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Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is the second most common form of muscular dystrophy, which is characterized by a reduction in the number of D4Z4 repeats on chromosome 4q35. Prenatal diagnosis of FSHD has been challenging due to the large quantity and high-quality DNA required for Southern blot (SB) analysis. Optical genome mapping (OGM) technology has shown promise in identifying repeat contraction disorders and presents a potential tool for the prenatal diagnosis of FSHD. Methods In this retrospective cohort study, we investigated the distribution of D4Z4 repeats in 100 unrelated healthy individuals from the Chinese Han population using peripheral blood samples and DLS labelling method. Additionally, prenatal diagnosis using OGM was performed in 12 FSHD families at Peking Union Medical College Hospital between January 2021 and December 2023. The prenatal samples included 2 amniotic cell cultures and 10 chorionic villus samples (CVS), with 9 labeled using DLS and 4 using NLRS method. Results Among the 100 healthy controls, the distribution of D4Z4 repeats varied, with 3 individuals having borderline 10 repeat counts on 4qA, and the most frequent count being 14 units. One individual with mosaicism was also identified. In the cohort of 12 FSHD families,14 prenatal diagnoses were performed. Of these 14 cases, 4 fetuses tested positive for 4qA contraction, with repeat counts ranging from 2 to 4. In both families that underwent two rounds of prenatal diagnosis, the first diagnosis indicated the presence of FSHD, leading to pregnancy termination, while the second diagnosis confirmed the presence of healthy fetuses. The overall positive rate was 28.57%. Conclusion Our findings demonstrate that OGM is an accurate and effective method for the prenatal diagnosis of FSHD. The application of OGM in prenatal settings could offer significant benefits to families affected by FSHD with reproductive concerns. more...

Abstract Optical genome mapping (OGM) offers high consistency in simultaneously detecting structural and copy number variants. This study aimed to retrospectively evaluate the efficacy and potential applications of OGM in preconception genetic counseling. Herein, 74 samples from 37 families were included, and their results of OGM were compared to conventional methods, namely karyotyping (KT) and chromosomal microarray analysis (CMA), which identified 27 variants across 16 positive families. Notably, OGM achieved a concordance rate of 94.7% and 100% with KT and CMA, respectively, presenting an overall concordance of 96.3%, as it missed detecting a centromeric translocation. Additionally, OGM detected two cryptic balanced translocations and a small deletion in three families that were missed by conventional methods, improving the diagnostic rate by 5.4%, along with assisting in the diagnoses of six families (16.2%) by identifying complex rearrangements and confirming cryptic translocations. The combination of KT with OGM yielded the highest diagnostic rate in all families. Overall, the findings of this study present the notable potential of OGM for its application, combined with KT per requirement, in clinical settings to improve the efficiency and accuracy of diagnoses and rapid screening of individuals seeking preconception genetic counseling. more...

Abstract Background Congenital muscular dystrophies (CMDs) and myopathies (CMYOs) are a clinically and genetically heterogeneous group of neuromuscular disorders that share common features, such as muscle weakness, hypotonia, characteristic changes on muscle biopsy and motor retardation. In this study, we recruited eleven families with early-onset neuromuscular disorders in China, aimed to clarify the underlying genetic etiology. Methods Essential clinical tests, such as biomedical examination, electromyography and muscle biopsy, were applied to evaluate patient phenotypes. Whole exome sequencing was used to screen for prospective variants responsible for muscular diseases, followed by co-segregation analysis in the families and prenatal diagnosis via Sanger sequencing, if appropriate. Nanopore sequencing and optical genome mapping were applied for detecting complicated genome rearrangements. Results Fourteen variants in nine genes (ATL1, LMNA, KLHL40, FKRP, DMD, ACTA1, MSTO1, RYR1 and LAMA2) associated with congenital muscular conditions were identified in the ten families mentioned above. Among them, five novel variants, c.1153_1155del in LMNA, c.577 A > G in ACTA1, c.694T > G in MSTO1, c.5938del in LAMA2, and a rare genome fusion ogm[GRCh38] fus(X; X)(p22.31;p21.1) involving DMD, have not been recorded in public databases to the best of our knowledge. Conclusions CMDs and CMYOs were probably responsible for most of the cases (9/11) of genetic muscular defects in this study. Molecular analysis is highly beneficial for the precise diagnosis, genetic counseling and prenatal diagnosis of families suspected of having genetic muscular disorders. Clinical trial number Not applicable. more...

Abstract Background The clinical diagnosis of Fabry Disease (FD) can be challenging due to the clinical heterogeneity, especially in females. Patients with FD often experience a prolonged interval between the onset of symptoms and receiving a diagnosis. Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications. Although next-generation sequencing, which analyzes numerous genes, has been successfully used for FD diagnosis and can detect complex variants, an effective and rapid tool for identifying a wide range of variants is imminent, contributing to decrease the diagnostic delay. Methods The comprehensive Analysis of FD (CAFD) assay was developed for FD genetic diagnosis, employing long-range PCR coupled with long-read sequencing to target the full-length GLA gene and its flanking regions. Its clinical performance was assessed through a comparative analysis with Sanger sequencing. Results Genetic testing was performed on 82 individuals, including 48 probands and 34 relatives. The CAFD assay additionally identified variants in two probands: one had a novel and de novo pathogenic variant with a 1715 bp insertion in intron 4, and the other carried two deep intronic VUS variants in cis-configuration also in intron 4. In total, CAFD identified 47 different variants among 48 probands. Of these, 42 (89.36%, 42/47) were pathogenic, while 5 (10.64%, 5/47) were VUS. Sixteen (34.04%, 16/47) of the variants were novel, including 15 SNV/Indels and one large intronic insertion. Pedigree analysis of 21 probands identified four de novo disease-causing variants. Hence, FD exhibits not only variable clinical presentations but also a wide spectrum of variants. Utilizing a comprehensive testing algorithm for diagnosing FD, which includes enzyme activity, clinical features, and genetic testing, the diagnostic yield of CAFD is 97.92% (47/48), which is higher than that of conventional Sanger sequencing, at 95.83% (46/48). Conclusion The duration between initial clinical presentation and diagnosis remains long and winding. CAFD provides precise diagnosis for a wide spectrum of GLA variants, promoting timely diagnosis and appropriate treatment for FD patients. more...

Abstract Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD. more...

Abstract Background Kagami–Ogata syndrome (KOS) and Temple syndrome (TS) are two imprinting disorders characterized by the absence or reduced expression of maternal or paternal genes in the chromosome 14q32 region, respectively. We present a rare prenatally diagnosed case of recurrent KOS inherited from a mother affected by TS. Case presentation The woman’s two affected pregnancies exhibited recurrent manifestations of prenatal overgrowth, polyhydramnios, and omphalocele, as well as a small bell-shaped thorax with coat-hanger ribs postnatally. Prenatal genetic testing using a single-nucleotide polymorphism array detected a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother, leading to the diagnosis of KOS. Additionally, the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region and presented with short stature and small hands and feet, indicating a diagnosis of TS. Conclusions Given the rarity of KOS as an imprinting disorder, accurate prenatal diagnosis of this rare imprinting disorder depends on two factors: (1) increasing clinician recognition of the clinical phenotype and related genetic mechanism, and (2) emphasizing the importance of imprinted regions in the CMA workflow for laboratory analysis. more...

In remote areas, particularly in developing countries, there is a growing interest in off-grid solar PV systems for their ability to provide clean and affordable electricity. However, these systems often face limitations in powering essential amenities, including sports facilities, due to restricted capabilities and inadequate battery storage. To address these challenges and promote energy independence, this paper proposes an AI-enabled sports-system peer-to-peer (P2P) energy exchange network within the digital economy. This innovative system leverages AI to optimize energy distribution specifically for sports-related infrastructures, ensuring efficient use of solar power and improved energy availability for both recreational and community needs. The proposed P2P network operates on a three-part Internet of Things (IoT) framework, facilitating automatic energy sharing among interconnected systems. This approach not only enhances the performance of existing solar power setups but also ensures that energy demands for sports facilities are met effectively. Feasibility studies of this system reveal promising outcomes, including a 13.67% increase in community energy independence and a 12.20% reduction in overall energy consumption. The AI-powered sports-system network demonstrates its potential to support sustainable development and improve the quality of life in remote areas by integrating sports and energy needs within the digital economy context. more...

Abstract Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs. A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and Genotype-Tissue Expression (GTEx) portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links. Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and Phenome-Wide Association Study analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications. This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications. more...

Abstract Fetal growth restriction (FGR), a leading cause of perinatal morbidity and mortality, is caused by fetal, maternal, and placental factors. Uniparental disomy (UPD) is a rare condition that leads to imprinting effects, low-level mosaic aneuploidies and homozygosity for pathogenic variants. In the present study, UPD events were detected in 5 women with FGR by trio exome sequencing (trio-WES) of a cohort of 150 FGR cases. Furthermore, noninvasive prenatal testing results of the 5 patients revealed a high risk of rare autosomal trisomy. Trio-WES showed no copy-number variations (CNVs) or nondisease-causing mutations associated with FGR. Among the 5 women with FGR, two showed gene imprinting, and two exhibited confined placental mosaicism (CPM) by copy number variant sequencing (CNV-seq). The present study showed that in FGR patients with UPD, the detection of imprinted genes and CPM could enhance the genetic diagnosis of FGR. more...

Background: Peripartum cardiomyopathy (PPCM) is a rare disease that causes maternal morbidity and mortality worldwide. However, the etiology of PPCM is still unclear, and the rate of recovery varies between patients. Understanding the genetic factors underpinning PPCM may provide new insights into its pathogenesis. Methods: This genetic study screened six patients with severe PPCM and their family members using a panel of 204 genes associated with inherited cardiomyopathy. Results: The six probands progressed to severe cardiac dysfunction during follow-up, with a low left ventricular ejection fraction of more...

The aberrant activation of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), downstream effectors of the Hippo signaling pathway, has been implicated in hepatocellular carcinoma(HCC). The microRNAs (miRNAs) works as a tumor suppressors that influence the proliferation, migration and apoptosis of tumor cells by modulating Hippo-YAP/TAZ signaling during hepatic tumorigenesis. Exploring the role of miRNAs in regulating Hippo YAP/TAZ pathway in HCC can provide new ideas for the diagnosis and treatment of HCC. more...

Abstract Background Infantile myofibromatosis (IM) is a rare disorder characterized by the formation of nodules in the skin, muscle, bone, and, more rarely, visceral organs. Very few cases are detected prenatally, and the final diagnosis cannot be made until pathology is completed after birth. Here, we present a case of disseminated form IM (DFIM) with a diagnosis established on prenatal genetic grounds. Case presentation A woman at 23 weeks of gestation was referred for ultrasound evaluation of fetal kidney abnormality. Generalized masses in the skin and muscle of the fetus developed at 28 weeks. Prenatal genetic testing identified the pathogenic heterozygous variant c.1681C > T (p.R561C) of the PDGFRB gene inherited from the asymptomatic father. Intrauterine demise occurred at 31 weeks. Autopsy confirmed DFIM with involvement of the heart and kidney. All cases of prenatally detected IM were reviewed, revealing an association of high mortality with DFIM. Conclusions Prenatal IM diagnosis is difficult. Initial detection is always based on ultrasound. DFIM has high mortality. The germline p.R561C mutation in PDGFRB may cause fetal demise due to severe visceral involvement of IM. Prenatal genetic testing provides a diagnosis before pathological results are available, leading to better counseling and management of pregnancy with a fetus with IM. more...

Osteogenesis, osteoclastogenesis, and angiogenesis play crucial roles in bone regeneration. Parathyroid hormone (PTH), an FDA-approved drug with pro-osteogenic, pro-osteoclastogenic and proangiogenic capabilities, has been employed for clinical osteoporosis treatment through systemic intermittent administration. However, the successful application of PTH for local bone defect repair generally requires the incorporation and delivery by appropriate carriers. Though several scaffolds have been developed to deliver PTH, they suffer from the weaknesses such as uncontrollable PTH release, insufficient porous structure and low mechanical strength. Herein, a novel kind of NIR-activable scaffold (CBP/MBGS/PTHrP-2) with dual-mode PTHrP-2 (a PTH derivative) release capability is developed to synergistically promote osteogenesis and angiogenesis for high-efficacy bone regeneration, which is fabricated by integrating the PTHrP-2-loaded hierarchically mesoporous bioactive glass (MBG) into the N-hydroxymethylacrylamide-modified, photothermal agent-doped, poly(N-isopropylacrylamide)-based thermosensitive hydrogels through assembly process. Upon on/off NIR irradiation, the thermoresponsive hydrogel gating undergoes a reversible phase transition to allow the precise control of on-demand pulsatile and long-term slow release of PTHrP-2 from MBG mesopores. Such NIR-activated dual-mode delivery of PTHrP-2 by this scaffold enables a well-maintained PTHrP-2 concentration at the bone defect sites to continually stimulate vascularization and promote osteoblasts to facilitate and accelerate bone remodeling. In vivo experiments confirm the significant improvement of bone reparative effect on critical-size femoral defects of rats. This work paves an avenue for the development of novel dual-mode delivery systems for effective bone regeneration. more...

Quiescent galaxies generally possess denser cores than star-forming galaxies with similar mass. As a measurement of the core density, the central stellar mass surface density within a radius of 1 kpc (Σ _1 ) was thus suggested to be closely related to galaxy quenching. Massive star-forming galaxies with high Σ _1 do not fit into this picture. To understand the origin of such galaxies, we compare the spatially resolved stellar population and star formation properties of massive (>10 ^10.5 M _⊙ ) blue spiral galaxies with high and low Σ _1 , divided by Σ _1 = 10 ^9.4 M _⊙ kpc ^−2 , based on the final release of MaNGA integral field unit data. We find that both high-Σ _1 and low-Σ _1 blue spirals show large diversities in stellar population and star formation properties. Despite the diversities, high-Σ _1 blue spirals are statistically different from the low-Σ _1 ones. Specifically, the radial profiles of the luminosity-weighted age and Mgb/〈Fe〉 show that high-Σ _1 blue spirals consist of a larger fraction of galaxies with younger and less α -element-enhanced centers than their low-Σ _1 counterparts, ∼55% versus ∼30%. The galaxies with younger centers mostly have higher central specific star formation rates, which still follow the spaxel-based star formation main-sequence relation. Examinations of the H α velocity field and the optical structures suggest that galactic bars or galaxy interactions should be responsible for the rejuvenation of these galaxies. The remaining ∼45% of high-Σ _1 blue spirals are consistent with the inside-out growth scenario. more...

Morphological classification conveys abundant information on the formation, evolution, and environment of galaxies. In this work, we refine a two-step galaxy morphological classification framework ( USmorph ), which employs a combination of unsupervised machine-learning and supervised machine-learning techniques, along with a self-consistent and robust data-preprocessing step. The updated method is applied to galaxies with I _mag < 25 at 0.2 < z < 1.2 in the COSMOS field. Based on their Hubble Space Telescope/Advanced Camera for Survey I -band images, we classify them into five distinct morphological types: spherical (SPH, 15,200), early-type disk (17,369), late-type disk (21,143), irregular disk (IRR, 28,965), and unclassified (UNC, 17,129). In addition, we have conducted both parametric and nonparametric morphological measurements. For galaxies with stellar masses exceeding 10 ^9 M _☉ , a gradual increase in effective radius from SPHs to IRRs is observed, accompanied by a decrease in the Sérsic index. Nonparametric morphologies reveal distinct distributions of galaxies across the G ini− M _20 and C − A parameter spaces for different categories. Moreover, different categories exhibit significant dissimilarity in their G _2 and Ψ distributions. We find morphology to be strongly correlated with redshift and stellar mass. The consistency of these classification results with expected correlations among multiple parameters underscores the validity and reliability of our classification method, rendering it a valuable tool for future studies. more...

Abstract Food recall is a major ingredient in food safety with existing literature focusing mainly on its direct impacts. Few studies focus on possible spillover effects. It is hypothesized that food recalls have a spillover effect on the recalled brand and purchase channel. As a test of this hypothesis, a 2-purchase channel by 3-recall strategy scenario experiment was conducted on spillover effects of a milk recall in Beijing, China. The results indicate that food-safety scares have significant negative impacts on consumers’ purchase intention on the recalled brand and purchase channel, and the impacts are more significant for online than offline marketing. However, voluntary recalls by online firms help mitigate these negative effects and restore consumers’ purchase intention more than offline voluntary recalls. An online food incident creates an issue of trust toward general online platforms. Online vendors should take greater care in guaranteeing food safety and actively take restorative actions such as voluntary recalls after a food safety incident. Results provide empirical evidence for industry organizations and governments to stipulate a strict food safety and incident resolution system for e-commerce. more...

ObjectiveTo investigate the influencing factors and prognosis of immune checkpoint inhibitor-related pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) patients during or after receiving immune checkpoint inhibitors(ICIs).MethodsThe clinical and laboratory indicator data of 222 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors at the First Affiliated Hospital of Zhengzhou University between December 2017 and November 2021 were collected retrospectively. The patients were divided into a CIP group (n=41) and a non-CIP group (n=181) according to whether they developed CIP or not before the end of follow-up. Logistic regression was used to evaluate risk factors of CIP, and Kaplan‒Meier curves were used to describe the overall survival (OS) of different groups. The log-rank test was used to compare the survival of different groups.ResultsThere were 41 patients who developed CIP, and the incidence rate of CIP was 18.5%. Univariate and multivariate logistic regression analyses showed that low pretreatment hemoglobin (HB) and albumin (ALB) levels were independent risk factors for CIP. Univariate analysis suggested that history of chest radiotherapy was related to the incidence of CIP. The median OS of the CIP group and non-CIP were 15.63 months and 30.50 months (HR:2.167; 95%CI: 1.355-3.463, P more...

Mitochondrial autophagy plays a contributary role in the pathogenesis of retina degeneration (RD). ZYAN1 is a novel proline hydroxylase domain (PHD) inhibitor that can enhance the expression of hypoxia-inducible factor 1-alpha (HIF-1α). This study investigated whether ZYAN1 could alleviate progressive photoreceptor loss and oxidative damage in a pharmacologically induced RD model via the modulation of mitophagy. ZYAN1 was injected into the vitreous body of the RD model, and the retinal autophagy level was analyzed. The therapeutic effects of ZYAN1 were evaluated via a function examination, a morphological assay, in situ reactive oxygen species (ROS) detection, and an immunofluorescence assay. It was shown that the thickness of the outer nuclear layer (ONL) increased significantly, and visual function was efficiently preserved via ZYAN1 treatment. The mitochondria structure of photoreceptors was more complete in the ZYAN1-treated mice, and the number of autophagosomes also increased significantly. Membrane disc shedding and ROS overproduction were alleviated after ZYAN1 treatment, and the axonal cilia were more structurally intact. A Western blot analysis showed that the expression levels of the autophagy-related proteins LC3-B, Beclin-1, and ATG5 increased significantly after ZYAN1 treatment, while the expression of P62 was down-regulated. Moreover, the expression levels of HIF-1α and BNIP3 were up-regulated after ZYAN1 treatment. Therefore, an intravitreal injection of ZYAN1 can act as part of the pharmacologic strategy to modulate mitophagy and alleviate oxidative stress in RD. These findings enrich our knowledge of RD pathology and provide insights for the discovery of a therapeutic molecule. more...

Abstract. Objective:. This study was to supply information of the Duchenne muscular dystrophy (DMD) mutational spectrum in 303 Chinese families and further offer 5-year clinical experience of DMD/Becker muscular dystrophy genetic counseling and prenatal diagnosis. Methods:. In this retrospective cohort study, three hundred and five pregnancies in 303 pregnant women who has a birth history of DMD/Becker muscular dystrophy patients underwent prenatal diagnosis using multiplex ligation-dependent probe amplification followed by Sanger sequencing between January 2014 and December 2018 at Peking Union Medical College Hospital. The mean age of pregnant women was (33.0 ± 4.1) years old. Karyotype analysis was performed to exclude fetal abnormal karyotype. Results:. The detection rate of DMD gene mutation in 303 probands was (296/303) 97.7% with seven families having a negative genetic diagnosis. The mutational spectrum comprised of large arrangements in 288/303 (95.0%) and small mutations in 8/303 (2.6%). Carrier testing was performed among 204 pregnant women among whom, 108 mothers had the same mutation as family proband. Of the 305 pregnancies underwent prenatal diagnosis, 55 of 173 male fetuses were affected. We also performed karyotype analysis and found three abnormal karyotypes of trisomy 21. We even found a fetus with DMD gene mutation and trisomy 21 in a same fetus by further analysis. We also identified two times of germline mosaicism. Conclusion:. This study demonstrated the distribution and mutation profile of 303 probands and 305 fetuses. Furthermore, considering the possbility of maternl germilne mosaicism, prenatal diagnosis should be suggested to mothers with a proband whether they carry the causative mutation in their blood or not. more...

BackgroundSentinel lymph node (SLN) biopsy has been widely recognized as an excellent surgical and staging procedure for early-stage breast cancer, and its development has greatly improved the detection of micrometastases. However, the axillary treatment of micrometastasis has been the subject of much debate.MethodsWe identified 427,131 women diagnosed with breast cancer from 2010 to 2018 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients whose nodal status was micrometastases (pTxN1miM0) were classified into two groups: the SLNB only group and SLNB with complete ALND group, and we used these classifications to carry out propensity-score matching (PSM) analysis. The primary and secondary endpoints were OS and BCSS, respectively. We then implemented the Kaplan-Meier method and Cox proportional hazard model and used Fine and Gray competitive risk regression to identify factors associated with the risk of all-cause mortality.ResultsAfter the PSM, 1,833 pairs were included in total. The SLNB with complete ALND showed no significant difference in OS (HR=1.04, 95% CI: 0.84-1.28, P=0.73) or BCSS (HR= 1.03, 95% CI: 0.79-1.35, P=0.82) compared to the SLNB only group, and axillary treatment was not associated with breast cancer-specific death (BCSD) (HR=1.13, 95% CI: 0.86-1.48, P=0.400) or other cause-specific death (OCSD) (HR=0.98, 95% CI:0.70-1.38, P=0.920). There was no statistically significant difference in the cumulative incidence of BCSD (Grey’s test, P=0.819) or OCSD (Grey’s test, P=0.788) for between the two groups either. For different molecular subtypes, patients in the SLNB only group showed no statistically significant differences from those in the SLNB with complete ALND group with Luminal A (HR=1.00, 95% CI:0.76-1.32, P=0.98) or Luminal B (HR=0.82, 95% CI:0.42-1.62, P=0.55) but similar OS to HER2-enriched (HR=1.58, 95% CI:0.81-3.07, P=0.19) or triple negative breast cancers (HR=1.18, 95% CI:0.76-1.81, P=0.46).ConclusionsOur results suggest that in early breast cancer patients with micrometastasis, complete ALND does not seem to be required and that SLNB suffices to control locoregional and distant disease, with no significant adverse effects on survival compared to complete ALND. more...

A metal- and aldehyde-free visible-light-driven photoredox-neutral alkene acylarylation with readily available cyanoarenes is described. A variety of 3-(arylmethyl)chroman-4-ones (i.e., homoisoflavonoids) and analogs are efficiently synthesized with good functional group tolerance. This mild protocol relies on a phosphoranyl radical-mediated acyl radical-initiated cyclization and selective radical-radical coupling sequence, and is also further highlighted by subsequent derivatization to chromone and 2H-chromene as well as its application in the three-component alkene acylarylation. more...

In order to improve the infrared detection and discrimination ability of the smart munition to the dynamic armor target under the complex background, the multi-line array infrared detection system is established based on the combination of the single unit infrared detector. The surface dimension features of ground armored targets are identified by size calculating solution algorithm. The signal response value and the value of size calculating are identified by the method of fuzzy recognition to make the fuzzy classification judgment for armored target. According to the characteristics of the target signal, a custom threshold de-noising function is proposed to solve the problem of signal preprocessing. The multi-line array infrared detection can complete the scanning detection in a large area in a short time with the characteristics of smart munition in the steady-state scanning stage. The method solves the disadvantages of wide scanning interval and low detection probability of single unit infrared detection. By reducing the scanning interval, the number of random rendezvous in the infrared feature area of the upper surface is increased, the accuracy of the size calculating is guaranteed. The experiments results show that in the fuzzy recognition method, the size calculating is introduced as the feature operator, which can improve the recognition ability of the ground armor target with different shape size. more...

Objective: Mosaicism is a common biological phenomenon in organisms and has been reported in many types of chromosome abnormalities, including the absence of heterozygosity (AOH). Due to the detection limitations of the sequencing approach, mosaic AOH events are rarely assessed in clinical cases. Herein, we report the performance of mosaic AOH identification using a low-pass (5~8-fold) WGS method (termed ‘CMA-seq’, an abbreviation for ‘Chromosome Analysis by Sequencing’) in fetal genetic diagnosis. Methods: Thirty AOH-negative, eleven constitutional AOH, and three mosaic AOH samples were collected as training data sets to develop the algorithm and evaluate the suitable thresholds for distinguishing mosaic AOH. Twenty-four new chromosomal aberrant cases, along with sixteen constitutional AOH samples, which were previously ascertained via the SNP-array-based method, were used as a validation data set to measure the performance in terms of sensitivity and specificity of this algorithm. Results: A new statistic, ‘D-value’, was implemented to identify and distinguish constitutional and mosaic AOH events. The reporting thresholds for constitutional and mosaic AOH were also established. In the validation set consisting of 24 new cases, seven constitutional AOH cases and 1 mosaic AOH case were successfully identified, indicating that the results were consistent with those of the SNP-array-based method. The results of all sixteen constitutional AOH validation samples also met the threshold requirements. Conclusions: In this study, we developed a new bioinformatic algorithm to accurately distinguish mosaic AOH from constitutional AOH by low-pass WGS. However, due to the small sample size of the training data set, the algorithm proposed in this manuscript still needs further refinements. more...

Peroxisomes have been proved playing roles in infection of several plant pathogens. Although the contribution of a portion of peroxins in pathogenicity was demonstrated, most of them are undocumented in fungi, especially, Botrytis cinerea. The homologs of Pex8, Pex10, and Pex12 in B. cinerea were functionally characterized in this work using gene disruption strategies. Compared with the wild-type strain (WT), the Δbcpex8, Δbcpex10, and Δbcpex12 mutants exhibited significant reduction in melanin production, fatty acid utilization, and decreased tolerance to high osmotic pressure and reactive oxygen species (ROS). The mycelial growth and conidiation of were significantly inhibited in Δbcpex8, Δbcpex10, and Δbcpex12 strains. The mycelial growth rates of Δbcpex8, Δbcpex10, and Δbcpex12 were reduced by 32, 35, and 34%, respectively, compared with WT and ectopic transformant (ET), and the conidiation was reduced by approximately 89, 27, and 88%, respectively. The conidial germination, germ tube elongation, and the formation of initiate infection structures (IFSs) were also reduced by the deletion of the genes. The pathogenicity was tested on the leaves of tobacco and strawberry, and fruits of tomato. On the leaves of tobacco and strawberry, the Δbcpex8, Δbcpex10, and Δbcpex12 mutants could not induce necrotic lesions, and the lesions on tomato fruits infected with the mutants were significantly reduced than those of the wide type. The results indicated that BcPEX8, BcPEX10, and BcPEX12 are indispensable for the development and pathogenicity of B. cinerea. more...

BackgroundNecroptosis is considered to be a new form of programmed necrotic cell death, which is associated with metastasis, progression and prognosis of various types of tumors. However, the potential role of necroptosis-related genes (NRGs) in the triple negative breast cancer (TNBC) is unclear.MethodsWe extracted the gene expression and relevant clinicopathological data of TNBC from The Cancer Genome Atlas (TCGA) databases and the Gene Expression Omnibus (GEO) databases. We analyzed the expression, somatic mutation, and copy number variation (CNV) of 67 NRGs in TNBC, and then observed their interaction, biological functions, and prognosis value. By performing Lasso and COX regression analysis, a NRGs-related risk model for predicting overall survival (OS) was constructed and its predictive capabilities were verified. Finally, the relationship between risk_score and immune cell infiltration, tumor microenvironment (TME), immune checkpoint, and tumor mutation burden (TMB), cancer stem cell (CSC) index, and drug sensitivity were analyzed.ResultsA total 67 NRGs were identified in our analysis. A small number of genes (23.81%) detected somatic mutation, most genes appeared to have a high frequency of CNV, and there was a close interaction between them. These genes were remarkably enriched in immune-related process. A seven-gene risk_score was generated, containing TPSG1, KRT6A, GPR19, EIF4EBP1, TLE1, SLC4A7, ESPN. The low-risk group has a better OS, higher immune score, TMB and CSC index, and lower IC50 value of common therapeutic agents in TNBC. To improve clinical practicability, we added age, stage_T and stage_N to the risk_score and construct a more comprehensive nomogram for predicting OS. It was verified that nomogram had good predictive capability, the AUC values for 1-, 3-, and 5-year OS were 0.847, 0.908, and 0.942.ConclusionOur research identified the significant impact of NRGs on immunity and prognosis in TNBC. These findings were expected to provide a new strategy for personalize the treatment of TNBC and improve its clinical benefit. more...

Spectral induced polarization (SIP) and bender element (BE) techniques show a high sensitivity to particle size, particle distribution and content of generated hydration products, which essentially govern the efficiency of ground improvement. In this context, both SIP and BE were integrated on a column setup to monitor the processes of lime and cement stabilization. A 5 mmol/L Na2CO3 solution was injected into the sand-lime mixture to produce CaCO3 precipitation, while deionized water was injected into the sand-cement mixture to induce the hydration of cement. The average diameters of the precipitated particles or clusters were calculated from the relaxation time, which was a significant parameter of SIP signals, via the Schwarz equation. Two pairs of BE were used to demonstrate the heterogeneity of the product precipitation, which was probably caused by the location of the inflow and outflow on the SIP-BE column. SIP and BE showed the capability of nondestructively monitoring the spatiotemporal chemical evolution processes, which could be helpful for engineering applications. more...

Abstract Background Nano-drug delivery systems show considerable promise for effective cancer therapy. Polymeric micelles have attracted extensive attention as practical nanocarriers for target drug delivery and controlled drug delivery system, however, the distribution of micelles and the release of the drug are difficult to trace in cancer cells. Therefore, the construction of a redox-sensitive multifunctional drug delivery system for intelligent release of anticancer drugs and simultaneous diagnostic imaging and therapy remains an attractive research subject. Results To construct a smart drug delivery system for simultaneous imaging and cancer chemotherapy, mPEG-ss-Tripp was prepared and self-assembled into redox-sensitive polymeric micelles with a diameter of 105 nm that were easily detected within cells using confocal laser scanning microscopy based on aggregation-induced emission. Doxorubicin-loaded micelles rapidly released the drug intracellularly when GSH reduced the disulfide bond. The drug-loaded micelles inhibited tumor xenografts in mice, while this efficacy was lower without the GSH-responsive disulfide bridge. These results establish an innovative multi-functional polymeric micelle for intracellular imaging and redox-triggered drug deliver to cancer cells. Conclusions A novel redox-sensitive drug delivery system with AIE property was constructed for simultaneous cellular imaging and intelligent drug delivery and release. This smart drug delivery system opens up new possibilities for multifunctional drug delivery systems. more...

Food hoarding is prevalent during the COVID-19 pandemic. To investigate the mechanism of urban consumers' food hoarding behaviors, we categorize hoarding motives into rational and irrational ones. Using random online survey samples from three cities in China, we employ the multivariate probit model to investigate the rational and irrational motives on food hoarding behavior. Our results confirmed the existence of both rational and irrational food hoarding, and also found factors attributing to the different buying behaviors. The amount of food at hand and the expectation on the infection possibility of COVID-19 are two major factors affecting rational hoarding. Bad mood and herd psychology are factors contributing to panic buying. This study provides an empirical evidence to support intervention policies aiming at mitigating panic buying behavior. more...

Objective: Absence of homozygosity (AOH) is a genetic characteristic known to cause human diseases mainly through autosomal recessive or imprinting mechanisms. The importance and necessity of accurate AOH detection has become more clinically significant in recent years. However, it remains a challenging task for sequencing-based methods thus far. Methods: In this study, we developed and optimized a new bioinformatic algorithm based on the assessment of minimum sequencing coverage, optimal bin size, the Z-score threshold of four types of allele count and the frequency for accurate genotyping using 28 AOH negative samples, and redefined the AOH detection cutoff value. We showed the performance of chromosome analysis by five-fold coverage whole genome sequencing (CMA-seq) for AOH identification in 27 typical prenatal/postnatal AOH positive samples, which were previously confirmed by chromosomal microarray analysis with single nucleotide polymorphism array (CMA/SNP array). Results: The blinded study indicated that for all three forms of AOH, including whole genomic AOH, single chromosomal AOH and segmental AOH, and all kinds of sample types, including chorionic villus sampling, amniotic fluid, cord blood, peripheral blood and abortive tissue, CMA-seq showed equivalent detection power to that of routine CMA/SNP arrays (750K). The subtle difference between the two methods is that CMA-seq is prone to detect small inconsecutive AOHs, while CMA/SNP array reports it as a whole. Conclusion: Based on our newly developed bioinformatic algorithm, it is feasible to detect clinically significant AOH using CMA-seq in prenatal diagnosis. more...

Based on independent shear measurements using the Dark Energy Camera Legacy Survey/DR8 imaging data, we measure the weak lensing signals around isolated central galaxies (ICGs) from Sloan Digital Sky Survey/DR7 at z ∼ 0.1. The projected stellar mass density profiles of satellite galaxies are further deduced, using photometric sources from the Hyper Suprime-cam survey. The signals of ICGs + their extended stellar halos are taken from Wang et al. All measurements are compared with predictions by the IllustrisTNG300-1 simulation. We find, overall, a good agreement between observation and TNG300. In particular, a correction to the stellar mass of massive observed ICGs is applied based on the calibration of He et al., which brings a much better agreement with TNG300 predicted lensing signals at ${\mathrm{log}}_{10}{M}_{* }/{M}_{\odot }\gt 11.1$ . In real observation, red ICGs are hosted by more massive dark matter halos and have more satellites and more extended stellar halos than blue ICGs at fixed stellar mass. However, in TNG300 there are more satellites around blue ICGs at fixed stellar mass, and the outer stellar halos of red and blue ICGs are similar. The stellar halos of TNG galaxies are more extended compared with real observed galaxies, especially for blue ICGs with ${\mathrm{log}}_{10}{M}_{* }/{M}_{\odot }\gt 10.8$ . We find the same trend for TNG100 galaxies and for true halo central galaxies. The tensions between TNG and real galaxies indicate that satellite disruptions are stronger in TNG. In both TNG300 and observation, satellites approximately trace the underlying dark matter distribution beyond 0.1 R _200 , but the fraction of total stellar mass in TNG300 does not show the same radial distribution as real galaxies. more...

Cancer remains one of the top culprits causing disease-related deaths. A lack of effective multi-cancer therapeutic targets has limited the prolongation of cancer patients’ survival. Therefore, it is important to explore novel oncogenic genes or versatile targets and perform a comprehensive analysis to assess their roles in the process of tumorigenesis. OSBPL3 protein is an intracellular lipid receptor of the oxysterol-binding protein superfamily, which participates in some pathological and physiological processes in tumor progression. However, its clinical roles and potential mechanisms in cancers remain unknown. Thus, we aimed to systematic explore the potential oncogenic roles of OSBPL3 across thirty-three tumors using multiple web-based and publicly available tools, including the Cancer Genome Atlas, Gene Expression Omnibus, Genotype-Tissue Expression, cBioPortal, and Human Protein Atlas database. OSBPL3 is highly expressed in major subtypes of cancers, distinctly associated with the prognosis of tumor patients. We observed X676_splice/V676G alteration in the oxysterol domain and frequent mutations of OSBPL3 involve cell survival in skin cutaneous melanoma. We also first presented that the expression of OSBPL3 was associated with tumor mutational burden (TMB) in nine cancer types. Additionally, OSBPL3 shows an enhanced phosphorylation level at S426, S251, and S273 loci within the pleckstrin homology domain in multiple tumors, such as breast cancer or lung adenocarcinoma. And OSBPL3 expression was associated with active immune cells (CD8+ T cells) and cancer-associated fibroblasts in breast cancer, colon adenocarcinoma, and kidney renal clear cell carcinoma and immune checkpoint genes in more than 30 tumors, but weakly associated with immune suppressive cells (myeloid-derived suppressor cells, T regulatory cells). Moreover, protein processing and mRNA metabolic signaling pathways were involved in the functional mechanisms of OSBPL3. Our study first demonstrated that a novel agent OSBPL3 plays an important role in tumorigenesis from the perspective of publicly available databases and clinical tumor samples in various cancers, which comprehensively provide insights into its biological functions and may be helpful for further investigation. more...

Abstract Background In this study, we investigated the association of time-varying serum albumin levels with mortality over a 5-year period in one cohort of patients undergoing long-term peritoneal dialysis (PD) therapy. Methods The participants in this study enrolled 302 patients who underwent long-term PD at a single PD center in Taiwan. We reviewed medical records from 2011 to 2015 retrospectively. Time-averaged albumin level and serum albumin reach rate (defined as the percentage of serum albumin measurements that reached ≥3.5 g/dL) were applied as the predictor variables in the first 2 years (2011–2012). All-cause mortality was used as the outcome variable in the subsequent 3 years (2013–2015). Hazard function of all-cause mortality in the study participants was examined by using Cox proportional hazard regression models . Results Patients with different albumin reach rates (75– more...

Background/Aims: Studies on the long-term clinical benefits of hemodiafiltration (HDF) and high-flux hemodialysis (HFHD) are very limited. This study aimed to investigate the hospitalization rate and aortic arch calcification (AAC) of these two dialysis modalities over 6 years. Methods: Participants who received regular HDF and HFHD in one hospital-facilitated hemodialysis center were prospectively enrolled after matching for age, sex, and diabetes between January 2009 and December 2014. Medical records were reviewed retrospectively on demographics, laboratory variables, calcified scores in aortic arch measured by chest radiography, and rates of hospital admission. Cox proportional hazard regression and linear regression were used to obtain the outcome results. Results: The HDF and HFHD groups consisted of 108 and 102 participants, respectively. Levels of laboratory variables including small soluble solutes and Kt/V were not statistically different over the 6-year period between the HDF and HFHD groups. Calcified scores of the aortic arch increased over 6 years in both groups. The changes in the mean calcified scores were significant when compared between the two groups (0.44–1.82 in HFHD, 0.79–1.8 in HDF, respectively, p = 0.008). Hospitalization rates were 735 per 1,000 patients in the HDF group and 852 per 1,000 patients in the HFHD group, respectively. No significant difference was observed in frequency and days of hospitalization between HDF and HFHD. Conclusion: Hospitalization rates and AAC were observed to be equal for HDF and HFHD. more...

Background: The COVID-19 pandemic has led to various social distancing practices such as mandatory working from home, which aim to reduce the spread of SARS-CoV-2. The purpose of this study was to compare the mental health impacts between men and women being forced to work from home following a COVID-19 outbreak. Methods: This study analyzed data collected from two rounds of surveys conducted in four cities in China: Beijing, Chengdu, Changsha, and Wuhan. A total of 940 individual responses were analyzed in this study. Multiple linear regression and ordinal logistic models were used to analyze the relationship between being forced to work from home, demographic variables, work-related variables, COVID-19 variables, family ties variables, and mental health variables. Results: The analysis showed that being forced to work from home was associated with worse mental health in men, but not among women. Married men reported better mental health compared with unmarried men, while the association between marital status and mental health was the opposite in women. Mental health was worse among those in higher job positions for both men and women. In addition, being forced to work from home was also associated with worse mental health among young, high-income men, and highly educated women. Conclusions: The impacts of the COVID-19 pandemic are far-reaching and amy persist for years. Furthermore, the number of workers who choose to work from home is expected to increase. The findings of this study can inform policy-making that will improve the mental health of employees working from home, with particular attention to men forced to work from home. more...

Abstract Background Frequent injection of high-dose methylprednisolone (MP) is used to treat spinal cord injury (SCI), but free MP is associated with various side effects and its water solubility is low, limiting potential dosing regimes and administration routes. Albumin-based nanoparticles, which can encapsulate therapeutic drugs and release cargo in a controlled pattern, show high biocompatibility and low toxicity. The Nogo protein, expressed on the surface of oligodendrocytes, can inhibit axonal growth by binding with the axonal Nogo receptor (NgR). Peptide NEP1-40, an NgR antagonist, can bind specifically to Nogo, significantly improving functional recovery and axon growth in the corticospinal tract. Therefore, we hypothesized that delivering MP within nanoparticles decorated with NEP1-40 could avoid the disadvantages of free MP and enhance its therapeutic efficacy against SCI. Results We used human serum albumin to prepare MP-loaded NPs (MP-NPs), to whose surface we conjugated NEP1-40 to form NEP1-40-MP-NPs. Transmission electron microscopy indicated successful formation of nanoparticles. NEP1-40-MP-NPs were taken up significantly better than MP-NPs by the Nogo-positive cell line RSC-96 and were associated with significantly higher Basso–Beattie–Bresnahan locomotor scores in rats recovering from SCI. Micro-computed tomography assay showed that NEP1-40-MP-NPs mitigated SCI-associated loss of bone mineral density and accelerated spinal cord repair. Conclusions NEP1-40-MP-NPs can enhance the therapeutic effects of MP against SCI. This novel platform may also be useful for delivering other types of drugs. more...

Age-related macular degeneration (AMD) is a progressive neurodegeneration disease that causes photoreceptor demise and vision impairments. In AMD pathogenesis, the primary death of retinal neurons always leads to the activation of resident microglia. The migration of activated microglia to the ongoing retinal lesion and their morphological transformation from branching to ameboid-like are recognized as hallmarks of AMD pathogenesis. Activated microglia send signals to Müller cells and promote them to react correspondingly to damaging stimulus. Müller cells are a type of neuroglia cells that maintain the normal function of retinal neurons, modulating innate inflammatory responses, and stabilize retinal structure. Activated Müller cells can accelerate the progression of AMD by damaging neurons and blood vessels. Therefore, the crosstalk between microglia and Müller cells plays a homeostatic role in maintaining the retinal environment, and this interaction is complicatedly modulated. In particular, the mechanism of mutual regulation between the two glia populations is complex under pathological conditions. This paper reviews recent findings on the crosstalk between microglia and Müller glia during AMD pathology process, with special emphasis on its therapeutic potentials. [ABSTRACT FROM AUTHOR] more...

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders. more...

Magnaporthe oryzae, a fungal pathogen that causes rice blast, which is the most destructive disease of rice worldwide, has the potential to perform both asexual and sexual reproduction. MAT loci, consisting of MAT genes, were deemed to determine the mating types of M. oryzae strains. However, investigation was rarely performed on the development and molecular mechanisms of the sexual reproduction of the fungus. In the present work, we analyzed the roles of two MAT loci and five individual MAT genes in the sex determination, sexual development and pathogenicity of M. oryzae. Both of the MAT1-1 and MAT1-2 loci are required for sex determination and the development of sexual structures. MAT1-1-1, MAT1-1-3 and MAT1-2-1 genes are crucial for the formation of perithecium. MAT1-1-2 impacts the generation of asci and ascospores, while MAT1-2-2 is dispensable for sexual development. A GFP fusion experiment indicated that the protein of MAT1-1-3 is distributed in the nucleus. However, all of the MAT loci or MAT genes are dispensable for vegetative growth, asexual reproduction, pathogenicity and pathogenicity-related developments of the fungus, suggesting that sexual reproduction is regulated relatively independently in the development of the fungus. The data and methods of this work may be helpful to further understand the life cycle and the variation of the fungus. more...