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Abstract Free flap reconstruction for postoperative tissue defects in oral and maxillofacial tumors is a critical component of reconstructive surgery. Identifying risk factors for flap necrosis is essential for improving surgical outcomes and patient quality of life. A retrospective study was conducted on patients who underwent free flap reconstruction between January 2020 and December 2023. Patients were included if they had comprehensive medical records and at least a six-month follow-up. We excluded those with a history of flap necrosis, uncontrolled systemic diseases, non-adherence to postoperative care, or concurrent malignancy treatments. Data on demographics, comorbidities, flap characteristics, and operative details were collected and analyzed using univariate analysis and logistic regression tests. Univariate analysis did not find a significant correlation between flap necrosis and factors such as hyperlipidemia, lymph node metastasis, or flap type. However, diabetes mellitus, oral infections, and albumin levels below 35 g/L were significantly associated with flap necrosis. Multivariate logistic regression showed diabetes mellitus increased the odds of flap necrosis by approximately ninefold, and oral infection increased it by over tenfold. Diabetes mellitus, oral infection, and low albumin levels are significant risk factors for flap necrosis in free flap reconstruction after oral and maxillofacial surgery. Prompt identification and management of these factors are crucial to mitigate the risk of flap necrosis.

Abstract Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Self-assembled monolayers (SAMs) with short organic chains terminated with specific functional groups are attractive for modifying surface properties for a variety of applications, including being a copper diffusion barrier layer on Si wafer. However, SAM formation is process-sensitive and ideal SAM is difficult to obtain, both of which need to carefully deal with before practical use. Herein we developed a system to achieve seamless electroless deposited copper (ELD Cu) film on an amino-terminated silane SAM modified Si wafer with the help of a bifunctional polyvinyl alcohol-capped Pd nanocluster (PVA-Pd) catalyst. The PVA-Pd acts as a catalyst for ELD Cu as well as a healing agent to fix defects of the amino silane SAM. The sheet resistance, cross-sectional morphology analysis and adhesion of ELD Cu on the Si wafer are extensively studied. By controlling the abundancy of PVA in PVA-Pd, the diffusion barrier property of a flawed amino-terminated silane SAM remains reliably effective even after a 500 °C rapid thermal annealing (RTA), evidencing the superior healing function of PVA. The whole thickness of the PVA-Pd/amino-terminated silane SAM before and after RTA is 〜6 nm and 〜2 nm, respectively, which is applicable for advanced microelectronic manufacturing.

Abstract Background Brucellosis is a severe zoonotic disease that is often overlooked, particularly in impoverished countries. Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes. However, there is currently a lack of established indicators or biomarkers for diagnosing these complications. Therefore, this study aimed to investigate potential warning signs of focal complications in human brucellosis, with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients. Methods A multi-center cross-sectional study was conducted in China from December 2019 to August 2021. The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a questionnaire survey and medical record system. The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used for variable screening and model evaluation. Results A total of 880 participants diagnosed with human brucellosis were enrolled. The median age of the patients was 50 years [interquartile range (IQR): 41.5–58.0], and 54.8% had complications. The most common organ system affected by complications was the osteoarticular system (43.1%), with peripheral arthritis (30.0%), spondylitis (16.6%), paravertebral abscess (5.0%), and sacroiliitis (2.7%) being the most prevalent. Complications in other organ systems included the genitourinary system (4.7%), respiratory system (4.7%), and hematologic system (4.6%). Several factors were found to be associated with focal brucellosis. These factors included a long delay in diagnosis [odds ratio (OR) = 3.963, 95% confidence interval (CI) 1.906–8.238 for > 90 days], the presence of underlying disease (OR = 1.675, 95% CI 1.176–2.384), arthralgia (OR = 3.197, 95% CI 1.986–5.148), eye bulging pain (OR = 3.482, 95% CI 1.349–8.988), C-reactive protein (CRP) > 10 mg/L (OR = 1.910, 95% CI 1.310–2.784) and erythrocyte sedimentation rate (ESR) elevation (OR = 1.663, 95% CI 1.145–2.415). The optimal cutoff value in ROC analysis was > 5.4 mg/L for CRP (sensitivity 73.4% and specificity 51.9%) and > 25 mm/h for ESR (sensitivity 47.9% and specificity 71.1%). Conclusions More than 50% of patients with brucellosis experienced complications. Factors such as diagnostic delay, underlying disease, arthralgia, eye pain, and elevated levels of CRP and ESR were identified as significant markers for the development of complications. Therefore, patients presenting with these conditions should be closely monitored for potential complications, regardless of their culture results and standard tube agglutination test titers.

Abstract Objectives Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. Methods C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin–eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. Results In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1β and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. Conclusion This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.

Abstract Renal vein thrombosis (RVT) is a rare vascular complication that occurs after renal transplantation and usually results in irreversible kidney damage and graft loss. We report the case of a patient who underwent right iliac fossa allogeneic kidney transplantation and developed RVT combined with ipsilateral thrombosis from the popliteal to the femoral veins, with extension to the common iliac veins, 4 months after transplantation. Under unfractionated heparin anticoagulation, an Aegisy (Life Tech Scientific Co., Ltd., Shenzhen, China) vena cava filter was placed to prevent pulmonary embolism. Percutaneous mechanical thrombectomy combined with balloon angioplasty was performed to aspirate the thrombus and successfully dilate the narrow venous lumen. The patient’s renal function was restored postoperatively. Ultrasonography showed the allograft and ipsilateral lower extremity deep veins to be fluent and patent. To conclude, in patients with RVT after renal transplantation, percutaneous mechanical thrombectomy in conjunction with balloon angioplasty can be performed with desirable outcomes and no severe adverse effects. This method reduces the risk of bleeding from exposure to systemic intravenous thrombolysis and avoids surgery-associated trauma.

The economic burden of brucellosis care on patients can lead to significant financial strain, despite partial coverage by medical insurance. However, there is limited research on the out-of-pocket costs faced by brucellosis patients. Therefore, our study aimed to investigate the costs and out-of-pocket expenses of brucellosis care, specifically examining the varying socioeconomic status of patients in Xinjiang, China. We collected cost and demographic data from 563 respondents and their hospital bills and employed latent variable analysis to assess socioeconomic status. The majority of patients belonged to the middle and lower socioeconomic status categories (85.97%), and they were primarily farmers and herders (82.77%). The median direct cost per brucellosis episode was USD 688.65, with out-of-pocket expenses amounting to USD 391.44. These costs exceeded both the 2020 Xinjiang and national per capita health expenditures (USD 233.66 and USD 267.21, respectively). Notably, the overall medical reimbursement rate was 48.60%, and for outpatient costs, it was merely 12.82%. Despite higher out-of-pocket costs among high socioeconomic status patients, the percentage of income spent was higher (37.23%) for patients in the lower socioeconomic status group compared to other groups (16.25% and 12.96%). In conclusion, our findings highlight that brucellosis patients are predominantly from the middle and lower socioeconomic status, with high out-of-pocket expenses placing them under significant financial pressure. Moreover, there is notable inequity in economic consequences across different socioeconomic status groups. These results call for policy interventions aimed at reducing brucellosis-related poverty and promoting equitable access to care.

Invasive alien ants (IAAs) are among the most aggressive, competitive, and widespread invasive alien species (IAS) worldwide. Wasmannia auropunctata, the greatest IAAs threat in the Pacific region and listed in “100 of the world’s worst IAS”, has established itself in many countries and on islands worldwide. Wild populations of W. auropunctata were recently reported in southeastern China, representing a tremendous potential threat to China’s agricultural, economic, environmental, public health, and social well-being. Estimating the potential geographical distribution (PGD) of W. auropunctata in China can illustrate areas that may potentially face invasion risk. Therefore, based on the global distribution records of W. auropunctata and bioclimatic variables, we predicted the geographical distribution pattern of W. auropunctata in China under the effects of climate change using an ensemble model (EM). Our findings showed that artificial neural network (ANN), flexible discriminant analysis (FDA), gradient boosting model (GBM), Random Forest (RF) were more accurate than categorical regression tree analysis (CTA), generalized linear model (GLM), maximum entropy model (MaxEnt) and surface distance envelope (SRE). The mean TSS values of ANN, FDA, GBM, and RF were 0.820, 0.810, 0.843, and 0.857, respectively, and the mean AUC values were 0.946, 0.954, 0.968, and 0.979, respectively. The mean TSS and AUC values of EM were 0.882 and 0.972, respectively, indicating that the prediction results with EM were more reliable than those with the single model. The PGD of W. auropunctata in China is mainly located in southern China under current and future climate change. Under climate change, the PGD of W. auropunctata in China will expand to higher-latitude areas. The annual temperature range (bio7) and mean temperature of the warmest quarter (bio10) were the most significant variables affecting the PGD of W. auropunctata in China. The PGD of W. auropunctata in China was mainly attributed to temperature variables, such as the annual temperature range (bio7) and the mean temperature of the warmest quarter (bio10). The populations of W. auropunctata in southern China have broad potential invasion areas. Developing strategies for the early warning, monitoring, prevention, and control of W. auropunctata in southern China requires more attention.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

The adoption of DNA-based assessments for biodiversity monitoring has been on the rise. However, the effectiveness of DNA-based taxonomic assignments heavily relies on the availability and reliability of DNA barcode libraries. There is growing demand for a comprehensive understanding of aquatic biodiversity and the critical role of Chironomidae, specifically Stenochironomus in freshwater ecosystems. Therefore, our objective is to develop a reference barcode library for Stenochironomus in China. From 2016 to 2021, we collected Stenochironomus specimens in diverse Chinese landscapes using malaise traps, light traps, and sweep nets. These specimens were carefully preserved for DNA extraction and barcode sequencing. Our analysis unveiled 36 unique operational taxonomic units from 180 COI barcode sequences through a Neighbor-Joining tree and Automatic Barcode Gap Discovery program, highlighting a significant diversity within the Stenochironomus species. The findings emphasize the constraints of conventional morphological identification methods, especially for species with ambiguous morphologies. It also underscores the effectiveness of DNA barcoding in revealing hidden species diversity, known as cryptic species. Consequently, this study advocates for an integrated taxonomic approach, combining morphological and molecular data, to refine species identification and conservation strategies.

BackgroundThe development of touchscreen-based assessments of upper extremity function could benefit people with multiple sclerosis (MS) by allowing convenient, quantitative assessment of their condition. The Pinching Test forms a part of the Floodlight smartphone app (F. Hoffmann-La Roche Ltd, Basel, Switzerland) for people with MS and was designed to capture upper extremity function. ObjectiveThis study aimed to evaluate the Pinching Test as a tool for remotely assessing upper extremity function in people with MS. MethodsUsing data from the 24-week, prospective feasibility study investigating the Floodlight Proof-of-Concept app for remotely assessing MS, we examined 13 pinching, 11 inertial measurement unit (IMU)–based, and 13 fatigability features of the Pinching Test. We assessed the test-retest reliability using intraclass correlation coefficients [second model, first type; ICC(2,1)], age- and sex-adjusted cross-sectional Spearman rank correlation, and known-groups validity (data aggregation: median [all features], SD [fatigability features]). ResultsWe evaluated data from 67 people with MS (mean Expanded Disability Status Scale [EDSS]: 2.4 [SD 1.4]) and 18 healthy controls. In this cohort of early MS, pinching features were reliable [ICC(2,1)=0.54-0.81]; correlated with standard clinical assessments, including the Nine-Hole Peg Test (9HPT) (|r|=0.26-0.54; 10/13 features), EDSS (|r|=0.25-0.36; 7/13 features), and the arm items of the 29-item Multiple Sclerosis Impact Scale (MSIS-29) (|r|=0.31-0.52; 7/13 features); and differentiated people with MS-Normal from people with MS-Abnormal (area under the curve: 0.68-0.78; 8/13 features). IMU-based features showed similar test-retest reliability [ICC(2,1)=0.47-0.84] but showed little correlations with standard clinical assessments. In contrast, fatigability features (SD aggregation) correlated with 9HPT time (|r|=0.26-0.61; 10/13 features), EDSS (|r|=0.26-0.41; 8/13 features), and MSIS-29 arm items (|r|=0.32-0.46; 7/13 features). ConclusionsThe Pinching Test provides a remote, objective, and granular assessment of upper extremity function in people with MS that can potentially complement standard clinical evaluation. Future studies will validate it in more advanced MS. Trial RegistrationClinicalTrials.gov NCT02952911; https://clinicaltrials.gov/study/NCT02952911

Abstract Background Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. Methods Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. Results The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation. Conclusions The p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.

An efficient dearomative (3 + 2) cycloaddition of para-quinamines and 2-nitrobenzofurans has been developed. This reaction proceeds smoothly under mild conditions and affords a series of benzofuro[3,2-b]indol-3-one derivatives in good to excellent yields (up to 98%) with perfect diastereoselectivities (all cases > 20:1 dr). The scale-up synthesis and versatile derivatizations demonstrate the potential synthetic application of the protocol. A plausible reaction mechanism is also proposed to account for the observed reaction process. This work represents the first instance of the N-triggered dearomative (3 + 2) cycloaddition of 2-nitrobenzofurans.

The role of lifespan-regulating protein expression in specific tissues in C. elegans is murky. Here, the authors provide clarity by inducible degradation of longevity-related proteins, demonstrating that intestinal DAF-2 is a major determinant of lifespan in the worm.

Abstract To find the risk of time thresholds of PROM for infectious diseases of term neonates. A multi-center prospective cohort study including pregnancies with PROM at term with a single fetus were conducted. Time thresholds of the duration from PROM to delivery were examined in 2-h increments to assess the rates of infectious neonatal diseases. 7019 pregnancies were included in the study. Neonatal pneumonia and sepsis were most frequent infectious diseases in neonates born from mother with PROM at term. Rates of early-onset pneumonia varied significantly when comparing length of time of PROM greater than 16 h vs. less than 16 h (for EOP in 3 days of life, adjusted OR 1.864, 95% CI 1.159 ~ 2.997, p = 0.010; for EOP in 7 days of life, adjusted OR 1.704, 95% CI 1.104 ~ 2.628, p = 0.016). Neonates born from mother of whom the length of time from PROM to delivery ≥ 16 h were at a higher risk of acquiring EOP.

Abstract Background Perinatal complications are common burdens for neonates born from mother with pPROM. Physicians and parents sometimes need to make critical decisions about neonatal care with short- and long-term implications on infant’s health and families and it is important to predict severe neonatal outcomes with high accuracy. Methods The study was based on our prospective study on 1001 preterm infants born from mother with pPROM from August 1, 2017, to March 31, 2018 in three hospitals in China. Multivariable logistic regression analysis was applied to build a predicting model incorporating obstetric and neonatal characteristics available within the first day of NICU admission. We used enhanced bootstrap resampling for internal validation. Results One thousand one-hundred pregnancies with PROM at preterm with a single fetus were included in our study. SNO was diagnosed in 180 (17.98%) neonates. On multivariate analysis of the primary cohort, independent factors for SNO were respiratory support on the first day,, surfactant on day 1, and birth weight, which were selected into the nomogram. The model displayed good discrimination with a C-index of 0.838 (95%CI, 0.802–0.874) and good calibration performance. High C-index value of 0.835 could still be reached in the internal validation and the calibration curve showed good agreement. Decision curve analysis showed if the threshold is > 15%, using our model would achieve higher net benefit than model with birthweight as the only one predictor. Conclusion Variables available on the first day in NICU including respiratory support on the first day, the use of surfactant on the first day and birthweight could be used to predict the risk of SNO in infants born from mother with pPROM with good discrimination and calibration performance.

Abstract Digital health technologies enable remote and therefore frequent measurement of motor signs, potentially providing reliable and valid estimates of motor sign severity and progression in Parkinson’s disease (PD). The Roche PD Mobile Application v2 was developed to measure bradykinesia, bradyphrenia and speech, tremor, gait and balance. It comprises 10 smartphone active tests (with ½ tests administered daily), as well as daily passive monitoring via a smartphone and smartwatch. It was studied in 316 early-stage PD participants who performed daily active tests at home then carried a smartphone and wore a smartwatch throughout the day for passive monitoring (study NCT03100149). Here, we report baseline data. Adherence was excellent (96.29%). All pre-specified sensor features exhibited good-to-excellent test–retest reliability (median intraclass correlation coefficient = 0.9), and correlated with corresponding Movement Disorder Society–Unified Parkinson's Disease Rating Scale items (rho: 0.12–0.71). These findings demonstrate the preliminary reliability and validity of remote at-home quantification of motor sign severity with the Roche PD Mobile Application v2 in individuals with early PD.

α-Substituted-7-azaindoline amides and α,β-unsaturated 7-azaindoline amides have emerged as new versatile synthons for various metal-catalyzed and organic-catalyzed asymmetric reactions, which have attracted much attention from chemists. In this review, the progress of research on 7-azaindoline amides in the asymmetric aldol reaction, the Mannich reaction, the conjugate addition, the 1,3-dipole cycloaddition, the Michael/aldol cascade reaction, aminomethylation and the Michael addition-initiated ring-closure reaction is discussed. The α-substituted-7-azaindoline amides, as nucleophiles, are classified according to the type of α-substituted group, whereas the α,β-unsaturated 7-azaindoline amides, as electrophiles, are classified according to the type of reaction.

Exploring the properties of magnetic metal on the semiconductor surface is of great significance for the application of magnetic recording materials. Herein, DFT calculations are carried out to explore the properties of the iron–silicon interface structures (nFe/DASF) formed by depositing n Fe atoms on the reconstructed Si(111)-(7×7) surface (DASF). The stable nFe/DASF structures are studied in the cases of the adsorption and permeation of Fe atoms on the DASF. In both cases, Fe atoms are not very dispersed and prefer binding with Si atoms rather than the adsorbed Fe atoms, because the Fe-Si interaction is stronger than the Fe-Fe interaction. As the n value increases, the average binding energy (Eb_ave) of Fe generally firstly becomes more negative and then becomes less negative, with the presence of a 7Fe wheel as a stable geometry on the upmost surface. The presence of the 7Fe wheel is attributed to the enhanced Fe-Si interaction in this wheel compared to other geometries. CO adsorption occurs at the central Fe site of the 7Fe wheel which is greatly influenced by the surrounding Si atoms but is little influenced by the additional Fe atoms in the interlayer.

Abstract X-linked hypophosphatemic rickets (XLH) is characterized by increased circulating fibroblast growth factor 23 (FGF23) concentration caused by PHEX (NM_000444.5) mutations. Renal tubular resorption of phosphate is impaired, resulting in rickets and impaired bone mineralization. By phenotypic-genetic linkage analysis, two PHEX pathogenic mutations were found in two XLH families: c.433 G > T, p.Glu145* in exon 4 and c.2245 T > C, p.Trp749Arg in exon 22. Immunofluorescence showed that the localization of p.Glu145* and p.Trp749Arg mutant and secretory PHEX (secPHEX) changed, with decreased expression. In a HEK293T cell model co-transfected with PHEX, secPHEX, and FGF23, wild-type PHEX, secPHEX, and FGF23 proteins were distributed in the cell membrane or endoplasmic reticulum, while the mutant was located in the nuclear membrane and cytoplasm. qPCR of p.Glu145* revealed decreased PHEX and secPHEX mRNA expression in cells, with no difference in mRNA expression of p.Trp749Arg. Both mutations decreased intracellular PHEX endopeptidase activity. Western blot analysis showed decrease in mutant and secPHEX protein expression and no FGF23 protein expression in single-transfected PHEX and secPHEX cells. In cells co-transfected with FGF23, PHEX and secPHEX mutation promoted FGF23 expression. Dual-luciferase reporter gene was used to detect the effect of PHEX on FGF23 promoter. The dual-luciferase reporter gene showed that after PHEX overexpression, the activity of mutant firefly luciferase was significantly higher than that of wild type. The regulatory mechanism between PHEX and FGF23 is still unclear, but we found that PHEX is a direct transcriptional inhibitor of FGF23 and affects the expression of FGF23. This study verified the pathogenicity of the two variants and revealed the possible regulatory mechanism between PHEX and FGF23.

BackgroundDevelopment of endovascular interventional techniques gradually replaced traditional open surgery and has become the preferred treatment for renal aneurysms. This study aimed to analyze the clinical characteristics of renal artery aneurysm (RAA) and the safety and efficacy of intravascular interventional treatment.Materials and MethodsWe retrospectively analyzed the clinical characteristics and imaging data of 23 aneurysms in 18 patients with RAA. The technical success rate, complication rate, mortality rate, reintervention rate, and use of embolization materials were evaluated.ResultsIn 18 patients with RAA (age, 32–72 years, average age, 52.2 ± 11.2 years), a total of 23 aneurysms were found (diameter 0.5–5.5 cm, average diameter 2.2 ± 1.4 cm). Among them, 11 cases (61.1%) were discovered accidentally, and the remaining patients were diagnosed due to the following major complaints: four cases (22.2%) presented low back pain, two (11.1%) were due to high blood pressure, and one (5.5%) had low back pain with gross hematuria. A total of 14 aneurysms in 13 patients received endovascular interventional therapy. The technical success rate of 13 patients with renal aneurysms was 100%. Three of the 18 patients were lost to follow-up, and the remaining were followed up for 4–89 months. There was no recurrence of the aneurysm or displacement of the stent or coil.ConclusionEndovascular treatment for RAA has a high success rate, low complication rate, and low reintervention rate. It has the advantage of less trauma and is flexible and more targeted for different types of renal aneurysms.

PurposeElimination communication (EC) is considered to be a milestone in a child's development. Nowadays, a trend toward an older age at EC initiation has been observed globally, probably due to the convenience of disposable diaper use in daily life. The study aimed to identify potential risk factors for disposable diaper dependence (DDD) and evaluate whether an early/proper EC can reduce the risk of DDD among children in China.MethodsA cross-sectional study was performed on 13,500 children in mainland China from October 2019 to March 2020. An anonymous questionnaire was used to collect information including the sociodemographic characteristics, details about DDD and EC, and the effect of DDD on the quality of life of children. Data were analyzed by SPSS and R software.ResultsThe overall prevalence of DDD was 4.17% (4.31% in boys; 4.02% in girls) and decreased with age, from 8.71% at 2 years to 0.73% at 6 years (χ2trend = 210.392, P 0.7) indicated satisfactory discriminative ability of the nomogram. The calibration diagrams showed favorable consistency between the prediction of the nomogram and actual observations.ConclusionOur findings indicate the joint contribution of age, location, caregivers’ education level and EC to DDD in Chinese preschool-aged children. Timely cessation of the use of disposable diapers and early/proper EC may help to reduce the risk of DDD in children.

BackgroundSuperior mesenteric vein (SMV) thrombosis is a rare intestinal ischemic disease. The clinical manifestations of patients differ, and most experience gastrointestinal symptoms.Case summaryA 45-year-old female patient presented with persistent abdominal pain and abnormal vaginal bleeding for 7 days. A physical examination revealed significant abdominal tenderness with positive rebound tenderness. A laboratory examination revealed a white blood cell count of 27 × 109/l, hemoglobin level of 52 g/L, and D-dimer of 4.54 mg/l. Enhanced computed tomography revealed a thickening and swelling of the jejunum and ileum in the left upper quadrant and portal vein. Filling defects in the main lumen and branch lumen suggested the possibility of portal vein and superior mesenteric vein thrombosis. Symptoms improved after treatment with low-molecular-weight heparin and warfarin. One month later, the patient developed occasional dull pain in the left lower quadrant, with long strips of discharge. An electronic colonoscopy revealed avascular necrosis and tissue exfoliation of the intestinal mucosa. After the continuation of warfarin therapy, the abdominal pain resolved. Five months later, the patient experienced recurrent abdominal pain and vomiting. A physical examination revealed a blood pressure of 75/49 mm Hg. An incomplete ileus with the portal and superior mesenteric vein thrombosis was diagnosed, partial jejunectomy and gastrointestinal bypass anastomosis were performed, and warfarin was continued postoperatively.ConclusionThe intestinal mucosal shedding observed, in this case, was caused by SMV thrombosis, which enriched the clinical manifestations of the disease and provided a new basis for the clinical diagnosis of SMV thrombosis.

Azadirachta consists of 2 species and 1 variety indigenous to the tropical areas of the Indo-Malayan region. They are evergreen trees for multi-purpose utilization featured by containing azadirachtin. The complete chloroplast (cp) genome of Azadirachta indica, A. indica var. siamensis and Azadirachta excelsa were reported in this study, which was 160,876 bp, 160,477 bp, and 160,361 bp in length respectively. The whole cp genomes encode 131 genes (37 tRNA genes, 8 rRNA genes, and 86 protein-coding genes) in both A. indica and A. excelsa, while A. indica var. siamensis do not have the rrn4.5S gene in the inverted repeat regions. The phylogenetic analysis indicated that A. indica var. siamensis and A. exselsa were closely related and A. indica was separated from these two species, which suggested that A. siamensis could be a species rather than a variety.

Tobacco smoking is considered to be one of the main risk factors in the development of chronic pain. Long-term chronic exposure to nicotine and other forms of tobacco have been shown to be associated with an increased incidence of pain. Studies have shown that acupuncture can help smokers to reduce their desire to smoke, reduce their withdrawal symptoms, and avoid a relapse after treatment. However, little has been reported about the effects of acupuncture on pain sensitivity caused by long-term smoking. Models of hyperalgesia were established in rats exposed to nicotine for 6 weeks. After 6 weeks of continuous nicotine exposure, electroacupuncture at bilateral acupoints Zusanli (ST36) and Taichong (LR3) was performed 20 minutes per day for 6 days at a continuous wave with a frequency of 2 Hz and a stimulus intensity of 1 mA. The results revealed that electroacupuncture treatment increased the mechanical response threshold of hind paw of nicotine-dependent rats with hyperalgesia and up-regulated the protein expression of pain-related factors μ-opioid receptor, β-endorphin and glutamic acid decarboxylase 65 in the spinal cord and midbrain periaqueductal gray and the protein expression of glutamic acid decarboxylase 67 in the spinal cord. These findings suggest that electroacupuncture treatment has positive analgesic effects on pain sensitivity caused by long-term chronic nicotine exposure. One possible mechanism for the improved analgesia is that electroacupuncture increases the expression of pain-related factors in the spinal cord and midbrain periaqueductal gray. This study was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Miami (#18-167) on December 12, 2018.

In this research, a metal-free diastereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and cyclopentene-1,3-diones which can efficiently lead to the desymmetrization of cyclopentene-1,3-diones is developed. With the developed protocol, a series of tetracyclic spirooxindoles containing pyrrolidine and cyclopentane subunits can be smoothly obtained with good results (up to 99% yield and 91:9 dr). Furthermore, the methodology can be extended to trifluoromethyl-substituted iminomalonate, and the corresponding formal [3+2] cycloaddition reaction affords bicyclic heterocycles containing fused pyrrolidine and cyclopentane moieties in moderate yields with >20:1 dr. The synthetic potential of the methodology is demonstrated by the scale-up experiment and by versatile transformations of the products.

An unprecedented N-alkylation of 3-nitroindoles with para-quinone methides was developed for the first time. Using potassium carbonate as the base, a wide range of structurally diverse N-diarylmethylindole derivatives were obtained with moderated to good yields via the protection group migration/aza-1,6-Michael addition sequences. The reaction process was also demonstrated by control experiments. Different from the previous advances where 3-nitrodoles served as electrophiles trapping by various nucleophiles, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs for construction of various N-diarylmethylindoles.

BackgroundNeutrophil extracellular traps (NETs) are web-like structures formed by neutrophils, and their main function is antimicrobial defense. Moreover, NETs have numerous roles in the pathogenesis and progression of cancers. However, the potential roles of NET-related genes in renal cell carcinoma remain unclear. In this study, we comprehensively investigated the NETs patterns and their relationships with tumor environment (TME), clinicopathological features, prognosis, and prediction of therapeutic benefits in the clear cell renal cell carcinoma (ccRCC) cohort.MethodsWe obtained the gene expression profiles, clinical characteristics, and somatic mutations of patients with ccRCC from The Cancer Genome Atlas database (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress datasets, respectively. ConsensusCluster was performed to identify the NET clusters. The tumor environment scores were evaluated by the “ESTIMATE,” “CIBERSORT,” and ssGSEA methods. The differential analysis was performed by the “limma” R package. The NET-scores were constructed based on the differentially expressed genes (DEGs) among the three cluster patterns using the ssGSEA method. The roles of NET scores in the prediction of immunotherapy were investigated by Immunophenoscores (TCIA database) and validated in two independent cohorts (GSE135222 and IMvigor210). The prediction of targeted drug benefits was implemented using the “pRRophetic” and Gene Set Cancer Analysis (GSCA) datasets. Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to identify the reliability of the core genes’ expression in kidney cancer cells.ResultsThree NET-related clusters were identified in the ccRCC cohort. The patients in Cluster A had more metabolism-associated pathways and better overall survival outcomes, whereas the patients in Cluster C had more immune-related pathways, a higher immune score, and a poorer prognosis than those in Cluster B. Based on the DEGs among different subtypes, patients with ccRCC were divided into two gene clusters. These gene clusters demonstrated significantly different immune statuses and clinical features. The NET scores were calculated based on the ten core genes by the Gene Set Variation Analysis (GSVA) package and then divided ccRCC patients into two risk groups. We observed that high NET scores were associated with favorable survival outcomes, which were validated in the E-MTAB-1980 dataset. Moreover, the NET scores were significantly associated with immune cell infiltration, targeted drug response, and immunotherapy benefits. Subsequently, we explored the expression profiles, methylation, mutation, and survival prediction of the 10 core genes in TCGA-KIRC. Though all of them were associated with survival information, only four out of the 10 core genes were differentially expressed genes in tumor samples compared to normal tissues. Finally, RT-PCR showed that MAP7, SLC16A12, and SLC27A2 decreased, while SLC3A1 increased, in cancer cells.ConclusionNETs play significant roles in the tumor immune microenvironment of ccRCC. Identifying NET clusters and scores could enhance our understanding of the heterogeneity of ccRCC, thus providing novel insights for precise individual treatment.

Background Acute heart failure is the most frequent cause of unplanned hospital admission in elderly patients. Various biomarkers have been evaluated to better assess the status of these patients and prevent decompensation. Recently, voice has been suggested as a cost‐effective and noninvasive way to monitor disease progression. This study evaluates speech and pause alterations in patients with acute decompensated and stable heart failure. Specifically, we aim to identify a vocal biomarker that could be used to monitor patients with heart failure and to prevent decompensation. Methods and Results Speech and pause patterns were evaluated in 68 patients with acute and 36 patients with stable heart failure. Voice recordings were performed using a web‐browser based application that consisted of 5 tasks. Speech and pause patterns were automatically extracted and compared between acute and stable patients and with clinical markers. Compared with stable patients, pause ratio was up to 14.9% increased in patients with acute heart failure. This increase was largely independent of sex, age, and ejection fraction and persisted in patients with lower degrees of edema or dyspnea. Furthermore, pause ratio was positively correlated with NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) after controlling for acute versus stable heart failure. Collectively, our findings indicate that the pause ratio could be useful in identifying acute heart failure, particularly in patients who do not display traditional indicators of decompensation. Conclusions Speech and pause patterns are altered in patients with acute heart failure. Particularly, we identified pause ratio as an easily interpretable vocal biomarker to support the monitoring of heart failure decompensation.

Abstract Background Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have shown that heterozygous protein S (PROS1) mutations increase the risk of thrombosis. More than 300 PROS1 mutations have been identified; among them, only a small number of mutations have been reported its possible mechanism to reduce plasma protein S (PS) levels. However, whether PROS1 mutations affect protein structure and why it can induce PSD remains unknown. Methods The clinical phenotypes of the members of a family with thrombosis were collected. Their PS activity was measured using the coagulation method, whereas their protein C and antithrombin III activities were measured using methods such as the chromogenic substrate method. The proband and her parents were screened for the responsible mutation using second-generation whole exon sequencing, and the members of the family were verified for suspected mutations using Sanger sequencing. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to detect the mRNA and protein expression of PROS1. Results In this family, the proband with venous thrombosis of both lower extremities, the proband’s mother with pulmonary embolism and venous thrombosis of both lower extremities, and the proband’s younger brother had significantly lower PS activity and carried a PROS1 c. 1820 T > C:p.Leu607Ser heterozygous mutation (NM_000313.3). However, no such mutations were found in family members with normal PS activity. The PS expression in the cell lysate and supernatant of the Leu607Ser mutant cells decreased, while mRNA expression increased. Immunofluorescence localization showed that there was no significant difference in protein localization before and after mutation. Conclusions The analysis of family phenotype, gene association, and cell function tests suggest that the PROS1 Leu607Ser heterozygous mutation may be a pathogenic mutation. Serine substitution causes structural instability of the entire protein. These data indicate that impaired PS translation and synthesis or possible secretion impairment is the main pathogenesis of this family with hereditary PSD and thrombophilia.

[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent isolated yields. This reaction concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins for accessing highly functionalized polyheterocyclic compounds. A gram-scale experiment was also carried out to verify the practicability of the methodology.

Despite highly effective vaccines, Marek’s disease (MD) causes great economic loss to the poultry industry annually, largely due to the continuous emergence of new MD virus (MDV) strains. To explore the pathogenic characteristics of newly emerged MDV strains, we selected two strains (AH/1807 and DH/18) with clinically different pathotypes. We studied each strain’s infection process and pathogenicity and observed differences in immunosuppression and vaccine resistance. Specific pathogen-free chickens, unvaccinated or vaccinated with CVI988, were challenged with AH/1807 or DH/18. Both infections induced MD damage; however, differences were observed in terms of mortality (AH/1807: 77.8%, DH/18: 50%) and tumor rates (AH/1807: 50%, DH/18: 33.3%). The immune protection indices of the vaccine also differed (AH/1807: 94.1, DH/18: 61.1). Additionally, while both strains caused interferon-β and interferon-γ expression to decline, DH/18 infection caused stronger immunosuppression than AH/1807. This inhibition persisted even after vaccination, leading to increased replication of DH/18 that ultimately broke through vaccine immune protection. These results indicate that both strains have different characteristics, and that strains such as DH/18, which cause weaker pathogenic damage but can break through vaccine immune protection, require further attention. Our findings increase the understanding of the differences between epidemic strains and factors underlying MD vaccination failure in China.

Infectious bursal disease (IBD) is caused by infectious bursal disease virus (IBDV), which has a genome consisting of two segments of double-stranded linear RNA. IBDVs have been traditionally divided into four phenotypes based on their pathogenicity and antigenicity, including classic, variant, very virulent, and attenuated IBDV. With the emergences of divergent molecular characteristics of novel strains produced by continuous mutations and recombination, it is increasingly difficult to define new IBDV strains using the traditional descriptive classification method. The most common classification scheme for IBDV with segmented genome is based solely on segment A, while the significance of segment B has been largely neglected. In this study, an improved scheme for IBDV genotype classification based on the molecular characteristics of both VP2 (a viral capsid protein encoded by segment A) and VP1 (an RNA-dependent RNA polymerase protein encoded by segment B) was proposed for the first time. In this scheme, IBDV was classified into nine genogroups of A and five genogroups of B, respectively; the genogroup A2 was further divided into four lineages. The commonly used phenotypic classifications of classic, variant, very virulent, and attenuated IBDVs correspond to the A1B1, A2B1, A3B2, and A8B1 genotypes of the proposed classification scheme. The novel variant IBDVs including the strains identified in this study were classified as belonging to genotype A2dB1. The flexibility and versatility of this improved classification scheme will allow the unambiguous identification of existing and emerging IBDV strains, which will greatly facilitate molecular epidemiology studies of IBDV.

BackgroundRemote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. ObjectiveThe aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. MethodsThis analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts—the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. ResultsParticipants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). ConclusionsThese results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.

BackgroundThe analgesic effect produced by the intra-arterial injection of lidocaine in patients undergoing uterine artery embolization has been proven to be safe and effective. Nevertheless, a significant degree of pain is typically experienced after the operation, and pain management is crucial. Methylprednisolone, which provides an anti-inflammatory effect, is widely used in the treatment of several diseases. To date, methylprednisolone has not been used after uterine artery embolization.MethodsA total of 131 patients with uterine leiomyoma were retrospectively enrolled. Forty-five patients (control group) were treated with embolized microspheres for bilateral uterine artery embolization. Fifty (study group) and 36 (lidocaine group) patients were administered lidocaine mixed with embolized microspheres during embolization, and in addition, the study group was administered methylprednisolone. Completed pain scales at different time points during surgery were obtained from patients undergoing uterine artery embolization. Efficacy against pain was evaluated by comparing the pain score, inflammatory index, and use of sufentanil within 24 h followed by a Kruskal-Wallis Test and a least significant difference post-hoc analysis.ResultsThe postoperative pain scores at 1, 4, and 7 h after uterine artery embolization in the study group (3.08 ± 2.09, 2.46 ± 1.93, and 2.38 ± 1.85, respectively) were significantly lower than those in the control group (4.84 ± 2.36, 4.16 ± 1.87, and 3.56 ± 1.93, respectively) and the lidocaine group (3.50 ± 2.10, 3.30 ± 1.88, and 3.28 ± 1.89, respectively). At the first 24 h after embolization, the total usage of sufentanil in the study group (31.4 ± 4.16) was significantly lower than those in the control group (45.7 ± 6.51) and the lidocaine group (38.3 ± 6.25). At 1 and 4 h, the pain scores of the lidocaine group were significantly lower than those of the control group. In addition, at the first 24 h after embolization, the total usage of sufentanil in the lidocaine group was significantly lower than that in the control group.ConclusionLidocaine in combination with methylprednisolone can significantly alleviate pain and reduce the usage of sufentanil after bilateral uterine artery embolization. Thus, methylprednisolone is a recommended addition to the therapeutic regimen after embolization.

Sitosterolemia (OMIM ##210250), also known as phytosterolemia, is a rare autosomal recessive disorder caused by mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or member 8 (ABCG8) genes. This leads to abnormal functions of the transporter sterolin-1 protein encoded by ABCG5 and sterolin-2 protein encoded by ABCG8, respectively, which can hinder the formation of stable ABCG5/G8 heterodimers, decreasing its ability to transport sterols. As a result, phytosterols in tissue or plasma are significantly increased, leading to early onset atherosclerosis-related diseases and xanthelasma of tendons and skin. In this study, whole exome sequencing was performed on a Chinese Han proband with sitosterolemia to capture the target gene and screen for suspected pathogenic mutations. Sanger sequencing of the family members was performed to verify the relationship between family genetics and phenotypes. The structural and functional changes in the transporter sterolin-1 protein after the responsible mutation were predicted using bioinformatics analysis. A novel compound heterozygous mutation in the ABCG5 gene (NM_022436) was identified in a proband with sitosterolemia, one of which was inherited from the father: c.296T >G (p.M99R), and one from the mother: c.−76 C >T. SIFT, Polyphen2, and Mutation Taster software predicted that p.M99R may be the responsible variant and a novel variant. RNAFold software predicts that c.−76 C >T may affect the transcriptional information or the binding of RNA binding proteins by regulating the structure of RNA, and ultimately affect gene transcription or RNA stability and translation. Swiss model software predicts that the amino acid sequence around p.M99R is highly conserved, and p.M99R leads to instability of the tertiary structure of the ABCG5/ABCG8 heterodimer. GPS 5.0 predicted that M99R affects the phosphorylation of nearby amino acid sequences, and DUET and VarSite software predicted that M99R affects the stability of sterolin-1 and cause disease. The p.M99R and c.−76 C >T mutations led to the formation of unstable heterodimers, which disturbed sterol absorption and excretion in vivo. The compound heterozygous variants c.296 T >G (p.m99r) and C.−76 C >T on exon 3 of ABCG5 in this family may be the molecular genetic basis of sitosterolemia.

Abstract Background Considering the widespread of coronavirus disease 2019 (COVID-19) pandemic in the world, it is important to understand the spatiotemporal development of the pandemic. In this study, we aimed to visualize time-associated alterations of COVID-19 in the context of continents and countries. Methods Using COVID-19 case and death data from February to December 2020 offered by Johns Hopkins University, we generated time-associated balloon charts with multiple epidemiological indicators including crude case fatality rate (CFR), morbidity, mortality and the total number of cases, to compare the progression of the pandemic within a specific period across regions and countries, integrating seven related dimensions together. The area chart is used to supplement the display of the balloon chart in daily new COVID-19 case changes in UN geographic regions over time. Javascript and Vega-Lite were chosen for programming and mapping COVID-19 data in browsers for visualization. Results From February 1st to December 20th 2020, the COVID-19 pandemic spread across UN subregions in the chronological order. It was first reported in East Asia, and then became noticeable in Europe (South, West and North), North America, East Europe and West Asia, Central and South America, Southern Africa, Caribbean, South Asia, North Africa, Southeast Asia and Oceania, causing several waves of epidemics in different regions. Since October, the balloons of Europe, North America and West Asia have been rising rapidly, reaching a dramatically high morbidity level ranging from 200 to 500/10 000 by December, suggesting an emerging winter wave of COVID-19 which was much bigger than the previous ones. By late December 2020, some European and American countries displayed a leading mortality as high as or over 100/100 000, represented by Belgium, Czechia, Spain, France, Italy, UK, Hungary, Bulgaria, Peru, USA, Argentina, Brazil, Chile and Mexico. The mortality of Iran was the highest in Asia (over 60/100 000), and that of South Africa topped in Africa (40/100 000). In the last 15 days, the CFRs of most countries were at low levels of less than 5%, while Mexico had exceptional high CFR close to 10%. Conclusions We creatively used visualization integrating 7-dimensional epidemiologic and spatiotemporal indicators to assess the progression of COVID-19 pandemic in terms of transmissibility and severity. Such methodology allows public health workers and policy makers to understand the epidemics comparatively and flexibly.

Heteroarene 1, n-zwitterions are powerful and versatile building blocks in the construction of heterocycles and have received increasing attention in recent years. In particular, pyridinium and quinolinium 1,4-zwitterions have been widely studied and used in a variety of cyclization reactions due to their air stability, ease of use, and high efficiency. Sulfur- and nitrogen-based pyridinium and quinolinium 1,4-zwitterions, types of emerging heteroatom-containing synthons, have attracted much attention from chemists. These 1,4-zwitterions, which contain multiple reaction sites, have been successfully used in the synthesis of three- to eight-membered cyclic compounds over the last decade. In this review, we present the exciting progress made in the field of cyclization reactions of sulfur- and nitrogen-based pyridinium and quinolinium 1,4-zwitterions. Moreover, the mechanistic insights, the transition states, some synthetic applications, and the challenges and opportunities are also discussed. We hope to provide an overview for synthetic chemists who are interested in the heterocycle synthesis from cyclization reaction with pyridinium and quinolinium 1,4-zwitterions pyridinium and quinolinium 1,4-zwitterions.

Catalytic asymmetric dearomative [3+2] cycloaddition of α-imino γ-lactones with either 3-nitroindoles or 2-nitrobenzofurans by using a chiral copper complex as the catalyst was developed. A wide range of structurally diverse polyheterocyclic compounds containing spirocyclic-fused butyrolactone-pyrrolidine-indoline and butyrolactone–pyrrolidine–dihydrobenzofuran skeletons could be smoothly obtained with excellent results (>99:1 dr and 98% ee). The potential synthetic applications of this methodology were also demonstrated by the scale-up experiment and by the diverse transformations of one product. This method is characterized by high asymmetric induction, wide functional group tolerance and scalability, and attractive product diversification.

Abstract Background The northeastern part of the Qinghai-Tibet Plateau (QTP) presents a high number of plateau loach species. As one of the three major groups of fishes distributed on the QTP, plateau loach has high ecological value. However, the taxonomy and systematics of these fish are still controversial, and a large number of new species have been reported. The reason for this phenomenon is that the degree of morphological variation is low, the phylogenetic information provided by morphological and anatomical features used for species identification is relatively poor, and many cryptic species are observed. Based on the high-density sampling points from the biodiversity hotspots surveyed, this study aims to evaluate the biodiversity of plateau loach in the northeastern part of the QTP and reveal the hidden diversity by comparing morphological species with molecular operational taxonomic units (MOTUs). Results After careful identification and comparison of the morphology and DNA barcoding of 1630 specimens, 22 species were identified, with 20 considered valid local species and two identified as new species that had not been previously described. Based on the combination of morphological and molecular methods, a total of 24 native species were found, two of which were cryptic species: Triplophysa robusta sp1 and Triplophysa minxianensis sp1. Fourteen of the 24 species form clusters of barcodes that allow them to be reliably identified. The remaining cases involved 10 closely related species, including rapidly differentiated species and species that seemed to have experienced incomplete lineage sorting or showed introgressions. Conclusions The results highlight the need to combine traditional taxonomies with molecular methods to correctly identify species, especially closely related species, such as the plateau loach. This study provides a basis for protecting the biodiversity of plateau loach.

Gestational diabetes mellitus (GDM) refers to different degrees of glucose tolerance abnormalities that occur during pregnancy or are discovered for the first time, which can have a serious impact on the mother and the offspring. The screening of GDM mainly relies on the oral glucose tolerance test (OGTT) at 24–28 weeks of gestation. The early diagnosis and intervention of GDM can greatly improve adverse pregnancy outcomes. However, molecular markers for early prediction and diagnosis of GDM are currently lacking. Therefore, looking for GDM-specific early diagnostic markers has important clinical significance for the prevention and treatment of GDM and the management of subsequent maternal health. Circular RNA (circRNA) is a new type of non-coding RNA. Recent studies have found that circRNAs were involved in the occurrence and development of malignant tumors, metabolic diseases, cardiovascular and cerebrovascular diseases, etc., and could be used as the molecular marker for early diagnosis. Our previous research showed that circRNAs are differentially expressed in serum of GDM pregnant women in the second and third trimester, placental tissues during cesarean delivery, and cord blood. However, the mechanism of circular RNA in GDM still remains unclear. This article focuses on related circRNAs involved in insulin resistance and β-cell dysfunction, speculating on the possible role of circRNAs in the pathophysiology of GDM under the current research context, and has the potential to serve as early molecular markers for the diagnosis of GDM.

Infectious bursal disease (IBD), caused by IBD virus (IBDV), is one of the most devastating and immunosuppressive diseases of the poultry and has been a constraint on the sustainable poultry production around the globe including Pakistan. While the disease is threatening the poultry industry, the nature of predominant strains of IBDV in Pakistan remained ill-defined. In this study, an epidemiology survey was conducted in the main chicken-farming regions of Pakistan. The batch of Pakistan IBDVs genes simultaneously covering both VP1 and VP2 were amplified, sequenced, and analyzed. The unique segment-reassortant IBDVs (vv-A/Uniq-B), carrying segment A from vvIBDV and segment B from one unique ancestor, were identified as one important type of circulating strains in Pakistan. The data also discovered the characteristic molecular features of Pakistan IBDVs, which will contribute to scientific vaccine selection and effective prevention of the disease.

Abstract. Objective:. This study was aimed to determine the changes in CXCR2 expression in preeclampsia placenta and its correlation with clinical parameters. Methods:. Sixty-four gravidas ranging in age from 25 to 42 years referred to the obstetrics unit of the West China Second University Hospital from April 2012 to October 2012 were recruited in this case-control study; women were diagnosed and divided into early-onset preeclampsia group (n = 22), late-onset preeclampsia group (n = 22), and healthy pregnancy group (n = 20). After immunolocalized in human placenta, the levels of CXCR2 protein and messenger ribonucleic acid (mRNA) were detected by enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction. Correlations between placental CXCR2 protein expression with systolic blood pressure and lactate dehydrogenase (LDH) in early-onset preeclampsia were examined using Pearson or Spearman's correlation coefficients. Results:. Placental CXCR2 protein and mRNA expression in early-onset preeclampsia was significantly lower than it was in placentas from healthy pregnancy pregnancies and late-onset preeclampsia (P

An increasing ecological phase shift from coral-dominated reefs to macroalgae-dominated reefs as a result of anthropogenic impacts, such as eutrophication, sedimentation, and overfishing, has been observed in many reef systems around the world. Ocean warming is a universal threat to both corals and macroalgae, which may alter the outcome of competition between them. Therefore, in order to explore the effects of indirect and direct exposure to macroalgae on the physiological, biochemical, and genetic expression of corals at elevated temperature, the coral Acropora hyacinthus and highly invasive green algae Caulerpa taxifolia were chosen. Physiologically, the results exhibited that, between the control and direct contact treatments, the density and chlorophyll a content of zooxanthella decreased by 53.1% and 71.2%, respectively, when the coral indirectly contacted with the algae at an ambient temperature (27 °C). Moreover, the enzyme activities of superoxide dismutase (SOD) and catalase (CAT) in coral tissue were enhanced by interacting with algae. After an increase of 3 °C, the density and chlorophyll a content of the zooxanthella reduced by 84.4% and 93.8%, respectively, whereas the enzyme activities of SOD and CAT increased 2.3- and 3.1-fold. However, only the zooxanthellae density and pigment content decreased when Caulerpa taxifolia was co-cultured with Acropora hyacinthus at 30 °C. Molecularly, different from the control group, the differentially expressed genes (DEGs) such as Rab family, ATG family, and Casp7 genes were significantly enriched in the endocytosis, autophagy, and apoptosis pathways, regardless of whether Acropora hyacinthus was directly or indirectly exposed to Caulerpa taxifolia at 27 °C. Under thermal stress without algae interaction, the DEGs were significantly enriched in the microbial immune signal transduction pathways, such as the Toll-like receptor signaling pathway and TNF signaling pathway, while multiple cellular immunity (IFI47, TRAF family) and oxidative stress (CAT, SODC, HSP70) genes were upregulated. Inversely, compared with corals without interaction with algae at 30 °C, the DEGs of the corals that interacted with Caulerpa taxifolia at 30 °C were remarkably enriched in apoptosis and the NOD-like receptor signaling pathway, including the transcription factors such as the Casp family and TRAF family. In conclusion, the density and chlorophyll a content of zooxanthella maintained a fading tendency induced by the macroalgae at ambient temperatures. The oxidative stress and immune response levels of the coral was elevated at 30 °C, but the macroalgae alleviated the negative effects triggered by thermal stress.

Phalaenopsis stobartiana Reichenbach f. 1877 is mainly distributed in Yunnan province of China and has a high ornamental and breeding value. Here, we reported the chloroplast genome of P. stobartiana. The length of the chloroplast genome was 145,900 bp, encoding 120 genes. The average GC content was 36.8%. Phylogenetic analysis revealed that P. stobartiana and P. wilsonii are closely related. The chloroplast genome could be used for further phylogenetic research, and provide molecular data for future genetic protection and breeding programs.

Abstract Background NPL4 is an important cofactor of the valosin-containing protein (VCP)–NPL4–UFD1 complex. The VCP–NPL4–UFD1 has been considered as a ubiquitin proteasome system (UPS) regulator and response to protein degradation. While NPL4 plays important roles in various diseases, little is known about its functions in bladder cancer (BC). Methods MTT assays and colony forming test were performed to evaluate cell proliferation ability and Western blotting was used to detect protein expression. Cyclin D1 mRNA expression was detected using qRT-PCR, and coimmunoprecipitation (CoIP) was used to detect protein–protein interactions. Results NPL4 was upregulated in BC tissue and correlated with poor prognosis. Upregulation of NPL4 promoted cell proliferation while suppression of NPL4 reduced BC cell proliferation. Upregulation of NPL4 led to overexpression of cyclin D1 by enhancing its mRNA stability. Moreover, NPL4 was found to bind directly to DXO and induce its degradation. DXO was downregulated in BC tissue and regulated BC cell proliferation by destabilizing cyclin D1 mRNA. DXO-mediated NPL4 regulated BC cell proliferation by stabilizing cyclin D1 expression. Conclusions The NPL4/DXO/cyclin D1 axis exert crucial role in BC cell growth and is associated with prognosis and may represent a potential therapeutic target for BC.

AIM: To analyze the influencing factors of visual acuity in cataract patients with high myopia after phacoemulsification combined with IOL implantation, and to explore the correlation between the integrity of ellipsoidal zone and postoperative visual acuity.METHODS: Retrospective case review. A total of 96(106 eyes)cataract with high myopia patients were enrolled into this study. All patients received phacoemulsification and IOL implantation after preoperative examination. After 6mo of follow-up, the changes of BCVA were compared between preoperative and postoperative 1wk, 1mo, 3mo and 6mo. Compared the integrity of ellipsoidal zone with different ranges of BCVA before and after 6mo surgery. At the same time, the relevant influencing factors affecting postoperative BCVA were analyzed.RESULTS: The median BCVA of preoperative and postoperative 1wk, 1mo, 3mo and 6mo eyes were 0.80(0.50, 1.70), 0.51(0.28, 1.30), 0.50(0.09, 0.60), 0.30(0.22, 0.90)and 0.30(0.22, 0.70), respectively, there were significant differences(PPPP>0.05).CONCLUSION: The visual acuity improved after phacoemulsification combined with IOL implantation for cataract with high myopia. Postoperative visual acuity was correlated with the integrity of ellipsoidal zone and preoperative visual acuity.

The aim of this study was to improve the quality of semen samples by using a novel double-tube (DT) method. The DT method was developed to select sperm and compared with traditional swim-up (SU) technique for 31 semen samples. Sperm DNA integrity were tested with TUNEL and SCSA. Content of antisperm antibodies (ASA) in the semen was measured by ELISA and MAR. Levels of the caspase-3 in the sperm were assessed by western blotting. After SU and DT, 15 couples and 16 couples were underwent IVF-ET. The number of RCDs, the percentage of SDF and DFI, ASA and the level of caspase-3 were significantly decreased after DT and SU ( p = .001 and p < .001). When the DT and SU compared, there were significant changes in the number of RCD, the percentage of SDF and DFI, ASA and the level of caspase-3 ( p < 0.05-0.001). There was a higher cleavage rate ( p = .017) and a lower abortion rate ( p < .05) in DT-IVF group than in SU-IVF group. DT selection yielded spermatozoa with low RCDs, DFI, ASA, and caspase-3 which would be benefit for ART.

Background: The aim of this study was to describe the epidemiology of prelabour rupture of membranes (PROM) in China and to assess the association between clinical practice following the guidelines and early neonatal infections. Methods: We conducted a prospective cohort study of 15926 deliveries in ShenZhen Baoan Women's and Children's Hospital, Xibei Women's and Children's Hospital and Chengdu Women's and Children's Hospital between August 1, 2017, to March 31, 2018. Clinical data were collected for each participant. The epidemiology of PROM was described. The association between PROM with early neonatal infectious outcomes and the influence of the implementation of the guideline on early neonatal infectious outcomes were assessed. Findings: The incidence of PROM was 18•7%. PROM was showed to be a risk factor for neonatal infectious diseases (adjusted OR 1•92, 95%CI 1•49~2•49, p