Clinical sequencing reveals diagnostic, therapeutic, and prognostic biomarkers for adult-type diffuse gliomas.

Diffuse gliomas in adults are highly infiltrative and largely incurable. Whole exome sequencing (WES) has been demonstrated very useful in genetic analysis. Here WES was performed to characterize genomic landscape of adult-type diffuse gliomas to discover the diagnostic, therapeutic and prognostic biomarkers. Somatic and germline variants of 66 patients with adult-type diffuse gliomas were detected by WES based on the next-generation sequencing. TCGA and CGGA datasets were included to analyze the integrated diagnosis and prognosis. Among 66 patients, the diagnosis of 9 cases was changed, in which 8 cases of astrocytoma were corrected into IDH-wildtype glioblastoma (GBM), and 1 oligodendroglioma without 1p/19q co-deletion into astrocytoma. The distribution of mutations including ATRX/TP53 differed in three cohorts. The genetic mutations in GBM mainly concentrated on the cell cycle, PI3K and RTK pathways. The mutational landscape of astrocytoma was more similar to that of GBM, with the highest frequency in germline variants. Patients with IDH-mutant astrocytoma harboring SNVs of PIK3CA and PIK3R1 showed a significantly worse overall survival (OS) than wild-type patients. AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS -mutated colorectal cancer.

Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS -mutated mCRC. Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS -mutated mCRC. Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro , and we validated the efficacy of the drugs in vivo . Methods: HTS was performed using 3-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with 2 clinically ready libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the effects of the drugs on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts. Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS -mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell cycle progression and increases in microtubule stability that resulted in significantly higher defects in the mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS -mutant patient-derived xenograft mouse models. Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS -mutated, metastatic CRC.

Investigation of TMEM41A's function in breast cancer prognosis and its connection to immune cell infiltration.

BACKGROUND: Globally, breast cancer is the most common type of malignant tumor. It has been demonstrated that TMEM41A is abnormally expressed in a number of cancers and is linked to a dismal prognosis. TMEM41A's involvement in breast cancer remains unknown, though. METHODS: Data from databases such as TCGA were used in this study. Expression differences were compared using non-parametric tests. Cox regression analysis was employed, and analyses such as Nomogram were used to assess the significance of TMEM41A in predicting the prognosis of breast cancer. Lastly, it was looked into how immune cell infiltration in breast cancer is related to TMEM41A expression levels. RESULTS: The results suggest that TMEM41A is overexpressed in breast cancer and correlates with poor prognosis (P = 0.01), particularly in early-stage and ductal A breast cancer (P < 0.01). Breast cancer patients' expression of TMEM41A was found to be an independent risk factor (HR = 1.132, 95% CI 1.036-1.237) by multifactorial Cox regression analysis. The Nomogram prediction model's c-index was 0.736 (95% CI 0.684-0.787). The results of GSEA biofunctional enrichment analysis included the B cell receptor signaling pathway (P < 0.05). Ultimately, there was a significant correlation (P < 0.05) between TMEM41A expression in breast cancer and an infiltration of twenty immune cells. CONCLUSIONS: Breast cancer tissues overexpress TMEM41A, which is linked to immune cell infiltration and prognosis (particularly in early stage and luminal A breast cancer). Overexpression of TMEM41A is anticipated to serve as a novel prognostic indicator and therapeutic target for breast cancer.

Kidney function-specific cut-off values of high-sensitivity cardiac troponin T for the diagnosis of acute myocardial infarction.

Background: The diagnosis of acute myocardial infarction (AMI) using high-sensitivity cardiac troponin T (hs-cTnT) remains challenging in patients with kidney dysfunction. Methods: In this large, multicenter cohort study, a total of 20 912 adults who underwent coronary angiography were included. Kidney function-specific cut-off values of hs-cTnT were determined to improve the specificity without sacrificing sensitivity, as compared with that using traditional cut-off value (14 ng/L) in the normal kidney function group. The diagnostic accuracy of the novel cut-off values was validated in an independent validation cohort. Results: In the derivation cohort (n = 12 900), 3247 patients had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Even in the absence of AMI, 50.2% of participants with eGFR <60 mL/min/1.73 m2 had a hs-cTnT concentration ≥14 ng/L. Using 14 ng/L as the threshold of hs-cTnT for diagnosing AMI led to a significantly reduced specificity and positive predictive value in patients with kidney dysfunction, as compared with that in patients with normal kidney function. The kidney function-specific cut-off values were determined as 14, 18 and 48 ng/L for patients with eGFR >60, 60-30 and <30 mL/min/1.73 m2, respectively. Using the novel cut-off values, the specificities for diagnosing AMI in participants with different levels of kidney dysfunction were remarkably improved (from 9.1%-52.7% to 52.8-63.0%), without compromising sensitivity (96.6%-97.9%). Similar improvement of diagnostic accuracy was observed in the validation cohort (n = 8012). Conclusions: The kidney function-specific cut-off values of hs-cTnT may help clinicians to accurately diagnose AMI in patients with kidney dysfunction and avoid the potential overtreatment in practice.

Glycolysis in Peritubular Endothelial Cells and Microvascular Rarefaction in CKD.

BACKGROUND: Peritubular endothelial cell dropout leading to microvascular rarefaction is a common manifestation of chronic kidney disease (CKD). The role of metabolism reprogramming in peritubular endothelial cell loss in CKD is undetermined. METHODS: Single-cell sequencing and metabolic analysis were used to characterize metabolic profile of peritubular endothelial cells from CKD patients and from CKD mouse models. In vivo and in vitro models demonstrated metabolic reprogramming in peritubular endothelial cells in conditions of CKD and its contribution to microvascular rarefaction. RESULTS: Here, we identified glycolysis as a top dysregulated metabolic pathway in peritubular endothelial cells from CKD patients. Specifically, CKD peritubular endothelial cells were hypoglycolytic while displaying an anti-angiogenic response with decreased proliferation and increased apoptosis. The hypoglycolytic phenotype of peritubular endothelial cells was recapitulated in CKD mouse models and in peritubular endothelial cells stimulated by hydrogen peroxide (H2O2). Mechanically, oxidative stress, through activating a redox sensor kruppel-like transcription factor 9, downregulated the glycolytic activator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3) expression, thereby reprogramming peritubular endothelial cells towards a hypoglycolytic phenotype. PFKFB3 overexpression in peritubular endothelial cells restored H2O2-induced reduction in glycolysis and cellular ATP levels, and enhanced the G1/S cell cycle transition, enabling peritubular endothelial cells to improve proliferation and reduce apoptosis. Consistently, restoration of peritubular endothelial cell glycolysis in CKD mice, via overexpressing endothelial Pfkfb3, reversed the anti-angiogenic response in peritubular endothelial cells and protected the kidney from microvascular rarefaction and fibrosis. In contrast, suppression of glycolysis by endothelial Pfkfb3 deletion exacerbated microvascular rarefaction and fibrosis in CKD mice. CONCLUSIONS: Our study revealed a disrupted regulation of glycolysis in peritubular endothelial cells as an initiator of microvascular rarefaction in CKD. Restoration of peritubular endothelial cell glycolysis in CKD kidney improved microvascular rarefaction and ameliorated fibrotic lesions.

PSD-ELGAN: A pseudo self-distillation based CycleGAN with enhanced local adversarial interaction for single image dehazing.

Compared to pixel-level content loss, domain-level style loss in CycleGAN-based dehazing algorithms just imposes relatively soft constraints on the intermediate translated images, resulting in struggling to accurately model haze-free features from real hazy scenes. Furthermore, globally perceptual discriminator may misclassify real hazy images with significant scene depth variations as clean style, thereby resulting in severe haze residue. To address these issues, we propose a pseudo self-distillation based CycleGAN with enhanced local adversarial interaction for image dehazing, termed as PSD-ELGAN. On the one hand, we leverage the characteristic of CycleGAN to generate pseudo image pairs during training. Knowledge distillation is employed in this unsupervised framework to transfer the informative high-quality features from the self-reconstruction network of real clean images to the dehazing generator of paired pseudo hazy images, which effectively improves its haze-free feature representation ability without increasing network parameters. On the other hand, in the output of dehazing generator, four non-uniform image patches severely affected by residual haze are adaptively selected as input samples. The local discriminator could easily distinguish their hazy style, thereby further compelling the dehazing generator to suppress haze residues in such regions, thus enhancing its dehazing performance. Extensive experiments show that our PSD-ELGAN can achieve promising results and better generality across various datasets.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Omega-3 PUFAs slow organ aging through promoting energy metabolism.

Energy metabolism disorder, mainly exhibiting the inhibition of fatty acid degradation and lipid accumulation, is highly related with aging acceleration. However, the intervention measures are deficient. Here, we reported Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs), especially EPA, exerted beneficial effects on maintaining energy metabolism and lipid homeostasis to slow organ aging. As the endogenous agonist of peroxisome proliferator-activated receptor α (PPARα), Omega-3 PUFAs significantly boosted fatty acid ß-oxidation and ATP production in multiple aged organs. Consequently, Omega-3 PUFAs effectively inhibited age-related pathological changes, preserved organ function, and retarded aging process. The beneficial effects of Omega-3 PUFAs were also testified in mfat-1 transgenic mice, which spontaneously generate abundant endogenous Omega-3 PUFAs. In conclusion, our study innovatively demonstrated Omega-3 PUFAs administration in diet slow aging through promoting energy metabolism. The supplement of Omega-3 PUFAs or fat-1 transgene provides a promising therapeutic approach to promote healthy aging in the elderly.

Inverse association between serum chloride levels and the risk of atrial fibrillation in chronic kidney disease patients.

Background: Electrolyte abnormalities are common symptoms of chronic kidney disease (CKD), but previous studies have mainly focussed on serum potassium and sodium levels. Chloride is an important biomarker for the prognosis of various diseases. However, the relationship between serum chloride levels and atrial fibrillation (AF) in CKD patients is unclear. Objective: In this study, we sought to determine the association between serum chloride homeostasis and AF in CKD patients. Methods: In this retrospective cohort study, we included patients who met the diagnostic criteria for CKD in China between 2000 and 2021. Competing risk regression for AF was performed. The associations of the baseline serum chloride concentration with heart failure (HF) and stroke incidence were also calculated by competing risk regression. The association of baseline serum chloride levels with all-cause death was determined by a Cox regression model. Results: The study cohort comprised 20 550 participants. During a median follow-up of 350 days (interquartile range, 123-730 days), 211 of the 20 550 CKD patients developed AF. After multivariable adjustment, every decrease in the standard deviation of serum chloride (5.02 mmol/l) was associated with a high risk for AF [sub-hazard ratio (sHR) 0.78, 95% confidence interval (CI) 0.65-0.94, P = .008]. These results were also consistent with those of the stratified and sensitivity analyses. According to the fully adjusted models, the serum chloride concentration was also associated with a high risk for incident HF (sHR 0.85, 95% CI 0.80-0.91, P < .001), a high risk for incident stroke (sHR 0.87, 95% CI 0.81-0.94, P < .001), and a high risk for all-cause death [hazard ratio (HR) 0.82, 95% CI 0.73-0.91, P < .001]. Conclusion: In this CKD population, serum chloride levels were independently and inversely associated with the incidence of AF. Lower serum chloride levels were also associated with an increased risk of incident HF, stroke, and all-cause death.

Phosphorus fertilization enhanced overwintering, root system and forage yield of late-seeded alfalfa in sodic soils.

Sowing date and soil fertility are very important factors in the overwintering and production performance of alfalfa (Medicago sativa L.), yet there's a knowledge gap in knowledge on how late-seeded alfalfa responds to phosphorus (P) fertilization. A field study was conducted in Inner Mongolia from 2020 to 2022 using a split-plot design. The main plots consisted of five sowing dates (31 July, 8, 16, and 24 August, and 1 September), while the subplots involved five P application rates (0, 40, 70, 100, and 130 kg P2O5 ha-1). Throughout the growing seasons, the overwintering rate, root traits, forage yield, and yield components were measured. The results revealed a consistent decrease in overwintering ability and productivity with the delayed sowing. This reduction in overwintering rate was mainly due to diminished root traits, while the decrease in forage yield was largely associated with a reduction in plants per square meter. However, P fertilizer application to late-seeded alfalfa demonstrated potential in enhancing the diameter of both the crown and taproot, thus strengthening the root system and improving the overwintering rate, the rate of increase ranges from 11.6 to 49%. This adjustment could also improve the shoots per square meter and mass per shoot, increasing by 9.4-31.3% and 15.0-27.1% respectively in 2 years, which can offset the decline in forage yield caused by late sowing and might even increase the forage yield. Regression and path analysis indicated that alfalfa forage yield is primarily affected by mass per shoot rather than shoots per square meter. This study recommended that the sowing of alfalfa in similar regions of Inner Mongolia should not be later than mid-August. Moreover, applying P fertilizer (P2O5) at 70.6-85.9 kg ha-1 can enhance the forage yield and persistence of late-seeded alfalfa. Therefore, appropriate late sowing combined with the application of P fertilizer can be used as an efficient cultivation strategy for alfalfa cultivation after a short-season crop harvest in arid and cold regions.

A new isoprenyl-phenol-type meroterpenoid from mangrove endophytic fungus Aspergillus sp. GXNU-Y65.

Asperphenol A (1), a new isoprenyl-phenol-type meroterpenoid, was isolated from the mangrove endophytic fungus Aspergillus sp. GXNU-Y65 together with five known compounds (2-6). All structures were assigned using extensive NMR spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1-6 were evaluated for their cytotoxic activity against A549 and T24 human cancer cell lines. Among them, compounds 1 and 5 exhibited moderate inhibitory activities against T24 cancer cell lines with the IC50 values of 26.71 and 43.50 µM, respectively.

Association of accelerometer-derived "weekend warrior" moderate to vigorous physical activity, chronic kidney disease and acute kidney injury.

OBJECTIVE: To examine the relationship between an accelerometer-derived "weekend warrior" pattern, characterized by achieving the most moderate to vigorous physical activity (MVPA) over 1-2 days, as opposed to more evenly distributed patterns, with risk of chronic kidney disease (CKD) and acute kidney injury (AKI). METHODS: 77,977 participants without prior kidney diseases and with usable accelerometer data (collected between 2013 and 2015) were included from the UK Biobank. Three physical activity patterns were compared: active weekend warrior pattern (achieving ≥150 min MVPA per week and accumulating ≥50 % of total MVPA in 1-2 days), active regular pattern (achieving ≥150 min MVPA but not meeting active weekend warrior criteria per week), and inactive pattern (<150 min MVPA per week). The study outcomes included incident CKD and AKI, ascertained through self-report data and data linkage with primary care, hospital admissions, and death registry records. RESULTS: During a median follow-up of 6.8 years, 1324 participants developed CKD and 1515 developed AKI. In multivariable-adjusted models, when compared with inactive participants, individuals with active weekend warrior pattern (CKD: hazard ratio [HR], 0.79, 95 % confidence interval [CI], 0.69-0.89; AKI: HR, 0.70, 95 %CI, 0.62-0.79) and those with active regular pattern (CKD: HR, 0.81, 95 %CI, 0.69-0.95; AKI: HR, 0.79, 95 %CI, 0.68-0.91) exhibited a similar and significantly lower risk of incident CKD and AKI. Similar findings were observed at the median threshold of ≥230.4 min of MVPA per week. CONCLUSION: Concentrated MVPA within 1 to 2 days is as effective as distributed ones in decreasing the risk of renal outcomes.

Transplantation of miR-145a-5p modified M2 type microglia promotes the tissue repair of spinal cord injury in mice.

BACKGROUND: The traumatic spinal cord injury (SCI) can cause immediate multi-faceted function loss or paralysis. Microglia, as one of tissue resident macrophages, has been reported to play a critical role in regulating inflammation response during SCI processes. And transplantation with M2 microglia into SCI mice promotes recovery of motor function. However, the M2 microglia can be easily re-educated and changed their phenotype due to the stimuli of tissue microenvironment. This study aimed to find a way to maintain the function of M2 microglia, which could exert an anti-inflammatory and pro-repair role, and further promote the repair of spinal cord injury. METHODS: To establish a standard murine spinal cord clip compression model using Dumont tying forceps. Using FACS, to sort microglia from C57BL/6 mice or CX3CR1GFP mice, and further culture them in vitro with different macrophage polarized medium. Also, to isolate primary microglia using density gradient centrifugation with the neonatal mice. To transfect miR-145a-5p into M2 microglia by Lipofectamine2000, and inject miR-145a-5p modified M2 microglia into the lesion sites of spinal cord for cell transplanted therapy. To evaluate the recovery of motor function in SCI mice through behavior analysis, immunofluorescence or histochemistry staining, Western blot and qRT-PCR detection. Application of reporter assay and molecular biology experiments to reveal the mechanism of miR-145a-5p modified M2 microglia therapy on SCI mice. RESULTS: With in vitro experiments, we found that miR-145a-5p was highly expressed in M2 microglia, and miR-145a-5p overexpression could suppress M1 while promote M2 microglia polarization. And then delivery of miR-145a-5p overexpressed M2 microglia into the injured spinal cord area significantly accelerated locomotive recovery as well as prevented glia scar formation and neuron damage in mice, which was even better than M2 microglia transplantation. Further mechanisms showed that overexpressed miR-145a-5p in microglia inhibited the inflammatory response and maintained M2 macrophage phenotype by targeting TLR4/NF-κB signaling. CONCLUSIONS: These findings indicate that transplantation of miR-145a-5p modified M2 microglia has more therapeutic potential for SCI than M2 microglia transplantation from epigenetic perspective.

Motion Artifact Correction for OCT Microvascular Images Based on Image Feature Matching.

Optical coherence tomography angiography (OCTA), a functional extension of optical coherence tomography (OCT), is widely employed for high-resolution imaging of microvascular networks. However, due to the relatively low scan rate of OCT, the artifacts caused by the involuntary bulk motion of tissues severely impact the visualization of microvascular networks. This study proposes a fast motion correction method based on image feature matching for OCT microvascular images. First, the rigid motion-related mismatch between B-scans is compensated through the image feature matching based on the improved oriented FAST and rotated BRIEF algorithm. Then, the axial motion within A-scan lines in each B-scan image is corrected according to the displacement deviation between the detected boundaries achieved by the Scharr operator in a non-rigid transformation manner. Finally, an optimized intensity-based Doppler variance algorithm is developed to enhance the robustness of the OCTA imaging. The experimental results demonstrate the effectiveness of the method.

Cannabinoid receptor 2 plays a key role in renal fibrosis through inhibiting lipid metabolism in renal tubular cells.

AIMS: Renal fibrosis is a common feature in various chronic kidney diseases (CKD). Tubular cell damage is a main characterization which results from dysregulated fatty acid oxidation (FAO) and lipid accumulation. Cannabinoid Receptor 2 (CB2) contributes to renal fibrosis, however, its role in FAO dysregulation in tubular cells is not clarified. In this study, we found CB2 plays a detrimental role in lipid metabolism in tubular cells. METHODS: CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, ß-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of ß-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed. RESULTS: CB2 activates ß-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to ß-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2. CONCLUSIONS: This study highlights CB2 disrupts FAO in tubular cells through ß-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis.

Large-Scale Proteomics Improve Prediction of Chronic Kidney Disease in People With Diabetes.

OBJECTIVE: To develop and validate a protein risk score for predicting chronic kidney disease (CKD) in patients with diabetes and compare its predictive performance with a validated clinical risk model (CKD Prediction Consortium [CKD-PC]) and CKD polygenic risk score. RESEARCH DESIGN AND METHODS: This cohort study included 2,094 patients with diabetes who had proteomics and genetic information and no history of CKD at baseline from the UK Biobank Pharma Proteomics Project. Based on nearly 3,000 plasma proteins, a CKD protein risk score including 11 proteins was constructed in the training set (including 1,047 participants; 117 CKD events). RESULTS: The median follow-up duration was 12.1 years. In the test set (including 1,047 participants; 112 CKD events), the CKD protein risk score was positively associated with incident CKD (per SD increment; hazard ratio 1.78; 95% CI 1.44, 2.20). Compared with the basic model (age + sex + race, C-index, 0.627; 95% CI 0.578, 0.675), the CKD protein risk score (C-index increase 0.122; 95% CI 0.071, 0.177), and the CKD-PC risk factors (C-index increase 0.175; 95% CI 0.126, 0.217) significantly improved the prediction performance of incident CKD, but the CKD polygenic risk score (C-index increase 0.007; 95% CI -0.016, 0.025) had no significant improvement. Adding the CKD protein risk score into the CKD-PC risk factors had the largest C-index of 0.825 (C-index from 0.802 to 0.825; difference 0.023; 95% CI 0.006, 0.044), and significantly improved the continuous 10-year net reclassification (0.199; 95% CI 0.059, 0.299) and 10-year integrated discrimination index (0.041; 95% CI 0.007, 0.083). CONCLUSIONS: Adding the CKD protein risk score to a validated clinical risk model significantly improved the discrimination and reclassification of CKD risk in patients with diabetes.

Transcriptomic analysis of reproductive organs of pregnant mice post toxoplasma gondii infection reveals the potential factors that contribute to poor prognosis.

Toxoplasma gondii is an obligate intracellular parasite of phylum Apicomplexa that poses a huge threat to pregnant hosts, and induces tragic outcomes for pregnant hosts, fetuses and newborns. However, the molecular mechanism underlying the tragic consequences caused by T. gondii remains to be revealed. In the present study, we applied RNA-seq to study the transcriptomic landscape of the whole reproductive organ of pregnant mice post T. gondii infection, aiming to reveal the key altered biological characters of reproductive organs of pregnant mice that could contribute to the tragic outcomes caused by T. gondii infection. The results of the present study showed that the transcriptome of reproductive organs of pregnant mice was significantly altered by T. gondii infection. A total of 2,598 differentially expressed genes (DEGs) were identified, including 1,449 upregulated genes and 1,149 downregulated genes. Enrichment analysis of the DEGs showed that the significantly altered features of reproductive organs of pregnant mice were excessive inflammatory responses, downregulated metabolism processes, and congenital diseases. The chemotaxis of immune cells in the reproductive organs of infected pregnant mice could also be reshaped by 19 differentially expressed chemokines and 6 differentially expressed chemokine receptors that could contribute to the damages of reproductive organ in pregnant mice. Overall, the findings of present study may help to understand the pathogenic mechanism of the acute T. gondii infection in reproductive organs of pregnant mice, and it could also help to improve toxoplasmosis therapeutics for pregnant individuals.

Cryptosporidium spp. Infection and Genotype Identification in Pre-Weaned and Post-Weaned Calves in Yunnan Province, China.

BACKGROUND: Cryptosporidium is a globally distributed zoonotic protozoan parasite in humans and animals. Infection is widespread in dairy cattle, especially in calves, resulting in neonatal enteritis, production losses and high mortality. However, the occurrence of Cryptosporidium spp. in pre- and post-weaned calves in Yunnan Province remains unclear. METHODS: We collected 498 fecal samples from Holstein calves on 10 different farms in four regions of Yunnan Province. Nested PCR and DNA sequencing were used to determine the infection, species and genotypes of Cryptosporidium spp. in these animals. RESULTS: The overall occurrence of Cryptosporidium spp. in Holstein calves was 32.9% (164/498), and the prevalence in pre- and post-weaned calves was 33.5% (106/316) and 31.9% (58/182), respectively. Four Cryptosporidium species were identified in these animals, namely C. bovis (n = 119), C. parvum (n = 23), C. ryanae (n = 20) and C. andersoni (n = 2). Based on sequencing analysis of the 60 kDa glycoprotein gene of C. bovis, C. parvum and C. ryanae, six subtypes of C. bovis (XXVIe, XXVIb, XXVIf, XXVIa XXVIc and XXVId), two subtypes of C. parvum (IIdA19G1 and IIdA18G1) and four subtypes of C. ryanae (XXIf, XXId, XXIe and XXIg) were identified. CONCLUSIONS: These results provide essential information to understand the infection rate, species diversity and genetic structure of Cryptosporidium spp. populations in Holstein pre-weaned and post-weaned calves in Yunnan Province. Further, the presence of IIdA18G1 and IIdA19G1 in C. parvum implies significant animal and public health concerns, which requires greater attention and more preventive measures.

Opportunistic use of chest low-dose computed tomography (LDCT) imaging for low bone mineral density and osteoporosis screening: cutoff thresholds for the attenuation values of the lower thoracic and upper lumbar vertebrae.

Background: Osteoporosis remains substantially underdiagnosed and undertreated worldwide. Chest low-dose computed tomography (LDCT) may provide a valuable and popular opportunity for osteoporosis screening. This study sought to evaluate the feasibility of the screening of low bone mineral density (BMD) and osteoporosis with mean attenuation values of the lower thoracic compared to upper lumbar vertebrae. The cutoff thresholds of the mean attenuation values in Hounsfield units (HU) were derived to facilitate implementation of opportunistic screening using chest LDCT. Methods: The participants aged 30 years or older who underwent chest LDCT and quantitative computed tomography (QCT) examinations from August 2018 to October 2020 in our hospital were consecutively included in this retrospective study. A region of interest (ROI) was placed in the trabecular bone of each vertebral body to measure the HU values. The correlations of mean HU values of lower thoracic (T11-T12) and upper lumbar (L1-L2) vertebrae with age and lumbar BMD obtained with QCT were performed using the Pearson correlation coefficient, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was generated to determine the cutoff thresholds for distinguishing low BMD from normal and osteoporosis from non-osteoporosis. Results: A total of 1,112 participants were included in the final study cohort (743 men and 369 women, mean age 58.2±8.9 years; range, 32-88 years). The mean HU values of T11-T12 and L1-L2 were significantly different among 3 QCT-defined BMD categories of osteoporosis, osteopenia, and normal (P<0.001). The differences in HU values between T11-T12 and L1-L2 in each category of bone status were statistically significant (P<0.001). The mean HU values of T11-T12 (r=-0.453, P<0.001) and L1-L2 (r=-0.498, P<0.001) had negative correlations with age. Positive correlations were observed between the mean HU values of T11-T12 (r=0.872, P<0.001) and L1-L2 (r=0.899, P<0.001) with BMD. The optimal cutoff thresholds for distinguishing low BMD from normal were average T11-T12 ≤157 HU [AUC =0.941, 95% confidence interval (CI): 0.925-0.954, P<0.001] and L1-L2 ≤138 HU (AUC =0.950, 95% CI: 0.935-0.962, P<0.001), as well as distinguishing osteoporosis from non-osteoporosis were average T11-T12 ≤125 HU (AUC =0.960, 95% CI: 0.947-0.971, P<0.001) and L1-L2 ≤107 HU (AUC =0.961, 95% CI: 0.948-0.972, P<0.001). There was no significant difference between the AUC values of T11-T12 and L1-L2 for low BMD (P=0.07) and osteoporosis (P=0.92) screening. Conclusions: We have conducted a study on low BMD and osteoporosis screening using mean attenuation values of lower thoracic and upper lumbar vertebrae. Assessment of mean attenuation values of T11-T12 and L1-L2 can be used interchangeably for low BMD and osteoporosis screening using chest LDCT, and their cutoff thresholds were established.