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In recent years, the effects of air pollutants on the neurodevelopmental disorders in children have received widespread attention. Early life is a critical period of rapid brain development, and exposure to air pollutants during this period may permanently alter brain function. This paper reviewed the epidemiological studies on the association between exposure to air pollutants during early life and children's neurodevelopmental disorders in recent years, with focus on outdoor air pollutants (e.g., PM2.5, PM10, NOx, and CO) and indoor air pollutants (e.g., cooking oil fumes, tobacco and mosquito incense smoke, and formaldehyde from home decoration), and summarized their possible biological mechanisms. Most studies indicate that pollutants in different periods and at different levels of exposure during early life can negatively affect children's neurodevelopment and that there may be a dose-response relationship between certain air pollutants and children's neurodevelopment. Current research on the effects of indoor air pollutants on children's neurodevelopment focus on exposure to tobacco smoke, while other indoor air pollutants such as cooking oil fumes and organic compounds produced by interior decorative materials are less well reported and their underlying biological mechanisms are not yet clear. Further epidemiological studies, animal and cellular experiments are needed to provide evidence for the neurodevelopmental toxicity of air pollutant exposure in the future, aiming to provide a theoretical basis for environmental eugenics and promote healthy development of children.

Abstract Background Cryptosporidium is a highly pathogenic parasite responsible for diarrhea in children worldwide. Here, the epidemiological status and genetic characteristics of Cryptosporidium in children with or without diarrhea were investigated with tracking of potential sources in Wenzhou City, China. Methods A total of 1032 children were recruited, 684 of whom had diarrhea and 348 without, from Yuying Children’s Hospital in Wenzhou, China. Samples of stool were collected from each participant, followed by extraction of DNA, genotyping, and molecular identification of Cryptosporidium species and subtypes. Results Twenty-two of the 1032 (2.1%) children were infected with Cryptosporidium spp. with 2.5% (17/684) and 1.4% (5/348) in diarrhoeic and asymptomatic children, respectively. Four Cryptosporidium species were identified, including C. parvum (68.2%; 15/22), C. felis (13.6%; 3/22), C. viatorum (9.1%; 2/22), and C. baileyi (9.1%; 2/22). Two C. parvum subtypes named IIdA19G1 (n = 14) and IInA10 (n = 1), and one each of C. felis (XIXa) and C. viatorum (XVaA3g) subtype was found as well. Conclusions This is the first research that identified Cryptosporidium in children of Wenzhou, China, using PCR. Identification of zoonotic C. parvum, C. felis, C. viatorum, and their subtypes indicate potential cross-species transmission of Cryptosporidium between children and animals. Additionally, the presence of C. baileyi in children suggests that this species has a wider host range than previously believed and that it possesses the capacity to infect humans.

IntroductionEnterocytozoon bieneusi, an obligatory intracellular fungus, is prevalent among animals and humans. Due to their close interaction with humans and their extensive regional distribution, brown rats (Rattus norvegicus) are important pathogen reservoirs. To assess the zoonotic transmission potential of E. bieneusi, a molecular investigation was conducted on 817 R. norvegicus from four cities in Heilongjiang Province, China.MethodsA total of 817 R. norvegicus were collected from four cities in Heilongjiang Province, China. The genotyping of E. bieneusi was conducted through PCR amplification of the small subunit ribosomal RNA (SSU rRNA)’s internal transcribed spacer (ITS) segments. Phylogenetic and similarity analyses were used to examine zoonotic potential and genetic characteristics of the E. bieneusi-positive specimens.ResultsAmong the 817 R. norvegicus, the total infection rate was 33.3% (272/817). Seventy-five genotypes were identified, including 14 known genotypes D (n = 167), A (n = 15), HLJ-CP1 (n = 12), WR8 (n = 6), EbpC (n = 2), BEB6 (n = 1), CS-4 (n = 1), CHPM1 (n = 1), Henan-II (n = 1), HNH-22 (n = 1), HNH-25 (n = 1), I (n = 1), JLD-XI (n = 1), SDD5 (n = 1), and 61 novel genotypes designated as SHWR1 (n = 10), SYSWR1 (n = 2), and SHWR2 to SHWR17, SYSWR2 to SYSWR36 and QTHWR1 to QTHWR8 (n = 1, each). Moreover, 10 samples exhibited mixed genotype infections, including D + A (n = 3), D + EbpC (n = 1), D + HLJ-CP1 (n = 1), D + SHWR1 (n = 1), D + SHWR16 (n = 1), D + SHWR17 (n = 1), SDD5 + WR8 (n = 1), and CS-4 + SYSWR36 (n = 1). Phylogenetic analysis grouped the genotypes into three main groups: group 1 (n = 67), group 2 (n = 5), and group 9 (n = 3).DiscussionThe high prevalence and genetic diversity of E. bieneusi in Heilongjiang Province’s R. norvegicus imply that these animals spread the pathogen. The R. norvegicus that E. bieneusi carries can spread zoonotic disease, making it a serious hazard to the local human population. Therefore, it is imperative to raise awareness about the dangers posed by R. norvegicus and implement measures to reduce their population to prevent environmental contamination.

This study aimed to determine the optimal planting density of floating bed plants for purifying wastewater treatment plant tailwater and realizing the resourceful use of wastewater. Three commonly used floating bed plants, Iris, Zelkova, and water onion, were selected, and a self-designed and assembled floating bed frame was used as the plant carrier. Simulated wastewater treatment plant tailwater was treated for 28 days, and the pH value, chemical oxygen demand (COD), NH4+−N, TN, TP, and plant growth were continuously monitored. The results showed that the best water purification effect was achieved when the planting density was 67 plants/m2. Thalia dealbata and Scirpus were found to have better TN and NH4+−N removal effects than Iris, while Iris had a superior TP removal effect compared to Thalia dealbata and Scirpus. Additionally, Thalia dealbata had a better COD removal effect than Iris and Scirpus. Therefore, the optimal planting density for constructing an ecological floating bed was determined to be 67 plants/m2.

Shrews play a crucial role as repositories for diverse pathogens linked to zoonotic infectious diseases. However, the genetic information regarding Cryptosporidium in Chinese shrews remains unexplored. The objectives of this study were twofold: to determine the occurrence rate of Cryptosporidium spp. in wild shrews residing in the southern part of Zhejiang Province, China, and to investigate their genetic characteristics. A total of 282 wild shrews were captured between April and October of 2023. The detection of Cryptosporidium in fecal samples, collected from each animal's rectum, was performed using PCR and sequencing of the partial small subunit of ribosomal RNA (SSU rRNA) gene. The 60-kDa glycoprotein (gp60) gene was utilized to further subtype the positive samples of C. viatorum and C. parvum. All animals were identified as Suncus murinus, and a positive result for Cryptosporidium was obtained in 14.2 % (40/282) of the samples. The following species and genotypes were identified: C. ratti (n = 19), C. parvum (n = 2), C. viatorum (n = 1), Cryptosporidium rat genotype IV (n = 13), and Cryptosporidium skunk genotype (n = 5). Furthermore, the subtypes IIdA15G1 and XVdA3 were detected within C. parvum and C. viatorum, respectively. Molecular evidence indicates that S. murinus is concurrently infected with rodent-adapted and zoonotic species/genotypes, actively contributing to the dissemination of cryptosporidiosis.

Epithelial cells function as the primary line of defense against invading pathogens. However, bacterial pathogens possess the ability to compromise this barrier and facilitate the transmigration of bacteria. Nonetheless, the specific molecular mechanism employed by Mycobacterium tuberculosis (M.tb) in this process is not fully understood. Here, we investigated the role of Rv2569c in M.tb translocation by assessing its ability to cleave E-cadherin, a crucial component of cell-cell adhesion junctions that are disrupted during bacterial invasion. By utilizing recombinant Rv2569c expressed in Escherichia coli and subsequently purified through affinity chromatography, we demonstrated that Rv2569c exhibited cell wall-associated serine protease activity. Furthermore, Rv2569c was capable of degrading a range of protein substrates, including casein, fibrinogen, fibronectin, and E-cadherin. We also determined that the optimal conditions for the protease activity of Rv2569c occurred at a temperature of 37°C and a pH of 9.0, in the presence of MgCl2. To investigate the function of Rv2569c in M.tb, a deletion mutant of Rv2569c and its complemented strains were generated and used to infect A549 cells and mice. The results of the A549-cell infection experiments revealed that Rv2569c had the ability to cleave E-cadherin and facilitate the transmigration of M.tb through polarized A549 epithelial cell layers. Furthermore, in vivo infection assays demonstrated that Rv2569c could disrupt E-cadherin, enhance the colonization of M.tb, and induce pathological damage in the lungs of C57BL/6 mice. Collectively, these results strongly suggest that M.tb employs the serine protease Rv2569c to disrupt epithelial defenses and facilitate its systemic dissemination by crossing the epithelial barrier.

Abstract Anti‐HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2‐positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold‐silver hollow nanoshells (AuAg HNSs) with exceptional near‐infrared (NIR) absorption capability, the small‐molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo‐and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT‐modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF‐κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

Abstract The combination of the first‐line standard chemotherapeutic drug doxorubicin hydrochloride (DOX) and the molecular‐targeted drug Herceptin (HCT) has emerged as a promising strategy for human epidermal growth receptor 2 (HER‐2) overexpressing breast cancer treatment. However, insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application. Herein, an in situ forming gold nanorods (AuNRs)‐sodium alginate (ALG) hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable, dual‐stimuli‐responsive drug release, photothermal ablation, and drug‐antibody synergistic therapy. The photothermal agent AuNRs, anticancer drug DOX, and anticancer antibody HCT were mixed in ALG solution, and after injection, the soluble ALG was quickly transformed into a hydrogel in the presence of Ca2+ in the body. Significantly, the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70% under 808 nm laser irradiation. The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix. In addition, the drug release rate and the releasing degree are also sensitive to the pH. In vitro studies demonstrated that the PEI‐AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK‐BR‐3 cells. In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites. The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER‐2 overexpressing cancer therapy.

Abstract The World Health Organization (WHO) prioritizes pneumococcal disease as a vaccine-preventable disease and recommends the inclusion of pneumococcal conjugate vaccines (PCV) in national immunization programs worldwide. However, PCV is not included in the National Immunization Program in China and has low vaccination coverage due to its high cost. To address this, Weifang City implemented an innovative strategy for a 13-valent PCV (PCV13) on June 1, 2021. This strategy aimed to provide one dose of PCV13 free of charge for children aged 6 months to 2 years in registered households and to adopt a commercial insurance model with one dose of PCV13 free of charge in 2023 for children over 2 years old. The Health Commission of Weifang and other departments conducted a comprehensive investigation and considered various factors, such as vaccine effectiveness, safety, accessibility, vaccine price, and immunization schedules, for eligible children (under 5 years old). Stakeholder opinions were also solicited before implementing the policy. The Commission negotiated with various vaccine manufacturers to maximize its negotiating power and reduce vaccine prices. The implementation plan was introduced under the Healthy Weifang Strategy. Following the implementation of this strategy, the full course of vaccination coverage increased significantly from 0.67 to 6.59%. However, vaccination coverage is still lower than that in developed countries. Weifang's PCV13 vaccination innovative strategy is the first of its kind in Chinese mainland and is an active pilot of non-immunization program vaccination strategies. To further promote PCV13 vaccination, Weifang City should continue to implement this strategy and explore appropriate financing channels. Regions with higher levels of economic development can innovate the implementation of vaccine programs, broaden financing channels, improve accessibility to vaccination services, and advocate for more localities to incorporate PCV13 into locally expanded immunization programs or people-benefiting projects. A monitoring and evaluation system should also be established to evaluate implementation effects. Graphical Abstract

AbstractContext Jiang-Zhi-Ning (JZN), a traditional Chinese medicinal formula, is used to treat hyperlipidemia in clinics.Objective To screen the hypolipidemic “bioequivalent substance system (BSS)” of JZN and elucidate the potential hypolipidemic mechanism.Materials and methods In vitro, the TG content in HepG2 cells was determined after the intervention of the combination of advantageous components (CAC) by uniform design. In vivo, hyperlipidemia models were established by Triton WR-1339 (400 mg/kg; i.p.) in male ICR mice, and corresponding treatments were administered via oral administration once. The mice were divided into 12 groups (n = 5): control, hyperlipidemic model, simvastatin (positive control, 20 mg/kg), gradient doses of JZN granules (2, 4 and 8 g/kg) and the hypolipidemic effective extraction (HEE) of JZN (120, 240 and 480 mg/kg) and CAC groups (20, 40 and 160 mg/kg). Serum TC, TG, LDL-C and HDL-C were performed after 24 h. Transcriptomics and qRT–PCR technology were used to explore the mechanism of the “BSS” of JZN.Results In vitro, the ratio of CAC was determined. CAC could reduce the TG content in HepG2 cells (77.21%). Compared with the model group, the high dose of CAC could markedly decrease the levels of TC (61.86%), TG (105.54%) and LDL-C (39.38%) and increase the level of HDL-C (232.67%). CAC was proved to be the “BSS”. Transcriptomics and qRT–PCR analysis revealed CAC regulated non-alcoholic fatty liver disease, bile secretion, PPAR and adipocytokine signalling pathway.Discussion and conclusions These findings provided new feasible ideas and methods for the elucidation of the pharmacodynamic material basis.

Abstract The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. Furthermore, gain of function of the melanocortin action through overexpression of MC4R, POMC or its derived peptides had little effect on obesity prevention or reversal. These results reveal a bias of the melanocortin action towards protection of weight loss and provide a neural basis behind the well-known, but mechanistically ill-defined, predisposition to obesity development.

Abstract Background Cryptosporidiosis is a zoonotic intestinal infectious disease caused by Cryptosporidium spp., and its transmission is highly influenced by climate factors. In the present study, the potential spatial distribution of Cryptosporidium in China was predicted based on ecological niche models for cryptosporidiosis epidemic risk warning and prevention and control. Methods The applicability of existing Cryptosporidium presence points in ENM analysis was investigated based on data from monitoring sites in 2011–2019. Cryptosporidium occurrence data for China and neighboring countries were extracted and used to construct the ENMs, namely Maxent, Bioclim, Domain, and Garp. Models were evaluated based on Receiver Operating Characteristic curve, Kappa, and True Skill Statistic coefficients. The best model was constructed using Cryptosporidium data and climate variables during 1986‒2010, and used to analyze the effects of climate factors on Cryptosporidium distribution. The climate variables for the period 2011‒2100 were projected to the simulation results to predict the ecological adaptability and potential distribution of Cryptosporidium in future in China. Results The Maxent model (AUC = 0.95, maximum Kappa = 0.91, maximum TSS = 1.00) fit better than the other three models and was thus considered the best ENM for predicting Cryptosporidium habitat suitability. The major suitable habitats for human-derived Cryptosporidium in China were located in some high-population density areas, especially in the middle and lower reaches of the Yangtze River, the lower reaches of the Yellow River, and the Huai and the Pearl River Basins (cloglog value of habitat suitability > 0.9). Under future climate change, non-suitable habitats for Cryptosporidium will shrink, while highly suitable habitats will expand significantly (χ 2 = 76.641, P

ObjectivesRecent researches have demonstrated good correlation between vascular endothelial growth factor (VEGF) and diabetic nephropathy (DN); however, this relationship seems less clear-cut when VEGF was measured in blood samples. We tended to explore the possible association between serum VEGF and glycemic control and diabetic nephropathy severity in Chinese older adults with type 2 diabetes mellitus (T2DM).Materials and methodsThis study retrospectively enrolled 595 older T2DM adults at random. Participants were clinically grouped across the urine albumin-to-creatinine ratio (UACR) and the HbA1c tertiles by genders. Linear regressions were performed for the correlation of VEGF with HbA1c and UACR and binary logistic regressions for the odds of DN after adjusting for confounders. The receiver operating characteristic (ROC) curves were conducted for the predictive value of VEGF for DN.ResultsBoth males and females with DN exhibited higher VEGF levels than non-DN (P < 0.001). Furthermore, a positive correlation of VEGF with UACR and HbA1c was presented regardless of adjusting confounding factors (P < 0.001). Serum VEGF level and fasting plasma glucose (FPG) were independent risk factors of DN in older adults of both genders (P < 0.05), while the risk prediction of DN by HbA1c only reflected in female patients (P < 0.05). The ROC curve of VEGF for DN had the area under curve (AUC) of 0.819 for males and 0.793 for females, indicating the clinical value of serum VEGF as a predictive biomarker.ConclusionsSerum VEGF was strongly associated with UACR and HbA1c in both genders, and could be regarded as a predictive biomarker for glycemic control and diabetic nephropathy in older adults with T2DM.

Abstract Background Opportunistic infections are a ubiquitous complication in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi are common opportunistic intestinal pathogens in humans. In China, despite the number of HIV/AIDS patients being extremely large, only a few studies have investigated opportunistic infections caused by intestinal pathogens in this patient population. The aims of this study were to elucidate the occurrence and genetic characteristics of Cryptosporidium spp., G. duodenalis, and E. bieneusi in HIV/AIDS patients. Methods We collected fecal specimens from 155 HIV/AIDS patients (one from each patient). All of the specimens were examined for the presence of the pathogens by genotyping using polymerase chain reaction and sequencing of the small subunit ribosomal RNA gene for Cryptosporidium spp.; the triosephosphate isomerase, β-giardin and glutamate dehydrogenase genes for G. duodenalis; and the internal transcribed spacer region of the rRNA gene for E. bieneusi. The Cryptosporidium-positive specimens were further subtyped by polymerase chain reacion and sequencing of the 60-kDa glycoprotein gene. Results Six (3.9%), three (1.9%), and eight (5.2%) HIV/AIDS patients were positive for Cryptosporidium spp., G. duodenalis, and E. bieneusi, respectively. No statistical differences were observed in occurrence rate between the groups by gender, clinical symptom (diarrhea), and CD4+ cell count. Four Cryptosporidium species were identified: Cryptosporidium hominis (n = 2), Cryptosporidium parvum (n = 1), Cryptosporidium meleagridis (n = 1), and Cryptosporidium andersoni (n = 2). Furthermore, two C. hominis subtypes (IeA12G3T3 and IaA28R4) were detected. Three G. duodenalis-positive specimens were successfully amplified and sequenced at the triosephosphate isomerase and β-giardin loci, which led to the identification of assemblages C and B, respectively. Seven genotypes (D, Type IV, EbpC, Peru11, EbpD, A, and I) were identified in E. bieneusi-positive specimens. Conclusions Our findings should increase awareness of AIDS-related opportunistic intestinal pathogens, and indicate the need for routine examination in clinical practice for the detection of Cryptosporidium spp., G. duodenalis, and E. bieneusi. Homology analyses of the three intestinal pathogens at the nucleotide and/or amino acid levels indicated their zoonotic potential. Graphical Abstract

Automatic classification of dermatological images is an important technology that assists doctors in performing faster and more accurate classification of skin diseases. Recently, convolutional neural networks (CNNs) and Transformer networks have been employed in learning respectively the local and global features of lesion images. However, existing works mainly focus on utilizing a single neural network for feature extraction, which limits the model classification performance. In order to tackle this problem, a novel fusion model, named ConvNeXt-ST-AFF, is proposed in this paper, by combining the strengths of ConvNeXt and Swin Transformer (ConvNeXt-ST in the model’s name). In the proposed model, the pretrained ConvNeXt and Swin Transformer networks extract local and global features from images, which are then fused using Attentional Feature Fusion (AFF) submodules (AFF in the model’s name). Additionally, in order to enhance the model’s attention on the regions of skin lesions during training, an Efficient Channel Attention (ECA) module is incorporated into the ConvNeXt network. Moreover, the proposed model employs a denoising module to reduce the influence of artifacts and improve the image contrast. The results, obtained by experiments conducted on two datasets, demonstrate that the proposed ConvNeXt-ST-AFF model has higher classification ability, according to multiple evaluation metrics, compared to the original ConvNeXt and Swin Transformer, and other state-of-the-art classification models.

A series of new nanobiotechnology-based methods have been developed toward achieving safe and efficient cancer treatment. Gold nanorods (AuNRs) have attracted increasing attention owing to their unique optical characteristics, good biocompatibility, and low toxicity, and they have thus been widely used in tumor treatment. In this study, an AuNR-based system was designed by attaching microRNA-192 (miR-192) to polydopamine-coated AuNRs (AuNR@PDA) to explore the possibility of combining genetic and photothermal therapies. RNA/AuNR@PDA exhibited an excellent thermal conversion efficiency under near-infrared (NIR) laser irradiation and excellent biocompatibility. Thus, photothermal therapy (PTT) was combined with gene therapy, which was effected by miR-192, a genetic drug that inhibits cancer cell growth. The combinatory treatment approach entailing the AuNRs-based drug carrier system exhibited encouraging antitumor efficacy.

BackgroundHeterozygous pathogenic variants in HNF4A gene cause maturity-onset diabetes of the young type 1 (MODY1). The mutation carriers for MODY1 have been reported to be relatively rare, in contrast to the most frequently reported forms of MODY2 and MODY3.MethodsWhole exome sequencing (WES) and Sanger sequencing were performed for genetic analysis of MODY pedigrees. Tertiary structures of the mutated proteins were predicted using PyMOL software.ResultsThree heterozygous missense mutations in the HNF4A gene, I159T, W179C, and D260N, were identified in the probands of three unrelated MODY families using WES, one of which (W179C) was novel. Cascade genetic screening revealed that the mutations co-segregated with hyperglycemic phenotypes in their families. The molecular diagnosis of MODY1 has partly transformed its management in clinical practice and improved glycemic control. The proband in family A successfully converted to sulfonylureas and achieved good glycemic control. Proband B responded well to metformin combined with diet therapy because of his higher body mass index (BMI). The proband in family C, with paternal-derived mutations, had markedly defective pancreatic β-cell function due to the superposition effect of T2DM susceptibility genes from the maternal grandfather, and he is currently treated with insulin. In silico analysis using PyMOL showed that the I159T and D260N mutations altered polar interactions with the surrounding residues, and W179C resulted in a smaller side chain.DiscussionWe identified three heterozygous missense mutations of HNF4A from Chinese MODY families. Structural alterations in these mutations may lead to defects in protein function, further contributing to the hyperglycemic phenotype of mutation carriers.

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsⅢ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate AsⅢ in arsenic-nickel complex by nickel acetate gradient method. The AsⅢ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of AsⅢ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’ apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified AsⅢ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.

IntroductionCandida palmioleophila is a rare human pathogenic fungus, which has been poorly characterized at the genome level. In this study, we reported the first fatal case of C. palmioleophila infection in China and investigate the microevolution of C. palmioleophila in the human host environment.MethodsA series of C. palmioleophila stains were collected from the patient at different time points for routine microbial and drug sensitivity testing. The first C. palmioleophila isolate 07202534 was identified by de novo whole genome sequencing. The in vitro and in vivo genetic evolutionary characteristics of C. palmioleophila were discussed based on the analysis of bioinformatics data.ResultsThe six C. palmioleophila isolates displayed dose-dependent sensitivity to fluconazole. The C. palmioleophila genome contained homologous genes such as CDR1 and MDR1, which were recognized to be related to azole resistance. In addition, amino acid variation was detected at F105L and other important sites of ERG11. In addition, the mean divergence time between C. palmioleophila and Scheffersomyces stipites CBS 6054 was 406.04 million years, indicating that C. palmioleophila originated earlier than its closest relative. In addition, the six strains of C. palmioleophila isolated form the patient had higher homology and fewer mutation sites, which indicated the stability in C. palmioleophila genome. We also found that C. palmioleophila had a wide natural niche and may evolve slowly.DiscussionWe believe that this study will contribute to improve our understanding of the genetic evolution, pathogenicity, and drug resistance of C. palmioleophila and will aid in the prevention and control of its spread.

Highlights Fabrication, characterizations and photothermal properties of MXenes are systematically described. Photothermal-derived antibacterial performances and mechanisms of MXenes-based materials are summarized and reviewed. Recent advances in the derivative applications relying on antibacterial properties of MXenes-based materials, including in vitro and in vivo sterilization, solar water evaporation and purification, and flexible antibacterial fabrics, are investigated. Abstract The pernicious bacterial proliferation and emergence of super-resistant bacteria have already posed a great threat to public health, which drives researchers to develop antibiotic-free strategies to eradicate these fierce microbes. Although enormous achievements have already been achieved, it remains an arduous challenge to realize efficient sterilization to cut off the drug resistance generation. Recently, photothermal therapy (PTT) has emerged as a promising solution to efficiently damage the integrity of pathogenic bacteria based on hyperthermia beyond their tolerance. Until now, numerous photothermal agents have been studied for antimicrobial PTT. Among them, MXenes (a type of two-dimensional transition metal carbides or nitrides) are extensively investigated as one of the most promising candidates due to their high aspect ratio, atomic-thin thickness, excellent photothermal performance, low cytotoxicity, and ultrahigh dispersibility in aqueous systems. Besides, the enormous application scenarios using their antibacterial properties can be tailored via elaborated designs of MXenes-based materials. In this review, the synthetic approaches and textural properties of MXenes have been systematically presented first, and then the photothermal properties and sterilization mechanisms using MXenes-based materials are documented. Subsequently, recent progress in diverse fields making use of the photothermal and antibacterial performances of MXenes-based materials are well summarized to reveal the potential applications of these materials for various purposes, including in vitro and in vivo sterilization, solar water evaporation and purification, and flexible antibacterial fabrics. Last but not least, the current challenges and future perspectives are discussed to provide theoretical guidance for the fabrication of efficient antimicrobial systems using MXenes.

Abstract The abnormal expression of long non-coding RNAs (LncRNAs) in platelet-derived microparticles (PMPs) is closely related to immune disorders and may lead to antiphospholipid antibody syndrome and recurrent miscarriage. To understand the association between the LncRNAs in PMPs and RM/APS, the differences in the expression of LncRNAs in RM/APS patients and healthy controls were analyzed. Microarray analysis and RT-qPCR detection proved that RM/APS patient exhibited high levels of LncNR_040117 expression. The lentiviral silent expression transfection of HTR-8/SVneo cells indicated that LncNR_040117 downregulation decreased the activity of HTR-8/SVneo cells and inhibited the MAPK signaling pathway, further confirming the biomarker proficiency of LncNR_040117 for RM/APS. After that, we proposed a β-In2S3@g-C3N4 nanoheterojunction-based photoelectrochemical (PEC) biosensor to achieve the ultrasensitive detection of LncNR_040117. The nanoheterojunction aids in the effective separation of photogenerated carriers and significantly improve the photocurrent response of the biosensor. The conjugation of LncNR_040117 onto the PEC biosensing platform increased the steric hindrance between electrolyte and electrode, subsequently decreasing the photocurrent signal. The PEC biosensor showed a wide detection range of 0.1–106 fM and a low limit of detection of 0.025 fM. For clinical sample testing, the results of the PEC and RT-qPCR were highly consistent. Overall, LncNR_040117 in PMPs was identified as an effective biomarker for RM/APS and could be accurately detected by the proposed PEC biosensor, which is expected to provide a reliable diagnostic platform for RM/APS.

Abstract Cryptosporidium spp. and Giardia duodenalis are commonly detected intestinal protozoa species in humans and animals, contributing to global gastroenteritis spread. The present study examined the prevalence and zoonotic potential of Cryptosporidium spp. and G. duodenalis in Himalayan marmots and Alashan ground squirrels in China's Qinghai-Tibetan Plateau area (QTPA) for the first time. Four hundred ninety-eight intestinal content samples were collected from five counties of QTPA of Gansu province, China. All samples were examined for Cryptosporidium spp. and G. duodenalis by PCR amplification. The resultant data were statistically analyzed by chi-square, Fisher's test and Bonferroni correction using SPSS software 25. 0. Cryptosporidium positive samples were further subtyped through analysis of the 60-kDa glycoprotein (gp60) gene sequence. A total of 11 and 8 samples were positive for Cryptosporidium spp. and G. duodenalis, respectively. Prevalence of Cryptosporidium spp. and G. duodenalis were 2.5% (10/399) and 1.5% (6/399) in Himalayan marmots, 1.0% (1/99) and 2.0% (2/99) in Alashan ground squirrels, respectively. Sequence analysis confirmed the presence of C. rubeyi (n = 2), ground squirrel genotype II (n = 7), chipmunk genotype V (n = 1) and horse genotype (n = 1). The horse genotype was further subtyped as novel subtype VIbA10. G. duodenalis zoonotic assemblages A (n = 1), B (n = 6), E (n = 1) were identified in the present study. This is the first study to identify Cryptosporidium spp. and G. duodenalis in Himalayan marmots and Alashan ground squirrels, suggesting the potential zoonotic transmission of the two pathogens in QTPA.

Open innovation crowdsourcing can help enterprises meet the challenges of a rapidly changing environment and improve their innovation performance. This study introduces network externalities as influencing factors of the crowdsourcing open innovation synergy mechanism. This study constructed the game payment matrix of the crowdsourcing open innovation synergy mechanism, and the evolutionary game method obtained the equilibrium solution of the crowdsourcing open innovation synergy mechanism. The impact of changes in the main influencing factors on the issuers' and receivers’ willingness to collaborate and innovate was explored through numerical and case studies. The study shows that the higher the synergy benefit and its allocation coefficient need to be within a reasonable range for the willingness to collaborate and innovate to increase; the lower the original cost of both parties, and the higher the cost reduction coefficient under the policy support of the crowdsourcing platform, the higher the willingness to collaborate and innovate; the higher the network externality and the lower the penalty for breach of contract, the higher the desire to collaborate and innovate. The study recommends strengthening non-school education to guide innovation for all, and refining relevant policies to tailor innovation to local conditions. This study provides a new perspective and theoretical guidance for enterprises to build a crowdsourcing open innovation synergy mechanism and is a valuable reference for open innovation management.

Objective: To investigate the effect and clinical significance of myeloid-derived suppressor cells (MDSCs) levels and serum miRNA-21 expression in advanced non-small cell lung cancer (NSCLC) patients. Methods: Advanced NSCLC patients treated at the First People’s Hospital of Tongxiang City, Zhejiang Province, between July 2021 and June 2022 were included in this study. MDSCs in the peripheral circulation were assessed by flow cytometry, and serum miRNA-21 expression was assessed by q-PCR. The effects of miRNA-21 on MDSC proliferation and ARG-1 and inducible nitric oxide synthase (iNOS) secretion from MDSCs were examined using in vitro cell experiments. In addition, the correlation between MDSC and CEA, CRP and Ki67 was analyzed. Results: Compared with those in the peripheral circulation of individuals in the control group, the expression levels of polymorphonuclear-MDSCs (PMN-MDSCs) and miRNA-21 in the peripheral circulation of NSCLC patients were significantly higher, and the two groups were significantly positively correlated. In in vitro cell experiments, miRNA-21 mimics promoted MDSC proliferation and increased ARG-1 and iNOS secretion and miRNA-21 inhibtor has an opposite result. In addition, PMN-MDSCs in the peripheral circulation of NSCLC patients were significantly positively correlated with carcinoembryonic antigen (CEA), C-reactive protein (CRP), and Ki67. Conclusion: The blood of advanced NSCLC patients contains high levels of MDSCs and miRNA-21, and the two may interact to impact on NSCLC.

Ammonia (NH3) emissions affect the environment, the climate, and human health and originate mainly from agricultural sources like urea fertilizers. Such losses from urea fertilizer can be avoided by different application techniques like incorporation. However, the knowledge of the effect of these techniques on NH3 emissions is very limited and ambiguous since incorporation can also promote nitrous oxide (N2O) emissions. Three different principles of fertilizer incorporation methods were compared in three different soils (sandy, loamy, and clayey) at two moisture levels of 70% and 30% water-holding capacity (WHC), shallow mixing at 2 cm, injection with the slit technique at 5 cm, and deep complete incorporation at 5 cm simulating plow incorporation. The laboratory study was conducted with open dynamic incubation chambers where NH3 emissions were monitored with washing bottles while N2O emissions were studied with gas chromatographic (GC) measurements. The highest cumulative NH3 emissions occurred at low soil moisture levels in sandy soil (34% of the N applied). A maximum reduction in emissions by 87% was achieved with slit injection and 82% with deep injection compared to standard surface application. The reduction effect was positively related to increasing clay content. N2O emissions were delayed and highest from sandy soil. Overall, all urea incorporation techniques showed great potential for mitigating NH3 emissions on the clayey soil; for sandy and drier soils, only deeper or closed slot injection were consistently effective. However, connected to the surface incorporation at the higher moisture level, a relevant increase in N2O emissions compared to surface application was observed. Therefore, an increase in N2O emissions by urea incorporation may rule out specific incorporation techniques for NH3 emissions reduction from field-applied urea. In agricultural practice, a lower reduction in NH3 by fertilizer incorporation can be assumed in sandy soils or under dry soil conditions, as well as a more challenging technical implementation.

Abstract Background Giardia duodenalis is a common parasitic diarrheal agent in humans, especially in developing countries. The aim of this study was to investigate the prevalence and multilocus genetic characterization of G. duodenalis in patients with diarrhea and animals in northeastern China, and to assess the epidemiological role of animals in the transmission of human giardiasis. Methods A total of 1739 fecal specimens from 413 diarrheal patients and 1326 animals comprising 16 mammal species were collected in Heilongjiang Province of China and screened for G. duodenalis by PCR and sequencing of the SSU rRNA gene. All G. duodenalis-positive specimens were subtyped by PCR and sequencing of the bg, tpi, and gdh genes. To detect additional mixed infections of different assemblages, assemblage A/B/E-specific PCRs were performed to amplify the tpi gene. Results Sequence analysis of the SSU rRNA gene determined the prevalence of G. duodenalis (5.81%, 24/413) in diarrheal patients, with a peak in minors aged 5–17 years, and identified assemblages A and B. MLG-AII and MLG-B1 were obtained based on concatenated nucleotide sequences of the bg, tpi, and gdh genes, with MLG-AII being identical to a cat-derived isolate reported previously. By sequence analysis of the SSU rRNA gene, G. duodenalis was detected in 214 (16.14%) animals belonging to 11 mammal species, with the prevalence ranging from 1.69 to 53.85%, and assemblages A to G were identified. Sequence analysis of the bg, tpi, and gdh genes from 46 specimens produced 31 MLGs, including MLG-AI (n = 1), MLG-B2–B8 (n = 18), and MLG-E1–E23 (n = 27). Conclusions The finding of G. duodenalis in diarrheal patients enhances consciousness of detecting G. duodenalis in clinical practice and emphasizes the importance of health education in local inhabitants, especially in the age group of 5–17 years. The identification of seven assemblages (A to G) and 33 MLGs reveals genetic heterogeneity of G. duodenalis in the investigated areas. Due to insufficient homology data on the zoonotic transmission of G. duodenalis, the precise epidemiological role that animals play in the transmission of human giardiasis needs to be assessed by more large-scale molecular epidemiological investigations of local humans and animals. Graphical Abstract

Abstract Chemodynamic therapy (CDT) based on Fenton or Fenton-like reactions is an emerging cancer treatment that can both effectively fight cancer and reduce side effects on normal cells and tissues, and it has made important progress in cancer treatment. The catalytic efficiency of Fenton nanocatalysts(F-NCs) directly determines the anticancer effect of CDT. To learn more about this new type of therapy, this review summarizes the recent development of F-NCs that are responsive to tumor microenvironment (TME), and detailedly introduces their material design and action mechanism. Based on the deficiencies of them, some effective strategies to significantly improve the anticancer efficacy of F-NCs are highlighted, which mainly includes increasing the temperature and hydrogen peroxide concentration, reducing the pH, glutathione (GSH) content, and the dependence of F-NCs on acidic environment in the TME. It also discusses the differences between the effect of multi-mode therapy with external energy (light and ultrasound) and the single-mode therapy of CDT. Finally, the challenges encountered in the treatment process, the future development direction of F-NCs, and some suggestions are analyzed to promote CDT to enter the clinical stage in the near future. Graphical Abstract

Accurate segmentation of lesions can provide strong evidence for early skin cancer diagnosis by doctors, enabling timely treatment of patients and effectively reducing cancer mortality rates. In recent years, some deep learning models have utilized complex modules to improve their performance for skin disease image segmentation. However, limited computational resources have hindered their practical application in clinical environments. To address this challenge, this paper proposes a lightweight model, named GSCEU-Net, which is able to achieve superior skin lesion segmentation performance at a lower cost. GSCEU-Net is based on the U-Net architecture with additional enhancements. Firstly, the partial convolution (PConv) module, proposed by the FasterNet model, is modified to an SConv module, which enables channel segmentation paths of different scales. Secondly, a newly designed Ghost SConv (GSC) module is proposed for incorporation into the model’s backbone, where the Separate Convolution (SConv) module is aided by a Multi-Layer Perceptron (MLP) and the output path residuals from the Ghost module. Finally, the Efficient Channel Attention (ECA) mechanism is incorporated at different levels into the decoding part of the model. The segmentation performance of the proposed model is evaluated on two public datasets (ISIC2018 and PH2) and a private dataset. Compared to U-Net, the proposed model achieves an IoU improvement of 0.0261 points and a DSC improvement of 0.0164 points, while reducing the parameter count by 190 times and the computational complexity by 170 times. Compared to other existing segmentation models, the proposed GSCEU-Net model also demonstrates superiority, along with an advanced balance between the number of parameters, complexity, and segmentation performance.

Heteroatom doping, particularly with nonmetallic atoms such as N, P, and S, has proven to be an effective strategy for modulating the fluorescent properties of carbon dots (CDs). However, there are few reports on the regulation of the photoluminescence of CDs by transition-metal doping. In this work, nickel-doped CDs (Ni-CDs) were fabricated using the hydrothermal approach. Ni atoms were incorporated into the sp2 domains of the CDs through Ni-N bonds, resulting in an increased degree of graphitization of the Ni-CDs. Additionally, Ni-atom doping served to shorten the electron transition and recombination lifetimes, and suppress the nonradiative recombination process, resulting in an absolute fluorescence quantum yield of 54.7% for the Ni-CDs. Meanwhile, the as-prepared Ni-CDs exhibited excellent biocompatibility and were utilized for fluorescent bioimaging of HeLa cells. Subsequently, the Ni-CDs were employed as fluorescent anticounterfeiting inks for the successful encryption of two-dimensional barcodes. Our work demonstrates a novel heteroatom doping strategy for the synthesis of highly fluorescence-emitting CDs.

PurposeThe aim of our study was to determine whether delta red blood cell distribution (ΔRDW) improves neurological outcomes in acute ischemic stroke (AIS) patients 2 years after intravenous thrombolysis (IVT) therapy.MethodsAIS patients who received IVT between January 2013 and December 2019 were retrospectively analyzed. In accordance with their mRS scores, the patients were divided into two groups. A binary logistic regression analysis was conducted to determine the influencing factors of adverse functional outcomes. It was decided to evaluate the variables' the predictive ability by using the area under the receiver operating characteristic. For the poor neurological recovery risk model, features were selected using the LASSO regression model. We also developed a predictive model based on logistic regression analysis, which combined the features selected in the minimum absolute contraction and selection operator regression models. An evaluation of the discrimination, calibration, and clinical applicability of the predictive model was conducted using the C index, calibration chart, and decision curve analysis. Internal validation was evaluated via bootstrapping.ResultsBinary logistic regression analysis showed that ΔRDW was an independent influencing factor for poor neurofunctional outcomes. The most appropriate ΔRDW cut-off value for predicting the recovery of poor neurological outcomes was 18.9% (sensitivity: 89.9%, specificity: 78.6%, p < 0.001). The predictive factors included in the nomogram were age, the occurrence of CHD, stroke, AF, ΔRDW, NIHSS score at onset, interval time from onset to IVT, and whether there were indwelling urine catheters and gastric tubes. The model has not only a good discrimination ability, which was indicated by an overall C index of 0.891 (95% confidence interval: 0.829–0.953), but also a considerable calibration ability. Decision curve analysis showed that the nomogram of adverse neurological outcomes recovery was useful in the clinical practice when intervention was implemented above the threshold of 1% possibility of adverse neurological outcomes recovery.ConclusionIn patients with AIS after thrombolysis, the ΔRDW is a potential influencing factor that can be readily used to predict the likelihood of poor neurological function recovery.

Stem cell therapy is a promising treatment for knee osteoarthritis, but few bibliometric studies have been performed on the subject. Bibliometric analysis is helpful for identifying the most influential studies in a specific field and can evaluate the global research trends in stem cell therapy for knee osteoarthritis. The Web of Science Core Collection was searched for publications from 2001 to 2021. Publication performance was analyzed using several bibliometric parameters, including VOSviewer, to identify the research landscape of trends in topics, and CiteSpace was investigated to identify the keywords that have the strongest citation bursts. From 2001 to 2021, in total, 1,345 publications explored the research on stem cells in knee osteoarthritis. The United States contributed the largest number of publications and at the top list of international collaborations. Tokyo Medical and Dental University ranked first among institutions in the overall number of articles and citations. The journal of Osteoarthritis and Cartilage had the largest number of publications. Sekiya Ichiro was the most cited author, with 32 articles. The keywords with the most frequent occurrence were “osteoarthritis,” “mesenchymal stem cells,” and “cartilage,” in descending order of frequency. “fibroblast growth factor” and “extracellular vesicle” were the first and last searched theme terms, respectively. The number of publications on stem cells for knee osteoarthritis stays growing. Cartilage repair and paracrine function are current research hotspots for the stem cell therapy mechanism. Stem cell therapy has gradually advanced from basic research to the clinical application stage.

Arsenic trioxide (ATO) combined with all trans retinoic acid (ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia (APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients' compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel (PPSG) loaded with ATO and ATRA was developed. ATO+ATRA-PPSG (AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO+ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transformation and application.

Abstract Blastocystis hominis and Cystoisospora belli are considered to be common opportunistic intestinal protozoa in HIV/AIDS patients. In order to investigate the prevalence and genetic characteristics of B. hominis and C. belli in HIV/AIDS patients, a total of 285 faecal samples were individually collected from HIV/AIDS patients in Guangxi, China. B. hominis and C. belli were investigated by amplifying the barcode region of the SSU rRNA gene and the internal transcribed spacer 1 (ITS-1) region of the rRNA gene, respectively. Chi-square test or Fisher’s exact test were conducted to assess the risk factors related to B. hominis and C. belli infection. The prevalence of B. hominis and C. belli was 6.0% (17/285) and 1.1% (3/285) respectively. Four genotypes of B. hominis were detected, with ST3 (n = 8) and ST1 (n = 6) being predominant, followed by ST6 (n = 2) and ST7 (n = 1). Females had a statistically higher prevalence of B. hominis (11.6%) than males (4.2%). The statistical analysis also showed that the prevalence of B. hominis was significantly associated with age group and educational level. Our study provides convincing evidence for the genetic diversity of B. hominis, which indicates its potential zoonotic transmission and is the first report on the molecular characteristics of C. belli in HIV/AIDS patients in China.

BackgroundPLA2G6-associated neurodegeneration (PLAN) is a heterogeneous group of neurodegenerative diseases caused by biallelic PLA2G6 mutations, covering diseases such as infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). The study aims to report the clinical and genetic features of a series of PLAN patients.MethodsThe clinical and radiological findings of five Chinese patients from three families were collected. Whole-exome next generation sequencing (NGS) was applied to identify the genetic causes. Co-segregation analysis of the detected candidate variants were performed in their families. The pathogenicity of identified novel variants was predicted by in silico analysis.ResultsNGS revealed compound heterozygous variants of PLA2G6 gene in all five patients. There were six PLA2G6 variants identified, including two known variants (c.116G>A, c.238G>A) and four novel variants (c.2120dupA, c.2071C>G, c.967G>A, c1534T>A). ACMG predicts c.2120dupA to be pathogenic, c.2071C>G and c.1534T>A to be likely pathogenic, and c1534T>A to be of uncertain significance. Clinically, four patients fell into the diagnosis of ANAD, and 1 into the diagnosis of AREP. Brain imaging revealed cerebellar atrophy, iron deposition in bilateral globus pallidus, and substantia nigra in three cases.ConclusionsFour novel pathogenic variants were discovered and the pathogenic variant spectrum of the PLA2G6 gene was expanded.

Abstract To tackle the aggravating electromagnetic wave (EMW) pollution issues, high-efficiency EMW absorption materials are urgently explored. Metal–organic framework (MOF) derivatives have been intensively investigated for EMW absorption due to the distinctive components and structures, which is expected to satisfy diverse application requirements. The extensive developments on MOF derivatives demonstrate its significantly important role in this research area. Particularly, MOF derivatives deliver huge performance superiorities in light weight, broad bandwidth, and robust loss capacity, which are attributed to the outstanding impedance matching, multiple attenuation mechanisms, and destructive interference effect. Herein, we summarized the relevant theories and evaluation methods, and categorized the state-of-the-art research progresses on MOF derivatives in EMW absorption field. In spite of lots of challenges to face, MOF derivatives have illuminated infinite potentials for further development as EMW absorption materials.

Acoustic levitation supplies a containerless state to eliminate natural convection and heterogeneous crystal nucleation and thus provides a highly uniform and ultra clean condition in the confined levitating area. Herein, we attempt to make full use of these advantages to fabricate well dispersed metal nanoparticles. The gold nanoparticles, synthesized in an acoustically levitated droplet, exhibited a smaller size and improved catalytic performance in 4-nitrophenol reduction were synthesized in an acoustically levitated droplet. The sound field was simulated to understand the impact of acoustic levitation on gold nanoparticle growth with the aid of crystal growth theory. Chemical reducing reactions in the acoustic levitated space trend to occur in a better dispersed state because the sound field supplies continuous vibration energy. The bubble movement and the cavitation effect accelerate the nucleation, decrease the size, and the internal flow inside levitated droplet probably inhibit the particle fusion in the growth stage. These factors lead to a reduction in particle size compared with the normal wet chemical synthetic condition. The resultant higher surface area and more numerous active catalytic sites contribute to the improvement of the catalytic performance.

Soil organic carbon (SOC) is the largest and most important terrestrial carbon pool, and it can influence global environmental management and food security. However, the spatial variability of SOC in cultivated areas and the relative controlling factors that drive the variations across different spatial scales are still not clear. On the basis of 2745 soil samples collected during 2006–2011, the spatial variability of SOC was first obtained from all of Jilin Province. Then, five categories of predictors, including climate, topography, soil, vegetation, and management practice, were selected to establish the environmental datasets at seven target scales (500 m, 1 km, 2.5 km, 5 km, 10 km, 25 km, and 50 km). Last, a machine learning method (random forest) was used to analyze the scale behaviors of these predictors on SOC variations. The results showed that the SOC content in Jilin Province had a moderate spatial dependence. Across all seven scales, elevation, precipitation, and temperature-related variables always had an important impact on SOC variation. Topography-related predictors had higher importance (relative importance (RI): 30.76%–44.20%) at the 1 km to 50 km scale, especially in the eastern humid mountainous ecoregion, while management practices had the largest importance (RI: 19%–29.20%) at the 500 m to 2.5 km scale in the central semihumid plain ecoregion. For the western semiarid plain, precipitation had higher importance (RI: 18.88%–23.68%) across all seven scales. Understanding the scale behaviors of environmental factors on SOC variations will be useful for improving soil health, food security and global environmental management.

Background and PurposeThe diagnosis of multiple system atrophy (MSA) remains challenging in clinical practice. This study investigated the value of hypointense signals in the putamen (“black straight-line sign”) in diffusion-weighted imaging (DWI) of brain MRI for distinguishing (MSA) from Parkinson's disease (PD).MethodsWe retrospectively enrolled 30 MSA patients, 30 PD patients, and 30 healthy controls who had undergone brain MRI between 2016 and 2020. Two readers independently assessed the signal intensity of the bilateral putamen on DWI. The putaminal hypointensity was scored using 4-point visual scales. Putaminal hypointensity and the presence of a “black straight-line sign” were statistically compared between MSA and PD or healthy controls.ResultsThe mean scores of putaminal hypointensity in DWI in the MSA group were significantly higher than in both the PD (U = 315.5, P = 0.034) and healthy control groups (U = 304.0, P = 0.022). Uni- or bilateral putaminal hypointensity in DWI with a score ≥2 was identified in 53.3% (16/30), 16.7% (5/30), and 13.3% (4/30) of MSA, PD, and healthy controls, respectively, with significant differences between MSA and PD (X2 = 8.864, P = 0.003) or healthy controls (X2 = 10.800, P = 0.001). Notably, the “black straight-line sign” of the putamen was observed in 16/30 (sensitivity 53.3%) patients with MSA, while it was absent in PD and healthy controls (specificity 100%). There were no significant differences for the presence of “black straight-line sign” in the MSA-P and MSA-C groups (X2 = 0.433, P = 0.510).ConclusionThe “black straight-line sign” of the putamen in DWI of head MRIs has the potential to serve as a diagnostic marker for distinguishing MSA from PD.

The urgent requirement of minimising the worldwide cost of corrosion, accompanied by the increasingly pivotal role of advanced oxide materials, highlights the importance of understanding the mechanisms of material oxidation at the atomic level, which could help us to precisely control the oxidation processes. Nowadays, we are able to model and predict how the surface structures of materials evolve during oxidation based on the cross-fertilisation of various computational techniques. This review first overviews the state-of-the-art first-principles and force-field-based approaches for modelling surface reactions. Then, classical theories and recent advances in understanding the atomic-scale oxidation of bulk materials are introduced, from the initial solid-gas interactions to the subsequent oxide film growth. Defect-promoted oxidation mechanisms will be discussed in detail. Finally, distinct oxidation mechanisms of nanomaterials are discussed, including nanoparticles, nanowires, and two-dimensional materials, which are significantly different from their bulk counterparts and could result in novel oxide nanostructures with unique properties. This review provides a systematic overview of the central role of computational techniques in probing the atomic-scale oxidation mechanisms, which could further guide the synthesis of oxide-based cutting-edge materials such as ultra-thin oxide films and hollow oxide nanostructures.

Due to the extensive development model of ''focusing on development with high investment'' for a long time, the resources input of industry in Liaoning is seriously mismatched with economic output, resulting in serious waste of resources. In view of this, the consumption of virtual water and embodied energy was calculated through the input-output model, and they were incorporated into the undesired super-SBM to compare the virtual water efficiency, embodied energy efficiency and virtual water-embodied energy coupling efficiency of 23 sectors. Finally, we analyzed the dynamic change in coupling efficiency using the Malmquist index model. The results showed that: (1) Food and Tobacco was the largest consumer of virtual water, accounting for 31.3% of total consumption; Petroleum Product Processing was the largest consumer of embodied energy, accounting for 24.4% of total consumption. (2) Regarding the embodied resource transferring pattern, the total industrial transferrable flux decreased by 40.2% (virtual water) and 12.5% (embodied energy) from 2012 to 2018. Smelting and Pressing of Metals was not only an important supplier but also a significant recipient, receiving metal ore resources and transferring them to different equipment manufacturers. (3) On the whole, the embodied energy efficiency was greater than the virtual water efficiency, but neither had reached the production frontier in most sectors. The coupling efficiency of the overall industry showed a ''V'' trend, but the efficiency value did not reach 1. (4) Although total factor productivity (TFP) and the corresponding decomposition factors were significantly different in 23 sectors, pure technical efficiency (PEC) obviously restricted TFP in most sectors. In addition, scale efficiency (SEC) maintained a stable balanced, especially in heavy manufacturing industry. In contrast, technology efficiency (TC) severely constrained TFP especially in Chemical Products and Production and Supply of Water.

Abstract Objective This study aimed to investigate mitochondrial changes and the mitochondrial antiviral‐signaling protein (MAVS)‐type I interferon (IFN1) signaling pathway in the muscles of anti‐melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients. Methods Eleven anti‐MDA5 DM and ten antibody‐negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN‐stimulated gene 15, which are components of the MAVS‐IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed. Results Anti‐MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P

Background: Parkinson’s disease (PD) is a common selective and progressive neurodegenerative disorder of nigrostriatal dopaminergic (DA) neurons. Quercetin is a bioflavonoid with antioxidant, anti-inflammatory, anti-aging and anti-cancer properties. However, the exact mechanism by which quercetin exerts its protective effect on DAergic neurons remains unclear. Purpose: To investigate the underlying molecular mechanism of quercetin’s protective effect on DA neurons using 1-methyl-4-phenylpyridinium (MPP+)-induced PD ferroptosis model in vitro. Methods: MPP+ was used to induce cytotoxicity in SH-SY5Y/primary neurons. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The expression levels of ferroptosis-related proteins (NCOA4, SLC7A11, Nrf2, and GPX4) were determined by Western blotting. Malondialdehyde (MDA), iron, and GPX4 levels were assesed using corresponding assay kits. Lipid peroxidation was assessed by C11-BODIPY staining. Results: In the MPP+-induced ferroptosis model of SH-SY5Y cells, the expressions of SLC7A11 and GPX4 were inhibited, and the expression of NCOA4 protein was increased, causing the overproduction of MDA and lipid peroxidation. Quercetin can reduce the above changes caused by MPP+, that is, reduce the protein expression of NCOA4 in SH-SY5Y cells, increase SLC7A11 and GPX4 partially inhibited by MPP+, and reduce MDA overproduction and lipid peroxidation to protect DA neurons. Nrf2 inhibitor ML385 could inhibit quercetin-induced increase of GPX4 and SLC7A11 protein expression, indicating that the protective effect of quercetin was mediated through Nrf2. Conclusions: The results of this study suggest that quercetin regulates ferroptosis through Nrf2-dependent signaling pathways, thereby inhibiting MPP+-induced neurotoxicity in SH-SY5Y/primary neurons.

Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway.Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining.Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor.Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.