Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

OBJECTIVES: To investigate the effect of orexin-A-mediated regulation of ionotropic glutamate receptors for promoting motor function recovery in rats with spinal cord injury (SCI). METHODS: Thirty-six newborn SD rats (aged 7-14 days) were randomized into 6 groups (n=6), including a normal control group, a sham-operated group, and 4 SCI groups with daily intrathecal injection of saline, DNQX, orexin-A, or orexin-A+DNQX for 3 consecutive days after PCI. Motor function of the rats were evaluated using blood-brain barrier (BBB) score and inclined plane test 1 day before and at 1, 3, and 7 days after SCI. For patch-clamp experiment, spinal cord slices from newborn rats in the control, sham-operated, SCI, and SCI+orexin groups were prepared, and ventral horn neurons were acutely isolated to determine the reversal potential and dynamic indicators of glutamate receptor-mediated currents under glutamate perfusion. RESULTS: At 3 and 7 days after SCI, the orexin-A-treated rats showed significantly higher BBB scores and grip tilt angles than those with other interventions. Compared with those treated with DNQX alone, the rats receiving the combined treatment with orexin and DNQX had significantly higher BBB scores and grip tilt angles on day 7 after PCI. In the patch-clamp experiment, the ventral horn neurons from SCI rat models exhibited obviously higher reversal potential and greater rise slope of glutamate current with shorter decay time than those from sham-operated and orexin-treated rats. CONCLUSIONS Orexin-A promotes motor function recovery in rats after SCI possibly by improving the function of the ionotropic glutamate receptors.
Animals ; Spinal Cord Injuries/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, Ionotropic Glutamate/metabolism* ; Recovery of Function/drug effects* ; Orexins/pharmacology* ; Male ; Female ; Animals, Newborn ; Neuropeptides/pharmacology* ; Intracellular Signaling Peptides and Proteins/pharmacology*

OBJECTIVE To explore the effects of the water extract of Morinda officinalis on the expressions of sex hormones and receptors in bisphenol A （BPA）-contaminated mice. METHODS Totally 60 male Kunming mice were randomly divided into control group， model group， and low-dose， medium-dose and high-dose groups of M. officinalis water extract （20， 40， 60 mg/kg）， with 12 mice in each group. The model group and M. officinalis water extract groups were given BPA intragastrically [50 mg/（kg·d）， once a day， for 4 consecutive weeks] to establish the BPA-contamination model of mice. After modeling， each drug group was gavaged with the corresponding drug solution， once a day， for 4 consecutive weeks. After the last medication， the body weight and testicular weight of the mice in each group were weighed， the histopathological changes in the testis were observed， and the serum sex hormones [luteinizing hormone （LH）， follicle-stimulating hormone （FSH）] contents and the mRNA and protein expressions of LH receptor （LHR） and FSH receptor （FSHR） in the testicular tissues were detected. RESULTS Compared with the control group， the testicular tissues of mice in the model group had structural degeneration， loose connections between spermatogenic cells and Sertoli cells， obvious lacunae and reduced number of spermatogenic cells； the mRNA and protein expressions of LHR and FSHR in testicular tissues were significantly down-regulated （P＜0.01）， but there were no significant changes in their body weights， testicular weights， and serum contents of LH and FSH （P＞0.05）. Compared with the model group， the histopathological changes of testicular tissues of mice in each dose group of M. officinalis water extract were improved to different degrees， and the mRNA and protein expressions of LHR and FSHR in testicular tissues were up-regulated to different degrees （P＜0.05 or P＜ 0.01）， and some indicator levels were similar to those of the control group （P＞0.05）. However， there were no significant changes in their body weights， testicular weights， and serum contents of LH and FSH （P＞0.05）. CONCLUSIONS The water extract of M. officinalis has a certain improvement effect on testicular injury in BPA-contaminated mice， which might be related to its increase in the mRNA and protein expressions of LHR and FSHR.

Abstract OBJECTIVE Neuroblastoma(NB) is a prevailing pediatric extracranial solid tumor that accounts for 10%-15% of all childhood cancer-related fatalities. Despite significant strides made in NB therapy through multimodal approaches, the survival rate of high-risk NB patients remains at approximately 50%. Consequently, there is an urgent need to identify novel molecular targets for NB treatment. Recent studies have shown that MYCN oncogene amplification is present in about 25% of NB cases and is a crucial determinant of poor prognosis for high-risk NB patients. Since MYC family proteins, including MYCN, are inherently disordered proteins, MYCN lacks a defined ligand binding site along with a large protein-protein interaction surface. Current treatment approaches for MYCN-amplified NB patients do not include direct targeting of MYCN itself, since the absence of a “drugable” pocket renders it challenging. Notably, no direct MYC-targeting drugs are currently available. There is an existing association between Aurora A kinase(AURKA) and MYCN, whereby they form a complex to fortify MYCN stability. However, MYCN is inherently unstable, with a half-life of only 30 min, but AURKA intervenes by facilitating its stability through a direct protein-protein interaction, hence protecting it from proteasomal degradation. This interaction potentially augments tumor cell proliferation and invasiveness. Notably, AURKA has been verified as a transcriptional target of MYCN. The present study endeavors to employ computer-aided drug design technology to probe AURKA inhibitors discerned from a natural product library of traditional Chinese medicine(TCM), thereby identifying a novel drug for treating NB. METHODS Collected from the YaTCM database, a total of 47 696 natural compounds from TCM were subjected to preprocessing including protonation, deionization, hydrogenation, stereoisomerism, conformation generation, and energy minimization. Of these, 58 048 compounds were initially screened as potential ligands for the library. Utilizing “Lipinski Ro5” and “Verber Ro3” guidelines, 22 227 hit compounds were selected from the library that met the screening criteria. Initially, crystal structures of AURKA and its inhibitor AA35 were downloaded from the RCSB PDB database. The spatial coordinates of AA35 were set as the center of the binding pocket for AURKA, and a 10 Å * 10 Å * 10 Å space around the pocket was designated as the active space. A comprehensive drug screening platform integrating lead-likeness filtering, pharmacokinetic prediction, molecular docking, flexible docking, and molecular dynamics(MD) simulations were established to excavate potential aurora kinase A inhibitors from the TCM compound library, which were further validated by MD simulations. RESULTS A grand total of 6 220 Chinese herbal remedies had been meticulously curated within the YaTCM database. Out of these, an impressive 47 696 Chinese herbal monomers had undergone a rigorous series of flexible docking tests, resulting in the selection of the top ten molecules with the most favorable docking scores. The aforementioned molecules underwent AMDE parameter and toxicity predictions. It was discovered that with the exception of a few compounds such as Tryptophane, 3'-Methoxydaidzein, and Burttinol D(which might elicit liver toxicity), 3'-Methoxydaidzein and Pratensein(which might elicit kidney toxicity), and 3-Deoxysappanone B(which had moderate oral toxicity), as well as Tryptophane(with an oral bioavailability of less than 50%), five compounds including Compound X, (+)-Sesamin dicatechol, Tuberosin, Abrine, and Maackiain, displayed favorable pharmacokinetic parameters and low toxicity predictions. Moreover, all of these compounds exhibited a high binding affinity with the inhibitor active pocket of AURKA. In this study, Compound X, despite its cumbersome name, was referred to as “Compound X”. Upon focusing on Compound X as the subject of investigation, it was discovered that its phenolic framework could readily interact with the hydrophobic cavity constituted of hydrophobic amino acids, namely TYR199, VAL182, LEU178, LEU208, and VAL206. Notably, Compound X could partake in Pi-Pi interactions with TYR199 and create hydrogen bonds with HIS201, GLU175, and LYS166. Computational studies via MD simulations confirmed that Compound X could form a stable receptor-ligand complex with the receptor. Impressively, the inclusion of Compound X significantly reduced the stability of the AURKA-MYCN complex. CONCLUSION This study concludes that Compound X can be used as an AURKA inhibitor for the treatment of NB, which is a novel finding based on the combination of various virtual screening techniques from the natural product database of TCM.

Studies of human and mammalian have revealed that environmental exposure can affect paternal health conditions as well as those of the offspring. However, studies that explore the mechanisms that meditate this transmission are rare. Recently, small noncoding RNAs (sncRNAs) in sperm have seemed crucial to this transmission due to their alteration in sperm in response to environmental exposure, and the methodology of microinjection of isolated total RNA or sncRNAs or synthetically identified sncRNAs gradually lifted the veil of sncRNA regulation during intergenerational inheritance along the male line. Hence, by reviewing relevant literature, this study intends to answer the following research concepts: (1) paternal environmental factors that can be passed on to offspring and are attributed to spermatozoal sncRNAs, (2) potential role of paternal spermatozoal sncRNAs during the intergenerational inheritance process, and (3) the potential mechanism by which spermatozoal sncRNAs meditate intergenerational inheritance. In summary, increased attention highlights the hidden wonder of spermatozoal sncRNAs during intergenerational inheritance. Therefore, in the future, more studies should focus on the origin of RNA alteration, the target of RNA regulation, and how sncRNA regulation during embryonic development can be sustained even in adult offspring.
Animals ; Environmental Exposure ; Epigenesis, Genetic ; Female ; Humans ; Male ; Mammals/genetics* ; Pregnancy ; RNA, Small Untranslated/genetics* ; Spermatozoa

The accurate annotation of transcription start sites(TSSs)and their usage are critical for the mechanistic understanding of gene regulation in different biological contexts.To fulfill this,specific high-throughput experimental technologies have been developed to capture TSSs in a genome-wide manner,and various computational tools have also been developed for in silico pre-diction of TSSs solely based on genomic sequences.Most of these computational tools cast the problem as a binary classification task on a balanced dataset,thus resulting in drastic false positive predictions when applied on the genome scale.Here,we present DeeReCT-TSS,a deep learning-based method that is capable of identifying TSSs across the whole genome based on both DNA sequence and conventional RNA sequencing data.We show that by effectively incorporating these two sources of information,DeeReCT-TSS significantly outperforms other solely sequence-based methods on the precise annotation of TSSs used in different cell types.Furthermore,we develop a meta-learning-based extension for simultaneous TSS annotations on 10 cell types,which enables the identification of cell type-specific TSSs.Finally,we demonstrate the high precision of DeeReCT-TSS on two independent datasets by correlating our predicted TSSs with experimentally defined TSS chromatin states.The source code for DeeReCT-TSS is available at https://github.-com/JoshuaChou2018/DeeReCT-TSS_release and https://ngdc.cncb.ac.cn/biocode/tools/BT007316.

【Objective】 To compare the clinical efficacy of unilateral biportal endoscopic （UBE） and microscopic discectomy in the treatment of lumbar disc herniation （LDH） and to explore the safety and effectiveness of this operation. 【Methods】 A total of 87 LDH patients from July 2018 to July 2021 were analyzed retrospectively， including 42 cases of unilateral biportal endoscopic discectomy and 45 cases of microscopic discectomy. Analysis was based on comparison of perioperative metrics， operation time， and estimated blood loss. Clinical outcomes were evaluated using visual analogue scale （VAS）， Oswestry disability index （ODI） and modified Macnab criterion. 【Results】 All patients were followed up for 13.3±1.18 months. In UBE group， operation time （57.12±6.35） min was shorter than that in the microscope group （62.21±7.09） min and estimated blood loss （29.31±3.62） mL was smaller than that in the microscope group （51.77±8.43） mL， with a significant difference （P<0.05）. The two groups of patients had significantly lower back pain VAS score， leg pain VAS score， and ODI index than those before operation （P<0.05）. The VAS score of lower back pain at 3 days after operation and the ODI index at 1 month after operation were significantly lower in UBE group than in the microscope group （P<0.05）. At other time points， there was no significant difference in lower back pain VAS score， leg pain VAS score or ODI index （P>0.05）. Dural sac tear occurred in 2 cases in UBE group and 3 cases in the microscope group； the incidence was not statistically significant （P>0.05）. Modified MacNab criterion evaluation at the last follow-up showed that 32 cases were excellent in UBE group， 7 cases were good， and 3 cases were fair， with the excellent and good rate of 92.9% （39/42）. The microscope group was excellent in 31 cases， good in 10 cases， and fair in 4 cases， with the excellent and good rate of 91.1% （41/45）. 【Conclusion】 UBE for LDH has a satisfactory short-term clinical efficacy， with the advantages of less trauma， greater efficiency， clear vision， and large operating space. Both UBE and microscopic discectomy can achieve good clinical results in treating LDH， but the former has the advantages of less trauma， high efficiency， and quick postoperative recovery.

Objective:To evaluate the efficacy of holographic image technology in robot-assisted laparoscopic radical prostatectomy (RARP).Methods:The clinical data of 34 patients with prostate cancer who underwent RARP in our hospital during October 2020 and December 2020 was analyzed retrospectively. The average age of the patients was 67.8 (52-78) years. The mean BMI was 25.8 (18.0-32.3) kg/m 2. The median level of PSA before surgery was 13.4 (2-149) ng/ml. Median prostate volume was 31.7 (9.5-159.1) ml. EAU risk groups for biochemical recurrence of localised and locally advanced prostate cancer were list as below: 5 cases of low-risk, 7 cases of medium-risk, 22 cases of high-risk. There were 9, 16, 9 cases with the ASA score of 1, 2, 3 point, respectively. Preoperative Gleason score of 34 patients were list as below: 9 cases in score ≤6 group, 15 cases in score=7 group, 10 cases in score ≥8 group. For clinical stage before the surgery, 13 cases ≤T 2a stage, 1 case in T 2b stage, 20 cases ≥T 2c stage. The engineers established holographic images of 34 patients based on multiparametric magnetic resonance imaging (mpMRI) and the reports before the operation. Surgeons can obtain the size and location of tumors, surrounding neurovascular bundles visually by revolving, assembling, disassembling and concealing images, which was helpful for pre-surgery planning. By manipulating the holographic images extracorporeally, surgeons can discriminate Internal sphincter of urinary bladder and vesicoprostatic muscle, neurovascular bundles, membranous part, seminal vesicle easily, which improves the operation accuracy. Results:All 34 cases underwent operation successfully without transferring to open surgery. The median operative time was 157.5 (95-276) min with an estimated blood loss of 50 (20-300) ml. The median drainage removal time was 2 d and median hospitalization time was 3.5 d, respectively. The catheters were removed within an average time of 20.5 d. For postoperative Gleason score, there were 2 cases in score ≤6 group, 16 cases in score =7 group, 8 cases in score ≥8 group and 8 cases can’t make a score. For clinical stage after the surgery, 10 cases were ≤T 2a stage, 1 case was T 2b stage, 23 cases were ≥cT 2c stage. 22 cases underwent pelvic lymph node dissection, including a patient with right iliac fossa lymph node metastasis. There were 2 cases with positive surgical margin and 3 cases with Clavien-DindoⅠcomplications. The rate of 1-month and 3-month urinary continence were 47.1% and79.4%, respectively, 8 cases recovered erectile function after 3 month. Conclusions:Holographic image technology can promote cancer dissection completely, achieve urinary continence early and reduce perioperative complications tremendously. The technology is the "intraoperative security" for the accurate surgical treatment of prostate cancer.

Nerve agents are used in civil wars and terrorist attacks, posing a threat to public safety. Acute exposure to nerve agents such as soman (GD) causes serious brain damage, leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation. However, data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited. Here, we evaluated the potential effects of transient receptor vanilloid 4 (TRPV4) in the treatment of soman-induced status epilepticus (SE) and secondary brain injury. We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures. Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity. TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure. Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity. The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1β and IL-18 increased in soman-exposed rat hippocampus. However, TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway. In conclusion, our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation. To our knowledge, this is the first study regarding the “dual-switch” function of TRPV4 in the treatment of soman intoxication.