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Abstract Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1–5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.

IntroductionIncreasing evidence shows that hyperactive aryl hydrocarbon receptor (AHR) signalling is involved in renal disease. However, no currently available intervention strategy is effective in halting disease progression by targeting the AHR signalling. Our previous study showed that barleriside A (BSA), a major component of Plantaginis semen, exhibits renoprotective effects.MethodsIn this study, we determined the effects of BSA on AHR expression in 5/6 nephrectomized (NX) rats. We further determined the effect of BSA on AHR, nuclear factor kappa B (NF-ƙB), and the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade in zymosan-activated serum (ZAS)-stimulated MPC5 cells.ResultsBSA treatment improved renal function and inhibited intrarenal nuclear AHR protein expression in NX-treated rats. BSA mitigated podocyte lesions and suppressed AHR mRNA and protein expression in ZAS-stimulated MPC5 cells. BSA inhibited inflammation by improving the NF-ƙB and Nrf2 pathways in ZAS-stimulated MPC5 cells. However, BSA did not markedly upregulate the expression of podocyte-specific proteins in the ZAS-mediated MPC5 cells treated with CH223191 or AHR siRNA compared to untreated ZAS-induced MPC5 cells. Similarly, the inhibitory effects of BSA on nuclear NF-ƙB p65, Nrf2, and AHR, as well as cytoplasmic cyclooxygenase-2, heme oxygenase-1, and AHR, were partially abolished in ZAS-induced MPC5 cells treated with CH223191 or AHRsiRNA compared with untreated ZAS-induced MPC5 cells. These results indicated that BSA attenuated the inflammatory response, partly by inhibiting AHR signalling.DiscussionBoth pharmacological and siNRA findings suggested that BSA mitigated podocyte lesions by improving the NF-ƙB and Nrf2 pathways via inhibiting AHR signalling. Therefore, BSA is a high-affinity AHR antagonist that abolishes oxidative stress and inflammation.

Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). Esterified AA is hydrolysed by phospholipase A2 into a free form that is further metabolized by COX, LOX and CYP450 to a wide range of bioactive mediators, including prostaglandins, lipoxins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. Increased mitochondrial oxidative stress is considered to be a central mechanism in the pathophysiology of the kidney. Along with increased oxidative stress, apoptosis, inflammation and tissue fibrosis drive the progressive loss of kidney function, affecting the glomerular filtration barrier and the tubulointerstitium. Recent studies have shown that AA and its active derivative eicosanoids play important roles in the regulation of physiological kidney function and the pathogenesis of kidney disease. These factors are potentially novel biomarkers, especially in the context of their involvement in inflammatory processes and oxidative stress. In this review, we introduce the three main metabolic pathways of AA and discuss the molecular mechanisms by which these pathways affect the progression of acute kidney injury (AKI), diabetic nephropathy (DN) and renal cell carcinoma (RCC). This review may provide new therapeutic targets for the identification of AKI to CKD continuum.

Renal fibrosis is increasingly recognized as a global public health problem. Acute kidney injury (AKI) and chronic kidney disease (CKD) both result in renal fibrosis. Oxidative stress and inflammation play central roles in progressive renal fibrosis. Oxidative stress and inflammation are closely linked and form a vicious cycle in which oxidative stress induces inflammation through various molecular mechanisms. Ample evidence has indicated that a hyperactive nuclear factor kappa B (NF-ƙB) signaling pathway plays a pivotal role in renal fibrosis. Hyperactive NF-ƙB causes the activation and recruitment of immune cells. Inflammation, in turn, triggers oxidative stress through the production of reactive oxygen species and nitrogen species by activating leukocytes and resident cells. These events mediate organ injury through apoptosis, necrosis, and fibrosis. Therefore, developing a strategy to target the NF-ƙB signaling pathway is important for the effective treatment of renal fibrosis. This Review summarizes the effect of the NF-ƙB signaling pathway on renal fibrosis in the context of AKI and CKD (immunoglobulin A nephropathy, membranous nephropathy, diabetic nephropathy, hypertensive nephropathy, and kidney transplantation). Therapies targeting the NF-ƙB signaling pathway, including natural products, are also discussed. In addition, NF-ƙB-dependent non-coding RNAs are involved in renal inflammation and fibrosis and are crucial targets in the development of effective treatments for kidney disease. This Review provides a clear pathophysiological rationale and specific concept-driven therapeutic strategy for the treatment of renal fibrosis by targeting the NF-ƙB signaling pathway.

Abstract Background Obstructive sleep apnea (OSA) is a modifiable risk factor for acute coronary syndrome (ACS), with high prevalence but low diagnostic rates. Therefore, it is particularly important to develop strategies for better screening for OSA in newly admitted ACS patients. Methods From March 2017 to October 2019, consecutive eligible patients with ACS underwent cardiorespiratory polygraphy during hospitalization. OSA was defined as an apnea–hypopnea index (AHI) ≥ 15 events/h. All anthropometric and oropharyngeal parameters are measured by specialist nurses. Results Finally, 761 ACS patients were recruited in the present study. Prevalence of moderate/severe OSA was 53.2% based on diagnostic criteria of AHI ≥ 15. Correlation analysis illustrated that AHI was positively correlated with anthropometric characteristics. In the multivariate model, only micrognathia (OR 2.02, 95% CI 1.02–4.00, P = 0.044), waist circumference (OR 1.08, 95% CI 1.04–1.11, P

This study takes tartary buckwheat, highland barley and oats as the main raw materials to analyze and develop a high-fiber noodles premixed powder. The premixed powder is blended as the following proportion: 40% plain flour, 30% tartary buckwheat, 10% highland barley and 20% oat. This proportion gives us 6.94% dietary fiber, 1.9% beta glucan, 0.8% total flavonoids in the premixed powder. Through single factor experiment, combined with the response surface analysis test and taking finished product breakout rate and cooking loss rate and sensory evaluation as a comprehensive index, this study discusses the effects of gluten, salt, sodium carbonate and konjac purified powder on the quality of premixed powder. Results show that the optimal proportion of the compound improver is: 5.4% gluten, 1.3% salt, 0.2% sodium carbonate,and 1.1% konjac refined powder, which makes the processing process of high fiber noodles premixed powder easier and the quality of finished products higher

Membranous nephropathy (MN) is a renal-limited non-inflammatory autoimmune disease in the glomerulus, which is the second or third main cause of end-stage kidney diseases in patients with primary glomerulonephritis. Substantial achievements have increased our understanding of the aetiology and pathogenesis of murine and human MN. The identification of nephritogenic autoantibodies against neutral endopeptidase, phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) antigens provide more specific concept-driven intervention strategies for treatments by specific B cell-targeting monoclonal antibodies to inhibit antibody production and antibody-antigen immune complex deposition. Furthermore, additional antibody specificities for antigens have been discovered, but their pathogenic effects are uncertain. Although anti-PLA2R and anti-THSD7A antibodies as a diagnostic marker is widely used in MN patients, many questions including autoimmune response development, antigenic epitopes, and podocyte damage signalling pathways remain unresolved. This review describes the current available evidence regarding both established and novel molecular mechanisms based on systems biology approaches (gut microbiota, long non-coding RNAs, metabolite biomarkers and DNA methylation) in MN, with an emphasis on clinical findings. This review further summarizes the applications of traditional Chinese medicines such as Tripterygium wilfordii and Astragalus membranaceus for MN treatment. Lastly, this review considers how the identification of novel antibodies/antigens and unresolved questions and future challenges reveal the pathogenesis of MN.

In order to improve the existing issues of bamboo shoot parfait such as the stiffness and lack of elasticity, taking sensory score as index, the effects of sodium bicarbonate, citric acid, single octylic acid glyceride, compound phosphate and sorbitol on the quality of bamboo shoots foam were studied by single factor test and orthogonal test. The experimental results showed that: When the addition of sodium bicarbonate, citric acid, monocaprylic glyceride, compound phosphate and sorbitol were at 0.15%, 0.02%,0.04%, 0.4% and 0.3% respectively, the bamboo shoot parfait was soft and elastic, and the sensory score reached 96.21 points. On this basis, the texture properties of the bamboo shoots parfait can be compared with those of the market samples. The texture properties of the bamboo shoots parfait were measured as follows:hardness 94.2, elasticity 0.92, chewability 711.51, viscosity 90.23, adhesion 537.79, which were similar to the texture properties of the market products.

In order to study the influence of the two-stage extrusion process on the quality of instant rice noodle, the key parameters of the two-stage extrusion process including: the first and second stage extruder barrel temperature, the first and second stage extruder screw speed, feeding speed, and the template hole diameter were taken as the single factor research objects, and the single factor experiment and response surface experiment were used to optimize them. The results show that the optimization of extrusion parameters can improve the quality of instant rice noodle in a certain range. The final optimization of the two-stage extrusion process parameters are as follows: the first stage extruder barrel temperature was 173 ℃,the second stage extruder barrel temperature was 39 ℃, the first stage extruder screw speed was 30 Hz, the second stage extruder screw speed was 20 Hz, the feeding speed was 11.8hz, and the template aperture was 0.7 mm. Under this condition, the instant rice noodle product is made with Strong fragrance and good comprehensive quality which can reach market product quality. This study can provide a reference for the continuous production of instant rice noodle.

Whole potato flour has high nutritional value, but it is limited in the processing of vermicelli because it cannot form a good gluten structure. In this study, single factor test and double factor test were used to optimize the vacuum and noodles process of whole potato flour noodle. The results showed that the water content had the greatest influence on the overall quality of whole potato flour, followed by the mixing time, the vacuum degree and rotation speed had little influence. The optimum parameters are 36% water addition, 12 minutes mixing time, 0.06 MPa vacuum degree and 60 R/min rotating speed. It provides practical data support for further industrial production of high proportion potato noodle products.

As one of the main food crops in the world, the rice quality and safety situation is not optimistic, the development of rice traceability system has become a hot topic at home and abroad. This paper summarizes the research status of rice traceability technology from two aspects including the origin diagnosis technology (such as: physical index fingerprint technology, stable isotope technology, multi-element analysis technology, near-infrared spectroscopy technology) and the traceability system technology (such as: physical identification technology, information coding technology, information transmission technology). Based on this analysis, the development trend of rice traceability system was analyzed, and new technologies will continue to be applied to the traceability system.

Glycemic Index, proposed by Dr.Jekins in 1970, was an index that measured blood sugar capacity of food. Recent research indicated that glycemic index had positive effects on therapy of diabetic patients and weight management for the overweight. In this paper, the author introduced the concept of glycemic index, food materials grading based on GI, the relationships between GI and food components, the physiological reaction of human separately consuming high GI or low GI food, the application of GI in prevention and cure of diabetes. The review will provided scientific evidences for medical treatment and designing nutritional meal for diabetic patients in comtemporary medical science.

Fresh and wet rice noodles are the traditional staple food of rice products in south China, which contain high moisture, therefore it is difficult to ensure the quality during processing.The effects of different addition quantities of the four quality improvers on the quality of fresh and wet rice noodles were compared with potato modified starch, sodium pyrophosphate, lecithin and sodium alginate as quality improvers, and the cooking loss rate and sensory evaluation of fresh and wet rice noodles as indicators.On this basis,orthogonal tests were designed, and it was found that when adding 5% modified potato starch (dry matter mass fraction, the same below), 0.4% sodium pyrophosphate, 0.4% lecithin and 0.3% sodium alginate, the cooking loss rate of fresh and wet rice noodles was 1.3% and the sensory score was 91.4, which reached the best under the same conditions.Then, the fresh wet rice noodles were prepared with the optimal adding amount of quality improvers selected by single factor experiments, and the noodles with the optimal adding amount of compound quality improvers selected by orthogonal experiment, with the broken rate, cooking loss rate, transmittance and gelatinization degree as the indexes, and the fresh wet rice noodles without quality improvers as control group.Under the same conditions, for the fresh and wet rice noodles with the optimal addition amount of compound quality improver, the broken rate reduced to 1.7%, cooking loss rate reduced to 1.3%, transmittance increased to 0.836, gelatinization degree increased to 92.1%, and the quality improvement effect was the best in the comparative experiment.

The quality improvement of dried noodles with high-content potato flour (33% of whole flour) was optimized by uniform design test. The main influencing factors on the quality were determined by regression analysis. The broken rate, cooking loss rate and sensory score were chosen as indicators. The results showed that the quality improver was the edible salt 0.31%, sodium carbonate 0.12%, konjac flour 0.34%, wheat gluten 2.80%, sodium polyacrylate 0.11%.With the improver the noodles cooking loss rate was 3.73%, the broken rate was 3.0% and the sensory score was 91.5. Through the research of quality improver, the quality of the sample is obviously better than the commercially available noodle, which solves the technical problems such as easy broken noodles, easy muddy soup and so on when cook dried noodles with high-content potato flour.

The effects of mono-hydrophilic colloid(xanthan gum,guar gum,sodium alginate,hydroxypropyl methylcellulose and carrageenan) on the anti-aging of tartary buckwheat parfait were studied with sensory evaluation and hardness as indexes,and three kinds of hydrophilic colloid with better anti-aging effect were screened out.Based on this,the optimal anti-aging agent of tartary buckwheat parfait was determined by response surface analysis method.The results showed that the optimal anti-aging agent formula was 0.13%of xanthan gum,0.17% of sodium alginate and 0.24% of carrageenan(calculated bytotal slurryweight).The storage time of tartary buckwheat parfait with compound hydrophilic colloids was prolonged by 2 times(14 days)of that without hydrocolloid the at-4 ℃.

Background: Chronic renal failure (CRF) results in significant dyslipidemia and profound changes in lipid metabolism. Polyporus umbellatus (PPU) has been shown to prevent kidney injury and subsequent kidney fibrosis.Methods: Lipidomic analysis was performed to explore the intrarenal profile of lipid metabolites and further investigate the effect of PPU and its main bioactive component, ergone, on disorders of lipid metabolism in rats induced by adenine. Univariate and multivariate statistical analyses were performed for choosing intrarenal differential lipid species in CRF rats and the intervening effect of n-hexane extract of PPU and ergone on CRF rats.Results: Compared with control group, decreased creatinine clearance rate indicated declining kidney function in CRF group. Based on the lipidomics, we identified 65 lipid species that showed significant differences between CRF and control groups. The levels of 12 lipid species, especially fatty acyl lipids including docosahexaenoic acid, docosapentaenoic acid (22n-3), 10,11-Dihydro-12R-hydroxy-leukotriene C4, 3-hydroxydodecanoyl carnitine, eicosapentaenoic acid, hypogeic acid and 3-hydroxypentadecanoic acid had a strong linear correlation with creatinine clearance rate, which indicated these lipid species were associated with impaired renal function. In addition, receiver operating characteristics analysis showed that 12 lipid species had high area under the curve values with high sensitivity and specificity for differentiating CRF group from control group. These changes are related to the perturbation of fatty acyl metabolism. Treatment with PPU and ergone improved the impaired kidney function and mitigated renal fibrosis. Both chemometrics and cluster analyses showed that rats treated by PPU and ergone could be separated from CRF rats by using 12 lipid species. Intriguingly, PPU treatment could restore the levels of 12 lipid species, while treatment with ergone could only reverse the changes of six fatty acids in CRF rats.Conclusion: Altered intrarenal fatty acyl metabolites were implicated in pathogenesis of renal fibrosis. PPU and ergone administration alleviated renal fibrosis and partially improved fatty acyl metabolism. These findings suggest that PPU exerted its renoprotective effect by regulating fatty acyl metabolism as a potential biochemical mechanism. Therefore, these findings indicated that fatty acyl metabolism played an important role in renal fibrosis and could be considered as an effective therapeutic avenue against renal fibrosis.

Background: Increasing evidence suggests a link between the gut microbiome and various diseases including hypertension and chronic kidney disease (CKD). However, studies examining the efficacy of controlling blood pressure and inhibiting the renin–angiotensin system (RAS) in preventing CKD progression are limited. Methods: In the present study, we used 5/6 nephrectomised (NX) and unilateral ureteral obstructed (UUO) rat models and cultured renal tubular epithelial cells and fibroblasts to test whether alisol B 23-acetate (ABA) can attenuate renal fibrogenesis by regulating blood pressure and inhibiting RAS. Results: ABA treatment re-established dysbiosis of the gut microbiome, lowered blood pressure, reduced serum creatinine and proteinuria, suppressed expression of RAS constituents and inhibited the epithelial-to-mesenchymal transition in NX rats. Similarly, ABA treatment inhibited expression of collagen I, fibronectin, vimentin, α-smooth muscle actin and fibroblast-specific protein 1 at both mRNA and protein levels in UUO rats. ABA was also effective in suppressing activation of the transforming growth factor-β (TGF-β)/Smad3 and preserving Smad7 expression in both NX and UUO rats. In vitro experiments demonstrated that ABA treatment inhibited the Wnt/β-catenin and mitochondrial-associated caspase pathways. Conclusion: These data suggest that ABA attenuated renal fibrosis through a mechanism associated with re-establishing dysbiosis of the gut microbiome and regulating blood pressure, and Smad7-mediated inhibition of Smad3 phosphorylation. Thus, we demonstrate ABA as a promising candidate for treatment of CKD by improving the gut microbiome and regulating blood pressure.

Chronic renal failure (CRF) is an irreversible deterioration of the renal functions that characterized by fluid electrolyte unbalance and metabolic-endocrine dysfunctions. Increasing evidence demonstrated that metabolic disturbances, especially dyslipidemia and profound changes in lipid and lipoprotein metabolism were involved in CRF. Identification of lipids associated with impaired kidney functions may play important roles in the understanding of biochemical mechanism and CRF treatment. Ultra-performance liquid chromatography coupled with high-definition mass spectrometry-based lipidomics was performed to identify important differential lipids in adenine-induced CRF rats and investigate the undergoing anti-fibrotic mechanism of Polyporus umbellatus (PPU) and ergone (ERG). Linear correlation analysis was performed between lipid species intensities and creatinine levels in serum. Adenine-induced rats exhibited declining kidney function and renal fibrosis. Compared with control rats, a panel of lipid species was identified in the serum of CRF rats. Our further study demonstrated that eight lipids, including leukotrienes and bile acids, presented a strong linear correlation with serum creatinine levels. In addition, receiver operating characteristics analysis showed that eight lipids exhibited excellent area under the curve for differentiating CRF from control rats, with high sensitivity and specificity. The aberrant changes of clinical biochemistry data and dysregulation of eight lipids could be significantly improved by the administration of PPU and ergone. In conclusion, CRF might be associated with the disturbance of leukotriene metabolism, bile acid metabolism and lysophospholipid metabolism. The levels of eicosanoids and bile acids could be used for indicating kidney function impairment in CRF. PPU could improve renal functions and either fully or partially reversed the levels of eicosanoids and bile acids.

Alisma orientale Juzepzuk (AO) is widely used for various diuretic and nephropathic treatments in traditional Chinese medicines (TCM). In a clinical setting, AO is used as both a lipid-lowering and tubular interstitial fibrosis agent. However, the mechanisms of AO for the treatment of renal interstitial fibrosis and abnormal lipid metabolism are not well-understood. In this study, pharmacological and UPLC-HDMS-based lipidomic approaches were employed to investigate the lipid-lowering and tubular interstitial fibrosis effect of AO on rats with adenine-induced chronic kidney disease (CKD). Rats with CKD showed increased serum levels of creatinine and urea, tubular damage, and tubular interstitial fibrosis. Moreover, multiple lipid species were identified in CKD rats. Among these lipids, polyunsaturated fatty acid, eicosapentaenoic acid, 8,9-epoxyeicosatrienoic acid, and docosahexaenoic acid levels were significantly decreased in CKD rats compared to control rats. In CKD rats, up-regulation of the NF-κB pathway may impair polyunsaturated fatty acid metabolism, causing renal fibrosis. In addition, CKD rats showed significantly decreased diglyceride levels and increased triglyceride levels compared to the control group. Pathway over-representation analysis demonstrated that 30 metabolic pathways were associated with lipid species. AO treatment suppressed up-regulation of inflammation, and partly restored the deregulation of polyunsaturated fatty acids and glycerolipids metabolism. Our results indicated that AO treatment attenuated renal fibrosis by down-regulating inflammation, and mitigating lipid metabolism in CKD rats. In conclusion, this study has identified the therapeutic lipid-lowering and anti-fibrosis effects of AO on CKD.

Ultraperformance liquid chromatography coupled with quadrupole time-of-flight synapt high-definition mass spectrometry metabolomics was used to characterize the urinary metabolic profiling of diet-induced hyperlipidaemia in a rat model. Analysis was done by orthogonal partial least squares discriminant analysis, correlation analysis, heat map analysis, and KEGG pathways analysis. Potential biomarkers were chosen by S-plot and were identified by accurate mass, isotopic pattern, and MS/MS fragments information. Significant differences in fatty acid, amino acid, nucleoside, and bile acid were observed, indicating the perturbations of fatty acid, amino acid, nucleoside, and bile acid metabolisms in diet-induced hyperlipidaemia rats. This study provides further insight into the metabolic profiling across a wide range of biochemical pathways in response to diet-induced hyperlipidaemia.

Multidrug resistance mediated by P-glycoprotein in cancer cells has been a major issue that cripples the efficacy of chemotherapy agents. Aimed for improved efficacy against resistant cancer cells, we designed and synthesized 25 oxindole derivatives based on indirubin by structure-activity relationship analysis. The most potent one was named PH II-7, which was effective against 18 cancer cell lines and 5 resistant cell lines in MTT assay. It also significantly inhibited the resistant xenograft tumor growth in mouse model. In cell cycle assay and apoptosis assay conducted with flow cytometry, PH II-7 induced S phase cell cycle arrest and apoptosis even in resistant cells. Consistently revealed by real-time PCR, it modulates the expression of genes related to the cell cycle and apoptosis in these cells, which may contributes to its efficacy against them. By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells. Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators. Taken together, PH II-7 is a dual-functional compound that features both the cytotoxicity against cancer cells and the inhibitory effect on P-gp mediated drug efflux.

DNA damage checkpoints arrest cell cycle progression to facilitate DNA repair. The ability to survive genotoxic insults depends not only on the initiation of cell cycle checkpoints but also on checkpoint maintenance. While activation of DNA damage checkpoints has been studied extensively, molecular mechanisms involved in sustaining and ultimately inactivating cell cycle checkpoints are largely unknown. Here, we explored feedback mechanisms that control the maintenance and termination of checkpoint function by computationally identifying an evolutionary conserved mitotic phosphorylation network within the DNA damage response. We demonstrate that the non-enzymatic checkpoint adaptor protein 53BP1 is an in vivo target of the cell cycle kinases Cyclin-dependent kinase-1 and Polo-like kinase-1 (Plk1). We show that Plk1 binds 53BP1 during mitosis and that this interaction is required for proper inactivation of the DNA damage checkpoint. 53BP1 mutants that are unable to bind Plk1 fail to restart the cell cycle after ionizing radiation-mediated cell cycle arrest. Importantly, we show that Plk1 also phosphorylates the 53BP1-binding checkpoint kinase Chk2 to inactivate its FHA domain and inhibit its kinase activity in mammalian cells. Thus, a mitotic kinase-mediated negative feedback loop regulates the ATM-Chk2 branch of the DNA damage signaling network by phosphorylating conserved sites in 53BP1 and Chk2 to inactivate checkpoint signaling and control checkpoint duration.

Background: Observational studies form the foundation of Long COVID knowledge, however combining data from Long COVID observational studies has multiple methodological challenges. This umbrella review synthesizes estimates of Long COVID prevalence and risk factors as well as biases and limitations in the primary and review literatures. Methods and findings: A systematic literature search was conducted using multiple electronic databases (PubMed, EMBASE, LitCOVID) from Jan 1, 2019 until June 9, 2023. Eligible studies were systematic reviews including adult populations assessed for at least one Long COVID symptom four weeks or more after SARS-CoV-2 infection. Overall and subgroup prevalence and risk factors as well as risk of bias (ROB) assessments were extracted and descriptively analyzed. The protocol was registered with PROSPERO (CRD42023434323). Fourteen reviews of 5–196 primary studies were included: 8 reported on Long COVID prevalence, 5 on risk/protective factors, and 1 on both. Prevalence of at least 1 Long COVID symptom ranged from 21% (IQR: 8.9%-35%) to 74.5% (95% CI: 55.6%-78.0%). Risk factor reviews found significant associations between vaccination status, sex, acute COVID-19 severity, and comorbidities. Both prevalence and risk factor reviews frequently identified selection and ascertainment biases. Using the AMSTAR 2 criteria, the quality of included reviews, particularly the prevalence reviews, were concerning for the adequacy of ROB assessments and justifications for conducting meta-analysis. Conclusion: A high level of heterogeneity render the interpretation of pooled prevalence estimates of Long COVID challenging, further hampered by the lack of robust critical appraisals in the included reviews. Risk factor reviews were of higher quality overall and suggested consistent associations between Long COVID risk and patient characteristics. [ABSTRACT FROM AUTHOR]

Face reenactment technology is widely applied in various applications. However, the reconstruction effects of existing methods are often not quite realistic enough. Thus, this paper proposes a progressive face reenactment method. First, to make full use of the key information, we propose adaptive convolution and instance normalization to encode the key information into all learnable parameters in the network, including the weights of the convolution kernels and the means and variances in the normalization layer. Second, we present continuous transitive facial expression generation according to all the weights of the network generated by the key points, resulting in the continuous change of the image generated by the network. Third, in contrast to classical convolution, we apply the combination of depth‐ and point‐wise convolutions, which can greatly reduce the number of weights and improve the efficiency of training. Finally, we extend the proposed face reenactment method to the face editing application. Comprehensive experiments demonstrate the effectiveness of the proposed method, which can generate a clearer and more realistic face from any person and is more generic and applicable than other methods. [ABSTRACT FROM AUTHOR]

The pneumonia outbreak caused by Severe Acute Respiratory Syndrome 2 (SARS‐CoV‐2) infection poses a serious threat to people worldwide. Although vaccines have been developed, antiviral drugs are still needed to combat SARS‐CoV‐2 infection due to the high mutability of the virus. SARS‐CoV‐2 main protein (Mpro) is a special cysteine protease that is a key enzyme for SARS‐CoV‐2 replication. It is encoded by peptides and is responsible for processing peptides into functional proteins, making it an important drug target. The paper reviews the structure and peptide‐like inhibitors of SARS‐CoV‐2 Mpro, also the binding mode and structure–activity relationship between the inhibitors and Mpro are introduced in detail. It is hoped that this review can provide ideas and help for the development of anti‐coronavirus drugs such as COVID‐19, and help to develop broad‐spectrum antiviral drug for the treatment of coronavirus diseases as soon as possible. [ABSTRACT FROM AUTHOR]

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme that catalyzes the de novo synthesis of pyrimidine. In recent years, various studies have shown that inhibiting this enzyme can treat autoimmune diseases such as rheumatoid arthritis (RA) and cancer. This study designed and synthesized a series of novel thiazolidone hDHODH inhibitors. Through biological activity evaluation, Compound 14 was found to have high inhibitory activity, with an IC50 value reaching nanomolar level. Preliminary structure–activity relationship studies found that the carboxyl group in R1 and the naphthalene in R2 are key factors in improving activity. Through molecular docking, the binding mode between inhibitors and proteins was elucidated. This study provides an important reference for further optimizing hDHODH inhibitors. [ABSTRACT FROM AUTHOR]