Scavenger receptor B2, a type III membrane pattern recognition receptor, senses LPS and activates the IMD pathway in crustaceans.

The immune deficiency (IMD) pathway is critical for elevating host immunity in both insects and crustaceans. The IMD pathway activation in insects is mediated by peptidoglycan recognition proteins, which do not exist in crustaceans, suggesting a previously unidentified mechanism involved in crustacean IMD pathway activation. In this study, we identified a Marsupenaeus japonicus B class type III scavenger receptor, SRB2, as a receptor for activation of the IMD pathway. SRB2 is up-regulated upon bacterial challenge, while its depletion exacerbates bacterial proliferation and shrimp mortality via abolishing the expression of antimicrobial peptides. The extracellular domain of SRB2 recognizes bacterial lipopolysaccharide (LPS), while its C-terminal intracellular region containing a cryptic RHIM-like motif interacts with IMD, and activates the pathway by promoting nuclear translocation of RELISH. Overexpressing shrimp SRB2 in Drosophila melanogaster S2 cells potentiates LPS-induced IMD pathway activation and diptericin expression. These results unveil a previously unrecognized SRB2-IMD axis responsible for antimicrobial peptide induction and restriction of bacterial infection in crustaceans and provide evidence of biological diversity of IMD signaling in animals. A better understanding of the innate immunity of crustaceans will permit the optimization of prevention and treatment strategies against the arising shrimp diseases.

M6A-mediated hsa_circ_0061179 inhibits DNA damage in ovarian cancer cells via miR-143-3p/TIMELESS.

Ovarian cancer (OC) is among the most common and deadly solid malignancies in women. Despite many advances in OC research, the incidence of OC continues to rise, and its pathogenesis remains largely unknown. Herein, we elucidated the function of hsa_circ_0061179 in OC. The levels of hsa_circ_0061179, miR-143-3p, TIMELESS, and DNA damage repair-related proteins in OC or normal ovarian tissues and cells were measured using real-time quantitative polymerase chain reaction and immunoblotting. The biological effects of hsa_circ_0061179 and miR-143-3p on proliferation, clone formation, DNA damage, and apoptosis of OC cells were detected by the cell counting kit-8 assay, 5-methylethyl-2'-deoxyuridine, flow cytometry, the comet assay, and immunofluorescence staining combined with the confocal microscopy. The interaction among hsa_circ_0061179, miR-143-3p, and TIMELESS was validated by the luciferase reporter assay. Mice tumor xenograft models were used to evaluate the influence of hsa_circ_0061179 on OC growth in vivo. We found that human OC biospecimens expressed higher levels of hsa_circ_0061179 and lower levels of miR-143-3p. Hsa_circ_0061179 was found to bind with miR-143-3p, which directly targets TIMELESS. Hsa_circ_0061179 knockdown or miR-143-3p overexpression suppressed the proliferation and clone formation of OC cells and increased DNA damage and apoptosis of OC cells via the miR-143-3p/TIMELESS axis. Furthermore, we demonstrated that METTL3 could direct the formation of has_circ_0061179 through a specific m6A modification site. YTHDC1 facilitated the cytoplasmic transfer of has_circ_0061179 by directly binding to the modified m6A site. Our findings suggest that hsa_circ_0061179 acts as the sponge of miR-143-3p to activate TIMELESS signaling and inhibits DNA damage and apoptosis in OC cells.

Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer.

Ovarian cancer (OC) is the most lethal gynecological tumor, characterized by its insidious and frequently recurring metastatic progression. Owing to limited early screening methods, over 70% of OC cases are diagnosed at advanced stages, typically stage III or IV. Recently, N6-methyladenosine (m6A) modification has emerged as a hotspot of epigenetic research, representing a significant endogenous RNA modification in higher eukaryotes. Numerous studies have reported that m6A-related regulatory factors play pivotal roles in tumor development through diverse mechanisms. Moreover, recent studies have indicated the aberrant expression of multiple regulatory factors in OC. Therefore, this paper comprehensively reviews research advancements concerning m6A in OC, aiming to elucidate the regulatory mechanism of m6A-associated regulators on pivotal aspects, such as proliferation, invasion, metastasis, and drug resistance, in OC. Furthermore, it discusses the potential of m6A-associated regulators as early diagnostic markers and therapeutic targets, thus contributing to the diagnosis and treatment of OC.

Ovarian cancer (OC) presents a formidable challenge in the medical field, often detected at advanced stages, necessitating urgent exploration of diagnostic and therapeutic avenues. This review delves into the intricate role of N6-methyladenosine (m6A) RNA modification in OC, a dynamic epigenetic process increasingly recognized for its regulatory role in cancer biology. Highlighting recent advancements, the review sheds light on how m6A-related factors influence crucial aspects of OC progression, including tumor growth, metastasis, and resistance to treatment. Specifically, m6A methyltransferases, binding proteins, and demethylases exert multifaceted effects on OC progression, influencing the expression of pivotal oncogenes and tumor suppressors. While promising, translating these insights into effective therapies requires further investigation. By comprehensively understanding the influence of m6A on OC, there lies hope for developing improved diagnostic techniques and novel treatment strategies to combat this complex disease.

Discovery of novel Akt1 inhibitors by an ensemble-based virtual screening method, molecular dynamics simulation, and in vitro biological activity testing.

Akt1, as an important member of the Akt family, plays a controlled role in cancer cell growth and survival. Inhibition of Akt1 activity can promote cancer cell apoptosis and inhibit tumor growth. Therefore, in this investigation, a multilayer virtual screening approach, including receptor-ligand interaction-based pharmacophore, 3D-QSAR, molecular docking, and deep learning methods, was utilized to construct a virtual screening platform for Akt1 inhibitors. 17 representative compounds with different scaffolds were identified as potential Akt1 inhibitors from three databases. Among these 17 compounds, the Hit9 exhibited the best inhibitory activity against Akt1 with inhibition rate of 33.08% at concentration of 1 µM. The molecular dynamics simulations revealed that Hit9 and Akt1 could form a compact and stable complex. Moreover, Hit9 interacted with some key residues by hydrophobic, electrostatic, and hydrogen bonding interactions and induced substantial conformation changes in the hinge region of the Akt1 active site. The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were - 34.44, - 63.37, and - 39.14 kJ mol-1, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for developing new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

Both epilepsy and anti-seizure medications affect bone metabolism in children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.

Spinal cord astrocyte P2X7Rs mediate the inhibitory effect of electroacupuncture on visceral hypersensitivity of rat with irritable bowel syndrome.

This study explored the role of P2X7 receptors in spinal cord astrocytes in the electroacupuncture-induced inhibition of visceral hypersensitivity (VH) in rats with irritable bowel syndrome (IBS). Visceral hypersensitivity of IBS was intracolonically induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Visceromotor responses to colorectal distension (CRD-20,40,60,80 mmHg) and abdominal withdrawal reflex scoring (AWRs) were recorded after electroacupuncture at bilateral Zusanli (ST36) and Sanyinjiao (SP6) acupoints to evaluate the analgesic effect of electroacupuncture on visceral pain in rats with IBS. Fluorocitric acid (FCA), an astrocyte activity inhibitor, was injected intrathecally before electroacupuncture intervention and AWRs were recorded. Western blot and real-time qPCR were used to detect the expression of NMDA and P2X7 receptor to observe the regulation effect of electroacupuncture on NMDA receptor in the spinal cord of rats with visceral hypersensitivity. Intrathecal injection of P2X7 agonist or antagonist was administered before electroacupuncture treatment. To observe the effect of P2X7 receptor in spinal astrocytes on the inhibition of visceral hyperalgesia by electroacupuncture, the changes of AWR score, NMDA receptor in the spinal cord, and GFAP expression in astrocytes were detected. Inflammation of the colon had basically subsided at day 21 post-TNBS; persistent visceral hypersensitivity could be suppressed by electroacupuncture. This analgesic effect could be inhibited by FCA. The analgesic effect, downregulation of NMDA receptor NR1 subunit, and P2X7 protein of electroacupuncture were all reversed by FCA. P2X7 receptor antagonist A740003 can cooperate with EA to carry out analgesic effect in rats with visceral pain and downregulate the expression of NR1, NR2B, and GFAP in spinal dorsal horn. However, the P2X7 receptor agonist BzATP could partially reverse the analgesic effect of EA, inhibiting the downregulatory effect of EA on the expression of NR1, NR2B, and GFAP. These results indicate that EA may downregulate the expression of the NMDA receptor by inhibiting the P2X7 receptor in the spinal cord, thereby inhibiting spinal cord sensitization in IBS rats with visceral pain, in which astrocytes are an important medium.

Kinetically and thermodynamically controlled one-pot growth of gold nanoshells with NIR-II absorption for multimodal imaging-guided photothermal therapy.

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.

Circulating IGFBP-3 and Interleukin 6 as Predictors of Osteoporosis in Postmenopausal Women: A Cross-Sectional Study.

Objective: To explore the relationship between circulating IGFBP-3, IL-6, and bone mineral density and the potential diagnostic role of circulating IGFBP-3 and IL-6 in postmenopausal women with osteoporosis. Methods: Eighty-five postmenopausal women at Soochow University's First Affiliated Hospital, Osteoporosis and Menopause Clinics, were recruited. Forty-five of 85 women were diagnosed with osteoporosis. Circulating IL-6, PTH, 1,25(OH)2D3, osteocalcin (OST), IGF-1, IGFBP-3, and bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) were measured in 40 ordinary and 45 osteoporotic women. A simple regression analysis calculated the correlation between age, BMD, IL-6, and IGFBP-3. Multiple stepwise regression analyses were conducted to determine which variables were independently related to BMD. The potential role of IGFBP-3 and IL-6 in the diagnosis of postmenopausal osteoporosis was predicted using the area under the receiver operating characteristic curve (ROC, AUC). Results: Age, years since menopause, and circulating IL-6, PTH, and IGFBP-3 were significantly higher in the osteoporosis group compared to the normal group. Osteoporotic women had substantially lower BMDs of the LS and FN than normal women. Age-related increases were found for IGFBP-3 and IL-6, whereas age-related decreases were observed for LS/FN BMD. IGFBP-3 and IL-6 were both negatively correlated with LS and FN BMD. Stepwise multiple regression analysis showed that IGFBP-3 and IL-6 were strong predictors of BMD in postmenopausal women. AUC cut-off values (IGFBP-3: 3.65, IL-6: 0.205) were best evaluated for the diagnosis of postmenopausal women with osteoporosis, and the AUC for circulating IGFBP-3 and IL-6 were 0.706 (95% CI 0.594-0.818) and 0.685 (95% CI 0.571-0.798), respectively. Conclusion: In this cross-sectional study of postmenopausal women, IGFBP-3 and IL-6 were negatively related to BMD. Circulating IGFBP-3 and IL-6 might be essential predictors of postmenopausal osteoporosis and can help predict osteoporotic fracture.

[Research progress and application status of circumcision].

Circumcision is the simplest, most commonly used and most effective treatment for male prepuce overlength, phimosis and other diseases. There has also been a shift from traditional circumcision to simpler, faster, less invasive, instrument-based methods. This paper reviews the surgical methods of circumcision(Traditional circumcision、Electrosurgical circumcision、Laser circumcision、Sleeve circumcision, Dermotomy at the base of penis, Shangring, Gomco, Mogen, PlastiBell, PrePex, Alisklamp and Disposable circumcision suture apparatus), hoping to provide reference for clinicians to choose the appropriate circumcision methods for patients.

[Study on the efficacy and complications of patients undergoing radical surgery and radical radiotherapy for localized prostate cancer].

OBJECTIVE: To compare the efficacy and complications of radical surgery (RP) and radical radiotherapy (RRT). METHODS: The clinical data of patients diagnosed with localized prostate cancer in General Hospital of Eastern Theater Command with RP and RRT from January 2015 to December 2019, Observed and recorded patient preoperative and postoperative PSA levels, biochemical Relapse-free Survival and clinical Relapse-free Survival,and the occurrence of hematuria, urinary incontinence, erectile dysfunction, ankylurethria, diarrhea, hemoproctia and radiocystitis. RESULTS: A total of 150 patients with localized prostate cancer were included in this study, including 105 patients with RP and 45 patients undergoing RRT. There was no significant difference between the complication rates of hematuria, urinary incontinence, erectile dysfunction and ankylurethria(P>0.05).Patients in the RRT group had higher rates of diarrhea(20.00% vs 2.86%), hemoproctia(15.56% vs 1.90%) and radiocystitis(13.33% vs 0%) than those in the RP group, with significant differences (P<0.05). The 5-year bRFS was lower than that in the RP group (95.1% vs 90.7%), with no statistical significance (P=0.832); the 5-year cRFS in the RP group was lower than that in the RRT group (91.2% vs 89.6%), with no significant difference (P=0.971). CONCLUSION: The incidence of diarrhea, hemoproctia and radiocystitis was lower in the RP group than in the RRT group, and the recurrence-free survival was not significantly different between the two groups.

["Scarless" circumcision technique retaining original appearance].

OBJECTIVE: To explore the safety and effectiveness of the "scarless" circumcision technique (a modified sleeve-style circumcision method) that preserves the original appearance, providing a more suitable surgical option for patients with redundant prepuce. METHODS: Clinical data of patients who underwent "scarless" circumcision at the Eastern Theater Command General Hospital from April 2022 to March 2023 were collected, with patients who underwent conventional circumcision (single-use stapler method) during the same period serving as the control group. The two groups were compared in terms of operation time, postoperative recovery time, incidence of postoperative complications, and patient satisfaction rates after surgery. RESULTS: The operation time for the study group was significantly longer than that of the control group; there was no significant difference in pain scores on the day of surgery between the two groups, but the pain scores on postoperative days 1, 3, and 7 were lower in the study group than in the control group; the postoperative recovery time was significantly shorter in the study group than in the control group; regarding postoperative complications: the control group had higher rates of edema, incision infection, and wound dehiscence than the study group. A satisfaction survey conducted 30 days postoperatively showed higher satisfaction in the study group than in the control group. CONCLUSION: The "scarless" circumcision technique that preserves the original appearance is safe and effective for patients with simple redundant prepuce and is a new surgical method with value for widespread adoption.

[Application of 1470 nm semiconductor laser in the treatment of benign prostatic hyperplasia in ultra-aged patients].

OBJECTIVE: To investigate the clinical effect and safety of transurethral 1470 nm semiconductor laser vaporization and cutting in the treatment of super high age and high risk benign prostatic hyperplasia. METHODS: The clinical data of 38 patients with super-high-risk prostate who underwent transurethral surgery in our hospital from April 2016 to December 2017 were retrospectively analyzed. All patients had obvious progressive dysuria. The diagnosis of benign prostatic hyperplasia was confirmed by urinary color Doppler ultrasound, anal finger examination, PSA, prostate biopsy, etc., and prostate cancer was excluded. Each patient was aged ≥85 years old and combined with one or more types. Senile basic diseases such as diabetes, hypertension, coronary heart disease, emphysema, sequelae of cerebral infarction, etc. The patients were randomly divided into two groups. The observation group was treated with transurethral 1470 nm semiconductor laser vaporization and the control group was treated with transurethral plasma electrotomy. To observe the changes of vital signs, bleeding, duration of surgery, postoperative bladder irrigation time, urinary catheter retention time, and changes of hemoglobin before and after surgery. Surgical safety. The international prostate symptom score (IPSS), quality of life score (QoL), maximum urinary flow rate (Qmax), and post-void residual urine volume (PVR) were evaluated 2 months after surgery and compared with preoperative evaluation to evaluate the surgical outcome. RESULTS: All 38 operations were successfully completed.The vital signs of the patients were stable during the operation. The average operation time of the observation group and the control group was (79.6±24.7 vs 69.5±19.8) min, P>0.05. The hemoglobin decreased by (6.9±3.0) g/L vs (13.2±4.0) g/L， after operation.P<0.05; postoperative bladder irrigation time (14.7±2.8 vs 23.5±5.3)h, P<0.05; average postoperative urinary catheter retention time (3.8±0.4 vs 5.7±0.9)d, P<0.05; average postoperative hospital stay (5.3±1.1 vs 7.2±1.9)d, P<0.05; all patients were followed up for 2 months, IPSS, QoL, Qmax, PVR and other indicators were significantly improved compared with preoperative, no major bleeding, urinary incontinence, cardiopulmonary failure and Significant urinary tract irritation symptoms occur. CONCLUSION: Compared with plasma electric resection, transurethral 1470 nm semiconductor laser treatment of benign prostatic hyperplasia has the advantages of high safety and remarkable effect, especially suitable for patients with high age and high risk.

[Influence factors of erectile dysfunction in patients with localized prostate cancer after radical surgery].

OBJECTIVE: To analyze the influential factors of erectile dysfunction (ED) in patients with localized prostate cancer (LPC) after radical surgery. METHODS: The clinical data of 150 male patients diagnosed with LPC and normal erectile function (EF) before surgery admitted to the Department of Urology of the Eastern Theatre General Hospital from January 2021 to January 2023 were retrospectively analyzed. The EF status of the patients 6 months after surgery was assessed using the International Erectile Function Index -5(IIEF-5). Age, Gleason score, PSA level, TNM stage, preoperative International prostatic symptom score (IPSS), preoperative prostate volume, smoking index, alcohol consumption index, educational level, comorbidities, operation mode, and psychosexual state were used as influencing factors to analyze their effects on postoperative ED. RESULTS: Of the 150 patients, 88 had ED and 62 had normal EF. Univariate analysis showed that age, preoperative IPSS, preoperative prostate volume, comorbidities and sexual and psychological status were significantly correlated with postoperative ED. Further multivariate logistic regression analysis showed that age, preoperative prostate volume, comorbidities and sexual and psychological status were independent factors influencing the occurrence of ED after RP in LPC patients. CONCLUSION: The recovery of sexual function of patients with localized prostate cancer after radical surgery is generally poor, and the incidence of ED is high. Its independent influencing factors include age, preoperative prostate volume, comorbidities and sexual psychological state, etc. Correct intervention of different influencing factors is required in clinical work. In order to provide a better diagnosis and treatment scheme for LPC patients undergoing radical treatment, reduce the incidence of postoperative ED and improve the quality of life of patients after surgery.

Risk of vigabatrin-associated brain abnormalities on MRI: A retrospective and controlled study.

OBJECTIVE: Vigabatrin (VGB) is the first-line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB. METHODS: Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non-VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed. RESULTS: A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty-three of the 25 VABAM cases have a peak dosage of VGB between 50 and 150 mg/kg/day. The earliest observation time of VABAM was 30 days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM. SIGNIFICANCE: In our study, the occurrence of VABAM was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of VGB was the risk factor of VABAM. Caution should be exercised that our data also suggest that VABAM may occur even using the conventional dosage of VGB (ie, 50-150 mg/kg/day). Therefore, even when using the conventional dosage of VGB, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving VGB.

Different effects of maternal homocysteine concentration, MTHFR and MTRR genetic polymorphisms on the occurrence of fetal aneuploidy.

RESEARCH QUESTION: Do maternal homocysteine (Hcy) concentrations, MTHFR and MTRR genes have effects on the occurrence of fetal aneuploidy? DESIGN: A total of 619 aneuploidy mothers and 192 control mothers were recruited in this study. Differences in distributions of maternal MTHFR 677C>T, MTHFR 1298A>C and MTRR 66A>G genetic polymorphisms and maternal Hcy concentrations between aneuploidy mothers and control mothers were analysed. RESULTS: The maternal MTHFR 677C>T polymorphism was found to be a risk factor for the occurrence of many fetal non-mosaic aneuploidies studied here, including trisomies 13, 15, 16, 18, 21, 22, TRA and TS. The maternal MTHFR 1298A>C polymorphism was found to be a risk factor specifically associated with the occurrence of fetal trisomy 15 and fetal TS. The maternal MTRR 66A>G polymorphism was found to be a risk factor only specifically associated with the occurrence of fetal trisomy 21. The Hcy concentrations of mothers of trisomies 22, 21, 18, 16, 15 and TS fetuses were significantly higher than the Hcy concentrations of control mothers. CONCLUSIONS: Overall, data suggested an association between these maternal polymorphisms and the susceptibility of fetal non-mosaic trisomy and Turner syndrome. However, these three maternal polymorphisms had different associations with the susceptibility of different fetal aneuploidies, and the elevated maternal Hcy concentration appeared to be a likely risk factor for fetal Turner syndrome and fetal trisomies.

S-nitrosylation of c-Jun N-terminal kinase mediates pressure overload-induced cardiac dysfunction and fibrosis.

Cardiac fibrosis (CF) is an irreversible pathological process that occurs in almost all kinds of cardiovascular diseases. Phosphorylation-dependent activation of c-Jun N-terminal kinase (JNK) induces cardiac fibrosis. However, whether S-nitrosylation of JNK mediates cardiac fibrosis remains an open question. A biotin-switch assay confirmed that S-nitrosylation of JNK (SNO-JNK) increased significantly in the heart tissues of hypertrophic patients, transverse aortic constriction (TAC) mice, spontaneously hypertensive rats (SHRs), and neonatal rat cardiac fibroblasts (NRCFs) stimulated with angiotensin II (Ang II). Site to site substitution of alanine for cysteine in JNK was applied to determine the S-nitrosylated site. S-Nitrosylation occurred at both Cys116 and Cys163 and substitution of alanine for cysteine 116 and cysteine 163 (C116/163A) inhibited Ang II-induced myofibroblast transformation. We further confirmed that the source of S-nitrosylation was inducible nitric oxide synthase (iNOS). 1400 W, an inhibitor of iNOS, abrogated the profibrotic effects of Ang II in NRCFs. Mechanistically, SNO-JNK facilitated the nuclear translocation of JNK, increased the phosphorylation of c-Jun, and induced the transcriptional activity of AP-1 as determined by chromatin immunoprecipitation and EMSA. Finally, WT and iNOS-/- mice were subjected to TAC and iNOS knockout reduced SNO-JNK and alleviated cardiac fibrosis. Our findings demonstrate an alternative mechanism by which iNOS-induced SNO-JNK increases JNK pathway activity and accelerates cardiac fibrosis. Targeting SNO-JNK might be a novel therapeutic strategy against cardiac fibrosis.

Machine Learning Assisted Doppler Features for Enhancing Thyroid Cancer Diagnosis: A Multi-Cohort Study.

BACKGROUND: This pilot study aims at exploiting machine learning techniques to extract color Doppler ultrasound (CDUS) features and to build an artificial neural network (ANN) model based on these CDUS features for improving the diagnostic performance of thyroid cancer classification. METHODS: A total of 674 patients with 712 thyroid nodules (TNs) (512 from internal dataset and 200 from external dataset) were randomly selected in this retrospective study. We used ANN to build a model (TDUS-Net) for classifying malignant and benign TNs using both the automatically extracted quantitative CDUS features (whole ratio, intranodular ratio, peripheral ratio, and number of vessels) and gray-scale ultrasound (US) features defined by the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS). Then, we compared the diagnostic performance of the model, the performance of another ANN model based on the gray-scale US features alone (TUS-Net), and that of radiologists. RESULTS: The TDUS-Net (0.898, 95% CI: 0.868-0.922) achieved a higher area under the curve (AUC) than that of TUS-Net (0.881, 95% CI: 0.850-0.908) in the internal tests. Compared with radiologists, TDUS-Net (AUC: 0.925, 95% CI: 0.880-0.958) performed better than radiologists (AUC: 0.810, 95% CI: 0.749-0.862) in the external tests. CONCLUSIONS: Applying a machine learning model by combining both gray-scale US features and CDUS features can achieve comparable or even higher performance than radiologists in classifying TNs.

Effect of folic acid supplementation on the change of plasma S-adenosylhomocysteine level in Chinese hypertensive patients: a randomized, double-blind, controlled clinical trial.

The relationship between folic acid and S-adenosylhomocysteine (SAH) is controversial. This study aims to explore the effect of different doses of folic acid supplementation on SAH levels in hypertensive patients and the modification of methylene-tetrahydrofolate reductase (MTHFR) C677T gene polymorphism. A randomized, double-blind, controlled clinical trial was conducted. Hypertensive patients aged 45-75 years without a history of stroke and cardiovascular disease were selected, who were randomly assigned to one of 8 dose groups. This trial has been registered with Trial Number: ChiCTR1800016135. In the total population, folic acid supplementation of 0.4-2.0 mg/day had no effect on SAH level (ß = 0.47, 95% CI: -0.86-1.79, p = 0.491), while folic acid supplementation of 2.4 mg/day significantly increased SAH level (ß = 1.93, 95% CI: 0.22-3.64, p = 0.027). Stratified analysis found that MTHFR C677T genotype CC supplemented with 2.4 mg/day folic acid had no effect on SAH level (ß = 0.30, 95% CI: -2.74-3.34, p = 0.847), while CT and TT genotype supplemented with 2.4 mg/day folic acid showed a significant increase in SAH level (CT: ß = 2.98, 95% CI: 0.34-5.62, p = 0.027; TT: ß = 3.00, 95% CI: -0.51-6.51, p = 0.095; CT combined with TT: ß = 2.99, 95% CI: 0.90-5.09, p = 0.005). In conclusion, supplementation of 2.4 mg/day folic acid can lead to increased SAH levels, especially in MTHFR C677T genotype CT and TT.

Association of HECW2 variants with developmental and epileptic encephalopathy and knockdown of zebrafish hecw2a.

Developmental and epileptic encephalopathy (DEE) is a severe encephalopathy in infants and early childhood. In this study we reported a recurrent de novo variant (c.3985C>T, p.R1330W) in HECW2 (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2) (MIM# 617245) identified by screening 240 patients with DEE and summarized clinical features of published DEE patients with HECW2 variants. Functionally, transcriptional knockdown of zebrafish hecw2a led to early morphological abnormalities in the brain tissues. These results suggest a potential functional link between HECW2 dysfunction and brain development.

Respiratory Variations in Peak Peripheral Artery Velocities and Waveforms for Rapid Assessment of Fluid Responsiveness in Traumatic Shock Patients.

BACKGROUND This study aimed to assess the correlation between the variability of the end-inspiratory and end-expiratory blood flow waveform and fluid responsiveness (FR) in traumatic shock patients who underwent mechanical ventilation by evaluating peripheral arterial blood flow parameters. MATERIAL AND METHODS A cohort of 60 patients with traumatic shock requiring mechanical ventilation-controlled breathing received ultrasound examinations to assess the velocity of carotid artery (CA), femoral artery (FA) and brachial artery (BA). A rehydration test was performed in which of 250 mL of 0.9% saline was administered within 30 min between the first and second measurement of cardiac output by echocardiography. Then, all patients were divided into 2 groups, a responsive group (FR+) and a non-responsive group (FR-). The velocity of end-inspiratory and end-expiratory peripheral arterial blood flow of all patients was ultrasonically measured, and the variability were measured between end-inspiratory and end-expiratory. RESULTS The changes in the end-inspiratory and end-expiratory carotid artery blood flow velocity waveforms of the FR+ groups were significantly different from those of the FR- group (P<0.001). A statistically significant difference in ΔVmax (CA), ΔVmax (BA), and ΔVmax (FA) between these 2 groups was found (all P<0.001). The ROC curve showed that DVmax (CA) and ΔVmax (BA) were more sensitive values to predict FR compared to ΔVmax (FA). The sensitivity of ΔVmax (CA), ΔVmax (FA), and ΔVmax (BA) was 70.0%, 86.7%, and 93.3%, respectively. CONCLUSIONS The study showed that periodic velocity waveform changes in the end-inspiratory and end-expiratory peripheral arterial blood flow can be used for quick assessment of fluid responsiveness.