COVID-19 epidemic investigation study of a follow-up cohort of patients with diabetic kidney disease.

Introduction: The impact of coronavirus disease 2019 (COVID-19) on diabetic kidney disease (DKD) patients in China is not fully understood. This study aimed to investigate infection status in a DKD cohort post-renal biopsy and analyze vaccination and infection rates, as well as symptom severity, across various renal pathologies in DKD patients. Methods: This epidemiological survey, centered on COVID-19, employed a Chinese DKD and renal puncture follow-up cohort. A customized questionnaire enabled standardized data gathering. It collected data on clinical characteristics, vaccination and infection statuses, and diverse pathological types. The study analyzed the relationship between vaccination and infection statuses across various pathological types, evaluating characteristics and treatment outcomes in patients with infections. Results: In total, 437 patients with DKD from 26 Chinese provinces were followed up for a median of 44.6 ± 20 months. COVID-19 infection, vaccination, and novel coronavirus pneumonia (NCP) rates were 73.68%, 59.3%, and 6.63%, respectively. Ten patients with NCP had severe pneumonia or died of COVID-19. Renal pathology revealed that 167 (38.22%) patients had diabetic nephropathy (DN), 171 (39.13%) had non-diabetic renal disease (NDRD), and 99 had DN and NDRD (22.65%). The DN group had the lowest vaccination (54.5%), highest all-cause mortality (3.6%), and highest endpoint rates (34.10%). Compared to patients who were not vaccinated pre-infection (117 cases), vaccinated patients (198 cases) had reduced NCP (6.6% vs. 13.7%), severity (1.0% vs. 3.4%), and endpoint (9.10% vs. 31.60%) rates. Conclusion: Vaccination can prevent infection and diminish COVID-19 severity in patients with DKD; therefore, increasing vaccination rates is particularly important. Clinical Trial registration: ClinicalTrails.gov, NCT05888909.

Detoxification and underlying mechanisms towards toxic alkaloids by Traditional Chinese Medicine processing: A comprehensive review.

BACKGROUND: Alkaloids have attracted enduring interest worldwide due to their remarkable therapeutic effects, including analgesic, anti-inflammatory, and anti-tumor properties, thus offering a rich source for lead compound design and new drug discovery. However, some of these alkaloids possess intrinsic toxicity. Processing (Paozhi) is a pre-treatment step before the application of herbal medicines in traditional Chinese medicine (TCM) clinics, which has been employed for centuries to mitigate the toxicity of alkaloid-rich TCMs. PURPOSE: To explore the toxicity phenotypes, chemical basis, mode of action, detoxification processing methods, and underlying mechanisms, we can gain crucial insights into the safe and rational use of these toxic alkaloid-rich herbs. Such insights have the great potential to offer new strategies for drug discovery and development, ultimately improving the quality of life for millions of people. METHODS: Literatures published or early accessed until December 31, 2023, were retrieved from databases including PubMed, Web of Science, and CNKI. The following keywords, such as "toxicity", "alkaloid", "detoxification", "processing", "traditional Chinese medicine", "medicinal plant", and "plant", were used in combination or separately for screening. RESULTS: Toxicity of alkaloids in TCM includes hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, and other forms of toxicity, primarily induced by pyrrolizidines, quinolizidines, isoquinolines, indoles, pyridines, terpenoids, and amines. Factors such as whether the toxic-alkaloid enriched part is limited or heat-sensitive, and whether toxic alkaloids are also therapeutic components, are critical for choosing appropriate detoxification processing methods. Mechanisms of alkaloid detoxification includes physical removal, chemical decomposition or transformation, as well as biological modifications. CONCLUSION: Through this exploration, we review toxic alkaloids and the mechanisms underlying their toxicity, discuss methods to reduce toxicity, and unravel the intricate mechanisms behind detoxification. These offers insights into the quality control of herbs containing toxic alkaloids, safe and rational use of alkaloid-rich TCMs in clinics, new strategies for drug discovery and development, and ultimately helping improve the quality of life for millions of people.

Bifidobacterium alleviate metabolic disorders via converting methionine to 5'-methylthioadenosine.

Dietary patterns and corresponding gut microbiota profiles are associated with various health conditions. A diet rich in polyphenols, primarily plant-based, has been shown to promote the growth of probiotic bacteria in the gastrointestinal tract, subsequently reducing the risk of metabolic disorders in the host. The beneficial effects of these bacteria are largely due to the specific metabolites they produce, such as short-chain fatty acids and membrane proteins. In this study, we employed a metabolomics-guided bioactive metabolite identification platform that included bioactivity testing using in vitro and in vivo assays to discover a bioactive metabolite produced from probiotic bacteria. Through this approach, we identified 5'-methylthioadenosine (MTA) as a probiotic bacterial-derived metabolite with anti-obesity properties. Furthermore, our findings indicate that MTA administration has several regulatory impacts on liver functions, including modulating fatty acid synthesis and glucose metabolism. The present study elucidates the intricate interplay between dietary habits, gut microbiota, and their resultant metabolites.

RPEMHC: improved prediction of MHC-peptide binding affinity by a deep learning approach based on residue-residue pair encoding.

MOTIVATION: Binding of peptides to major histocompatibility complex (MHC) molecules plays a crucial role in triggering T cell recognition mechanisms essential for immune response. Accurate prediction of MHC-peptide binding is vital for the development of cancer therapeutic vaccines. While recent deep learning-based methods have achieved significant performance in predicting MHC-peptide binding affinity, most of them separately encode MHC molecules and peptides as inputs, potentially overlooking critical interaction information between the two. RESULTS: In this work, we propose RPEMHC, a new deep learning approach based on residue-residue pair encoding to predict the binding affinity between peptides and MHC, which encode an MHC molecule and a peptide as a residue-residue pair map. We evaluate the performance of RPEMHC on various MHC-II-related datasets for MHC-peptide binding prediction, demonstrating that RPEMHC achieves better or comparable performance against other state-of-the-art baselines. Moreover, we further construct experiments on MHC-I-related datasets, and experimental results demonstrate that our method can work on both two MHC classes. These extensive validations have manifested that RPEMHC is an effective tool for studying MHC-peptide interactions and can potentially facilitate the vaccine development. AVAILABILITY: The source code of the method along with trained models is freely available at https://github.com/lennylv/RPEMHC.

SFTSV infection is associated with transient overproliferation of monoclonal lambda-type plasma cells.

The impairment of antibody-mediated immunity is a major factor associated with fatal cases of severe fever with thrombocytopenia syndrome (SFTS). By collating the clinical diagnosis reports of 30 SFTS cases, we discovered the overproliferation of monoclonal plasma cells (MCP cells, CD38+cLambda+cKappa-) in bone marrow, which has only been reported previously in multiple myeloma. The ratio of CD38+cLambda+ versus CD38+cKappa+ in SFTS cases with MCP cells was significantly higher than that in normal cases. MCP cells presented transient expression in the bone marrow, which was distinctly different from multiple myeloma. Moreover, the SFTS patients with MCP cells had higher clinical severity. Further, the overproliferation of MCP cells was also observed in SFTS virus (SFTSV)-infected mice with lethal infectious doses. Together, SFTSV infection induces transient overproliferation of monoclonal lambda-type plasma cells, which have important implications for the study of SFTSV pathogenesis, prognosis, and the rational development of therapeutics.

Simultaneous Prediction of Interaction Sites on the Protein and Peptide Sides of Complexes through Multilayer Graph Convolutional Networks.

Identifying the binding residues of protein-peptide complexes is essential for understanding protein function mechanisms and exploring drug discovery. Recently, many computational methods have been developed to predict the interaction sites of either protein or peptide. However, to our knowledge, no prediction method can simultaneously identify the interaction sites on both the protein and peptide sides. Here, we propose a deep graph convolutional network (GCN)-based method called GraphPPepIS to predict the interaction sites of protein-peptide complexes using protein and peptide structural information. We also propose a companion method, SeqPPepIS, for assisting with the lack of structural information and the flexibility of peptides. SepPPepIS replaces the peptide structural features in GraphPPepIS by learning features from peptide sequences. We performed a comprehensive evaluation of the benchmark data sets, and the results show that our two methods outperform state-of-the-art methods on the accurate interaction sites of both protein and peptide sides. We show that our methods can help improve protein-peptide docking. For docking data sets, our methods maintain robust performance in identifying binding sites, thereby enhancing the prediction of peptide binding poses. Finally, we visualized the analysis of protein and peptide graph embedding to demonstrate the learning ability of graph convolution in predicting interaction sites, which was mainly obtained through the shared parameters of a protein graph and peptide graph.

Chronic Hypoxia in Ovine Pregnancy Recapitulates Physiological and Molecular Markers of Preeclampsia in the Mother, Placenta, and Offspring.

BACKGROUND: Preeclampsia continues to be a prevalent pregnancy complication and underlying mechanisms remain controversial. A common feature of preeclampsia is utero-placenta hypoxia. In contrast to the impact of hypoxia on the placenta and fetus, comparatively little is known about the maternal physiology. METHODS: We adopted an integrative approach to investigate the inter-relationship between chronic hypoxia during pregnancy with maternal, placental, and fetal outcomes, common in preeclampsia. We exploited a novel technique using isobaric hypoxic chambers and in vivo continuous cardiovascular recording technology for measurement of blood pressure in sheep and studied the placental stress in response to hypoxia at cellular and subcellular levels. RESULTS: Chronic hypoxia in ovine pregnancy promoted fetal growth restriction (FGR) with evidence of fetal brain-sparing, increased placental hypoxia-mediated oxidative damage, and activated placental stress response pathways. These changes were linked with dilation of the placental endoplasmic reticulum (ER) cisternae and increased placental expression of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), combined with a shift towards an angiogenic imbalance in the maternal circulation. Chronic hypoxia further led to an increase in uteroplacental vascular resistance and the fall in maternal blood pressure with advancing gestation measured in normoxic pregnancy did not occur in hypoxic pregnancy. CONCLUSIONS: Therefore, we show in an ovine model of sea-level adverse pregnancy that chronic hypoxia recapitulates physiological and molecular features of preeclampsia in the mother, placenta, and offspring.

The OPG/RANKL/RANK system modulates calcification of common carotid artery in simulated microgravity rats by regulating NF-κB pathway.

Functional and structural adaptation of common carotid artery could be one of the important causes of postflight orthostatic intolerance after microgravity exposure, the mechanisms of which remain unclear. Recent evidence indicates that long-term spaceflight increases carotid artery stiffness, which might present a high risk to astronaut health and postflight working ability. Studies have suggested that vascular calcification is a common pathological change in cardiovascular diseases that is mainly manifested as an increase in vascular stiffness. Therefore, this study investigated whether simulated microgravity induces calcification of common carotid artery and to elucidate the underlying mechanisms. Four-week-old hindlimb-unweighted (HU) rats were used to simulate the deconditioning effects of microgravity on cardiovascular system. We found that simulated microgravity induced vascular smooth muscle cell (VSMC) osteogenic differentiation and medial calcification, increased receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) and RANK expression, and enhanced NF-κB activation in rat common carotid artery. In vitro activation of the RANK pathway with exogenous RANKL, a RANK ligand, increased RANK and osteoprotegerin (OPG) expression in HU rats. Moreover, the expression of osteogenic markers and activation of NF-κB in HU rats were further enhanced by exogenous RANKL but suppressed by the RANK inhibitor osteoprotegerin fusion protein (OPG-Fc). These results indicated that the OPG/RANKL/RANK system modulates VSMC osteogenic differentiation and medial calcification of common carotid artery in simulated microgravity rats by regulating the NF-kB pathway.

Effects of ultrasound-guided erector spinae plane block on the immune function and postoperative recovery of patients undergoing radical mastectomy.

BACKGROUND: To explore the effects of ultrasound-guided erector spinae plane (ESP) block on the immune function and postoperative recovery of patients undergoing radical mastectomy. METHODS: One hundred and four patients with breast cancer were randomly divided into the observation group and control group, with 52 cases in each group. The control group underwent induction of routine general anesthesia and thoracic paravertebral block, while the observation group underwent ultrasound-guided ESP block combined with general anesthesia. The recovery of autonomous respiration, eye opening, extubation time, postoperative eating, first anal exhaust, leaving bed and hospitalization time in both groups were statistically analyzed after surgery. The immune function indexes [CD4+, CD8+, interferon-γ (IFN-γ)] and the expression levels of serum neuropeptide Y (NPY), prostaglandin E2 (PGE2) and serotonin (5-HT) were compared between the two groups at 24 and 48 h before and after surgery. The visual analog scale (VAS) scores at rest and during exercise were recorded at 6, 12, 24, and 48 h after surgery. RESULTS: There was no significant difference in the recovery of autonomous respiration, eye opening, and extubation time between the two groups (P>0.05). However, postoperative eating, first anal exhaust, leaving bed, and hospitalization time in the observation group were shorter than those in the control group (P<0.05). At 24 and 48 h after surgery, compared with the control group, CD4+ and IFN-γ levels were increased significantly (P<0.05), CD8+ and levels of serum NPY, PGE2, 5-HT and the incidence of postoperative complications was decreased significantly in the observation group (P<0.05). VAS scores at rest and during exercise in the observation group were lower than those in the control group (P<0.05). At 5 and 10 min after intubation, the observation group had higher epinephrine (E) level and lower serum cortisol (Cor) level than the control group (P<0.05). CONCLUSIONS: The analgesic effect of ultrasound-guided ESP block is significant after radical mastectomy. There are few adverse reactions and few effects on immune function, and it can promote the postoperative recovery of patients.

A randomised trial: effects of different anesthesia methods on early perioperative pain sensitivity and cellular immune function in patients undergoing radical mastectomy.

BACKGROUND: This study sought to investigate the effects of transversus thoracic muscle plane-pectoral nerves (TTP-PECS) block combined with propofol anesthesia on early perioperative pain sensitivity and cellular immune function in patients undergoing radical mastectomy. METHODS: A total of 115 patients who underwent radical mastectomy for breast cancer at our hospital from January 2019 to January 2021 were selected as the study subjects. The patients were allocated to the control group (n=57) or observation group (n=58) using a random number method. The control group was given simple general anesthesia, and the observation group was given TTP-PECS block combined with propofol anesthesia. The recovery time, pain [visual analogue scoring (VAS)] scores, and incidences of adverse reactions were compared between the 2 groups. Hemodynamic indicators [i.e., heart rate (HR), mean arterial pressure (MAP)], stress indicators [i.e., blood glucose (GLU), epinephrine (E), cortisol (Cor)], and the cellular immune function ofthe2 groups before anesthesia (T0), at the end of operation (T1), 1day after operation (T2) and 3days after operation (T3) were recorded. RESULTS: The spontaneous respiration recovery time, time to full wakefulness and the extubation time of the observation group were shorter than those of the control group (P<0.05). The observation group had lower VAS scores than the control group at 2, 8, 12, and 24 h after operation (P<0.05). The levels of MAP, HR, GLU, E and Cor in the observation group at T1, T2, and T3 were lower than those in the control group (P<0.05). Compared to the control group, the observation group had increased cluster of differentiation (CD)3+, CD4+, and CD4+/CD8+ cells (P<0.05), but there were no significant differences in CD8+ and natural killer (NK) cells between the 2 groups (P>0.05). The incidence of adverse reactions in the observation group was lower than that in the control group (8.62% vs. 24.56%) (P<0.05). CONCLUSIONS: TTP-PECS block combined with propofol anesthesia can relieve pain, shorten the recovery time, stabilize the hemodynamic level, and alleviate the stress responses of patients undergoing radical mastectomy with a slight suppression of cellular immune function and high safety. TRIAL REGISTRATION: Chinese Clinical Trial Registration Center ChiCTR2100048438.

Suppressing Defect Formation in Metal-Organic Framework Membranes via Plasma-Assisted Synthesis for Gas Separations.

Metal-organic frameworks (MOFs) are considered as promising materials for membrane gas separations. Structural defects within a pure MOF membrane can considerably reduce its selectivity and possibly result in a nonselective separation. This work proposes a solution-phase synthesis with dielectric barrier discharge (DBD) plasma to suppress the formation of defects in the pure MOF membrane of CPO-8-BPY. Through comprehensive solid-state characterization with XRD, SEM, XPS, solid-state NMR, and XAFS, DBD plasma is demonstrated to facilitate deprotonation in the H2aip linker, which leads to a smaller and more uniform particle size of CPO-8-BPY. The narrow grain size distribution effectively reduces the pinhole-type defects in the pure CPO-8-BPY membrane and endows it with good ideal selectivity for H2/CH4 (αH2/CH4 = 28.2) and N2/CH4 (αN2/CH4 = 5.4). The selectivity for H2/CH4 of this membrane from a mixed-gas permeation test is found to be 15.4. Molecular simulations are also performed to gain insights into the gas transport properties of this MOF. The results suggest that ligand rotation plays an important role in CPO-8-BPY when being applied to the membrane separation of N2/CH4.

Traditional application and modern pharmacological research of Eucommia ulmoides Oliv.

As a Traditional Chinese Medicine, Eucommia ulmoides Oliv. has been used for the treatment of various diseases since ancient times, involving lumbar pain, knee pain, osteoporosis, hepatoprotection, paralysis, intestinal haemorrhoids, vaginal bleeding, abortion, spermatorrhoea, foot fungus, anti-aging etc. With the developing discovery of E. ulmoides extracts and its active components in various pharmacological activities, E. ulmoides has gained more and more attention. Up to now, E. ulmoides has been revealed to show remarkable therapeutic effects on hypertension, hyperglycemia, diabetes, obesity, osteoporosis, Parkinson's disease, Alzheimer's disease, sexual dysfunction. E. ulmoides has also been reported to possess antioxidant, anti-inflammatory, neuroprotective, anti-fatigue, anti-aging, anti-cancer and immunoregulation activities etc. Along these lines, this review summarizes the traditional application and modern pharmacological research of E. ulmoides, providing novel insights of E. ulmoides in the treatment of various diseases.

DAMpred: Recognizing Disease-Associated nsSNPs through Bayes-Guided Neural-Network Model Built on Low-Resolution Structure Prediction of Proteins and Protein-Protein Interactions.

Nearly one-third of non-synonymous single-nucleotide polymorphism (nsSNPs) are deleterious to human health, but recognition of the disease-associated mutations remains a significant unsolved problem. We proposed a new algorithm, DAMpred, to identify disease-causing nsSNPs through the coupling of evolutionary profiles with structure predictions of proteins and protein-protein interactions. The pipeline was trained by a novel Bayes-guided artificial neural network algorithm that incorporates posterior probabilities of distinct feature classifiers with the network training process. DAMpred was tested on a large-scale data set involving 10,635 nsSNPs from 2154 ORFs in the human genome and recognized disease-associated nsSNPs with an accuracy 0.80 and a Matthews correlation coefficient of 0.601, which is 9.1% higher than the best of other state-of-the-art methods. In the blind test on the TP53 gene, DAMpred correctly recognized the mutations causative of Li-Fraumeni-like syndrome with a Matthews correlation coefficient that is 27% higher than the control methods. The study demonstrates an efficient avenue to quantitatively model the association of nsSNPs with human diseases from low-resolution protein structure prediction, which should find important usefulness in diagnosis and treatment of genetic diseases.

Microarray Expression Profile of lncRNAs and mRNAs in Rats with Traumatic Brain Injury after A2B5+ Cell Transplantation.

Traumatic brain injury (TBI) may cause neurological damage, but an effective therapy and the associated mechanisms of action have not yet been elucidated. A TBI model was established using the modified Feeney method. A2B5+ cells, an oligodendroglial progenitor, were acquired from induced pluripotent stem cells (iPSCs) by mouse embryonic fibroblasts and were transplanted into the injured site. The neurological severity score (NSS) was recorded on 3 d, 7 d, 11 d, 15 d, and 19 d. Seven days after transplantation, oligodendrocytes 2 (Olig2) and myelin basic protein (MBP) were detected by immunohistochemistry (IHC) and Western blot (WB), and long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) were screened by microarray technology. Moreover, we took an intersection of the differentially expressed lncRNAs or mRNAs and scanned 10 kb upstream and downstream of the common lncRNAs. Meanwhile, Gene Ontology (GO) and pathway analysis on mRNAs was performed in the A2B5+ iPSC group. A2B5+ iPSCs survived and migrated around the injury site and differentiated into oligodendrocytes. Meanwhile, the increase in Olig2 and MBP were higher in A2B5+ cell-engrafted rats than that in TBI rats. However, the NSSs in the A2B5+ iPSC group were lower than that in the TBI group. Between the TBI and sham groups, 270 lncRNAs and 1,052 mRNAs were differently expressed ( P < 0.05, fold change (FC) > 2), while between the A2B5+ iPSC and TBI groups, 83 lncRNAs and 360 mRNAs were differently expressed ( P < 0.05, FC > 2). Meanwhile, 37 lncRNAs and 195 mRNAs were simultaneously changed in the 2 parts. Using bioinformatic analysis, we found the crucial lncRNA and mRNA were ENSRNOT00000052577 and Kif2c in the TBI brain with cell transplantation. This study demonstrated that A2B5+ iPSC grafts effectively improved neurological function, and the mechanism of action was associated with lncRNA and mRNA expression. Therefore, A2B5+ iPSC transplantation could be considered as a new method for the treatment of TBI, and ENSRNOT00000052577 and Kif2c may be new molecular targets or markers for functional improvement.

[Clinical outcomes of laparoscopic radical prostatectomy for high risk prostate cancer].

OBJECTIVE: To study the technique and clinical outcomes of laparoscopic radical prostatectomy for high risk prostate cancer. METHODS: A total of 65 patients with high risk prostate cancer were treated with surgery in the First Affiliated Hospital of Nanjing Medical University from January 2011 to June 2013. The mean age was 67 years (range 45-75 years). The mean preoperative prostate specific antigen (PSA) level was 26.7 µg/L (range 11.2-65.5 µg/L). The transrectal biopsy revealed Gleason score of 3+3 in 4 patients, Gleason 3+4 in 27 patients, Gleason 4+3 in 11 patients, Gleason 4+4 in 21 patients and Gleason 4+5 in 2 patients. The bone metastasis was excluded by scintigraphy examination. The surgical procedures were performed through transperitoneal approach. Extended pelvic lymph nodes dissection was performed after the removal of the prostate. Adjuvant radiotherapy or hormonal therapy was administrated according to the pathological results. Serum PSA was detected every 1 to 2 month and urinary continence was evaluated every 3 month in the first year, and then serum PSA was detected every 2 to 3 month. RESULTS: The mean operative time was (134±21) minutes and the median blood loss was (300±146) ml. Bladder neck reconstruction was performed in 15 cases. The drainage was removed on postoperative day 4 and the catheter was removed on day 7. Pathologic results demonstrated pT2 in 25 patients, pT3a in 28 patients, pT3b in 9 patients and pT4 in 3 patients. Positive surgical margin was presented in 15 patients. A median of 19 lymph nodes (range 11-24 nodes) were retrieved during lymphadenectomy and 11 patients had lymph nodes metastasis with a total of 19 positive nodes. Forty-three patients recovered continence after the removal of catheter. Eleven patients received adjuvant hormonal therapy and 19 patients received adjuvant radiation therapy. With the median of 20 months follow-up (range 12-30 months), 5 patients got biochemical recurrence. CONCLUSIONS: Laparoscopic radical prostatectomy with extended lymph nodes dissection for high risk prostate cancer is safe and technical feasible. It provides accurate information on tumor stage and grade. It is an important component of multimodality for the treatment of high risk prostate cancer.