVAILABILITY AND IMPLEMENTATION: The developed R package and code to reproduce all the results are available at https://github.com/QingCheng0218/MR.Corr2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Risk single-nucleotide polymorphism-mediated enhancer-promoter interaction drives keloids through long noncoding RNA down expressed in keloids.

BACKGROUND: Keloids represent one extreme of aberrant dermal wound healing and are characterized by fibroblast hyperproliferation and excessive deposition of extracellular matrix. Genetics is a major factor for predisposition to keloids and genome-wide association study has identified a single-nucleotide polymorphism (SNP) rs873549 at 1q41 as a susceptibility locus. The SNP rs873549, and the SNPs in strong linkage disequilibrium (LD) with rs873549, may be involved in keloid development. However, the functional significance of these SNPs in keloid pathogenesis remains elusive. OBJECTIVES: To investigate the function and mechanism of SNP rs873549 and the SNPs in strong LD with rs873549 in keloids. METHODS: SNPs in strong LD with rs873549 were analysed using Haploview. The expression levels of the genes near the susceptibility locus were analysed using quantitative real-time polymerase chain reaction. The interaction between rs1348270-containing enhancer and the long noncoding RNA down expressed in keloids (DEIK) (formerly RP11-400N13.1) promoter in fibroblasts was investigated using chromosome conformation capture. The enhancer activity of the rs1348270 locus was evaluated using luciferase reporter assay. Knockdown experiments were used to explore the function of DEIK in keloids. RNA-Seq was performed to investigate the mechanism by which DEIK regulates the expression of collagens POSTN and COMP. RESULTS: rs1348270, an enhancer-located SNP in strong LD with rs873549, mediated looping with the promoter of DEIK. The risk variant was associated with decreased enhancer-promoter interaction and DEIK down-expression in keloids. Mechanistically, downregulation of DEIK increased the expression of collagens POSTN and COMP through upregulating BMP2. Furthermore, correlation analysis revealed that DEIK expression was inversely correlated with BMP2, POSTN and COMP expression in both keloid and normal fibroblasts. CONCLUSIONS: Our findings suggest that the risk variant rs1348270 is located in an enhancer and is associated with the downregulation of DEIK in keloids, and that downregulation of DEIK increases the expression of collagens POSTN and COMP through BMP2 in keloid fibroblasts. These findings will help to provide a more thorough understanding of the role played by genetic factors in keloid development and may lead to new strategies for screening and therapy in keloid-susceptible populations.

Whole genome sequencing vs chromosomal microarray analysis in prenatal diagnosis.

BACKGROUND: Emerging studies suggest that whole genome sequencing provides additional diagnostic yield of genomic variants when compared with chromosomal microarray analysis in the etiologic diagnosis of infants and children with suspected genetic diseases. However, the application and evaluation of whole genome sequencing in prenatal diagnosis remain limited. OBJECTIVE: This study aimed to evaluate the accuracy, efficacy, and incremental yield of whole genome sequencing in comparison with chromosomal microarray analysis for routine prenatal diagnosis. STUDY DESIGN: In this prospective study, a total of 185 unselected singleton fetuses with ultrasound-detected structural anomalies were enrolled. In parallel, each sample was subjected to whole genome sequencing and chromosomal microarray analysis. Aneuploidies and copy number variations were detected and analyzed in a blinded fashion. Single nucleotide variations and insertions and deletions were confirmed by Sanger sequencing, and trinucleotide repeats expansion variants were verified using polymerase chain reaction plus fragment-length analysis. RESULTS: Overall, genetic diagnoses using whole genome sequencing were obtained for 28 (15.1%) cases. Whole genome sequencing not only detected all these aneuploidies and copy number variations in the 20 (10.8%) diagnosed cases identified by chromosomal microarray analysis, but also detected 1 case with an exonic deletion of COL4A2 and 7 (3.8%) cases with single nucleotide variations or insertions and deletions. In addition, 3 incidental findings were detected including an expansion of the trinucleotide repeat in ATXN3, a splice-sites variant in ATRX, and an ANXA11 missense mutation in a case of trisomy 21. CONCLUSION: Compared with chromosomal microarray analysis, whole genome sequencing increased the additional detection rate by 5.9% (11/185). Using whole genome sequencing, we detected not only aneuploidies and copy number variations, but also single nucleotide variations and insertions and deletions, trinucleotide repeat expansions, and exonic copy number variations with high accuracy in an acceptable turnaround time (3-4 weeks). Our results suggest that whole genome sequencing has the potential to be a new promising prenatal diagnostic test for fetal structural anomalies.

Clinical efficacy of ultrasound-guided stellate ganglion block combined with extracorporeal shock wave therapy on limb spasticity in patients with ischemic stroke.

INTRODUCTION: To observe the clinical efficacy of ultrasound-guided stellate ganglion block (SGB) + extracorporeal shock wave therapy (ESWT) for limb spasticity in patients with ischemic stroke. METHODS: A total of 60 patients with post-stroke limb spasticity in our hospital were selected and randomly divided into four groups (n = 15). In the control group, patients received routine rehabilitation training. Based on routine rehabilitation training, SGB group patients underwent ultrasound-guided SGB, ESWT group patients received ESWT, and SGB + ESWT group patients received ultrasound-guided SGB combined with ESWT. The total treatment course was one month. The Modified Barthel Index (MBI) score, Fugl-Meyer Assessment and upper limb rehabilitation training system were applied to evaluate the activities of daily living, upper limb motor function and upper limb performance before and after treatment. Finally, the improvement after treatment was compared among different groups. RESULTS: After treatment, compared with the control group, the MBI score and the upper limb score based on Fugl-Meyer Assessment in the SGB, ESWT, and SGB + ESWT groups were significantly increased (P < 0.05). Furthermore, compared with the SGB and ESWT groups, SGB + ESWT exhibited a higher upper limb function score (P < 0.05), while the MBI score was not significantly different (P > 0.05). In terms of upper limb performance ability, patients in the SGB, ESWT and SGB + ESWT groups had better fitting degree, participation and exertion of exercise than those in the control group, and the SGB + ESWT group patients had the same movement trajectory as robots. CONCLUSION: Ultrasound-guided SGB and ESWT can reduce the muscle tension of patients, alleviate spasticity, promote the motor function of the upper limb, and improve the working performance of patients. However, the effect of SGB combined with ESWT is better.

A phase III randomized, double-blind, placebo-controlled trial of the denosumab biosimilar QL1206 in postmenopausal Chinese women with osteoporosis and high fracture risk.

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.

Lymphatic Drainage System and Lymphatic Metastasis of Cancer Cells in the Mouse Esophagus.

BACKGROUND: Lymphatic metastasis is commonly seen in patients with esophageal squamous cell carcinoma (ESCC). Both lymphatic metastasis and the number of involved nodes are prognostic for post-operative survival. To better understand lymphatic metastasis of ESCC, there is a need to develop proper animal models. AIMS: This study is aimed to characterize the morphology and function of the lymphatic drainage system in the mouse esophagus. METHODS: Immunostaining and fluorescence imaging were used to visualize the lymphatic drainage system in the mouse esophagus. Tracers and cancer cells were orthotopically inoculated into the submucosa of the mouse esophagus to mimic lymphatic metastasis of T1 ESCC. RESULTS: Using immunostaining of a lymphatic vessel marker (LYVE1), we found that lymphatic vessels were located in the submucosa and muscularis propria of the mouse esophagus, similar to the human esophagus. In the esophagus of ProxTom mice expressing tdTomato in the lymphatic vessels, we discovered a microscopic meshwork of lymphatic vessels. Functionally, orthotopically inoculated tracers (Indian ink and FITC-dextran) were drained from the submucosa into peri-esophageal lymph nodes via lymphatic vessels. Orthotopically inoculated mouse cancer cells (LLC-eGFP, MOC2) metastasized from the submucosa to lymphatic vessels, peri-esophageal lymph nodes, and distant organs (liver and lung) in immunocompetent mice. Similarly, in immunodeficient mice, orthotopically inoculated human ESCC cells (KYSE450-eGFP-Luc) metastasized via the same route. CONCLUSION: We have characterized the morphology and function of the lymphatic drainage system of the mouse esophagus. These observations lay a foundation for mechanistic and therapeutic studies on lymphatic metastasis of T1 ESCC.

miR-342-5p inhibits odonto/osteogenic differentiation of human dental pulp stem cells via targeting Wnt7b.

OBJECTIVE: Human dental pulp stem cells (hDPSCs) constitute a promising source of stem cells in tissue engineering. However, the molecular mechanism of differentiation in hDPSCs remains largely unclear. MicroRNAs (miRNAs) play crucial roles in lineage-specific differentiation of stem cells. The present study investigated the function of miRNA-342-5p in the odonto/osteogenic differentiation of hDPSCs. METHODS: The miRNA array profiling and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) revealed the expression of miR-342-5p during odonto/osteogenic differentiation of hDPSCs. hDPSCs were treated with miR-342-5p mimic and inhibitor to investigate the regulatory roles of miR-342-5p in the differentiation of hDPSCs. Moreover, miR-342-5p inhibitor and small interference RNA (siRNA) targeting Wnt7b were applied to explore the regulatory mechanism of miR-342-5p. RESULTS: Downregulated miR-342-5p was observed during odonto/osteogenic differentiation of hDPSCs. The overexpression of miR-342-5p inhibited the odonto/osteogenic potential of DPSCs, as indicated by low levels of alkaline phosphatase activity, calcium deposition formation, and odonto/osteogenic differentiation markers, whereas silencing of miR-342-5p exhibited the opposite effect. When co-treated with siRNA targeting Wnt7b and miR-342-5p inhibitor in hDPSCs, the odonto/osteogenic potential and activation of Wnt7b/ß-catenin pathway were attenuated. CONCLUSIONS: This study showed that miR-342-5p inhibits the odonto/osteogenic differentiation of hDPSCs by interfering with Wnt/ß-catenin signaling via targeting Wnt7b.