Structural RNA components supervise the sequential DNA cleavage in R2 retrotransposon.

Retroelements are the widespread jumping elements considered as major drivers for genome evolution, which can also be repurposed as gene-editing tools. Here, we determine the cryo-EM structures of eukaryotic R2 retrotransposon with ribosomal DNA target and regulatory RNAs. Combined with biochemical and sequencing analysis, we reveal two essential DNA regions, Drr and Dcr, required for recognition and cleavage. The association of 3' regulatory RNA with R2 protein accelerates the first-strand cleavage, blocks the second-strand cleavage, and initiates the reverse transcription starting from the 3'-tail. Removing 3' regulatory RNA by reverse transcription allows the association of 5' regulatory RNA and initiates the second-strand cleavage. Taken together, our work explains the DNA recognition and RNA supervised sequential retrotransposition mechanisms by R2 machinery, providing insights into the retrotransposon and application reprogramming.

The inhibition of FTO attenuates the antifibrotic effect of leonurine in rat cardiac fibroblasts.

BACKGROUND: Myocardial fibrosis (MF) is a common pathological condition in cardiovascular diseases that often causes severe cardiac dysfunction. MF is characterized by changes in cardiomyocytes, cardiac fibroblasts (CFs), levels of collagen (Col) -1, -3, and overdeposition of the extracellular matrix. Our previous research showed that leonurine (LE) effectively inhibits collagen synthesis and differentiation of CFs, but the mechanism is not fully elucidated. Recent evidence indicates that fat mass and obesity-associated proteins (FTO) regulates the occurrence and development of MF. This study aimed to explore the role of FTO in the antifibrotic effects of LE. METHODS: Neonatal rat CFs were isolated, and induced using angiotensin II (Ang II) to establish a cell model of MF. Cell viability, wound healing and transwell assays were used to detect cell activity and migration ability. The protein and mRNA levels of MF-related factors were measured following stimulation with Ang II and LE under normal conditions or after FTO knockdown. The RNA methylation level was measured by dot blot assay. RESULTS: The results showed that LE (20, 40 µM) was not toxic to normal CFs. LE reduced the proliferation, migration and collagen synthesis of Ang II-induced CFs. Further investigation showed that FTO was downregulated by Ang II stimulation, whereas LE reversed this effect. FTO knockdown facilitated the migration of CFs, upregulated the protein levels of Col-3, α-SMA and Col-1 in Ang II and LE-stimulated CFs, and enhanced the fluorescence intensity of α-SMA. Furthermore, LE reduced N6-methyladenosine (m6A) RNA methylation, which was partially blocked by FTO knockdown. FTO knockdown also reduced the expression levels of p53 protein in Ang II and LE-stimulated CFs. CONCLUSIONS: Our findings suggest that the inhibition of FTO may attenuate the antifibrotic effect of LE in CFs, suggesting that FTO may serve as a key protein for anti-MF of LE.

Smooth endoplasmic reticulum aggregates in oocytes associated with increased risk of neonatal birth defects: A meta-analysis.

INTRODUCTION: Previous studies have indicated the association between smooth endoplasmic reticulum aggregates (SERa+) and poorer medically assisted reproduction outcomes. However, the link between SERa+ and neonatal outcomes remains controversial and open for debate. A comprehensive meta-analysis on the relation between SERa+ and the risk of birth defects is needed. MATERIAL AND METHODS: The literature search was conducted using the following databases: PubMed, Embase, Cochrane Libraries, Web of Science, and Chinese databases including China National Knowledge Infrastructure (CNKI) and Wan Fang from inception until July 2023. Risk ratio (RR) and 95% confidence interval (CI) were calculated by a fixed-effected model, while heterogeneity was assessed by forest plots and I2 statistic. Funnel plot was produced to assess publication bias. This meta-analysis has been registered on PROSPERO (CRD42022313387). RESULTS: The search resulted in 122 studies, 14 of which met the inclusion criteria. The analysis of birth defects revealed a higher risk (RR = 2.17, 95%CI 1.24 to 3.81, p = 0.007) in children derived from SERa+ cycle compared to SERa- cycles (711 vs. 4633). Meanwhile, in a subgroup analysis, the risk of birth defects was significantly increased in the SERa+ oocytes group as compared with the sibling SERa- oocytes group (RR = 3.53, 95%CI 1.21 to 10.24, p = 0.02). CONCLUSIONS: To conclude, our analysis indicated that SERa+ cycles/oocytes may have a potential risk of increased additional major birth defects comparing with SERa- cycles/oocytes. This conclusion may provide evidence-based support for clinicians in IVF clinical guidance and embryologists in prudent embryo selection strategy.

UPLC-MS/MS Method for Simultaneous Determination of Valnemulin and Its Metabolites in Crucian Carp: In Vivo Metabolism and Tissue Distribution Analyses.

Valnemulin (VML) is a semi-synthetic pleuromutilin derivative widely used to treat animal bacterial diseases. However, no study has comprehensively evaluated VML metabolism in aquatic animals, including crucian carp. This study aimed to investigate VML metabolism in crucian carp. VML metabolites in crucian carp were quantified via intraperitoneal injection and analyzed via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Three VML metabolites were detected in crucian carp via ultra-performance liquid chromatography-tandem quadrupole and time-of-flight mass spectrometry (UPLC-Q-TOF/MS) structural analysis. The enrichment and metabolism rules of the metabolites were summarized based on tissue distribution and concentration changes of the three metabolites. The metabolites were mainly found in the liver at 0.1 h after VML injection. The levels of the metabolites were abundant in the bile from 4 h to 12 h and in the skin after 72 h. The levels of the metabolites in the bile first increased, then decreased. The metabolism in the liver was completed at 72 h. The metabolites were detected in the skin following a 72 h period, which increased with time.

Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review.

BACKGROUND: In mammals, normal fertilization depends on the structural and functional integrity of the zona pellucida (ZP), which is an extracellular matrix surrounding oocytes. Mutations in ZP may affect oogenesis, fertilization and early embryonic development, which may cause female infertility. METHODS: A PubMed literature search using the keywords 'zona pellucida', 'mutation' and 'variant' limited to humans was performed, with the last research on June 30, 2022. The mutation types, clinical phenotypes and pregnancy outcomes were summarized and analyzed. The naive Bayes classifier was used to predict clinical pregnancy outcomes for patients with ZP mutations. RESULTS: A total of 29 publications were included in the final analysis. Sixty-nine mutations of the ZP genes were reported in 87 patients with different clinical phenotypes, including empty follicle syndrome (EFS), ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes. The phenotypes of patients were influenced by the types and location of the mutations. The most common effects of ZP mutations are protein truncation and dysfunction. Three patients with ZP1 mutations, two with ZP2 mutations, and three with ZP4 mutations had successful pregnancies through Intracytoplasmic sperm injection (ICSI) from ZFO or ZTO. A prediction model of pregnancy outcome in patients with ZP mutation was constructed to assess the chance of pregnancy with the area under the curve (AUC) of 0.898. The normalized confusion matrix showed the true positive rate was 1.00 and the true negative rate was 0.38. CONCLUSION: Phenotypes in patients with ZP mutations might be associated with mutation sites or the degree of protein dysfunction. Successful pregnancy outcomes could be achieved in some patients with identified ZP mutations. Clinical pregnancy prediction model based on ZP mutations and clinical characteristics will be helpful to precisely evaluate pregnancy chance and provide references and guidance for the clinical treatment of relevant patients.

Investigating the impact of SARS-CoV-2 infection on basic semen parameters and in vitro fertilization/intracytoplasmic sperm injection outcomes: a retrospective cohort study.

BACKGROUND: This study aimed to evaluate the influences of SARS-CoV-2 infection on semen parameters and investigate the impact of the infection on in vitro fertilization (IVF) outcomes. METHODS: This retrospective study enrolled couples undergoing IVF cycles between May 2020 and February 2021 at Tongji Hospital, Wuhan. Baseline characteristics were matched using propensity score matching. Participants were categorized into an unexposed group (SARS-COV-2 negative) and exposed group (SARS-COV-2 positive) based on a history of SARS-CoV-2 infection, and the populations were 148 and 50 after matching, respectively. IVF data were compared between the matched cohorts. Moreover, semen parameters were compared before and after infection among the infected males. The main measures were semen parameters and IVF outcomes, including laboratory and clinical outcomes. RESULTS: Generally, the concentration and motility of sperm did not significantly differ before and after infection. Infected males seemed to have fewer sperm with normal morphology, while all values were above the limits. Notably, the blastocyst formation rate and available blastocyst rate in the exposed group were lower than those in the control group, despite similar mature oocytes rates, normal fertilization rates, cleavage rates, and high-quality embryo rates. Moreover, no significant differences were exhibited between the matched cohorts regarding the implantation rate, biochemical pregnancy rate, clinical pregnancy rate, or early miscarriage rate. CONCLUSIONS: The results of this retrospective cohort study suggested that the semen quality and the chance of pregnancy in terms of IVF outcomes were comparable between the males with a history of SARS-CoV-2 infection and controls, although a decreased blastocyst formation rate and available blastocyst rate was observed in the exposed group, which needs to be reinforced by a multicenter long-term investigation with a larger sample size.

Rapamycin improves the quality and developmental competence of mice oocytes by promoting DNA damage repair during in vitro maturation.

BACKGROUND: Increasing evidence has shown that the mammalian target of rapamycin (mTOR) pathway plays a critical role in oocyte meiosis and embryonic development, however, previous studies reporting the effects of rapamycin on oocyte IVM showed different or even opposite results, and the specific mechanisms were not clear. METHODS: The immature oocytes from female mice underwent IVM with rapamycin at different concentrations to select an optimal dose. The maturation rate, activation rate, subsequent cleavage and blastocyst formation rates, spindle assembly, chromosome alignment, mitochondrial membrane potential (MMP), ROS levels, and DNA damage levels were evaluated and compared in oocytes matured with or without rapamycin. In addition, the expression levels of genes associated with mTORC1 pathway, spindle assembly, antioxidant function, and DNA damage repair (DDR) were also assessed and compared. RESULTS: Rapamycin at 10 nM was selected as an optimal concentration based on the higher maturation and activation rate of IVM oocytes. Following subsequent culture, cleavage and blastocyst formation rates were elevated in activated embryos from the rapamycin group. Additionally, oocytes cultured with 10 nM rapamycin presented decreased ROS levels, reduced chromosome aberration, and attenuated levels of γ-H2AX. No significant effects on the percentages of abnormal spindle were observed. Correspondingly, the expressions of Nrf2, Atm, Atr, and Prkdc in IVM oocytes were markedly increased, following the inhibition of mTORC1 pathway by 10 nM rapamycin. CONCLUSION: Rapamycin at 10 nM could ameliorate the developmental competence and quality of IVM oocytes of mice, mainly by improving the chromosome alignments. The inhibition of mTORC1 pathway, which involved in activating DDR-associated genes may act as a potential mechanism for oocyte quality improvement by rapamycin.

Individualized embryo selection strategy developed by stacking machine learning model for better in vitro fertilization outcomes: an application study.

BACKGROUND: To minimize the rate of in vitro fertilization (IVF)- associated multiple-embryo gestation, significant efforts have been made. Previous studies related to machine learning in IVF mainly focused on selecting the top-quality embryos to improve outcomes, however, in patients with sub-optimal prognosis or with medium- or inferior-quality embryos, the selection between SET and DET could be perplexing. METHODS: This was an application study including 9211 patients with 10,076 embryos treated during 2016 to 2018, in Tongji Hospital, Wuhan, China. A hierarchical model was established using the machine learning system XGBoost, to learn embryo implantation potential and the impact of double embryos transfer (DET) simultaneously. The performance of the model was evaluated with the AUC of the ROC curve. Multiple regression analyses were also conducted on the 19 selected features to demonstrate the differences between feature importance for prediction and statistical relationship with outcomes. RESULTS: For a single embryo transfer (SET) pregnancy, the following variables remained significant: age, attempts at IVF, estradiol level on hCG day, and endometrial thickness. For DET pregnancy, age, attempts at IVF, endometrial thickness, and the newly added P1 + P2 remained significant. For DET twin risk, age, attempts at IVF, 2PN/ MII, and P1 × P2 remained significant. The algorithm was repeated 30 times, and averaged AUC of 0.7945, 0.8385, and 0.7229 were achieved for SET pregnancy, DET pregnancy, and DET twin risk, respectively. The trend of predictive and observed rates both in pregnancy and twin risk was basically identical. XGBoost outperformed the other two algorithms: logistic regression and classification and regression tree. CONCLUSION: Artificial intelligence based on determinant-weighting analysis could offer an individualized embryo selection strategy for any given patient, and predict clinical pregnancy rate and twin risk, therefore optimizing clinical outcomes.

Analysis of maturation dynamics and developmental competence of in vitro matured oocytes under time-lapse monitoring.

BACKGROUND: To improve the developmental competence of in vitro cultured oocytes, extensive literature focused on maturation rate improvement with different additives in culture medium, while studies investigating the maturation dynamics of oocytes during in vitro maturation (IVM) and the influencing factors on oocyte viability are scarce. METHODS: The study involved a retrospective observation by time-lapse monitoring of the IVM process of 157 donated GV oocytes from 59 infertile couples receiving ICSI in 2019, in Tongji Hospital, Wuhan, China. The GV oocytes derived from controlled ovarian hyperstimulation (COH) cycles underwent rescue IVM (R-IVM), and the maturation dynamics, including GVBD time (GV-MI), time from GVBD to maturation (MI-MII), maturation time (GV-MII), and MII arrest duration (MII-ICSI), were recorded by time-lapse monitoring. The matured oocytes were inseminated at different MII arrest points and subsequent embryo developments were assessed. The effects of baseline clinical characteristics, oocyte diameters, and maturation dynamics on the developmental competence of the oocytes were also analyzed. RESULTS: Totally, 157 GV oocytes were collected. GVBD happened in 111 oocytes, with a median GV-MI duration of 3.7 h. The median MI-MII duration was 15.6 h and the median GV-MII duration was 19.5 h. The maturation rate reached 56.7% at 24 h and 66.9% at 48 h, and the clinical factors, including patient age, FSH level, AMH level, ovarian stimulation protocol, and serum estradiol and progesterone levels on hCG trigger day, showed no effects on the 24-h maturation rate. The normal fertilization rate of oocytes resuming meiosis within 8 h and matured within 24 h was significantly higher than that of oocytes resuming meiosis after 8 h and matured after 24 h. Furthermore, among those oocytes matured within 24 h, the high-quality embryo formation rate of oocytes resuming meiosis within 4.5 h and matured within 19 h was significantly higher. All stated time was measured from the start point of IVM. Additionally, for oocytes from patients with serum progesterone levels less than 1 ng/ml on hCG trigger day, the high-quality embryo formation rate was significantly increased. CONCLUSION: R-IVM technology could increase the available embryos for patients in routine COH cycles, but excessive culture beyond 24 h is not recommended. GV-MI duration of the oocyte, recorded by time-lapse system, and serum progesterone levels of patients on hCG trigger day can significantly affect the developmental potential of the IVM oocytes.

The relationship between a novel evaluation parameter of premature luteinization and IVF outcomes.

RESEARCH QUESTION: Can premature luteinization of granulosa cells (PLGC) act as a novel parameter of premature luteinization and affect IVF outcomes? STUDY DESIGN: In this retrospective cohort study, infertile patients undergoing fresh IVF cycles between January 2006 and December 2016 at the Reproductive Medicine Center in Tongji Hospital were included. A total of 42,468 cycles were conducted. Propensity score matching was carried out to match the baseline characteristics, and participants were assigned to the PLGC group and control group. The main outcomes were pregnancy rate and live birth rate. RESULTS: Patient characteristics and clinical outcomes were compared before and after matching. In general, the fate of oocytes in the PLGC group was much worse than those in the control group after matching, including metaphase II rate, two-pronuclei rate, available embryo rate, blastocyst formation rate, high-quality blastocyst rate, pregnancy rate, implantation rate and live birth rate. Among those potential risk factors, gonadotrophin duration, oestradiol and progesterone on HCG day were positively associated with the occurrence of PLGC in the multivariate logistic regression model, with gonadotrophin dosage negatively related. Moreover, cumulus-oocyte complexes with PLGC showed a high correlation with elevated progesterone levels over 1.5 ng/ml. CONCLUSIONS: Our findings demonstrated the adverse effect of PLGC on oocyte competency. In evaluating cumulus-oocyte complexes, PLGC provide an available novel parameter for premature luteinization judgement in clinical and individualized precise treatment. Close monitoring of progesterone level as well as critical analysis of progesterone elevation can reduce the occurrence of premature luteinization.

Targeted gold nanorods combined with low-intensity nsPEFs enhance antimelanoma efficacy in vitro.

High-intensity nanosecond pulsed electric fields (nsPEFs) are a novel treatment with promising applications for cell stimulation and tissue ablation, and many research studies have shown that gold nanorods (GNRs) are high-conductivity nanomaterials that can enhance electroporation for biomedical applications. In addition, the folic acid (FA) receptor has been demonstrated as a valuable therapeutic target that is highly expressed in a variety of cancers. To reduce the electric field strength required to treat tumors by nsPEFs, for the first time, gold nanorods with folic acid were proposed to achieve higher antimelanoma efficacy at lower electric field intensity in this study. The surface of polyethylene glycol-gold nanorods with good biocompatibility was further modified by folic acid (FA) to provide modified gold nanorods (GNR-PEG-FA) with specific targeted recognition of A375 melanoma cells. The binding of GNRs to A375 melanoma cells was observed by dark field microscopy. After combined treatment with nsPEFs and GNRs, cell viability was evaluated by a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis and the cell cycle. And active caspase 3 was also detected after treatment. The antimelanoma efficacy was enhanced in a pulsed electric field-dependent manner. More importantly, compared with the group of nsPEFs alone and gold nanorods without FA, treating cells with nsPEFs combined with GNR-PEG-FA resulted in a lower percentage of viable cells, higher percentages of necrosis and apoptosis and higher concentration of active caspase 3 and induced cell cycle arrest in S phase, effectively inhibiting the proliferation of A375 melanoma cells. nsPEFs combined with GNR-PEG-FA showed the best antimelanoma efficacy in vitro and effectively killed melanoma cells with low-intensity nsPEFs. The combined treatment of cells with nsPEFs and GNR-PEG-FA is expected to become a safer and more efficient physical treatment of melanomas.

Quantization-Mitigation-Based Trajectory Control for Euler-Lagrange Systems with Unknown Actuator Dynamics.

In this paper, we investigate a trajectory control problem for Euler-Lagrange systems with unknown quantization on the actuator channel. To address such a challenge, we proposed a quantization-mitigation-based trajectory control method, wherein adaptive control is employed to handle the time-varying input coefficients. We allow the quantized signal to pass through unknown actuator dynamics, which results in the coupled actuator dynamics for Euler-Lagrange systems. It is seen that our method is capable of driving the states of networked Euler-Lagrange systems to the desired ones via Lyapunov's direct method. In addition, the effectiveness and advantage of our method are validated with a comparison to the existing controller.

Amplitude screening improves performance of AMSA method for predicting success of defibrillation in swine model.

PURPOSE: A novel amplitude screening method, termed Optimal Amplitude Spectrum Area (Opt-AMSA) with the aim of improving the performance of the Amplitude Spectrum Area (AMSA) method, was proposed to optimize the timing of defibrillation. We investigated the effects of the Opt-AMSA method on the prediction of successful defibrillation when compared with AMSA in a porcine model of ventricular fibrillation (VF). METHOD: 60 male domestic pigs were untreated in the first 10 min of VF, then received cardiopulmonary resuscitation (CPR) for 6 min. Values of Opt-AMSA and AMSA were calculated every minute before defibrillation. Linear regression was used to evaluate the correlation between Opt-AMSA and AMSA. Receiver Operating Characteristic (ROC) analysis was conducted for the two methods and to compare their predictive values. RESULTS: The values of both AMSA and Opt-AMSA gradually decreased over time during untreated VF in all animals. The values of both methods of defibrillation were slightly increased after the implementation of CPR in animals that were successfully resuscitated, while there were no significant changes in either method in those who ultimately failed to resuscitate. The significant positive correlation between Opt-AMSA and AMSA was shown by Pearson correlation analysis. ROC analysis showed that Opt-AMSA (AUC = 0.87) significantly improved the performance of AMSA (AUC = 0.77) to predict successful defibrillation (Z = 2.27, P < 0.05). CONCLUSION: Both the Opt-AMSA and AMSA methods showed high potential to predict the success of defibrillation. Moreover, the Opt-AMSA method improved the performance of the AMSA method, and may be a promising tool to optimize the timing of defibrillation.

Improvement of depth resolution in depth-resolved wavenumber-scanning interferometry using wavenumber-domain least-squares algorithm: comparison and experiment.

It is important to improve the depth resolution in depth-resolved wavenumber-scanning interferometry (DRWSI) owing to the limited range of wavenumber scanning. In this work, a new nonlinear iterative least-squares algorithm called the wavenumber-domain least-squares algorithm (WLSA) is proposed for evaluating the phase of DRWSI. The simulated and experimental results of the Fourier transform (FT), complex-number least-squares algorithm (CNLSA), eigenvalue-decomposition and least-squares algorithm (EDLSA), and WLSA were compared and analyzed. According to the results, the WLSA is less dependent on the initial values, and the depth resolution δz is approximately changed from δz to δz/6. Thus, the WLSA exhibits a better performance than the FT, CNLSA, and EDLSA.

Acquired pure red cell aplasia due to treatment with clopidogrel: first case report.

A 62-year-old woman with hypertension, type 2 diabetes mellitus, hyperlipemia and coronary heart disease started taking clopidogrel, with no addition of any other new drugs. However, with the addition of the drug, the patient was diagnosed as having acquired pure red cell aplasia (PRCA), and no any other inducing factors were detected from the patient. Furthermore, with the withdrawal of clopidogrel from the treatment, the patient recovered from the PRCA and did not recur. Therefore, we report PRCA as a rare side effect of clopidogrel for the first time.

An acoustic method (Spectral Flux) to analyze ECG signals for optimizing timing for defibrillation in a porcine model of ventricular fibrillation.

Aim: Spectral Flux (SF), which is based on common algorithms in the audio processing field, was applied to quantitatively analyze ECG signals to optimize the timing of defibrillation. With the aim of proving the performance in optimizing the timing of defibrillation, SF was compared with Amplitude Spectrum Area (AMSA) in a porcine model of ventricular fibrillation (VF) in a retrospective analysis experiment. Methods: A total of 56 male domestic pigs, weighing 40 ± 5 kg, were induced to undergo VF. Animals were then left untreated for 10 min, and after 6 min of cardiopulmonary resuscitation (CPR) defibrillation was performed. The respective SF and AMSA values were calculated every minute during VF and CPR. Comparisons were made through receiver operating characteristic (ROC) curves, one-way analyses of variance (one-way ANOVA), and scatterplots for the successful initial defibrillation sample (positive samples, Group R) and the failed initial defibrillation sample (negative samples, Group N) to illustrate the performance in optimizing the timing of defibrillation for the AMSA and SF methods. Result: Values of SF and AMSA gradually decreased during the 10 min VF period and increased in during the 6 min CPR period. The scatterplots showed that both metrics had the ability to distinguish positive and negative samples (p < .001). Meanwhile, ROC curves showed that SF (area under the curve, AUC = 0.798, p < .001) had the same ability as AMSA (AUC = 0.737, p < .001) to predict the successful defibrillation (Z = 1.35, p = 0.177). Moreover, when comparing the values for AMSA and SF between the successful initial defibrillation samples (Group R) and the failed initial defibrillation samples (Group N), the results showed that the values of both AMSA and SF in Group R were significantly higher than those in Group N (p < .001). Conclusion: In the present study, SF method had the same ability as AMSA to predict successful defibrillation with significantly higher values in cases of successful defibrillation than the instances in which defibrillation failed. Additionally, SF method might be more stable than AMSA for filtering out the higher frequency interference signals due to the narrower frequency range and had higher specificity and predictive accuracy than AMSA. So SF method had high clinical potential to optimize the timing of defibrillation. Nevertheless, further animal and clinical studies are still needed to confirm the effectiveness and practicality of SF as a predictive module for defibrillators in clinical practice.

The Potential of Clostridium butyricum to Preserve Gut Health, and to Mitigate Non-AIDS Comorbidities in People Living with HIV.

A dramatic reduction in mortality among people living with HIV (PLWH) has been achieved during the modern antiretroviral therapy (ART) era. However, ART does not restore gut barrier function even after long-term viral suppression, allowing microbial products to enter the systemic blood circulation and induce chronic immune activation. In PLWH, a chronic state of systemic inflammation exists and persists, which increases the risk of development of inflammation-associated non-AIDS comorbidities such as metabolic disorders, cardiovascular diseases, and cancer. Clostridium butyricum is a human butyrate-producing symbiont present in the gut microbiome. Convergent evidence has demonstrated favorable effects of C. butyricum for gastrointestinal health, including maintenance of the structural and functional integrity of the gut barrier, inhibition of pathogenic bacteria within the intestine, and reduction of microbial translocation. Moreover, C. butyricum supplementation has been observed to have a positive effect on various inflammation-related diseases such as diabetes, ulcerative colitis, and cancer, which are also recognized as non-AIDS comorbidities associated with epithelial gut damage. There is currently scant published research in the literature, focusing on the influence of C. butyricum in the gut of PLWH. In this hypothesis review, we speculate the use of C. butyricum as a probiotic oral supplementation may well emerge as a potential future synergistic adjunctive strategy in PLWH, in tandem with ART, to restore and consolidate intestinal barrier integrity, repair the leaky gut, prevent microbial translocation from the gut, and reduce both gut and systemic inflammation, with the ultimate objective of decreasing the risk for development of non-AIDS comorbidities in PLWH.

An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified relapse of serous ovarian cancer.

Using 70 U/ml or 35 U/ml as CA125 routine abnormal threshold may result in omissions in the relapse detection of Ovarian cancer (OvCa). This study aimed to clarify the association between a biochemical relapse (only the elevation of CA125) and an image-identified relapse to predict the relapsed lesions better. 162 patients who achieved complete clinical response were enrolled from women diagnosed with stage I-IV serous ovarian, tubal, and peritoneal cancers from January 2013 to June 2019 at our center. The CA125 level of 2 × nadir was defined as the indicator of image-identified relapse (P < 0.001). Compared to CA125 level exceeding 35 U/ml, the 2 × nadir of CA125 improve the sensitivity of image-identified relapse (84.9% vs 67.4%, P < 0.001); the 2 × nadir value can act as an earlier warning relapse signal with a longer median time to image-identified relapse (2.7 vs. 0 months, P < 0.001). Of the relapsed population, there was no difference of CA125 changing trend between the neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) group after initial treatment. Compared with 35 U/ml, CA125 reaching 2 × nadir during the follow-up process might be a more sensitive and early relapse signal in patients with serous OvCa. This criterion may help guide patients to be recommended for imaging examination to detect potential relapse in time.

Identification method of thyroid nodule ultrasonography based on self-supervised learning dual-branch attention learning framework.

Thyroid ultrasound is a widely used diagnostic technique for thyroid nodules in clinical practice. However, due to the characteristics of ultrasonic imaging, such as low image contrast, high noise levels, and heterogeneous features, detecting and identifying nodules remains challenging. In addition, high-quality labeled medical imaging datasets are rare, and thyroid ultrasound images are no exception, posing a significant challenge for machine learning applications in medical image analysis. In this study, we propose a Dual-branch Attention Learning (DBAL) convolutional neural network framework to enhance thyroid nodule detection by capturing contextual information. Leveraging jigsaw puzzles as a pretext task during network training, we improve the network's generalization ability with limited data. Our framework effectively captures intrinsic features in a global-to-local manner. Experimental results involve self-supervised pre-training on unlabeled ultrasound images and fine-tuning using 1216 clinical ultrasound images from a collaborating hospital. DBAL achieves accurate discrimination of thyroid nodules, with a 88.5% correct diagnosis rate for malignant and benign nodules and a 93.7% area under the ROC curve. This novel approach demonstrates promising potential in clinical applications for its accuracy and efficiency.

Steep-slope vertical-transport transistors built from sub-5 nm Thin van der Waals heterostructures.

Two-dimensional (2D) semiconductor-based vertical-transport field-effect transistors (VTFETs) - in which the current flows perpendicularly to the substrate surface direction - are in the drive to surmount the stringent downscaling constraints faced by the conventional planar FETs. However, low-power device operation with a sub-60 mV/dec subthreshold swing (SS) at room temperature along with an ultra-scaled channel length remains challenging for 2D semiconductor-based VTFETs. Here, we report steep-slope VTFETs that combine a gate-controllable van der Waals heterojunction and a metal-filamentary threshold switch (TS), featuring a vertical transport channel thinner than 5 nm and sub-thermionic turn-on characteristics. The integrated TS-VTFETs were realised with efficient current switching behaviours, exhibiting a current modulation ratio exceeding 1 × 108 and an average sub-60 mV/dec SS over 6 decades of drain current. The proposed TS-VTFETs with excellent area- and energy-efficiency could help to tackle the performance degradation-device downscaling dilemma faced by logic transistor technologies.