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Mulberry leaf is abundant in bioactive ingredients, and their release could be affected by different treatment technologies. In this study, the mulberry leaf was treated with methods of superfine grinding (MG), wall-broken (MB), and water extraction-methanol precipitation (ME). Three processing mulberry leaves were equally added to the feed of largemouth bass (Micropterus salmoides), respectively, and the growth, liver health and intestinal microorganisms were analyzed. According to statistical analysis, the growth of the three experimental groups was remarkedly better than that of the control group fed with a basic diet. The MB group had a higher specific growth rate (SGR) and weight gain rate (WGR) than the MG and ME groups. Mulberry leaf supplementation could significantly reduced blood glucose and serum total cholesterol (TC), very low-density lipoprotein (VLDL) and triglyceride (TG) levels, improved hepatic glycogen, lipid and TG levels, and these parameter values of the MB group were superior to the other treatments. Additionally, MB treatment could up-regulate the expressions of gpx and cat in the liver compared with the control and boost the activities of antioxidant enzymes (GSH-Px and CAT). Meanwhile, MB supplementation suppressed the expressions of pro-inflammatory cytokines (TNFα and IL-8) and up-regulated anti-inflammatory cytokines (IL-10 and TGF-β) in liver compared to the control group. Accordingly, the hepatic histostructure showed an improvement in the treatment group, and mulberry leaf could also dramatically lower the apoptosis of hepatic cells, particularly in the MB group. Furthermore, MB treatment reduced gut dysbiosis by limiting the development of gram-negative and possibly dangerous bacteria. In sum, this study firstly disclosed that the biological effectiveness of mulberry leaf might be impacted by various processing techniques. Especially MB-treatment effectively ameliorates glucose, lipid metabolism and liver immunology in largemouth bass.

In order to study the effects of different cooking methods (frying, steaming and boiling) on the volatile flavor compounds in beef, solid phase microextraction (SPME) combined with gas chromatography-mass spectrometry (GC-MS) was used to analyze the volatile flavor compounds of beef. GC-MS method was used to isolate and identify volatile flavor compounds in beef samples treated with different cooking methods. The results showed that 114 volatile flavor compounds were isolated and identified from beef samples treated by different cooking methods. The ways of cooking had significant effects on the volatile flavor compounds of beef, among which frying had the strongest effect, followed by steaming, and boiling had the slightest effect. A total of 61 compounds were detected in raw beef, while 59, 33 and 60 compounds were detected in steamed beef, fried beef and boiled beef, respectively. There were 14 volatile flavor compounds in common in raw beef, steamed beef, fried beef and boiled beef, which were listed in the following: 2-hydroxy-pentanoic acid methyl ester, hexanoic acid, dimethyl-silanediol, 1-octene-3-ol, 1-pentanol, nonanal, decanal, hexanal, tetradecanal, octanal, acetone, 2,3-octanedione, 3,7,11,15-tetramethylhexadiene-2-ene, methoxy-phenyl-oxime. The main volatile flavor compounds in raw beef were hexanoic acid ethyl ester and hexanoic acid (the relative contents were 16.15% and 11.17%, respectively). The main volatile flavor compounds in boiled beef were nonanal and 2, 3-octanedione (13.44% and 11.94%, respectively). The main volatile flavor compounds in steamed beef was hexanal (relative content was 44.89%). The main volatile flavor compounds in fried beef were formaldehyde, nonanal and hexanal (19.49%, 17.66% and 9.58%, respectively). The results of principal component analysis (PCA) showed that esters, hydrocarbons, acids and aldehydes might be the main factors affecting the differentiation of volatile flavor compounds in different samples. The results from this study would provide a technical reference for beef processing.

Abstract Inspired by human brains, optoelectronic synapses are expected as one of significant steps for constructing neuromorphic systems. In addition, intensive attention has been paid to biodegradable and biocompatible materials for developing green electronics. In this regard, environmentally friendly organic optoelectronic synaptic transistors based on wood-derived cellulose nanopaper (WCN) as dielectric/substrate and nature chlorophyll-a as photoactive material are demonstrated. Both WCN and chlorophyll-a are biocompatible and biodegradable materials from natural organisms. Versatile synaptic behaviors have been well mimicked by the modulation of both electrical and optical signals. More significantly, optical wireless communication is experimentally emulated and the information processing capability is also verified in pattern recognition simulation. Furthermore, the flexible synaptic transistors exhibit no apparent synaptic performance degradation even when the bending radius is reduced to 1 mm. Our work may develop a promising approach for the development of green and flexible electronics in neuromorphic visual systems.

Abstract Background Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. Methods In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. Results DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. Conclusions We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

Abstract Background Hepatic epithelioid hemangioendothelioma (HEH) is extremely rare and the MRI features have never been investigated in a large group of patients. Methods A retrospective study was designed to review the MRI images of HEH patients. Two radiologists separately evaluated signal intensity (SI) on unenhanced imaging, morphological features, contrast-enhancement pattern at dynamic study. The MRI features were compared between patients with HEH and hepatic metastatic tumor (HMT). Results Fifty-seven HEH patients were included in this study and a total of 412 lesions were evaluated. On per-lesion analysis, the rate of coalescent lesion and subcapsular lesion were 18.2% and 39.8%, respectively. Capsular retraction and lollipop sign were observed in 47 lesions (11.4%) and 60 lesions (14.6%), respectively. Large lesions (> 5 cm) had the highest rate of coalescent lesion, subcapsular lesion, capsular retraction and lollipop sign. Target sign appeared in 196 lesions (47.6%) on T2 weighted (T2W) and 146 lesions (35.4%) on portal phase. Medium lesions (2–5 cm) had the highest rate of target sign on both T2W (72.9%) and portal phase (55.2%). On per-patient analysis, compare with HEH patients, HMT patients seldom had the appearance of lollipop sign (66.7% versus 6.4%, p

Anemarrhena asphodeloides is an immensely popular medicinal herb in China, which contains an abundant of mangiferin. As an important bioactive xanthone C-glycoside, mangiferin possesses a variety of pharmacological activities and is derived from the cyclization reaction of a benzophenone C-glycoside (maclurin). Biosynthetically, C-glycosyltransferases are critical for the formation of benzophenone C-glycosides. However, the benzophenone C-glycosyltransferases from Anemarrhena asphodeloides have not been discovered. Herein, a promiscuous C-glycosyltransferase (AaCGT) was identified from Anemarrhena asphodeloides. It was able to catalyze efficiently mono-C-glycosylation of benzophenone, together with di-C-glycosylation of dihydrochalcone. It also exhibited the weak O-glycosylation or potent S-glycosylation capacities toward 12 other types of flavonoid scaffolds and a simple aromatic compound with –SH group. Homology modeling and mutagenesis experiments revealed that the glycosylation reaction of AaCGT was initiated by the conserved residue H23 as the catalytic base. Three critical residues H356, W359 and D380 were involved in the recognition of sugar donor through hydrogen-bonding interactions. In particular, the double mutant of F94W/L378M led to an unexpected enzymatic conversion of mono-C- to di-C-glycosylation. This study highlights the important value of AaCGT as a potential biocatalyst for efficiently synthesizing high-value C-glycosides.

Abstract Clinical case We report a case of rheumatoid arthritis‐associated peripheral ulcerative keratitis (PUK) successfully treated with tocilizumab. Despite being treated with systemic corticosteroids and several disease‐modifying antirheumatic drugs, evern though received corneal transplantation, the patient was still going to lose her sight. Tocilizumab resulted in a good response with control of her systemic illness and preventing the progress of corneal lesions. Discussion Tocilizumab may be an additional tool for the patients with rheumatoid arthritis associated PUK that is refractory to other drugs.

ABSTRACT Corynebacterium striatum has recently received increasing attention due to its multiple antimicrobial resistances and its role as an invasive infection/outbreak agent. Recently, whole-genome sequencing (WGS)-based core genome multilocus sequence typing (cgMLST) has been used in epidemiological studies of specific human pathogens. However, this method has not been reported in studies of C. striatum. In this work, we aim to propose a cgMLST scheme for C. striatum. All publicly available C. striatum genomes, 30 C. striatum strains isolated from the same hospital, and 1 epidemiologically unrelated outgroup C. striatum strain were used to establish a cgMLST scheme targeting 1,795 genes (hereinafter referred to as 1,795-cgMLST). The genotyping results of cgMLST showed good congruence with core genome-based single-nucleotide polymorphism typing in terms of tree topology. In addition, the cgMLST provided a greater discrimination than the MLST method based on 6 housekeeping genes (gyrA, gyrB, hsp65, rpoB, secA1, and sodA). We established a clonal group (CG) threshold based on 104 allelic differences; a total of 56 CGs were identified from among 263 C. striatum strains. We also defined an outbreak threshold based on seven allelic differences that is capable of identifying closely related isolates that could give clues on hospital transmission. According to the results of analysis of drug-resistant genes and virulence genes, we identified CG4, CG5, CG26, CG28, and CG55 as potentially hypervirulent and multidrug-resistant CGs of C. striatum. This study provides valuable genomic epidemiological data on the diversity, resistance, and virulence profiles of this potentially pathogenic microorganism. IMPORTANCE Recently, WGS of many human and animal pathogens has been successfully used to investigate microbial outbreaks. The cgMLST schema are powerful genotyping tools that can be used to investigate potential epidemics and provide classification of the strains precise and reliable. In this study, we proposed the development of a cgMLST typing scheme for C. striatum, and then we evaluated this scheme for its applicability to hospital transmission investigations. This report describes the first cgMLST schema for C. striatum. The analysis of hospital transmission of C. striatum based on cgMLST methods has important clinical epidemiological significance for improving nosocomial infection monitoring of C. striatum and in-depth understanding of its nosocomial transmission routes.

USP1 (Ubiquitin-specific protease 1) is closely related to the prognosis of patients with liver cancer and plays an important role in DNA damage repair. C527 is a selective USP1 inhibitor (USP1i), which can regulate the protein ubiquitination to effectively inhibit the proliferation of cancer cells. However, its clinical application is hindered due to the poor water solubility and lack of tumor targeting. Moreover, the efficacy of single use of USP1i is still limited. Herein, a glutathione (GSH) sensitive amphiphilic polymer (poly (2-HD-co-HPMDA)-mPEG, PHHM) with disulfide bonds in the main chain was designed to encapsulate the USP1i as well as platinum (IV) prodrug (Pt (IV)–C12), resulting in the formation of composite nanoparticles, i.e., NP-Pt-USP1i. NP-Pt-USP1i can inhibit the DNA damage repair by targeting USP1 by the encapsulated USP1i, which ultimately increases the sensitivity of tumor cells to cisplatin and enhances the anti-cancer efficacy of cisplatin. Finally, an intraperitoneal tumor mice model and a patient-derived xenograft (PDX) of liver cancer mice model were established to prove that NP-Pt-USP1i could effectively inhibit the tumor growth. This work further validated the possibility of therapeutically target USP1 by USP1i in combination with DNA damaging alkylating agents, which could become a promising cancer treatment modality in the future.

BackgroundEarly detection of mild cognitive impairment (MCI) symptoms is an important step to its diagnosis and intervention. We developed a new screening test called “Efficient Online MCI Screening System” (EOmciSS) for use in community-dwelling older adults. It is a self-paced cognitive test to be completed within 10 minutes on tablets or smartphones in homes or care centers for older adults. ObjectiveThis study aims to test the validity of EOmciSS for identifying community-dwelling older adults with MCI risks. MethodsParticipants (N=827) completed EOmciSS and other screening tests for MCI. The psychometric properties tested were “subscale item difficulty,” “discriminative index,” “internal consistency,” and “construct validity.” We also tested between-group discrimination using the cross-validation method in an MCI group and a normal cognitive function (NCF) group. ResultsA total of 3 accuracy factors and 1 reaction time factor explained the structure of the 20 item factors. The difficulty level of accuracy factors (ie, “trail making,” “clock drawing,” “cube copying,” “delayed recall”) was 0.63-0.99, whereas that of the reaction time factor was 0.77-0.95. The discriminative index of the medium-to-high-difficulty item factors was 0.39-0.97. The internal consistency (Cronbach α) ranged from .41 (for few item factors) to .96. The training data set contained 9 item factors (CC-Acc1, P

The acceleration and heating of solar wind particles by magnetic reconnection are important mechanisms in space physics. Although alpha particles ( ^4 He ^2+ ) are the second most abundant population of solar wind ions, their kinetic behavior in solar wind magnetic reconnection is not well understood. Using the high-energy (1500–3000 eV) range of the Solar Wind Analyser/Proton–Alpha Sensor instrument on board Solar Orbiter, we study the kinetic features of alpha particles in an exhaust region of a Pestchek-like solar-wind reconnection event with a weak guide field. A pair of back-to-back compound discontinuities is observed in the exhaust region. We find that the plasma in the magnetic exhaust region is heated and bounded by slow shocks (SSs), while the accelerated reconnection jet is bounded by rotational discontinuities (RDs). The SSs are outside the RDs, which is not expected from the magnetohydrodynamical prediction. We suggest this different location of the discontinuities is due to the enhanced parallel temperature T _p _∥ > T _p _⊥ , which reduces the local Alfvén speed in the exhaust region, allowing the SSs to propagate faster than the RDs. Inside the exhaust region, the guide field is dominant. We find a two-population distribution of the alpha particles. These two populations are field aligned downstream the SSs and shift to have a perpendicular offset in the reconnection jet, suggesting that the change of the magnetic field at the RDs has similar timescales with the proton gyroperiod, but faster than those of the alpha particles, such that the alpha particles behave like pickup ions.

The trace magnetic power spectrum in the solar wind is known to be characterized by a double power law at scales much larger than the proton gyro-radius, with flatter spectral exponents close to −1 found at the lower frequencies below an inertial range with indices closer to [−1.5, −1.67]. The origin of the 1/ f range is still under debate. In this study, we selected 109 magnetically incompressible solar wind intervals ( δ ∣ B ∣/∣ B ∣ ≪ 1) from Parker Solar Probe encounters 1–13 that display such double power laws, with the aim of understanding the statistics and radial evolution of the low-frequency power spectral exponents from Alfvén point up to 0.3 au. New observations from closer to the Sun show that in the low-frequency range solar wind, turbulence can display spectra much shallower than 1/ f , evolving asymptotically to 1/ f as advection time increases, indicating a dynamic origin for the 1/ f range formation. We discuss the implications of this result on the Matteini et al. conjecture for the 1/ f origin as well as example spectra displaying a triple power law consistent with the model proposed by Chandran et al., supporting the dynamic role of parametric decay in the young solar wind. Our results provide new constraints on the origin of the 1/ f spectrum and further show the possibility of the coexistence of multiple formation mechanisms.

Parker Solar Probe and Solar Orbiter data are used to investigate the radial evolution of magnetic turbulence between 0.06 ≲ R ≲ 1 au. The spectrum is studied as a function of scale, normalized to the ion inertial scale d _i . In the vicinity of the Sun, the inertial range is limited to a narrow range of scales and exhibits a power-law exponent of, α _B = −3/2, independent of plasma parameters. The inertial range grows with distance, progressively extending to larger spatial scales, while steepening toward a α _B = −5/3 scaling. It is observed that spectra for intervals with large magnetic energy excesses and low Alfvénic content steepen significantly with distance, in contrast to highly Alfvénic intervals that retain their near-Sun scaling. The occurrence of steeper spectra in slower wind streams may be attributed to the observed positive correlation between solar wind speed and Alfvénicity.

PurposeTo verify the effects of multi-domain computerized cognitive training on intellectual function and adaptive functioning in children with intellectual developmental disorder (IDD).MethodsChildren with IDD were randomized to a multi-domain computerized cognitive training (CCT) group (n = 30) and control group (n = 30). Both groups received a 5-week training program. Intellectual function was assessed by Chinese-Wechsler Young Children scale (C-WYCSI) and adaptive functioning was assessed by the Chinese Vineland Adaptive Behavior Rating Scale (VABS-C), which were used at baseline, post-training, and 3-month follow-up.ResultsThere were significant differences for intellectual function and adaptive functioning between the two groups. The CCT group showed significant improvements in total full-scale intelligence quotient (FSIQ) score the Wechsler Intelligence Scale (F[60] = 31.97, p

BackgroundAlcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring.MethodsLabel-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers.ResultsA total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target.ConclusionThis proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.

Molybdenum is a trace dietary element necessary for the survival of humans. Some molybdenum-bearing enzymes are involved in key metabolic activities in the human body (such as xanthine oxidase, aldehyde oxidase and sulfite oxidase). Many molybdenum-based compounds have been widely used in biomedical research. Especially, MoS2-nanomaterials have attracted more attention in cancer diagnosis and treatment recently because of their unique physical and chemical properties. MoS2 can adsorb various biomolecules and drug molecules via covalent or non-covalent interactions because it is easy to modify and possess a high specific surface area, improving its tumor targeting and colloidal stability, as well as accuracy and sensitivity for detecting specific biomarkers. At the same time, in the near-infrared (NIR) window, MoS2 has excellent optical absorption and prominent photothermal conversion efficiency, which can achieve NIR-based phototherapy and NIR-responsive controlled drug-release. Significantly, the modified MoS2-nanocomposite can specifically respond to the tumor microenvironment, leading to drug accumulation in the tumor site increased, reducing its side effects on non-cancerous tissues, and improved therapeutic effect. In this review, we introduced the latest developments of MoS2-nanocomposites in cancer diagnosis and therapy, mainly focusing on biosensors, bioimaging, chemotherapy, phototherapy, microwave hyperthermia, and combination therapy. Furthermore, we also discuss the current challenges and prospects of MoS2-nanocomposites in cancer treatment.

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared via a drug-delivering-drug (DDD) strategy for cytosolic co-delivery of Poly I:C, a synthetic dsRNA analog to activate RIG-I signaling, and PTX, a commonly used chemotherapeutics, in which pure PTX nanorods were sequentially coated with Poly I:C and mannuronic acid via stimulating the RIG-I signaling axis. The co-delivery system with a diameter of 200 nm enables profound immunogenicity of cancer cells, exhibiting increased secretion of cytokines and chemokines, pronounced immune response in vivo, and significant inhibition of tumor growth. Also, we found that intracellularly sustained release of cytotoxic agents could elicit the immunogenicity of cancer cells. Overall, the intracellular asynchronous release of chemotherapeutics and immunomodulators is a promising strategy to promote the immunogenicity of cancer cells and augment the antitumor immune response.

Abstract Background Endoscopy biopsy (EB) is the standard diagnostic method for colorectal cancer (CRC), whereas its accuracy and efficiency in mucinous adenocarcinoma (MAC) initial diagnosis is unclear. Methods The initial EB and postoperative specimen (PS) pathological diagnosis of MAC from two centers were retrospectively collected and analyzed. The accuracy and efficiency of initial EB compared with PS pathological diagnosis were analyzed. The potential factors which would affect the initial EB diagnosis of MAC were analyzed. Results 280 and 78 eligible cases were enrolled in this study from two centers respectively. The initial EB diagnosis accuracy for MAC were 84.62% and 83.33%. However, among the cases of PS diagnosis with MAC, the diagnostic efficiency of initial EB was only 36.49% and 32.50% respectively. Lower tumor differentiation and more EB number were associated with an increased probability for the EB diagnosis of MAC, but only tumor differentiation was an independent diagnositic factor for EB in the two cohorts. Conclusions The accuracy of initial EB with MAC is high, but the diagnostic efficiency was extremely low. Tumor differentiation and EB number were associated with the diagnosis efficiency of MAC before surgery.

Abstract Background Measurement-based care (MBC) is an evidence-based practice for depression, but its use by clinicians remains low. Enhanced MBC (eMBC), which uses digital technologies, can help to facilitate the use of MBC by clinicians and patients. Understanding factors that act as barriers and drivers to the implementation of MBC and eMBC is important to support the design of implementation strategies, promoting uptake by clinicians and patients. Objective This situational analysis identifies barriers and facilitators to the implementation of standard and eMBC at mental health centers in Shanghai, China. Methods We used mixed methods to develop a comprehensive understanding of the factors influencing MBC and eMBC implementation in Shanghai. This study took place across three mental health centers in Shanghai. We used situational analysis tools to collect contextual information about the three centers, conducted surveys with n = 116 clinicians and n = 301 patients, conducted semi-structured interviews with n = 30 clinicians and six focus groups with a total of n = 19 patients. Surveys were analysed using descriptive statistics, and semi-structured interviews and focus groups were analysed using framework analysis. Results Several potential barriers and facilitators to MBC and eMBC implementation were identified. Infrastructure, cost, attitudes and beliefs, and perceptions about feasibility and efficacy emerged as both challenges and drivers to MBC and eMBC implementation in Shanghai. Conclusions The results of this study will directly inform the design of an implementation strategy for MBC and eMBC in Shanghai, that will be tested via a randomized controlled trial. This study contributes to the emerging body of literature on MBC implementation and, to the best of our knowledge, is the first such study to take place in Asia. This study identifies several factors that are relevant to the equitable delivery of MBC, recognizing the need to explicitly address equity concerns in global mental health implementation research.

2D metal–organic frameworks (2D‐MOFs) have been extensively studied as promising materials in the fields of electrocatalysis, drug delivery, electronic devices, etc. However, few studies have explored the application potential of 2D‐MOFs in novel neuromorphic computing devices. Herein, an optoelectronic neuromorphic transistor based on a 2D‐MOF/polymer charge‐trapping layer is reported. It is found that the large specific surface area, stable crystal structure, and highly accessible active sites in 2D‐MOFs make them excellent charge‐trapping materials for the devices, which are beneficial for mimicking the memory and learning functions observed in the organism's nervous systems. Different types of synaptic behaviors have been realized in the 2D‐MOF‐based neuromorphic devices under stimuli signal, e.g., paired‐pulse facilitation, excitatory postsynaptic current, short‐term memory, and long‐term memory. More interestingly, emotion‐adjustable learning behavior is realized by changing the value of the source–drain voltage. This work can shed light on the application of 2D‐MOFs in neuromorphic computing and will contribute to the further development of neuromorphic computing devices. An interactive preprint version of the article can be found at DOI: https://doi.org/10.22541/au.165530836.62586068/v1.

Adalimumab and secukinumab are commonly used for moderate to severe psoriasis vulgaris (PV). Although distinct individual responses to and impaired effectiveness of these biological agents occur occasionally, little is known about the underlying reasons. Here, we report a proteomic analysis of psoriatic lesions from patients treated with these drugs using data-independent acquisition mass spectrometry (DIA-MS). Thousands of differentially expressed proteins (DEPs) changed over 12 weeks of treatment. Network analysis showed that DEPs could interact and induce transformation in matrix components, metabolic regulation, and immune response. The results of parallel reaction monitoring (PRM) analysis suggested that S100s, STAT1, KRT2, TYMP, SOD2, HSP90AB1, TFRC, and COL5A1 were the most significantly changed proteins in both groups. There was a positive association between the Psoriasis Area and Severity Index (PASI) score and three proteins (TFRC, IMPDH2, KRT2). Our study findings suggest that inhibition of IL-17A and TNF-α can induce changes in multiple molecules in psoriatic lesions and have an overlapping influence on the immune response and process through direct or indirect effects.

Improving the survival rate of cardiomyocytes is the key point to treat most of the heart diseases, and targeting autophagy is a potential advanced therapeutic approach. Monitoring autophagic activity in cardiomyocytes in situ will be useful for studying autophagy-related heart disease and screening autophagy-modulating drugs. Zebrafish, Danio rerio, has been proven as an animal model for studying heart diseases in situ. Taken the advantage of zebrafish, especially the imaging of intact animals, here we generated two stable transgenic zebrafish lines that specifically expressed EGFP-map1lc3b or mRFP-EGFP-map1lc3b in cardiomyocytes under the promoter of myosin light chain 7. We first used a few known autophagy-modulating drugs to confirm their usefulness. By quantifying the density of autophagosomes and autolysosomes, autophagy inducers and inhibitors showed their regulatory functions, which were consistent with previous studies. With the two lines, we then found a significant increase in the density of autophagosomes but not autolysosomes in zebrafish cardiomyocytes at the early developmental stages, indicating the involvement of autophagy in early heart development. To prove their applicability, we also tested five clinical statins by the two lines. And we found that statins did not change the density of autophagosomes but reduced the density of autolysosomes in cardiomyocytes, implying their regulation in autophagic flux. Our study provides novel animal models for monitoring autophagic activity in cardiomyocytes in situ, which could be used to study autophagy-related cardiomyopathy and drug screening.

BackgroundHao-fountain syndrome (HAFOUS) is a neurodevelopmental syndrome characterized by global developmental and severe language delays, behavioral abnormalities (including autism), and mild dysmorphic impairment of intellectual development. It is a dominant genetic disease caused by USP7 gene (*602519) mutations on chromosome 16p13.2. So far, only 15 cases with 14 deleterious variants in the USP7 gene have been reported.Materials and methodsThis study describes three unrelated patients with USP7 variants. Besides, we identified novel de novo heterozygous USP7 variants using trio-whole exome sequencing and verified by Sanger sequencing. Furthermore, clinical characteristics were evaluated by reviewing the medical records.ResultsThe three identified variants, i.e., one frameshift variant (c.247_250del, p.Glu83Argfs × 18) and two missense variants (c.992A > G, p.Tyr331Cys; c.835T > G, p.Leu279Val) are unreported. The predominant clinical manifestations of the three patients included: DD/ID; language impairment; abnormal behavior; abnormal brain magnetic resonance (dilation of lateral ventricles, dilation of Virchow-Robin spaces, dilated the third ventricle, abnormal cerebral white matter morphology in bilateral occipital lobes, hypodysplasia of the corpus callosum, arachnoid cyst, delayed myelination, and widened subarachnoid space); some also had facial abnormalities.ConclusionIn summary, DD/ID is the most prevalent clinical phenotype of HAFOUS, although some patients also exhibit language and behavioral abnormalities. For the first time in China, we identified three variants of the USP7 gene using whole-genome sequence data. This work expands the USP7 gene mutation spectrum and provides additional clinical data on the clinical phenotype of HAFOUS.

IntroductionLuteal-phase ovarian stimulation has been proved to be feasible for producing competent oocytes/embryos and achieving live births, yet there is no standardized stimulation protocol for luteal-phase ovarian stimulation (LPS). The aim of this study was to explore the optimal timing of gonadotropin initiation in the LPS protocol for poor ovarian responders.MethodsThis was a retrospective cohort study conducted in the reproductive medicine center of a tertiary hospital. A total of 327 poor responders fulfilling Bologna criteria underwent LPS with IVF/ICSI treatment. HMG and letrozole were administrated after ovulation. Patients were stratified into three groups according to the gonadotropin start day: early, early-mid, and mid-late luteal phase. A freeze-all strategy was performed for all cycles. The duration of ovarian stimulation, total gonadotropin dose, number of oocytes retrieved, implantation rate, clinical pregnancy rate, and live birth rate after frozen/thawed embryo transfer cycles were included for evaluation.ResultsThe group accepted ovarian stimulation in the earlier phase tended to have a shorter duration of ovarian stimulation [8 (7,10) in early luteal group, 9 (8,10.25) in early-mid luteal group, and 11 (10,12) in mid-late luteal group; P 9 days) was more likely to occur in the early-mid and mid-late luteal groups, with the adjusted odds ratios 0.584 (0.327-1.042) and 0.116 (0.049-0.271), respectively (P-trend

BackgroundDifferent pathological subtypes of lung adenocarcinoma lead to different treatment decisions and prognoses, and it is clinically important to distinguish invasive lung adenocarcinoma from preinvasive adenocarcinoma (adenocarcinoma in situ and minimally invasive adenocarcinoma). This study aims to investigate the performance of the deep learning approach based on high-resolution computed tomography (HRCT) images in the classification of tumor invasiveness and compare it with the performances of currently available approaches.MethodsIn this study, we used a deep learning approach based on 3D conventional networks to automatically predict the invasiveness of pulmonary nodules. A total of 901 early-stage non-small cell lung cancer patients who underwent surgical treatment at Shanghai Chest Hospital between November 2015 and March 2017 were retrospectively included and randomly assigned to a training set (n=814) or testing set 1 (n=87). We subsequently included 116 patients who underwent surgical treatment and intraoperative frozen section between April 2019 and January 2020 to form testing set 2. We compared the performance of our deep learning approach in predicting tumor invasiveness with that of intraoperative frozen section analysis and human experts (radiologists and surgeons).ResultsThe deep learning approach yielded an area under the receiver operating characteristic curve (AUC) of 0.946 for distinguishing preinvasive adenocarcinoma from invasive lung adenocarcinoma in the testing set 1, which is significantly higher than the AUCs of human experts (P0.05) and junior thoracic surgeons (0.768, P>0.05).ConclusionsWe developed a deep learning model that achieved comparable performance to intraoperative frozen section analysis in determining tumor invasiveness. The proposed method may contribute to clinical decisions related to the extent of surgical resection.

IntroductionAlthough robot-assisted thoracoscopic surgery (RATS) has been widely applied in treating non-small cell lung cancer (NSCLC), its advantages remain unclear for very old patients. The present study compared the perioperative outcomes and survival profiles among RATS, video-assisted thoracoscopic surgery (VATS), and open lobectomy (OL), aiming to access the superiority of RATS for NSCLC patients aged ≥75 years.MethodsPathological IA-IIIB NSCLC patients aged ≥75 years who underwent RATS, VATS, or OL between June 2015 and June 2021 in Shanghai Chest Hospital were included. Propensity score matching (PSM, 1:1:1 RATS versus VATS versus OL) was based on 10 key prognostic factors. The primary endpoints were perioperative outcomes, and the secondary endpoints were disease-free (DFS), overall (OS), and cancer-specific survival (CS).ResultsA total of 504 cases (126 RATS, 200 VATS, and 178 OL) were enrolled, and PSM led to 97 cases in each group. The results showed that RATS led to: 1) the best surgical-related outcomes including the shortest operation duration (p

N6-Methyladenosine (m6A), the most abundant mammalian mRNA modification, has been reported to modulate various viral infections. Although it has been confirmed that RNA modifications can also modulate the replication and development of different parasites, the role of the RNA epitranscriptome in the regulation of host response post parasite infection remains to be elucidated. Here we report host spleen m6A epitranscriptome landscapes induced by different strains of the malaria parasite Plasmodium yoelii. We found that malaria parasite infection dramatically changes host spleen m6A mRNA modification and gene expression. Additionally, malaria parasite infection reprograms host immune response pathways by regulating the m6A modification enzymes. Collectively, our study is the first characterization of host spleen m6A methylome triggered by malaria parasite infections, and our data identify m6A modifications as significant transcriptome-wide marks during host-parasite interactions. We demonstrate that host mRNA methylation machinery can sense and respond to malaria parasite infections, and provide new insights into epitranscriptomic mechanisms underlying parasite-induced pathogenesis.

Optical‐resolution photoacoustic microscopy (OR‐PAM) technique is a noninvasive imaging technique that can be used to obtain high‐resolution images. This technique does not require the use of exogenous contrast agents. The technique can be effectively used to realize endogenous and exogenous imaging of microvasculature. However, the depth of focus (DOF) realized using OR‐PAM is low and inadequate to cover the entire 3D data for microvasculature imaging. A varying extent of signal‐to‐noise ratio (SNR) is recorded when varying depths of the 3D sample are studied. This significantly hindered the processes of image recognition, segmentation, and analysis. Herein, a deep learning‐based OR‐PAM technique to image and analyze 3D datasets is proposed. Endogenous and exogenous multi‐organ imaging data are sequentially imaged and segmented, and excellent generalization ability is observed. Wide‐field and ultradense exogenous 3D imaging of mouse brain vasculature located at different depths is obtained and segmented by OR‐PAM for the first time. The results reveal that the proposed method can be used for effectively imaging the entire microvasculature. The method can be potentially used for imaging the microcirculation system in clinics.

The formation and migration of helium bubbles lead to performance degradation of structural materials in nuclear reactors. Intrinsic structures in nuclear materials can significantly influence the behavior and distribution of these helium bubbles under irradiation. Micro-nano composite 304L stainless steel (MN304-La) possesses three main kinds of intrinsic structures: grain boundaries (GBs), dislocations, and La-rich nano-precipitates (NPs). In this study, the helium bubbles on different intrinsic structures in MN304-La after He+ ions implantation were characterized and analyzed. We compared the capabilities of different intrinsic structures in capturing helium bubbles and confirmed that NPs exhibit the strongest strength in capturing helium bubbles among the three kinds of intrinsic structures. We found that the competition of intrinsic structures for capturing helium bubbles depends on both the capture strength of the intrinsic structures and the capture distance to the helium bubbles.

Zygotes without a pronuclear (0PN) or with one pronuclear (1PN) were defined as abnormal fertilization in conventional in vitro fertilization (IVF). The removal of 0PN and 1PN zygotes from conventional IVF cycles has always been controversial. This study aimed to investigate the chromosomal aneuploidy rates of 0PN- and 1PN-derived blastocysts in conventional IVF cycles and to assess the concordance rate between TE-biopsy PGT-A and miPGT-A. TE biopsies and culture media with blastocoel fluid (CM-BF) samples were whole-genome amplified by multiple annealing and looping-based amplification cycle-based single-cell ChromInst method. Next generation sequencing was performed for comprehensive chromosomal screening on a NextSeq550 sequencer using the NextSeq 500/550 High Output kit v2. The aneuploidy rates of 0PN-derived blastocysts were 19.7% for TE-biopsy PGT-A, and 36.1% for miPGT-A; the concordance rate for ploidy was 77.0%; and the sensitivity and specificity were 83.3% and 75.5%, respectively. The aneuploidy rates of 1PN-derived blastocysts were 37.5% and 37.5% by TE-biopsy PGT-A and miPGT-A, respectively; the concordance rate between TE biopsies and CM-BF samples was 83.3%; and the sensitivity and specificity were 77.8% and 86.7%, respectively. Regarding TE-biopsy PGT-A, there were no significant differences in aneuploidy rates among 0PN-, 1PN- and 2PN-derived blastocysts (PGT-M cycles) (19.7% vs. 37.5% vs. 24.3%, P = 0.226), but the aneuploidy rate of 1PN-derived blastocysts was slightly higher than the other two groups. An increase in aneuploidy rates was observed for 0PN/1PN-derived day 6 blastocysts compared to 0PN/1PN-derived day 5 blastocysts (TE-biopsy PGT-A: 35.7% vs. 19.3%, P = 0.099; miPGT-A: 39.3% vs. 35.1%, P = 0.705). The present study is the first that contributes to understanding the chromosomal aneuploidies in 0PN- and 1PN-derived blastocysts in conventional IVF cycles using TE-biopsy PGT-A and miPGT-A. The clinical application value of 0PN- and 1PN-derived blastocysts in conventional IVF should be assessed using TE-biopsy PGT-A or miPGT-A due to the existence of chromosomal aneuploidies.. In terms of consistency, the miPGT-A using blastocoel fluid enriched culture medium is promising as an alternative to TE-biopsy PGT-A for aneuploidy testing of 0PN- or 1PN-derived blastocysts in conventional IVF.

Endoscopic ultrasound (EUS) has emerged as a widely utilized tool in the diagnosis of digestive diseases. In recent years, the potential of artificial intelligence (AI) in healthcare has been gradually recognized, and its superiority in the field of EUS is becoming apparent. Machine learning (ML) and deep learning (DL) are the two main AI algorithms. This paper aims to outline the applications and prospects of artificial intelligence-assisted endoscopic ultrasound (EUS-AI) in digestive diseases over the past decade. The results demonstrated that EUS-AI has shown superiority or at least equivalence to traditional methods in the diagnosis, prognosis, and quality control of subepithelial lesions, early esophageal cancer, early gastric cancer, and pancreatic diseases including pancreatic cystic lesions, autoimmune pancreatitis, and pancreatic cancer. The implementation of EUS-AI has opened up new avenues for individualized precision medicine and has introduced novel diagnostic and treatment approaches for digestive diseases.

Abstract 2D polymers (2DPs) have attracted increasing interests in sensors, catalysis, and gas storage applications. Furthermore, 2DPs with unique band structure and tunable photophysical properties also have immense potential for application in photonic neuromorphic computing. Here, photonic synaptic transistors based on 2DPs as the light‐tunable charge‐trapping medium are developed for the first time. The resulted organic transistors can successfully emulate common synaptic functions, including excitatory postsynaptic current, pair‐pulse facilitation, the transition of short‐term memory to long‐term memory, and dynamic filtering. Benefitting from the high photosensitivity of the 2DP, the devices can be operated under a low operating voltage of −0.1 V, and achieve an ultralow energy consumption of ~0.29 pJ per event. In addition, the heterostructure formed between the 2DP and organic semiconductor enables spectrum‐dependent synaptic responses, which facilitates the simulation of visual learning and memory processes in distinct emotional states. The underlying mechanism of spectrum‐dependent synaptic‐like behaviors is systematically validated with in situ atomic force microscopy based electrical techniques. The spectrum‐enabled tunability of synaptic behaviors further promotes the realization of optical logic functions and associative learning. This work inspires the new application of 2DPs in photonic synapses for future neuromorphic computing.

Abstract Background Since the COVID-19 pandemic, several therapeutic agents have been used in COVID-19 management. However, the results were controversial. Here, we aimed to evaluate the efficacy and safety of hydroxychloroquine (HCQ)/chloroquine (CQ) in COVID-19. Methods We retrospectively reviewed the medical charts of patients with COVID-19 admitted to an inpatient ward in Wuhan from 2020/Feb/08 to 2020/Mar/05. Patients with HCQ/CQ and age, gender, disease severity matched ones without HCQ/CQ were selected at a 1:2 ratio. The clinical, laboratory and imaging findings were compared between these two groups. The multivariate linear regression analysis was performed to identify the factors that might influence patients’ virus shedding periods (VSPs). Results A total of 14 patients with HCQ/CQ and 21 matched ones were analyzed. The HCQ/CQ treatment lasted for an average of 10.36 ± 3.12 days. The mean VSPs were longer in the HCQ/CQ treatment group (26.57 ± 10.35 days vs. 19.10 ± 7.80 days, P = 0.020). There were 3 patients deceased during inpatient period, two patients were with HCQ/CQ treatment (P = 0.551). In the multivariate linear regression analysis, disease durations at admission (t = 3.643, P = 0.001) and HCQ/CQ treatment (t = 2.637, P = 0.013) were independent parameters for patients’ VSPs. One patient with CQ had recurrent first-degree atrioventricular block (AVB) and obvious QTc elongation, another one complained about dizziness and blurred vision which disappeared after CQ discontinuation. One patient with HCQ had transient AVB. Conclusions In summary, we identify that the HCQ/CQ administration is not related to less mortality cases at later phase of COVID-19. More studies are needed to explore whether HCQ/CQ treatment would lead to SARS-Cov-2 RNA clearance delay or not.

Some patients with COVID-19 fail to clear the viral infection quickly, yet our understanding for the underlying immune characteristics is still lacking. Here the authors use single-cell RNA sequencing and other data form such patients to show that persistent infection is associated with immune suppression and reduced expression of ribosomal protein genes.

Neuroinflammation is a key mechanism underlying the cognitive impairment induced by PM2.5, and activated microglia plays an important role in this process. However, the mechanisms by which activated microglia induced by PM2.5 impair hippocampal neurons have not been fully elucidated. In this study, we focused on the role of HMGB1-NLRP3-P2X7R pathway which mediated the microglia activation in hippocampal neurons impairment induced by PM2.5 using a co-culture model of microglia and hippocampal neurons. We found that PM2.5 resulted in activated microglia and HMGB1-NLRP3 inflammatory pathway, and elevated proinflammatory cytokines of IL-18 and IL-1β in a dose-dependent manner. Notably, we next utilized previously reported pharmacological inhibitors or siRNA for HMGB1 and found that they significantly inhibited the activation of downstream NLRP3 and MAPK pathways derived from PM2.5 exposure, and down-regulated IL-18 and IL-1β in microglia. Furthermore, we employed co-cultured hippocampal neurons and microglia and found that reducing HMGB1 significantly decreased neuron impairment, apoptosis related protein of cl-caspase3, synaptic damage, and neurotransmitter receptor of 5-HT2A, along with notably elevated presynaptic and postsynaptic proteins of SYP and PSD-95, as well as learning and memory related proteins of p-CREB and BDNF. The neuronal impairment induced by PM2.5 could not be prevented in the case of simultaneous employment of HMGB1 siRNA and NLRP3 agonist. After silencing NLRP3 alone in microglia, hippocampal neurons demonstrated decreased excessive autophagy and up-regulated synaptic protein of GAP43 as well as learning and memory related protein of NCAM1. Therefore, we further studied how hippocampal neurons affected microglia under PM2.5 exposure, Further investigation indicated that silencing HMGB1 could affect the activation of P2X7R and reduce the release of ATP from hippocampal neurons, thus protecting the interaction between microglia and hippocampal neurons. The present work suggests that regulation of HMGB1-NLRP3-P2X7R pathway can inhibit the microglia activation induced by PM2.5 to alleviate hippocampal neuron impairment and stabilize the microenvironment between microglia and neurons. This contributes to maintaining the normal function of hippocampal neurons and alleviating the cognitive impairment derived from PM2.5 exposure.

Memory loss and aberrant neuronal network activity are part of the earliest hallmarks of Alzheimer’s disease (AD). Electroacupuncture (EA) has been recognized as a cognitive stimulation for its effects on memory disorder, but whether different brain regions or neural circuits contribute to memory recovery in AD remains unknown. Here, we found that memory deficit was ameliorated in 3×Tg-AD mice with EA-treatment, as shown by the increased number of exploring and time spent in the novel object. In addition, reduced locomotor activity was observed in 3×Tg-AD mice, but no significant alteration was seen in the EA-treated mice. Based on the functional magnetic resonance imaging, the regional spontaneous activity alterations of 3×Tg-AD were mainly concentrated in the accumbens nucleus, auditory cortex, caudate putamen, entorhinal cortex (EC), hippocampus, insular cortex, subiculum, temporal cortex, visual cortex, and so on. While EA-treatment prevented the chaos of brain activity in parts of the above regions, such as the auditory cortex, EC, hippocampus, subiculum, and temporal cortex. And then we used the whole-cell voltage-clamp recording to reveal the neurotransmission in the hippocampus, and found that EA-treatment reversed the synaptic spontaneous release. Since the hippocampus receives most of the projections of the EC, the hippocampus-EC circuit is one of the neural circuits related to memory impairment. We further applied diffusion tensor imaging (DTI) tracking and functional connectivity, and found that hypo-connected between the hippocampus and EC with EA-treatment. These data indicate that the hippocampus–EC connectivity is responsible for the recognition memory deficit in the AD mice with EA-treatment, and provide novel insight into potential therapies for memory loss in AD.

Background COVID‐19 is an infectious illness, featured by an increased risk of thromboembolism. However, no standard antithrombotic therapy is currently recommended for patients hospitalized with COVID‐19. The aim of this study was to evaluate safety and efficacy of additional therapy with aspirin over prophylactic anticoagulation (PAC) in patients hospitalized with COVID‐19 and its impact on survival. Methods and Results A total of 8168 patients hospitalized for COVID‐19 were enrolled in a multicenter‐international prospective registry (HOPE COVID‐19). Clinical data and in‐hospital complications, including mortality, were recorded. Study population included patients treated with PAC or with PAC and aspirin. A comparison of clinical outcomes between patients treated with PAC versus PAC and aspirin was performed using an adjusted analysis with propensity score matching. Of 7824 patients with complete data, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC. Propensity‐score matching yielded 298 patients from each group. In the propensity score‐matched population, cumulative incidence of in‐hospital mortality was lower in patients treated with PAC and aspirin versus PAC (15% versus 21%, Log Rank P=0.01). At multivariable analysis in propensity matched population of patients with COVID‐19, including age, sex, hypertension, diabetes, kidney failure, and invasive ventilation, aspirin treatment was associated with lower risk of in‐hospital mortality (hazard ratio [HR], 0.62; [95% CI 0.42–0.92], P=0.018). Conclusions Combination PAC and aspirin was associated with lower mortality risk among patients hospitalized with COVID‐19 in a propensity score matched population compared to PAC alone.

BackgroundTwo-thirds of major depressive disorder (MDD) patients initially present with somatic symptoms, yet no study has used approaches based on somatic symptoms to subtype MDD. This study aimed to classify MDD via somatic symptoms and tracked the prognosis of each subtype.MethodsData were obtained from the study of Algorithm Guided Treatment Strategies for Major Depressive Disorder (AGTs-MDD). We recruited 395 subjects who received monotherapy of mirtazapine or escitalopram and conducted 2-, 4-, 6-, 8-, and 12-week follow-up assessments (n = 311, 278, 251, 199, and 178, respectively). Latent profile analysis (LPA) was performed on somatic symptom items of the depression and somatic symptoms scale (DSSS). Generalized linear mixed models (GLMM) were used to study the longitudinal prognosis of the subtypes classed by LPA. Primary outcome measures were the Hamilton Depression Rating Scale (HAMD), HAMD score reduction rate, as well as somatic and depressive items of DSSS.ResultsThree subtypes of MDD were found, namely, depression with mild somatic symptoms (68.9%), depression with moderate somatic symptoms (19.2%), and depression with severe somatic symptoms (11.9%). Scores of HAMD (F = 3.175, p = 0.001), somatic (F = 23.594, p < 0.001), and depressive (F = 4.163, p < 0.001) DSSS items throughout the 12-week follow-up showed statistical difference among the three subtypes. The moderate group displayed a higher HAMD-17 score and a lower reduction rate at the 6th week, and more severe depressive symptoms both at the 4th and 6th weeks.ConclusionThe results indicate that somatic symptoms should be emphasized in patients with MDD, and more attention is needed for those with moderate somatic symptoms, which may be relevant to a worse prognosis.

Keloid disorder is a tumour-like disease with invasive growth and a high recurrence rate. Genetic contribution is well expected due to the presence of autosomal dominant inheritance and various genetic mutations in keloid lesions. However, GWAS failed to reveal functional variants in exon regions but single nucleotide polymorphisms in the non-coding regions, suggesting the necessity of innovative genetic investigation. This study employed combined GWAS, RNA-sequence and Hi-C analyses to dissect keloid disorder genetic mechanisms using paired keloid tissues and normal skins. Differentially expressed genes, miRNAs and lncRNAs mined by RNA-sequence were identified to construct a network. From which, 8 significant pathways involved in keloid disorder pathogenesis were enriched and 6 of them were verified. Furthermore, topologically associated domains at susceptible loci were located via the Hi-C database and ten differentially expressed RNAs were identified. Among them, the functions of six molecules for cell proliferation, cell cycle and apoptosis were particularly examined and confirmed by overexpressing and knocking-down assays. This study firstly revealed unknown key biomarkers and pathways in keloid lesions using RNA-sequence and previously reported mutation loci, indicating a feasible approach to reveal the genetic contribution to keloid disorder and possibly to other diseases that are failed by GWAS analysis alone.

Abstract Background We aimed to examine the effect of physical activity on different cognitive domains among patients with diabetes. Methods We used two waves of data from the Chinese Health and Retirement Longitudinal Study (CHARLS, 2013–2015), a nationally representative dataset of Chinese population aged over 45. Total physical activity scores were calculated based on the International Physical Activity Questionnaire (IPAQ). Executive function and episodic memory were used as measures of cognitive function. We conducted lagged dependent variable models to explore the association between physical activity and cognitive function in full sample as well as two different age groups (45–65, ≥65). Results: 862 diabetic patients were included. We found that diabetic participants who had greater level of physical activity at baseline were associated with better episodic memory function in 2 years (p

Groundwater droughts can explain developments and changes in groundwater from a climatological perspective. The North China Plain (NCP) is a typical underground funnel area. Therefore, groundwater drought studies in the NCP can provide better understanding of the local hydrogeological characteristics from new perspectives. In this paper, the GRACE groundwater drought index (GGDI) was used to evaluate groundwater drought events in the NCP. Additionally, a new method was proposed in this study for investigating groundwater drought events at the spatiotemporal scale. On this basis, the centroid theory was used to construct an appropriate groundwater drought migration model for the NCP. The results showed that (1) the groundwater drought frequency in the NCP was 24.54%. In addition, the most severe groundwater drought events in the study occurred in March 2020. (2) In total, 49 groundwater drought events occurred in the NCP over the 2003–2020 period. The most intense groundwater drought event occurred over the June 2018–December 2020 period (DE.49), covering the entire study area. DE.29 was the second most intense groundwater drought event over the August 2012–September 2013 period (14 months), resulting in a maximum arid area of 75.57% of the entire study area. (3) The migration of the groundwater drought events was in the southwest–northeast and northeast–southwest directions, which was consistent with the terrain inclination, while most of the groundwater drought centroids were concentrated in Area II. The groundwater drought event identification method and the groundwater drought migration model were effective and reliable for assessing groundwater drought events in the NCP and provided a better understanding of developments and changes in groundwater droughts, which is of great practical significance and theoretical value for the rational development and use of groundwater resources, as well as for guiding industrial and agricultural activities.

Objective: Older adults with sleep disorders (SDs) show impaired working memory abilities, and working memory processes are closely related to the prefrontal cortex (PFC). However, the neural mechanism of working memory impairment in older adults with SD remains unclear. This study aimed to investigate changes in PFC function among older adults with SD when carrying out the N-back task by functional near-infrared spectroscopy (fNIRS). Method: A total of 37 older adults with SDs were enrolled in this study and matched with 37 healthy older adults by gender, age, and years of education. Changes in PFC function were observed by fNIRS when carrying out the N-back task. Results: The accuracy on the 0-back and 2-back tasks in the SD group was significantly lower than that in the healthy controls (HC) group. The oxygenated hemoglobin (oxy-Hb) concentration of channel 8 which located in the dorsolateral prefrontal cortex (DLPFC) was significantly reduced in the SD group during the 2-back task, and the channel-to-channel connectivity between the PFC subregions was significantly decreased. Conclusions: These results suggest that patients with sleep disorders have a weak performance of working memory; indeed, the activation and functional connectivity in the prefrontal subregions were reduced in this study. This may provide new evidence for working memory impairment and brain function changes in elderly SDs.

Abstract Background Congenital adrenal hyperplasia (CAH) caused by P450 oxidoreductase deficiency (PORD) in 46, XX patients is characterized by genital ambiguity, primary amenorrhea, absent or incomplete sexual maturation, infertility, skeletal malformations and so on. But few pregnancies have been reported from these female patients with PORD. Case description A 29-year-old Chinese woman with PORD due to the compound heterozygous mutation (c.1370G > A/c.1196_1204del) in the P450 oxidoreductase (POR) gene had suffered from primary amenorrhea and infertility. She had one cancelled cycle of ovulation induction due to low serum estradiol(E2), high progesterone(P) levels and thin endometrium, then in vitro fertilization (IVF) was recommended. At the first IVF cycle, 4 oocytes were retrieved and 4 viable embryos were cryopreserved due to thin endometrium associated with low E2 and prematurely elevated P after ovarian stimulation, even though oral dexamethasone were used to control adrenal P overproduction at the same time. When basal P fell to

Abstract Bipolar disorder (BD) and major depressive disorder (MDD) have both common and distinct clinical features, that pose both conceptual challenges in terms of their diagnostic boundaries and practical difficulties in optimizing treatment. Multivariate machine learning techniques offer new avenues for exploring these boundaries based on clinical neuroanatomical features. Brain structural data were obtained at 3 T from a sample of 90 patients with BD, 189 patients with MDD, and 162 healthy individuals. We applied sparse partial least squares discriminant analysis (s-PLS-DA) to identify clinical and brain structural features that may discriminate between the two clinical groups, and heterogeneity through discriminative analysis (HYDRA) to detect patient subgroups with reference to healthy individuals. Two clinical dimensions differentiated BD from MDD (area under the curve: 0.76, P

Abstract Background Depression is seriously affecting the physical and mental health of young people worldwide. Subthreshold depression, as an early stage of depression, is essential for early prevention and treatment of depression. Tai Chi, as a traditional Chinese mind-body therapy, may become an alternative intervention. However, the neurophysiological mechanism of Tai Chi for young people with subthreshold depression remains unclear, restricting its further promotion and application. Therefore, rigorous randomized clinical trials are needed to further observe the intervention effect of Tai Chi on young adults with subthreshold depression and explore the neurophysiological mechanism. Method/design This report describes a two-arm, randomized, parallel controlled trial with allocation concealment and assessor blinding. A total of 64 eligible participants are randomly allocated to the Tai Chi group and the waiting list group in a 1:1 ratio. Participants in the Tai Chi group receive 12 weeks of Tai Chi training, with a total of 36 times and each for 60 min. Specifically, the participants in the waiting list group are requested to maintain their routine lifestyle. In this study, the primary outcome measure is the mean change in scores on the PHQ-9 and HAMD-17 between baseline and 12 weeks; the secondary outcomes are the mean change in the scores on CES-D, CPSS, GAD-7, and PSQI. Besides, the saliva cortisol levels and fMRI are monitored to explore the mechanism of action of Tai Chi on subthreshold depression. Discussion The protocol uses a randomized controlled trial to examine the effectiveness of Tai Chi for young adults with subthreshold depression and explore neurophysiological mechanisms. If the test results are positive, it can be verified that Tai Chi can promote the physical and mental health of young adults with subthreshold depression. Trial registration Chinese Clinical Trial Registry ChiCTR1900028289 . Registered on 17 December 2019

DNA is always one of the most important targets for cancer therapy due to its leading role in the proliferation of cancer cells. Phototherapy kills cancer cells by generating reactive oxygen species (ROS) and local hyperthermia under light. It has attracted extensive interest in the clinical treatment of tumors because of many advantages such as non-invasiveness, high patient compliance, and low toxicity and side effects. However, the short ROS diffusion distance and limited thermal diffusion rate make it difficult for phototherapy to damage DNA deep in the nucleus. Therefore, nucleus-targeting phototherapy that can destroy DNAs via in-situ generation of ROS and high temperature can be a very effective strategy to address this bottleneck. Recently, some emerging nucleus-targeting phototherapy nanodrugs have demonstrated extremely effective anticancer effects. However, reviews in the field are still rarely reported. Here, we comprehensively summarized recent advances in nucleus-targeting phototherapy in recent years. We classified nucleus-targeting phototherapy into three categories based on the characteristics of these nucleus-targeting strategies. The first category is the passive targeting strategy, which mainly targets the nucleus by adjusting the physicochemical characteristics of phototherapy nanomedicines. The second category is to mediate the phototherapy nanodrugs into the nucleus by modifying functional groups that actively target the nucleus. The third category is to assist nanodrugs enter into the nucleus in a light-controlled way. Finally, we provided our insights and prospects for nucleus-targeting phototherapy nanodrugs. This minireview provides unique insights and valuable clues in the design of phototherapy nanodrugs and other nucleus-targeting drugs.

Cancer cell lysosomes contain various hydrolases and non-degraded substrates that are corrosive enough to destroy cancer cells. However, many traditional small molecule drugs targeting lysosomes have strong side effects because they cannot effectively differentiate between normal and cancer cells. Most lysosome-based research has focused on inducing mild lysosomal membrane permeabilization (LMP) to release anticancer drugs from lysosomal traps into the cancer cell cytoplasm. In fact, lysosomes are particularly powerful “bombs”. Achieving cancer cell-selective LMP induction may yield high-efficiency anticancer effects and extremely low side effects. Nanodrugs have diverse and combinable properties and can be specifically designed to selectively induce LMP in cancer cells by taking advantage of the differences between cancer cells and normal cells. Although nanodrugs-induced LMP has made great progress recently, related reviews remain rare. Herein, we first comprehensively summarize the advances in nanodrugs-induced LMP. Next, we describe the different nanodrugs-induced LMP strategies, namely nanoparticles aggregation-induced LMP, chemodynamic therapy (CDT)-induced LMP, and magnetic field-induced LMP. Finally, we analyze the prospect of nanodrugs-induced LMP and the challenges to overcome. We believe this review provides a unique perspective and inspiration for designing lysosome-targeting drugs.