Spatial epigenome-transcriptome co-profiling of mammalian tissues.

Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1-5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Mediating Zn Ions Migration Behavior via ß-Cyclodextrin Modified Carbon Nanotube Film for High-Performance Zn Anodes.

Metallic Zn is considered as a promising anode material because of its abundance, eco-friendliness, and high theoretical capacity. However, the uncontrolled dendrite growth and side reactions restrict its further practical application. Herein, we proposed a ß-cyclodextrin-modified multiwalled carbon nanotube (CD-MWCNT) layer for Zn metal anodes. The obtained CD-MWCNT layer with high affinity to Zn can significantly reduce the transfer barrier of Zn2+ at the electrode/electrolyte interface, facilitating the uniform deposition of Zn2+ and suppressing water-caused side reactions. Consequently, the Zn||Zn symmetric cell assembled with CD-MWCNT shows a significantly enhanced cycling durability, maintaining a cycling life exceeding 1000 h even under a high current density of 5 mA cm-2. Furthermore, the full battery equipped with a V2O5 cathode displays an unparalleled long life. This work unveils a promising avenue toward the achievement of high-performance Zn metal anodes.

Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.

Priming of synaptic vesicles involves Munc13-catalyzed transition of the Munc18-1/syntaxin-1 complex to the SNARE complex in the presence of SNAP-25 and synaptobrevin-2; Munc13 drives opening of syntaxin-1 via the MUN domain while Munc18-1 primes SNARE assembly via domain 3a. However, the underlying mechanism remains unclear. In this study, we have identified a number of residues in domain 3a of Munc18-1 that are crucial for Munc13 and Munc18-1 actions in SNARE complex assembly and synaptic vesicle priming. Our results showed that two residues (Q301/K308) at the side of domain 3a mediate the interaction between the Munc18-1/syntaxin-1 complex and the MUN domain. This interaction enables the MUN domain to drive the opening of syntaxin-1 linker region, thereby leading to the extension of domain 3a and promoting synaptobrevin-2 binding. In addition, we identified two residues (K332/K333) at the bottom of domain 3a that mediate the interaction between Munc18-1 and the SNARE motif of syntaxin-1. This interaction ensures Munc18-1 to persistently associate with syntaxin-1 during the conformational change of syntaxin-1 from closed to open, which reinforces the role of Munc18-1 in templating SNARE assembly. Taken together, our data suggest a mechanism by which Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial.

BACKGROUND: Little is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy. METHODS: Patients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding. RESULTS: Among 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events. CONCLUSIONS: This study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH. TRIAL REGISTRATION: ISRCTN65203415.

Outdoor Artificial Light at Night and Reproductive Endocrine and Glucose Homeostasis and Polycystic Ovary Syndrome in Women of Reproductive Age.

BACKGROUND: Artificial light at night, a well-recognized circadian clock disrupter, causes disturbances in endocrine homeostasis. However, the association of artificial light at night with polycystic ovary syndrome (PCOS) is still unknown. This study examines the effects of outdoor artificial light at night on sex hormones, glucose homeostasis markers, and PCOS prevalence in Anhui Province, China. METHODS: We recruited 20,633 women of reproductive age from Anhui Medical University Reproductive Medicine Center. PCOS was diagnosed according to Rotterdam criteria. We estimated long-term (previous year) and short-term (previous month) artificial light at night values for residential addresses using 500 m resolution satellite imagery. We fitted multivariable models, using both linear and logistic regression, to estimate the association of artificial light at night with sex hormones, glucose homeostasis markers, and PCOS prevalence. RESULTS: Both long-term and short-term exposure to outdoor artificial light at night were negatively associated with follicle-stimulating hormone and luteinizing hormone levels, while positively associated with testosterone, fasting insulin, homeostasis model assessment-insulin resistance, and homeostasis model assessment-insulin resistance-ß levels. The second-highest quintile of artificial light at night was associated with increased PCOS prevalence (odds ratio [OR long-term ] = 1.4; 95% confidence interval [CI] = 1.2, 1.6 and OR short-term = 1.3; 95% CI = 1.1, 1.5) compared with the lowest quintile. In addition, prevalence of PCOS was linearly associated with long-term exposure to artificial light at night, but nonlinearly associated with short-term exposure. This association was more evident in younger, obese or overweight, moderately educated, rural women, and for the summer and fall seasons. CONCLUSION: Outdoor artificial light at night may be a novel risk factor for PCOS.

Coronary inflammation based on pericoronary adipose tissue attenuation in type 2 diabetic mellitus: effect of diabetes management.

BACKGROUND: Coronary inflammation plays crucial role in type 2 diabetes mellitus (T2DM) induced cardiovascular complications. Both glucose-lowering drug interventions (GLDIS) and glycemic control (GC) status potentially correlate coronary inflammation, as indicated by changes in pericoronary adipose tissue (PCAT) attenuation, and thus influence cardiovascular risk. This study evaluated the impact of GLDIS and GC status on PCAT attenuation in T2DM patients. METHODS: This retrospective study collected clinical data and coronary computed tomography angiography (CCTA) images of 1,342 patients, including 547 T2DM patients and 795 non-T2DM patients in two tertiary hospitals. T2DM patients were subgroup based on two criteria: (1) GC status: well: HbA1c < 7%, moderate: 7 ≤ HbA1c ≤ 9%, and poor: HbA1c > 9%; (2) GLDIS and non-GLDIS. PCAT attenuations of the left anterior descending artery (LAD-PCAT), left circumflex artery (LCX-PCAT), and right coronary artery (RCA-PCAT) were measured. Propensity matching (PSM) was used to cross compare PCAT attenuation of non-T2DM and all subgroups of T2DM patients. Linear regressions were conducted to evaluate the impact of GC status and GLDIS on PCAT attenuation in T2DM patients. RESULTS: Significant differences were observed in RCA-PCAT and LCX-PCAT between poor GC-T2DM and non-T2DM patients (LCX: - 68.75 ± 7.59 HU vs. - 71.93 ± 7.25 HU, p = 0.008; RCA: - 74.37 ± 8.44 HU vs. - 77.2 ± 7.42 HU, p = 0.026). Higher PCAT attenuation was observed in LAD-PCAT, LCX-PCAT, and RCA-PCAT in non-GLDIS T2DM patients compared with GLDIS T2DM patients (LAD: - 78.11 ± 8.01 HU vs. - 75.04 ± 8.26 HU, p = 0.022; LCX: - 71.10 ± 8.13 HU vs. - 68.31 ± 7.90 HU, p = 0.037; RCA: - 78.17 ± 8.64 HU vs. - 73.35 ± 9.32 HU, p = 0.001). In the linear regression, other than sex and duration of diabetes, both metformin and acarbose were found to be significantly associated with lower LAD-PCAT (metformin: ß coefficient = - 2.476, p=0.021; acarbose: ß coefficient = - 1.841, p = 0.031). CONCLUSION: Inadequate diabetes management, including poor GC and lack of GLDIS, may be associated with increased coronary artery inflammation in T2DM patients, as indicated by PCAT attenuation on CCTA, leading to increased cardiovascular risk. This finding could help healthcare providers identify T2DM patients with increased cardiovascular risk, develop improved cardiovascular management programs, and reduce subsequent cardiovascular related mortality.

Improving the level of the cytidine biosynthesis in E. coli through atmospheric room temperature plasma mutagenesis and metabolic engineering.

AIMS: Cytidine, as an important commercial precursor in the chemical synthesis of antiviral and antitumor drugs, is in great demand in the market. Therefore, the purpose of this study is to build a microbial cell factory with high cytidine production. METHODS AND RESULTS: A mutant E. coli NXBG-11-F34 with high tolerance to uridine monophosphate structural analogs and good genetic stability was obtained by atmospheric room temperature plasma (ARTP) mutagenesis combined with high-throughput screening. Then, the udk and rihA genes involved in cytidine catabolism were knocked out by CRISPR/Cas9 gene editing technology, and the recombinant strain E. coli NXBG-13 was constructed. The titer, yield, and productivity of cytidine fermented in a 5 l bioreactor were 15.7 g l-1, 0.164 g g-1, and 0.327 g l-1 h-1, respectively. Transcriptome analysis of the original strain and the recombinant strain E. coli NXBG-13 showed that the gene expression profiles of the two strains changed significantly, and the cytidine de novo pathway gene of the recombinant strain was up-regulated significantly. CONCLUSIONS: ARTP mutagenesis combined with metabolic engineering is an effective method to construct cytidine-producing strains.

Sulfonamidyl derivatives of sigmacidin: Protein-protein interaction inhibitors targeting bacterial RNA polymerase and sigma factor interaction exhibiting antimicrobial activity against antibiotic-resistant bacteria.

RNA polymerase is an essential enzyme involved in bacterial transcription, playing a crucial role in RNA synthesis. However, it requires the association with sigma factors to initiate this process. In our previous work, we utilized a structure-based drug discovery approach to create benzoyl and benzyl benzoic acid compounds. These compounds were designed based on the amino acid residues within the key binding site of sigma factors, which are crucial for their interaction with RNA polymerase. By inhibiting bacterial transcription, these compounds exhibited notable antimicrobial activity, and we coined them as sigmacidins to highlight their resemblance to sigma factors and the benzoic acid structure. In this study, we further modified the compound scaffolds and developed a series of sulfonamidyl benzoic acid derivatives. These derivatives displayed potent antimicrobial activity, with minimum inhibitory concentrations (MICs) as low as 1 µg/mL, demonstrating their efficacy against bacteria. Furthermore, these compounds demonstrated low cytotoxicity, indicating their potential as safe antimicrobial agents. To ascertain their mechanism of action in interfering with bacterial transcription, we conducted biochemical and cellular assays. Overall, this study showcases the effectiveness of sulfonamidyl benzoic acid derivatives as antimicrobial agents by targeting protein-protein interactions involving RNA polymerase and sigma factors. Their strong antimicrobial activity and low cytotoxicity implicate their potential in combating antibiotic-resistant bacteria.

Fate of contaminants of emerging concern in two wastewater treatment plants after retrofitting tertiary treatment for reduction of nitrogen discharge.

More and more previously designed wastewater treatment plants (WWTPs) are upgraded to tertiary treatment to meet the higher effluent discharge standards of conventional pollutants. Contaminants of emerging concern (CECs) can cause adverse effects on organisms and usually flow into WWTPs along with urban sewage. How the retrofitted WWTPs targeting conventional pollutants will influence the treatment efficiency of CECs is seldom discussed. This study investigates the removal of CECs in two full-scale newly retrofitted WWTPs (CD and JM WWTPs), containing high-efficiency sedimentation tank and denitrification deep bed filter for enhancing total nitrogen removal. The overall CEC removal efficiencies in the CD and JM WWTPs were 73.79 % and 93.63 %, respectively. Mass balance results indicated that CD WWTP and JM WWTP release a total of 36.89 and 88.58 g/d of CECs into the environment through effluent and excess sludge, respectively. Analysis of the concentration of CECs along the treatment process revealed most CECs were removed in the biological treatment units. The incorporation of newly constructed tertiary treatment proved beneficial for CEC removal and removed 2.93 % and 2.36 % CECs, corresponding to CEC removal of 2.92 and 27.49 g/d in the CD and JM WWTPs, respectively. The data of this study were further used to evaluate the suitability of the SimpleTreat model for simulating the fate of CECs in WWTPs. The predicted fraction of CECs discharged through the biological treatment effluent were generally within ten-fold difference from the measured results, highlighting its potential for estimating CEC removal in WWTPs.

Bisphenol Z exposure inhibits oocyte meiotic maturation by rupturing mitochondrial function.

The use of bisphenol A (BPA) has been restricted due to its endocrine-disrupting effects. As a widely used alternative to BPA today, environmental levels of bisphenol Z (BPZ) continue to rise and accumulate in humans. Oocyte quality is critical for a successful pregnancy. Nevertheless, the toxic impacts of BPZ on the maturation of mammalian oocytes remain unexplored. Therefore, the impacts of BPZ and BPA on oocyte meiotic maturation were compared in an in vitro mouse oocyte culture model. Exposure to 150 µM of both BPZ and BPA disrupted the assembly of the meiotic spindle and the alignment of chromosomes, and BPZ exerted stronger toxicological effects than BPA. Furthermore, BPZ resulted in aberrant expression of F-actin, preventing the formation of the actin cap. Mechanistically, BPZ exposure disrupted the mitochondrial localization pattern, reduced mitochondrial membrane potential and ATP content, leading to impaired mitochondrial function. Further studies revealed that BPZ exposure resulted in oxidative stress and altered expression of genes associated with anti-oxidative stress. Moreover, BPZ induced severe DNA damage and triggered early apoptosis in oocytes, accompanied by impaired lysosomal function. Overall, the data in this study suggest that BPZ is not a safe alternative to BPA. BPZ can trigger early apoptosis by affecting mitochondrial function and causing oxidative stress and DNA damage in oocytes. These processes disrupt cytoskeletal assembly, arrest the cell cycle, and ultimately inhibit oocyte meiotic maturation.

Identification of residues critical for the extension of Munc18-1 domain 3a.

BACKGROUND: Neurotransmitter release depends on the fusion of synaptic vesicles with the presynaptic membrane and is mainly mediated by SNARE complex assembly. During the transition of Munc18-1/Syntaxin-1 to the SNARE complex, the opening of the Syntaxin-1 linker region catalyzed by Munc13-1 leads to the extension of the domain 3a hinge loop, which enables domain 3a to bind SNARE motifs in Synaptobrevin-2 and Syntaxin-1 and template the SNARE complex assembly. However, the exact mechanism of domain 3a extension remains elusive. RESULTS: Here, we characterized residues on the domain 3a hinge loop that are crucial for the extension of domain 3a by using biophysical and biochemical approaches and electrophysiological recordings. We showed that the mutation of residues T323/M324/R325 disrupted Munc13-1-mediated SNARE complex assembly and membrane fusion starting from Munc18-1/Syntaxin-1 in vitro and caused severe defects in the synaptic exocytosis of mouse cortex neurons in vivo. Moreover, the mutation had no effect on the binding of Synaptobrevin-2 to isolated Munc18-1 or the conformational change of the Syntaxin-1 linker region catalyzed by the Munc13-1 MUN domain. However, the extension of the domain 3a hinge loop in Munc18-1/Syntaxin-1 was completely disrupted by the mutation, leading to the failure of Synaptobrevin-2 binding to Munc18-1/Syntaxin-1. CONCLUSIONS: Together with previous results, our data further support the model that the template function of Munc18-1 in SNARE complex assembly requires the extension of domain 3a, and particular residues in the domain 3a hinge loop are crucial for the autoinhibitory release of domain 3a after the MUN domain opens the Syntaxin-1 linker region.

Discovery of Novel Diphenyl Acrylonitrile Derivatives That Promote Adult Rats' Hippocampal Neurogenesis.

We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.

A Triply-Periodic-Minimal-Surface Structured Interphase based on Fluorinated Polymers Strengthening High-energy Lithium Metal Batteries.

The challenge of constructing a mechanically robust yet lightweight artificial solid-electrolyte interphase layer on lithium (Li) anodes highlights a trade-off between high battery safety and high energy density. Inspired by the intricate microstructure of the white sea urchin, we first develop a polyvinyl fluoride-hexafluoropropylene (PVDF-HFP) interfacial layer with a triple periodic minimal surface structure (TPMS) that could offer maximal modulus with minimal weight. This design endows high mechanical strength to an ordered porous structure, effectively reduces local current density, polarization, and internal resistance, and stabilizes the anode interface. At a low N/P ratio of ~3, using LiFePO4 as the cathode, Li anodes protected by TPMS-structured PVDF-HFP achieve an extremely low capacity-fading-rate of approximately 0.002 % per cycle over 200 cycles at 1 C, with an average discharge capacity of 142 mAh g-1. Meanwhile, the TPMS porous structure saves 50 wt % of the interfacial layer mass, thereby enhancing the energy density of the battery. The TPMS structure is conducive to large-scale additive manufacturing, which will provide a reference for the future development of lightweight, high-energy-density secondary batteries.

Structural Mechanism of Soluble N-ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Assembly in Lipid Bilayers Revealed by Solid-State NMR.

Synaptic vesicle fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, including synaptobrevin-2 (Syb-2), syntaxin-1 (Syx-1), and SNAP-25. However, it remains controversial whether the formation of thoroughly contacted α-helical bundle from the SNARE motifs to the end of the transmembrane domains (TMDs) is necessary for SNARE-mediated membrane fusion. In this study, we characterized the conformation of Syb-2 in different assembly states using a combination of dipolar- and scalar-based solid-state NMR experiments in lipid bilayers. Our spectral analysis revealed a highly dynamic nature of the Syb-2 TMD with considerable α-helical contents. Chemical shift perturbation and mutational analysis indicated that the coupling between Syb-2 and Syx-1 TMDs mediated by residue Gly-100 of Syb-2 together with high mobility of the C-terminal segment of Syb-2 TMD are required for inner membrane merger. Our results provide new insights into the role of the Syb-2 TMD in driving membrane fusion, which improves the current understanding of the structural mechanism of SNARE complex assembly. This study highlights the significance of membrane environments in elucidating the mechanism of membrane proteins.

Enantioselective Reductive Cross-Couplings of Olefins by Merging Electrochemistry with Nickel Catalysis.

The merger of electrochemistry and transition metal catalysis has emerged as a powerful tool to join two electrophiles in an enantioselective manner. However, the development of enantioselective electroreductive cross-couplings of olefins remains a challenge. Inspired by the advantages of the synergistic use of electrochemistry with nickel catalysis, we present here a Ni-catalyzed enantioselective electroreductive cross-coupling of acrylates with aryl halides and alkyl bromides, which affords chiral α-aryl carbonyls in good to excellent enantioselectivity. Additionally, this catalytic reaction can be applied to (hetero)aryl chlorides, which is difficult to achieve by other methods. The combination of cyclic voltammetry analysis with electrode potential studies suggests that the NiI species activates aryl halides by oxidative addition and alkyl bromides by single-electron transfer.

Coherent stepped-frequency waveform generation based on recirculating microwave photonic frequency conversion.

We propose a novel method for generating coherent and wideband stepped-frequency waveforms using recirculating microwave photonic frequency conversion (MWP-FC). By injecting a narrowband signal into an MWP-FC loop utilizing a dual-parallel Mach-Zehnder modulator (DPMZM), the signal frequency is continuously converted to produce a stepped-frequency waveform with a wide bandwidth. Within the MWP-FC loop, photo-electric conversion is achieved based on self-mixing detection, where the optical phase noise can be suppressed, guaranteeing stability and coherence of the generated signal. In a proof-of-concept experiment, a stepped-frequency signal with a frequency interval of 2 GHz and a bandwidth of about 16 GHz and a stepped-frequency chirp signal with a frequency interval of 3 GHz and a bandwidth of about 15 GHz are generated. In addition, coherence of the generated signals is verified by coherent integration and de-chirping.

Association of serum uric acid levels with bone mineral density and the presence of osteoporosis in Chinese patients with Parkinson's disease: a cross-sectional study.

INTRODUCTION: As the population ages, the incidence of osteoporosis among patients suffering from Parkinson's disease (PD) will surge continually, and the ensuing disability from falls is becoming a serious social burden. Due to its antioxidant properties, much literature has indicated the possible ability of serum uric acid (UA) to prevent ageing-related diseases caused by oxidative stress, including osteoporosis and PD. Therefore, this study was for exploring the connection of serum UA levels with bone mineral density (BMD) and the osteoporosis presence in Chinese PD patients. MATERIALS AND METHODS: A cross-sectional design was used to statistically analyze 42 clinical parameters obtained from 135 patients with PD treated in Wuhan Tongji Hospital during 2020-2022. Multiple stepwise linear regression and multiple logistic regression analyses were constructed for identifying the association of serum UA levels with BMD as well as osteoporosis in PD patients, respectively. With receiver operative characteristic (ROC) curves, the optimal cutoff value was acquired for serum UA in the diagnosis of osteoporosis. RESULTS: According to the regression analysis adjusted for confounders, serum UA levels in PD patients had positive correlation with BMD at each site and negative correlation with the presence of osteoporosis (P < 0.05 for all). ROC curves determined that the optimal cutoff value for UA to perform well in diagnosing osteoporosis in PD patients was 284.27 µmol/L (P < 0.001). CONCLUSION: Relatively higher serum UA levels in the physiological range can work as a biomarker of higher BMD, and were strongly linked to lower prevalence of osteoporosis in Chinese PD patients.

An integrated microfluidic chip for nucleic acid extraction and continued cdPCR detection of pathogens.

This paper introduces an enclosed microfluidic chip that integrates sample preparation and the chamber-based digital polymerase chain reaction (cdPCR). The sample preparation of the chip includes nucleic acid extraction and purification based on magnetic beads, which adsorb nucleic acids by moving around the reaction chambers to complete the reactions including lysis, washing, and elution. The cdPCR area of the chip consists of tens of thousands of regularly arranged microchambers. After the sample preparation processes are completed, the purified nucleic acid can be directly introduced into the microchambers for amplification and detection on the chip. The nucleic acid extraction performance and digital quantification performance of the system were examined using synthetic SARS-CoV-2 plasmid templates at concentrations ranging from 101-105 copies per µL. Further on, a simulated clinical sample was used to test the system, and the integrated chip was able to accurately detect SARS-CoV-2 virus particle samples doped with interference (saliva) with a detection limit of 10 copies per µL. This integrated system could provide a promising tool for point-of-care testing of pathogenic infections.

Competing risk nomogram for predicting prognosis of patients with spinal and pelvic chordoma: A SEER-based retrospective study.

PURPOSE: Recently, competing risk nomograms were widely applied to predict prognosis in numerous tumors other than chordoma. Here, we aimed to construct and validate a competing-risk-based prognostic nomogram to predict 3- and 5-year cancer-specific death (CSD) in patients with spinal and pelvic chordoma. METHODS: All chordoma patient data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) resource, and a total of 485 chordoma patients were eventually included in this study. Multivariate competing risk model and multivariate Cox model were used to determine independent prognostic factors, respectively, and the results of the two models were compared. Nomogram was employed to visualize the competing risk model. The discrimination, calibration, and clinical utility of this model were evaluated by Harrell concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Ten-fold cross-validation was further utilized to validate the prognostic nomogram. RESULTS: Significant prognostic factors affecting CSD were age (P = 0.016), localized involvement (P < 0.0001), and radical resection (P < 0.001) in the multivariate competing risk model. C-indexes were 0.799 and 0.76, and AUC were 0.812 and 0.778 for 3- and 5-year CSD. Calibration plots demonstrated the nomogram was well-fitted, and DCA indicated good clinical utility. The nomogram showed good performance in the 10-fold cross-validation. CONCLUSION: We successfully built the first competing-risk-based nomogram to predict clinical outcomes in patients with spinal and pelvic chordoma. This well-established nomogram hopes to help clinicians with precise prognostic assessment and thus improve clinical outcomes.