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To alleviate the dilemma of drug administration in Alzheimer's disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aβ 1-42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that seriously affects the life quality of patients. Topical administration of glucocorticoids is considered to be the most effective anti-inflammatory treatment. However, due to the barrier function of skin, only less than 20% of topical drug molecules could diffuse into the skin. Therefore, it is of great importance to develop an effective strategy to improve AD therapy. In this study, we reported a two-electrode microneedle patch (t-EMNP) composed of a polylactic acid-platinum (PLA-Pt) MN array and polylactic acid-platinum-polypyrrole (PLA-Pt-PPy) MN array for improving the transdermal drug delivery efficacy. The drug loading capability of MNs could be altered by employing different polymerization times and drug concentrations. The drug release rate of MNs could be changed by applying different voltages. We further developed a controlled transdermal drug delivery system (c-TDDS) based on this two-electrode microneedle patch (t-EMNP), exhibiting the remarkable performance of the electricity-triggered drug release profile. The drugs could be released with electrical stimulation, while there was almost no drug release without electrical stimulation. For AD treatment

Arteriovenous malformation (AVM)-derived ophthalmic artery (OphA) branches are not common, and their management is very challenging. We evaluated the safety and efficacy of Trans OphA ethanol embolotherapy for these lesions. We retrospectively reviewed 26 patients with AVMs fed by OphA, who underwent transOphA embolization using ethanol from February, 2015 to December, 2019. Sixty-six transOphA embolotherapy procedures (range, 1-4 procedures; mean, 2.5 procedures) were performed. Devascularization degree, visual field, visual acuity, and quality-of-life outcomes were compared and analyzed at follow up (mean, 32.6 months; month range 10-60). Complications were recorded. Twenty-five of the 26 patients (96%) reported complete or 90% AVM devascularization while one patient (4%) showed 70% devascularization. Eleven patients (42%) presented with visual acuity impairments; among them, 6 had improvements while 4 were completely relieved. Eight patients (30.7%) presented visual field defects, 3 had improvements while 4 were completely relieved. Ten patients (38.4%) presented with diplopia and exophthalmos with 2 being completely relieved while 6 had major improvements. Bleeding was controlled in all cases (100%). All patients (100%) exhibited cosmetic deformities with 17 being completely relieved. Moreover, all patients (100%) exhibited impaired daily life, which was resolved in 21 patients with 5 patients reporting major improvements. After endovascular treatment, there was no vision loss, death, or permanent disability in any patient. TransOphA ethanol embolotherapy is efficacious and safe for symptomatic resolution or improvement of AVMs fed by OphA with acceptable complications without the risk of visual impairment.

Patients with lung cancer at the same stage may have markedly different overall outcome and a lack of specific biomarker to predict lung cancer outcome. Heat-shock protein 90 β (HSP90β) is overexpressed in various tumor cells. In this study, the ELISA results of HSP90β combined with CEA, CA125, and CYFRA21-1 were used to construct a recursive partitioning decision tree model to establish a four-protein diagnostic model and predict the survival of patients with lung cancer. Survival analysis showed that the recursive partitioning decision tree could distinguish the prognosis between high- and low-risk groups. Results suggested that the joint detection of HSP90β, CEA, CA125, and CYFRA21-1 in the peripheral blood of patients with lung cancer is plausible for early diagnosis and prognosis prediction of lung cancer.

Traditional Chinese medicine (TCM) has played an indispensable role in clinical diagnosis and treatment. Based on a patient’s symptom phenotypes, computation-based prescription recommendation methods can recommend personalized TCM prescription using machine learning and artificial intelligence technologies. However, owing to the complexity and individuation of a patient’s clinical phenotypes, current prescription recommendation methods cannot obtain good performance. Meanwhile, it is very difficult to conduct effective representation for unrecorded symptom terms in an existing knowledge base. In this study, we proposed a subnetwork-based symptom term mapping method (SSTM) and constructed a SSTM-based TCM prescription recommendation method (termed TCMPR). Our SSTM can extract the subnetwork structure between symptoms from a knowledge network to effectively represent the embedding features of clinical symptom terms (especially the unrecorded terms). The experimental results showed that our method performs better than state-of-the-art methods. In addition, the comprehensive experiments of TCMPR with different hyperparameters (i.e., feature embedding, feature dimension, subnetwork filter threshold, and feature fusion) demonstrate that our method has high performance on TCM prescription recommendation and potentially promote clinical diagnosis and treatment of TCM precision medicine.

Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naïve or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors. Implications: We have established highly clinically relevant PDXs of ADT-induced dormant prostate cancer and identified two dormancy subtypes, leading to the development of a novel predicative gene signature that allows robust risk stratification of patients with prostate cancer to ADT or androgen-receptor pathway inhibitors.

To summarize a 10-year, single-institution experience with ethanol embolization of nasal arteriovenous malformations (NAVMs) in 52 patients.The present work was a retrospective study of 52 patients (aged between 1 and 67 years) with NAVMs who were treated with ethanol embolization between August 2009 and August 2019. The diagnosis of NAVMs was established based on clinical and imaging studies including ultrasound, computer tomography angiography, and digital subtract angiography. Embolization techniques used in the current study included transarterial, direct puncture, and a combination of both. The clinical and angiographic features, treatment methods, clinical outcomes, and complications were assessed within the mean period of 55.2 months (range, 1-119 months) after the last embolization.The total number of embolization sessions (140 embolization procedures in 52 pts) included transarterial approach (1 pt), direct puncture (2 pt), and a combination of transarterial and direct puncture (49 pts). There was a positive correlation between nidus size and treatment sessions (r = 0.780, P = 0.0005) and the amount of ethanol injected (r = 0.840, P = 0.0004). Results of the current study showed that the therapeutic outcomes were complete response in two patients (3.8%) without recurrence throughout the follow-up period (range, 1-119 months; mean, 55.2 months), and partial response in 50 patients (96.2%). A total of seven patients (13.5%) experienced one or more complications, including skin necrosis in one patient (1.9%), transient hemoglobinuria in five patients (9.6%), and skin blister in five patients (9.6%).The reported single-institution experience evidently indicated that ethanol embolotherapy has the potential to successfully devascularize NAVMs and also significantly improve symptoms and signs. Further, it was evident that the use of a combination of transarterial and direct puncture techniques has the potential to increase the rate of therapeutic response in patients with NAVMs.

Gait abnormalities have been widely investigated in the diagnosis and treatment of neurodegenerative diseases. However, it is still a great challenge to achieve a comfortable, convenient, sensitive and high-pressure resistant flexible gait detection sensor for real-time health monitoring. In this work, a polyaniline (PANI)@(polyacrylic acid (PAA)-polyvinyl alcohol (PVA)) (PANI@(PVA-PAA)) ternary network hydrogel with a uniaxially oriented porous featured structure was successfully prepared using a simple freeze-thaw method and

Overexpression of survivin is frequently observed in human malignancies and is associated with poor prognosis. The present study found that survivin is highly expressed in nasopharyngeal carcinoma (NPC) tumor tissues. Depleting survivin with shRNA inhibited cell viability, colony formation, and in vivo tumorigenesis of NPC cells. With a natural product screening, we identified Butein as a potential anti-tumor compound for NPC by reducing survivin protein level. Butein shortened the half-life of survivin and enhanced ubiquitination-mediated degradation. The mechanism study showed that Butein promoted the interaction between survivin and E3 ligase Fbxl7, and the knockdown of Fbxl7 compromised Butein-induced survivin ubiquitination. Butein suppressed the Akt-Wee1-CDK1 signaling and decreased survivin Thr34 phosphorylation, facilitating E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Moreover, Butein exhibited a strong in vivo anti-tumor activity, as the tumor volume of Butein-treated xenografts was reduced significantly. Butein alone or combined with cisplatin (CDDP) overcame chemoresistance in NPC xenograft tumors. Overall, our data indicate that Butein is a promising anti-tumor agent for NPC treatment.

The significant function of circRNAs in cancer was recognized in recent work, so a well-organized resource is required for characterizing the interactions between circRNAs and other functional molecules (such as microRNA and RNA-binding protein) in cancer. We previously developed cancer-specific circRNA database (CSCD), a comprehensive database for cancer-specific circRNAs, which is widely used in circRNA research. Here, we updated CSCD to CSCD2 (http://geneyun.net/CSCD2 or http://gb.whu.edu.cn/CSCD2), which includes significantly more cancer-specific circRNAs identified from a large number of human cancer and normal tissues/cell lines. CSCD2 contains >1000 samples (825 tissues and 288 cell lines) and identifies a large number of circRNAs: 1 013 461 cancer-specific circRNAs, 1 533 704 circRNAs from only normal samples and 354 422 circRNAs from both cancer and normal samples. In addition, CSCD2 predicts potential miRNA–circRNA and RBP–circRNA interactions using binding motifs from >200 RBPs and 2000 microRNAs. Furthermore, the potential full-length and open reading frame sequence of these circRNAs were also predicted. Collectively, CSCD2 provides a significantly enhanced resource for exploring the function and regulation of circRNAs in cancer.

Background and Objectives: This study aims to detect the prevalence of sarcopenia in community-dwelling older adults in Hunan Province, discuss factors related to lifestyle, and provide a reliable basis for the prevention and treatment of sarcopenia. Materials and Methods: In this study, a total of 1040 community-dwelling adults ≥ 60 years were examined for sarcopenia using a cluster stratified random sampling method, which was defined using the diagnostic criteria recommended by the Asian Working Group for Sarcopenia (AWGS) from September 2019 to March 2020. Multivariate logistic regression analysis was applied to determine the correlation between sarcopenia and smoking, drinking, nutritional status, physical activity, and sleep quality. Results: A total of 27.1% of the older adults were diagnosed with sarcopenia, with rates of 26.2% in men and 25.2% in women. Multiple logistic regression showed that advanced age (OR = 2.480, 95% CI: 1.730, 3.553), the risk of malnutrition (OR = 2.085, 95% CI: 1.440, 3.019), and malnutrition (OR = 1.212, 95% CI: 0.304, 4.834) were risk factors for sarcopenia. No falls in the previous year (OR = 0.616, 95% CI: 1.885, 1.209), normal weight (OR = 0.228, 95% CI: 0.109, 0.475), overweight (OR = 0.030, 95% CI: 0.013, 0.069), moderate physical activity (OR = 0.593, 95% CI: 0.377, 0.933), or high physical activity (OR = 0.417, 95% CI: 0.230, 0.755) were identified as protective factors for sarcopenia. Conclusions: The prevalence of sarcopenia was high among older adults in the community in Hunan Province. In addition, we found that lifestyle is an important factor in sarcopenia.

To explore the transcriptional gene expression profile up-regulated in human macrophages stimulated by interferon-γ (IFN-γ) and the underlying intracellular signaling mechanisms.RNA-seq was used to sequence and compare the differential gene expression profiles of human macrophage cell line U937 before and after IFN-γ stimulation, and the significantly up-regulated genes were screened out, which were verified by fluorescence-based real-time quantitative polymerase chain reaction (qPCR) in U937 and THP1 cell lines, respectively. JAK/STAT, MAPK/ERK and PI3K/AKT pathway inhibitors were added to simultaneously to the cultured U937 cells upon IFN-γ priming to detect their effects on the expressions of the up-regulated genes to explore the key regulatory mechanisms.RNA-seq and qPCR results showed that, the well-recognized chemokines CXCL9, CXCL10 and CXCL11, the APOL family including APOL1, APOL2, APOL3, APOL4, APOL6 and GBP family GBP1, GBP2, GBP3, GBP4 and GBP5 as well were significantly up-regulated in IFN-γ-stimulated U937 cells. JAK/STAT3 pathway inhibitor inhibited the upregulation of APOL1, APOL4, GBP1, GBP4 and GBP5 genes induced by IFN-γ, while MAPK/ERK pathway inhibitor inhibited the upregulation of CXCL10 gene. PI3K/AKT pathway inhibitor inhibited the upregulation of APOL1,APOL4, APOL6, GBP1 and GBP5 genes induced by IFN-γ, all three signal pathway inhibitors could inhibit the upregulation of CXCL9 gene, and none of them could inhibit the upregulation of APOL3 gene.Upon IFN-γ stimulation, some family molecules of APOL and GBP in macrophages are significantly up-regulated, and PI3K/AKT, JAK/STAT3 and MAPK/ERK pathways have positive regulation on their expressions, respectively.干扰素-γ刺激人巨噬细胞后的转录组变化与细胞内信号调控机制研究.探讨干扰素-γ（IFN-γ）刺激后人巨噬细胞内上调的转录组基因表达谱及其相应的细胞内信号调控机制.运用RNA-seq对IFN-γ刺激前后的人巨噬细胞系U937差异基因表达谱进行测序和比较，从中筛选出显著上调的基因，利用实时荧光定量PCR技术（qPCR）分别在U937和THP1两个巨噬细胞株内进行验证；在IFN-γ刺激U937细胞的同时，分别加入JAK/STAT3、MAPK/ERK和PI3K/AKT通路抑制剂，检测其对上调基因的影响，从中找出关键的调控机制.巨噬细胞经IFN-γ刺激后，RNA-seq筛选结合qPCR验证结果显示：趋化因子CXCL9、CXCL10、CXCL11，APOL家族包括APOL1、APOL2、APOL3、APOL4、APOL6以及GBP家族GBP1、GBP2、GBP3、GBP4、GBP5均显著上调。JAK/STAT3通路抑制剂抑制了IFN-γ诱导的APOL1、APOL4、GBP1、GBP4和GBP5基因上调表达，MAPK/ERK通路抑制剂抑制了IFN-γ诱导的CXCL10基因上调表达，PI3K/AKT通路抑制剂抑制了IFN-γ诱导的APOL1、APOL4、APOL6、GBP1和GBP5基因上调表达，三种信号通路抑制剂均能抑制IFN-γ诱导的CXCL9基因上调表达，三种通路抑制剂对IFN-γ诱导的APOL3基因上调均无抑制作用.IFN-γ刺激后巨噬细胞内APOL和GBP部分家族分子表现为显著上调，PI3K/AKT、JAK/STAT3和MAPK/ERK通路对其表达分别具有一定的正向调控作用.

Extensive behavioral and electrophysiological evidence has demonstrated that native translations are automatically activated when bilinguals read non-native words. The present study investigated the impact of cross-language orthography and phonology on Chinese–English bilingual lexicons with a masked priming paradigm. The masked primes and targets were either translation equivalents (TE), orthographically related through translation (OR), phonologically related through translation (PR), or unrelated control (UC). Participants retained the targets in memory and decided whether the delayed catch words matched the targets. ERP data showed significant masked translation priming effects, as reflected by decreased ERP amplitudes in the TE condition in the 300–600 ms time window from frontal to parietal electrode clusters. Importantly, compared with the UC condition, the PR rather than OR condition elicited less negative ERP waveforms in the 300–500 ms time window with a frontal distribution. Taken together, these temporal and spatial dynamics suggested an automatic cross-language co-activation at the phonological and semantic levels for different-script bilinguals.

Microneedle (MN) technology has been proven to be promising to become an effective drug delivery route of insulin for diabetes treatment, with the advantages of high delivery efficiency, convenient management, and minimal risk of infection. However, efforts are still required to verify the insulin activity in MNs for further clinical application. Moreover, it is also essential to study the diffusion properties of insulin to understand the ability of various MN materials to control insulin release. Herein, we have combined all-atom molecular dynamics simulation and coarse-grained dissipative particle dynamics to systematically study insulin's structural stability and diffusion coefficient in polyvinyl alcohol and hyaluronic acid solutions. The all-atom simulation reveals the dissimilarities in the interaction mode between insulin and the two polymers. It also points out that the presence of the two polymers would not irreversibly impact the secondary structure of insulin, thereby ensuring regular insulin expression in vivo. Mesoscopic simulation results manifest that the diffusion coefficient of insulin in hyaluronic acid (HA) solution is greater than that of the polyvinyl alcohol (PVA) system. Meanwhile, through the study of insulin centroid trajectory, we have claimed two different diffusion mechanisms of insulin in polymer solution: The movement of insulin in the HA and water solution follows the Brownian motion rule. In comparison, the hopping effect of insulin has been observed in the PVA solution due to poor intermolecular affinity as well as lower polymer water solubility. By summarizing different diffusion mechanisms, this study can provide theoretical guidance for preparing insulin-loaded dissolvable MNs.

Background Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development. Methods We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies. Results ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. Conclusion Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

Serodiagnosis of SARS-CoV-2 infection is impeded by immunological cross-reactivity among the human coronaviruses (HCoVs): SARS-CoV-2, SARS-CoV-1, MERS-CoV, OC43, 229E, HKU1, and NL63. Here we report the identification of humoral immune responses to SARS-CoV-2 peptides that may enable discrimination between exposure to SARS-CoV-2 and other HCoVs. We used a high-density peptide microarray and plasma samples collected at two time points from 50 subjects with SARS-CoV-2 infection confirmed by qPCR, samples collected in 2004–2005 from 11 subjects with IgG antibodies to SARS-CoV-1, 11 subjects with IgG antibodies to other seasonal human coronaviruses (HCoV), and 10 healthy human subjects. Through statistical modeling with linear regression and multidimensional scaling we identified specific peptides that were reassembled to identify 29 linear SARS-CoV-2 epitopes that were immunoreactive with plasma from individuals who had asymptomatic, mild or severe SARS-CoV-2 infections. Larger studies will be required to determine whether these peptides may be useful in serodiagnostics., Mishra, Huang et al. identify 29 linear SARS-CoV-2 epitopes that are immunoreactive with the plasma from individuals who had asymptomatic, mild, or severe SARS-CoV-2 infections. This study suggests the possibility of using these peptides to discriminate the exposure to SARS-CoV-2 and other human coronaviruses.

In order to explore the influence of nanoparticle-loaded edaravone on postoperative effects in patients with cerebral hemorrhage, a total of 120 patients who were diagnosed as cerebral hemorrhage and underwent minimally invasive hematoma removal at the designated hospital by the study from December 2014 to December 2018 were selected as research objects and divided into three groups according to the random number table method: edaravone treatment (ET) group, nanoparticle-loaded edaravone treatment (NET) group, and combined treatment (CT) group with 40 patients in each group. Three groups of patients underwent routine treatments based on their conditions, including regulating blood sugar, regulating blood pressure, anti-infection, nutritional support, and managing complications, in which 25 mg edaravone injection and 100 ml saline were added for patients in NET and CT group on the basis of the routine treatment of patients in ET group. The results showed that, after 15 days of standard treatment, the 40 patients in NET group had significantly improved neurological function than that before the treatment; the secretion of inflammatory factors in peripheral serum increased on the 7th day of treatment and decreased on the 14th day of treatment; there was no statistically significant difference in edema volume before treatment and the edema volume in the NET group was (11.56±0.44) mL after treatment, which was significantly smaller than that in ET group of (14.63±1.15) mL and the difference between the three groups was statistically significant (P

Alzheimer's disease (AD) is regarded as a progressive neurodegenerative dementia, characterized by degeneration of distinct neuronal populations. A case-control study was carried out using high-resolution mass spectrometry to explore AD-associated urinary metabolic biomarkers from 30 AD patients and 30 cognitively normal (CN) individuals. In total, 49 metabolites were determined and validated as known compounds using LC/MS analysis. Using the two-sample t-test statistical analysis (P 0.05), 19 metabolites were shown to be significantly different from AD to CN. A diagnostic model of the receiver operating characteristic curve was constructed with a combination of nine molecules out of 19 metabolites, it yielded a separation with an area under the curve value of 0.976 between the two groups. This study indicated that urinary metabolites showed a significant expression between AD and CN. AD-related metabolites enable to satisfy the diagnostic power of disease discrimination. In addition, as a noninvasive approach, urine collection is done easily in clinical diagnosis of AD.

Androgen deprivation therapy (ADT) is the standard therapy for men with advanced prostate cancer (PCa). PCa often responds to ADT and enters a dormancy period, which can be recognized clinically as a minimal residual disease. However, the majority of these patients will eventually experience a relapse in the form of castration-resistant PCa with poor survival. Therefore, ADT-induced dormancy is a unique time window for treatment that can provide a cure. The study of this well-recognized phase of prostate cancer progression is largely hindered by the scarcity of appropriate clinical tissue and clinically relevant preclinical models. Here, we report the utility of unique and clinically relevant patient-derived xenograft models in the study of the intrinsic immune landscape of dormant PCa. Using data from RNA sequencing, we have reconstructed the immune evasion mechanisms that can be utilized by dormant PCa cells. Since dormant PCa cells need to evade the host immune surveillance for survival, our results provide a framework for further study and for devising immunomodulatory mechanisms that can eliminate dormant PCa cells.

Seafood is rich in nutrients and plays a significant role in human health. However, seafood allergy is a worldwide health issue by inducing adverse reactions ranging from mild to life-threatening in seafood-allergic individuals. Seafood consists of fish and shellfish, with the major allergens such as parvalbumin and tropomyosin, respectively. In the food industry, effective processing techniques are applied to seafood allergens to lower the allergenicity of seafood products. Also, sensitive and rapid allergen-detection methods are developed to identify and assess allergenic ingredients at varying times. This review paper provides an overview of recent advances in processing techniques (thermal, nonthermal, combined [hybrid] treatments) and main allergen-detection methods for seafood products. The article starts with the seafood consumption and classification, proceeding with the prevalence and symptoms of seafood allergy, followed by a description of biochemical characteristics of the major seafood allergens. As the topic is multidisciplinary in scope, it is intended to provide information for further research essential for food security and safety.

Cancer cells can communicate with the tumor microenvironment and contribute to tumor progression. However, the effects of drug-resistant tumor cells on angiogenesis are unclear. Current anti-angiogenic strategies also have limitations and it would be useful to develop novel targets and treatment strategies. Here, our study showed that the conditioned medium and exosomes from 5-FU-resistant colon cancer cells promoted angiogenesis, and we observed that exosomal dipeptidyl peptidase IV (DPP4) was a potent inducer of this angiogenesis. DPP4-enriched exosomes increased periostin (POSTN) expression in human umbilical vein endothelial cells via Twist1 nuclear translocation or activating Smad signaling pathway, while silencing or inhibition of DPP4 neutralized those effects. The in vivo and clinical data indicated that high DPP4 expression was related to tumor progression. These findings indicate that DPP4 may be a target for inhibiting angiogenesis in 5-FU-resistant colon cancer. Furthermore, exosomal DPP4 concentrations may be a useful prognostic marker for colon cancer.

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors, but also posed computational challenges on how to integrate and utilize the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly two million cells from 76 high-quality tumor datasets across 28 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, malignant cell classification, cell clustering, cell-type annotation, differential expression analysis, and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching, and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.

Numerous studies have used human pluripotent stem cell-derived cerebral organoids to elucidate the mystery of human brain development and model neurological diseases in vitro, but the potential for grafted organoid-based therapy in vivo remains unknown. Here, we optimized a culturing protocol capable of efficiently generating small human cerebral organoids. After transplantation into the mouse medial prefrontal cortex, the grafted human cerebral organoids survived and extended projections over 4.5 mm in length to basal brain regions within 1 month. The transplanted cerebral organoids generated human glutamatergic neurons that acquired electrophysiological maturity in the mouse brain. Importantly, the grafted human cerebral organoids functionally integrated into pre-existing neural circuits by forming bidirectional synaptic connections with the mouse host neurons. Furthermore, compared to control mice, the mice transplanted with cerebral organoids showed an increase in freezing time in response to auditory conditioned stimuli, suggesting the potentiation of the startle fear response. Our study showed that subcortical projections can be established by microtransplantation and may provide crucial insights into the therapeutic potential of human cerebral organoids for neurological diseases.

An increasing number of studies have shown that long noncoding RNAs (lncRNAs) play important roles in tumor development and progression. However, their involvement in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Epigenetic regulation is one major mechanism utilized by cancer cells to control lncRNA expression. We identified that lncRNA VENTXP1 was epigenetically silenced in multiple cancer types, and its lower expression was correlated with poorer survival in HNSCC patients. Through in silico analysis and experimental validation, we identified miR-205-5p and its direct interacting partner of VENTXP1, which regulates HNSCC cell proliferation and tumorigenicity. Using RNA-seq and differential gene expression analysis, we further identified ANKRD2 as a miR-205-5p target, which plays an essential role in modulating NF-kB signaling. These findings suggest that VENTXP1 inhibits tumor growth via suppressing miR-205-5p/ANKRD2-mediated NF-kB signaling in HNSCC. Thus, pharmaceutical targeting of DNA methylation to restore VENTXP1 expression might constitute a therapeutic strategy for HNSCC.

Background Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. Method We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. Results We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. Conclusion Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

Objective This paper is aimed at investigating the clinical characteristics of primary Sjogren’s syndrome (pSS) with lymphocytic interstitial pneumonia (LIP). Methods The demographic data, clinical manifestations, laboratory and radiological findings, treatment, and prognosis from 15 cases of pSS-LIP patients were retrospectively analyzed. The data were compared with t test, χ2 test, and Pearson/Spearman correlation analysis. Results (1) Fifteen cases of patients with pSS-LIP are all females (100%). Compared with pSS with interstitial lung disease(pSS-ILD) patients, the incidence of dry cough, dental caries is higher in pSS-LIP patients. The incidence of shortness of breath, weight loss, and crackles is lower in pSS-LIP patients than that of pSS-ILD patients. (2) Compared with pSS-ILD patients, pSS-LIP patients had higher percentage of patients with ANA, anti-SSA52KD antibody, anti-SSA60KD antibody, and anti-SSB antibody, and the higher concentration of serum globulin. (3) Compared with pSS-ILD patients, the frequency of obstructive ventilation dysfunction is significantly higher and the frequency of diffusion dysfunction is significantly lower in pSS-LIP patients. (4) The most frequent HRCT findings in patients with pSS-LIP is cysts (100%), followed by ground-glass opacities (73.3%), nodular shadow (73.3%) among the pSS-LIP patients. Compared with PSS-ILD patients, the incidence of pulmonary nodule shadow is significantly higher in PSS-LIP patients, while that of grid shadow was significantly lower. (5) Compared with the baseline, the sum of the number, maximum diameter, and diameter of cysts in three levels of pSS-LIP patients showed an increasing trend after treatment. (6) Correlation analysis: The changes of ground-glass opacities were positively correlated with using GC or not, and those were negatively correlated with the dose of GC treatment. Besides, there is a positive correlation between the annual change rate of the maximum diameter of cysts (△Ømax1/t) and the use of CTX; there is a positive correlation between the annual change rate of the total diameter of cysts (△Øsum1/t) and the use of CTX. Conclusion To the patients of pSS-LIP, female were more common than male, and the onset of LIP was usually more insidious. Hyperglobulinemia and anti-SSA antibody were more prominent in patients with pSS-LIP. Pulmonary function showed the higher rate of obstructive ventilation dysfunction and the lower rate of diffusion dysfunction. The appearance of ground-glass opacities in pSS-LIP patients suggests that the infiltration of inflammatory cells increases, which may cause airway compression, the expansion of terminal bronchioles, and the formation of cysts. The more ground-glass opacities appear earlier, and the more appearance of new cysts later. Therapy with glucocorticoid may be effective on the ground-glass opacity during acute stage, and therapy with cyclophosphamide may be effective on the cysts during chronic stage. The heavier ground-glass opacity is at baseline, the more likely it will recur during maintenance treatment. So follow-up closely is needed.Key Points• It is the first clinical study with more cases of patients with pSS-LIP.• Female and hyperglobulinemia and anti-SSA antibody were more prominent in patients with pSS-LIP.• Pulmonary function showed the higher rate of obstructive ventilation dysfunction and the lower rate of diffusion dysfunction.• Therapy with glucocorticoid may be effective on the ground-glass opacity during acute stage, and therapy with cyclophosphamide may be effective on the cysts during chronic stage.

Background: Hashimoto’s thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid parenchyma, which ultimately leads to tissue destruction and loss of function. Caveolin-1 (Cav-1) is an essential structural constituent of lipid rafts in the plasma membrane of cells and is reported to be significantly reduced in thyrocytes from HT patients. However, the mechanism of Cav-1 involvement in HT pathogenesis is still largely unclear. Methods: Cav-1 expression in thyroid tissues from HT patients and euthyroid nodular goiter tissues was detected by immunohistochemistry staining. Cav-1 knockdown and overexpression were constructed by lentiviral transfection in the human thyroid follicular epithelial cell (TFC) line of Nthy-ori 3-1. The mRNA expression levels of chemokines in TFCs were determined by quantitative real-time PCR (qPCR). Cav-1 and peroxisome proliferator-activated receptor gamma (PPARγ) levels were analysed by qPCR and Western blot analysis. The migration ability of peripheral blood mononuclear cells (PBMCs) was detected by the Transwell assay. Results: In this study, Cav-1 and PPARγ expression was reduced in the thyroid tissues from HT patients. In vitro experiments showed that the expressions of chemokine (C-C motif) ligand 5 (CCL5) and migration of PBMCs were markedly increased, while the level of PPARγ was significantly decreased after the lentivirus-mediated knockdown of Cav-1 in Nthy-ori 3-1 cells. Interestingly, pioglitazone, a PPARγ agonist, not only upregulated PPARγ and Cav-1 proteins significantly, but also effectively reversed the Cav-1-knockdown-induced upregulation of CCL5 in Nthy-ori 3-1 cells and reduced the infiltration of lymphocytes. Conclusion: The inhibition of Cav-1 upregulated the CCL5 expression and downregulated the PPARγ expression in TFC while pioglitazone, a PPARγ agonist, reversed the detrimental consequence. This outcome might be a potential target for the treatment of lymphocyte infiltration into the thyroid gland and HT development.

To investigate the biomarker(s) that could affect the decision for immediate or delayed delivery in severe preeclampsia.Data on serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatinine, blood urea nitrogen (BUN), uric acid (UA) and platelet counts from 134 cases were collected and analysed.Higher UA levels were seen in case with immediate delivery. Higher stillbirth was seen in cases with delayed delivery.UA levels could be a potential management biomarker for immediate or delayed delivery in severe preeclampsia. However, the higher risk of stillbirth must be considered in delayed delivery.

Nowadays, the increasing prevalence of food allergy has become a public concern related to human health worldwide. Thus, it is imperative and necessary to provide some efficient methods for the management of food allergy. Some conventional processing methods (e.g., boiling and steaming) have been applied in the reduction of food immunoreactivity, while these treatments significantly destroy nutritional components present in food sources. Several studies have shown that novel processing techniques generally have better performance in retaining original characteristics of food and improving the efficiency of eliminating allergens. This review has focused on the recent advances of novel non-thermal processing techniques including high-pressure processing, ultrasound, pulsed light, cold plasma, fermentation, pulsed electric field, enzymatic hydrolysis, and the combination processing of them. Meanwhile, general information on global food allergy prevalence and food allergy pathology are also described. Hopefully, these findings regarding the modifications on the food allergens through various novel food processing techniques can provide an in-depth understanding in the mechanism of food allergy, which in turn possibly provides a strategy to adapt in the reduction of food immunoreactivity for the food industries.

Autophagy is a highly conserved process that is vital for tumor progression and treatment response. Although autophagy is proposed to maintain the stemness phenotype in adult diffuse glioma, the molecular basis of the link between autophagy and stemness is poorly understood, which makes it impossible to effectively screen for the population that will benefit from autophagy-targeted treatment. Here, ATG9B as essential for self-renewal capacity and tumor-propagation potential is identified. Notably, ASCL2 transcriptionally regulates the expression of ATG9B to maintain stemness properties. The ASCL2-ATG9B axis is an independent prognostic biomarker and indicator of autophagic activity. Furthermore, the highly effective blood-brain barrier (BBB)-permeable autophagy inhibitor ROC-325, which can significantly inhibit the progression of ASCL2-ATG9B axis

The strong tumorigenic capacity and treatment resistance made hepatocellular carcinoma (HCC) a huge threat to public health. ZNF165, the kruppel family of zinc-finger-containing transcription factors, is expressed in HCC; however, its specific role in HCC and the molecular mechanism are yet to be elucidated. In this study, we observed that ZNF165 was overexpressed in liver cancer tissues and the immune microenvironment; higher ZNF165 expression was correlated with lower overall survival in liver cancer patients. The ZNF165 knockdown in Bel7402 cells revealed the impairment of the tryptophan/kynurenine/AhR/CYP1A1 axis. Moreover, the knockdown of CYP1A1 significantly inhibited the proliferation and migration of HCC cells, and ZNF165 promoted the transcriptional activity of AhR by facilitating the nuclear translocation of CYP1A1. In conclusion, the present study argued that ZNF165 was highly expressed in liver tissues and the immune microenvironment. ZNF165 promoted the proliferation and migration of HCC cells by activating the tryptophan/kynurenine/AhR/CYP1A1 axis and promoting the expression of CYP1A1.

ObjectiveDuring total knee arthroplasty (TKA), tourniquet may negatively impact post-operative functional recovery. This study aimed at investigating the effects of tourniquet on pain and return to function.MethodsPubmed, Embase, and Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) published up to February 15th, 2020. Search terms included; total knee arthroplasty, tourniquet, and randomized controlled trial. RCTs evaluating the efficacies of tourniquet during and after operation were selected. Two reviewers independently extracted the data. Effect estimates with 95% CIs were pooled using the random-effects model. Dichotomous data were calculated as relative risks (RR) with 95% confidence intervals (CI). Mean differences (MD) with 95% CI were used to measure the impact of consecutive results. Primary outcomes were the range of motion (ROM) and visual analog scale (VAS) pain scores.ResultsThirty-three RCTs involving a total of 2,393 patients were included in this study. The mean age is 65.58 years old. Compared to no tourniquet group, the use of a tourniquet resulted in suppressed ROM on the 3rd post-operative day [MD, −4.67; (95% CI, −8.00 to −1.35)] and the 1st post-operative month [MD, −3.18; (95% CI, −5.92 to −0.44)]. Pain increased significantly when using tourniquets on the third day after surgery [MD, 0.39; (95% CI, −0.19 to 0.59)]. Moreover, tourniquets can reduce intra-operative blood loss [MD, −127.67; (95% CI, −186.83 to −68.50)], shorter operation time [MD, −3.73; (95% CI, −5.98 to −1.48)], lower transfusion rate [RR, 0.85; (95% CI, 0.73–1.00)], higher superficial wound infection rates RR, 2.43; [(5% CI, 1.04–5.67)] and higher all complication rates [RR, 1.98; (95% CI, 1.22–3.22)].ConclusionModerate certainty evidence shows that the use of a tourniquet was associated with an increased risk of higher superficial wound infection rates and all complication rates. Therefore, the findings did not support the routine use of a tourniquet during TKA.

Osteoporosis (OP) is a systemic bone disease characterized by decreased bone strength, microarchitectural changes in bone tissues, and increased risk of fracture. Its occurrence is closely related to various factors such as aging, genetic factors, living habits, and nutritional deficiencies as well as the disturbance of bone homeostasis. The dysregulation of bone metabolism is regarded as one of the key influencing factors causing OP. Cholesterol oxidation products (COPs) are important compounds in the maintenance of bone metabolic homeostasis by participating in several important biological processes such as the differentiation of mesenchymal stem cells, bone formation in osteoblasts, and bone resorption in osteoclasts. The effects of specific COPs on mesenchymal stem cells are mainly manifested by promoting osteoblast genesis and inhibiting adipocyte genesis. This review aims to elucidate the biological roles of COPs in OP development, starting from the molecular mechanisms of OP, pointing out opportunities and challenges in current research, and providing new ideas and perspectives for further studies of OP pathogenesis.

The paper summarizes professor总结林国华教授针灸分期论治卒中后吞咽功能障碍的经验。林国华教授总结其病机为精亏髓乏，元阳虚衰，谨遵“从阳引阴”之法，通调任督，重用阳经，分期结合辨经、辨位论治。口腔期阳明失约，面瘫舌痿，治疗以泻为用，重取阳明；吞咽期邪犯少阳，枢机不利，治以沟通表里，疏利少阳；食管期阳明脉虚，浊气不降，故以补为用，通补阳明。辅以针刺运动疗法，妙用岭南火针，为临床治疗卒中后吞咽功能障碍提供参考。.

Background Relapsing polychondritis (RP) patients with tracheal cartilage involvement are different from other patients. The objective of this study was to compare the clinical features and disease patterns between a respiratory involvement subgroup and a non-respiratory involvement subgroup according to chest computed tomography. Method We performed a retrospective cohort study collecting RP patients hospitalized at the Beijing Chao-Yang Hospital between January 2012 and August 2021. Results Respiratory involvement affected 59.7% of patients in our cohort. The incidence of costochondritis was more common in RP patients with respiratory involvement (p = 0.03); the incidence of inflammatory eye disease (p = 0.001) and auricular chondritis (p = 0.001) was less frequent in RP respiratory involvement patients.. Compared with the non-respiratory involvement subgroup the incidence of pulmonary infection marginally increased in the respiratory involvement subgroup (p = 0.06). Inflammatory indexes except for C-reactive protein to albumin ratio (CAR) were significantly higher in the respiratory involvement subgroup; analysis revealed no significant relationship between inflammatory indexes and pulmonary infection. Conclusion RP patients with respiratory involvement had a greater incidence of costochondritis and pulmonary infectionand lesser incidence of inflammatory eye diseases and auricular chondritis compared to non-respiratory involvement. Increasing inflammatory indexes suggests that patients with respiratory involvement had a higher disease activity index of RP. The difference in probability of survival was insignificant between subgroups.

Objective this retrospective study aims to compare the prevalence and diagnostic agreement of sarcopenic obesity (SO) using different obesity diagnostic methods among Chinese community-dwelling older adults. Methods SO was diagnosed with sarcopenia and obesity diagnostic methods. Sarcopenia was defined using the Asian Working Group for Sarcopenia criteria 2019 (AWGS2019). Four widely used indicators were used to define obesity: body mass index (BMI), waist circumference (WC), percent of body fat (PBF) and visceral fat area (VFA). Cohen’s kappa was used to analyse the diagnosis agreement of SO between different diagnostic methods. Results a total of 1,050 participants were included, including 347 men (71.3 ± 7.4 years) and 703 women (69.9 ± 7.5 years). The prevalence of sarcopenia was 25% in total participants, there was no difference between men (24.2%) and women (25.5%), (P = 0.705). With different obesity diagnostic methods, the obesity prevalence ranged from 4.1 to 42.2%, the SO prevalence was 0.1–7.9%. The diagnosis agreement of SO was poor-to-moderate (κ ranged from −0.002 to 0.682). Among the four diagnostic methods, AWGS combined with BMI had the poorest agreement (κ = −0.002 with other methods), AWGS combined with VFA had the best agreement (κ = 0.641 and 0.682 with AWGS combined with PBF and with AWGS combined with WC, respectively). Conclusion the prevalence of SO vary considerably and the diagnostic agreement is poor-to-moderate with non-uniform diagnostic methods. BMI has the lowest sensitivity, whereas VFA has the highest sensitivity in diagnosis of SO, and VFA has a relatively good diagnostic agreement with other diagnostic methods.

Diabetes is one of the most serious chronic diseases today. Patients with diabetes need frequent insulin injections or blood sampling to monitor blood glucose levels. The microneedles are a painless transdermal drug delivery system, which has great advantages in achieving self-management. There have been a lot of researches on microneedles used in diabetes treatment. Microneedle-based treatment of diabetes has also changed from a simple and reliable system to a complex and efficient system. This review introduces microfluidic, glucose response, and other contents based on microneedles, and some challenges in the development of microneedles.

Background Previous studies have revealed that current secondhand smoke exposure showed highly suggestive evidence for increased risk of simultaneous sleep problems in children. Data on the associations between early-life exposure to SHS with subsequent sleep problems in children were scarce. We aimed to evaluate the associations of early-life SHS exposure with sleep problems in children. Methods In this cross-sectional study, children were recruited from elementary and middle schools in Liaoning Province, China between April 2012 and January 2013. We assessed early-life SHS exposure (pregnancy and the first 2 years of life) via questionnaires. Sleep problems and different types of sleep-related symptoms were measured based on the validated tool of the Sleep Disturbance Scale for Children (SDSC). Generalized linear mixed models were applied to estimate the associations of early-life SHS exposure with sleep problems. Results We included a total of 45,562 children (22,657 [49.7%] males; mean [SD] age, 11.0 [2.6] years) and 6167 of them (13.5%) were exposed to early-life SHS during both pregnancy and the first 2 years of life. Compared with unexposed counterparts, children exposed to early-life SHS had higher total T-scores of SDSC (β = 4.32; 95%CI: 4.06, 4.58) and higher odds of increased sleep problems (OR = 2.14; 95%CI: 1.89, 2.42). When considering different sleep-related symptoms, the associations between early-life SHS exposure and symptom of sleep-wake transition disorders (i.e., bruxism) were the strongest in all analyses. Conclusions Early-life SHS exposure was associated with higher odds of global sleep problems and different sleep-related symptoms in children aged 6–18 years. Our findings highlight the importance to strengthen efforts to support the critical importance of maintaining a smoke-free environment especially in early life.

Postmenopausal osteoporosis (PMOP) and sarcopenia are common diseases that predominantly affect postmenopausal women. In the occurrence and development of these two diseases, they are potentially pathologically connected with each other at various molecular levels. However, the application of metabolomics in sarco-osteoporosis and the metabolic rewiring happening throughout the estrogen loss-replenish process have not been reported. To investigate the metabolic alteration of sarco-osteoporosis and the possible therapeutical effects of estradiol, 24 mice were randomly divided into sham surgery, ovariectomy (OVX), and estradiol-treated groups. Three-dimensional reconstructions and histopathology examination showed significant bone loss after ovariectomy. Estrogen can well protect against OVX-induced bone loss deterioration. UHPLC-Q-TOF/MS was preformed to profile semi- polar metabolites of skeletal muscle samples from all groups. Metabolomics analysis revealed metabolic rewiring occurred in OVX group, most of which can be reversed by estrogen supplementation. In total, 65 differential metabolites were identified, and pathway analysis revealed that sarco-osteoporosis was related to the alterations in purine metabolism, glycerophospholipid metabolism, arginine biosynthesis, tryptophan metabolism, histidine metabolism, oxidative phosphorylation, and thermogenesis, which provided possible explanations for the metabolic mechanism of sarco-osteoporosis. This study indicates that an UHPLC-Q-TOF/MS-based metabolomics approach can elucidate the metabolic reprogramming mechanisms of sarco-osteoporosis and provide biological evidence of the therapeutical effects of estrogen on sarco-osteoporosis.

Background With the rapid spread of COVID-19 worldwide, quick screening for possible COVID-19 patients has become the focus of international researchers. Recently, many deep learning-based Computed Tomography (CT) image/X-ray image fast screening models for potential COVID-19 patients have been proposed. However, the existing models still have two main problems. First, most of the existing supervised models are based on pre-trained model parameters. The pre-training model needs to be constructed on a dataset with features similar to those in COVID-19 X-ray images, which limits the construction and use of the model. Second, the number of categories based on the X-ray dataset of COVID-19 and other pneumonia patients is usually imbalanced. In addition, the quality is difficult to distinguish, leading to non-ideal results with the existing model in the multi-class classification COVID-19 recognition task. Moreover, no researchers have proposed a COVID-19 X-ray image learning model based on unsupervised meta-learning. Methods This paper first constructed an unsupervised meta-learning model for fast screening of COVID-19 patients (UMLF-COVID). This model does not require a pre-trained model, which solves the limitation problem of model construction, and the proposed unsupervised meta-learning framework solves the problem of sample imbalance and sample quality. Results The UMLF-COVID model is tested on two real datasets, each of which builds a three-category and four-category model. And the experimental results show that the accuracy of the UMLF-COVID model is 3–10% higher than that of the existing models. Conclusion In summary, we believe that the UMLF-COVID model is a good complement to COVID-19 X-ray fast screening models.

Background Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction is one of the hallmark effects of anti-GB therapies with temozolomide (TMZ). However, the non-classical form of autophagy, autophagy-based unconventional secretion, also called secretory autophagy and its role in regulating the sensitivity of GB to TMZ remains unclear. There is an urgent need to illuminate the mechanism and to develop novel therapeutic targets for GB. Methods Cancer genome databases and paired-GB patient samples with or without TMZ treatment were used to assess the relationship between HMGB1 mRNA levels and overall patient survival. The relationship between HMGB1 protein level and TMZ sensitivity was measured by immunohistochemistry, ELISA, Western blot and qRT-PCR. GB cells were engineered to express a chimeric autophagic flux reporter protein consisting of mCherry, GFP and LC3B. The role of secretory autophagy in tumor microenvironment (TME) was analyzed by intracranial implantation of GL261 cells. Coimmunoprecipitation (Co-IP) and Western blotting were performed to test the RAGE-NFκB-NLRP3 inflammasome pathway. Results The exocytosis of HMGB1 induced by TMZ in GB is dependent on the secretory autophagy. HMGB1 contributed to M1-like polarization of tumor associated macrophages (TAMs) and enhanced the sensitivity of GB cells to TMZ. Mechanistically, RAGE acted as a receptor for HMGB1 in TAMs and through RAGE-NFκB-NLRP3 inflammasome pathway, HMGB1 enhanced M1-like polarization of TAMs. Clinically, the elevated level of HMGB1 in sera may serve as a beneficial therapeutic-predictor for GB patients under TMZ treatment. Conclusions We demonstrated that enhanced secretory autophagy in GB facilitates M1-like polarization of TAMs to enhance TMZ sensitivity of GB cells. HMGB1 acts as a key regulator in the crosstalk between GB cells and tumor-suppressive M1-like TAMs in GB microenvironment and may be considered as an adjuvant for the chemotherapeutic agent TMZ.

Microplastics (MPs) from personal care and cosmetic products (PCCPs) pose a threat to aquatic environment due to the small size and the complexity of composition. Although the habits of personal care behaviors (PCBs) vary from individuals affecting MPs emissions, quantitative research is not sufficient to support high-precision emission estimates and targeted management decisions. Based on a questionnaire survey about PCBs and laboratory experiments on corresponding PCCPs utilization, this study proposed a bottom-up micro-simulation method to quantify MPs emissions combining multinomial logit model and categorized emission coefficients, and identified the impact of individual attributes on the emissions. The results show that the annual PCBs-derived MPs emissions amounted to 2931.8 trillion particles in China, of which teeth brushing, face washing, and bathing behavior accounted for 29%, 36% and 35%, respectively. The residents discharged an average of 2.18 million particles per capita per year with 95% confidence interval of 0.58-4.34 million particles. Gender, age and living region had greater impacts on PCBs-derived MPs emissions. The effect of living region was significantly related to local temperature and humidity. The estimation based on the MPs discharge characteristics of PCBs provides high-precision method regarding the MPs emission from people's daily life and contributes to further understanding the source of MPs and initiating environmental control strategies.

Objectives YTHDF1 is known as a m6A reader protein, and many researches of YTHDF1 focused on the regulation of mRNA translation efficiency. However, YTHDF1 is also related to RNA degradation, but how YTHDF1 regulates mRNA degradation is indefinite. Liquid‐liquid phase separation (LLPS) underlies the formation of membraneless compartments in mammal cells, and there are few reports focused on the correlation of RNA degradation with LLPS. In this research, we focused on the mechanism of YTHDF1 degraded mRNA through LLPS. Materials and Methods The CRISPR/Cas9 knock out system was used to establish the YTHDF1 knock out (YTHDF1‐KO) cell lines (HEK293 and HeLa) and METTL14 knock out (METTL14‐KO) cell line (HEK293). 4SU‐TT‐seq was used to check the half‐life changes of mRNAs. Actinomycin D and qPCR were used to test the half‐life changes of individual mRNA. RNA was stained with SYTO RNA‐select dye in wild type (WT) and YTHDF1‐KO HeLa cell lines. Co‐localization of YTHDF1 and AGO2 was identified by immunofluorescence. The interaction domain of YTHDF1 and AGO2 was identified by western blot. Phase separation of YTHDF1 was performed in vitro and in vivo. Fluorescence recovery after photobleaching (FRAP) was performed on droplets as an assessment of their liquidity. Results In this research, we found that deletion of YTHDF1 led to massive RNA patches deposited in cytoplasm. The results of 4SU‐TT‐seq showed that deletion of YTHDF1 would prolong the half‐life of mRNAs. Immunofluorescence data showed that YTHDF1 and AGO2 could co‐localize in P‐body, and Co‐IP results showed that YTHDF1 could interact with AGO2 through YT521‐B homology (YTH) domain. We confirmed that YTHDF1 could undergo phase separation in vitro and in vivo, and compared with AGO2, YTHDF1 was more important in P‐body formation. The FRAP results showed that liquid AGO2 droplets would convert to gel/solid when YTHDF1 was deleted. As AGO2 plays important roles in miRISCs, we also found that miRNA‐mediate mRNA degradation is related to YTHDF1. Conclusions YTHDF1 recruits AGO2 through the YTH domain. YTHDF1 degrades targeting mRNAs by promoting P‐body formation through LLPS. The deletion of YTHDF1 causes the P‐body to change from liquid droplets to gel/solid droplets, and form AGO2/RNA patches, resulting in a degradation delay of mRNAs. These findings reveal a previously unrecognized crosstalk between YTHDF1 and AGO2, raising a new sight of mRNA post‐transcriptional regulation by YTHDF1., Working model: YTHDF1 interacts with AGO2 (AGO2 perhaps along with miRNA) through YTH domain, then undergoes LLPS to aggregate more components of miRISCs, and leading to P‐body formation for mRNA degradation. Deficiency of YTHDF1 disrupts the interaction between YTHDF1 and AGO2, leads to the conversion of AGO2 liquid droplets to gels/solids and substantially increases the mRNA stability.

p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here, we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded the development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlated with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer. Significance: Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer.Cancer Res; 78(17); 4853–64. ©2018 AACR.

Background To study lymphatic recurrence distribution after radical surgery in the real world and guide clinical tumor volume delineation for regional lymph nodes during postoperative radiotherapy for lower thoracic squamous cell esophageal carcinomas. Methods We enrolled patients who underwent radical esophagectomy, without radiation before or after surgery, at 3 cancer hospitals. Patients were classified into groups according to tumor locations. We included patients with tumors in the lower thoracic segment and analyzed the postoperative lymph node recurrence mode. A cutoff value of 10% was used to differentiate high-risk lymph node drainage areas from others. Results We enrolled 1905 patients in the whole study series, including 652 thoracic esophageal carcinomas that met our inclusion criteria; there were 241 cases of lower thoracic esophageal carcinomas. 1st, 2nd, 4th, 7th, 8th groups of lymph nodes, according to the 8th edition of the AJCC classification, displayed as high-risk recurrence areas, representing 17.8%, 23.9%, 11.7%, 10.9% and 12.2% of lymph node recurrence. Stage III-IV tumors located in the lower segment of the thoracic esophagus showed a tendency to recur in the left gastric nodes (7.9%) and celiac nodes (10.6%). Conclusions According to our results, we recommended including the 4th, 7th and 8th groups of lymph nodes in the radiation field, and for patients with stage III-IV disease, the 17th and 20th groups of nodes should be irradiated during postoperative treatment. Whether including 1st/2nd groups in preventive irradiation needed more proofs.

To establish and validate a nomogram that predicts the risk of sarcopenia for community-dwelling older residents.Retrospective study.A total of 1050 community-dwelling older adults.Data from a survey of community-dwelling older residents (≥60 years old) in Hunan, China, from June to September 2019 were retrospectively analyzed. The survey included general demographic information, diet, and exercise habits. Sarcopenia diagnosis was according to 2019 Asian Working Group for Sarcopenia criteria. Participants were randomly divided into the development group and validation groups. Independent risk factors were screened by multivariate logistic regression analysis. Based on the independent risk factors, a nomogram model was developed to predict the risk of sarcopenia for community-dwelling older adults. Both in the development and validation sets, the discrimination, calibration, and clinical practicability of the nomogram were verified using receiver operating characteristic curve analysis, Hosmer-Lemeshow test, and decision curve analysis, respectively.Sarcopenia was identified in 263 (25.0%) participants. Age, body mass index, marital status, regular physical activity habit, uninterrupted sedentary time, and dietary diversity score were significant contributors to sarcopenia risk. A nomogram for predicting sarcopenia in community-dwelling older adults was developed using these factors. Receiver operating characteristic curve analysis showed that the area under the curve was 0.827 (95% CI 0.792-0.860) and 0.755 (95% CI 0.680-0.837) in the development and validation sets, respectively. The Hosmer-Lemeshow test yielded P values of .609 and .565, respectively, for the 2 sets. The nomogram demonstrated a high net benefit in the clinical decision curve in both sets.This study developed and validated a risk prediction nomogram for sarcopenia among community-dwelling older adults. Sarcopenia risk was classified as low (11%), moderate (11%-70%), and high (70%). This nomogram provides an accurate visual tool to medical staff, caregivers, and older adults for prediction, early intervention, and graded management of sarcopenia.

Dissipative Particle Dynamics (DPD) is a mesoscopic simulation program used to simulate the behavior of complex fluids. This work systematically reviews the use of DPD to simulate the self-assembly process of pH-sensitive drug-loaded nanoparticles. pH-sensitive drug-loaded nanoparticles have the characteristics of good targeting and slow release in the body, which is an ideal method for treating cancer and other diseases. As an excellent simulation method, DPD can help people explore the loading and release laws of drugs with complex molecular structures and has extensive applications in other medical fields. This article reviews the self-assembly process of pH-sensitive polymers under neutral conditions and explores the factors that affect the self-assembly structure. It points out that different hydrophilic-hydrophobic ratios, molecular structures, and component distributions will affect the morphology, stability and drug carrying capacity of micelles. This article also introduces the release mechanism of the drug in detail and introduces the factors that affect the release. This article can help relevant researchers to follow the latest advances in the DPD simulation and pH-sensitive drug nano-carrier and insight people to investigate the further application of DPD simulation in biomedical science.

Objective: To evaluate the effect of beinaglutide on weight loss and plasma protein patterns of inflammation/obesity relevant cytokines and biomarkers. Materials and methods: This study involved 36 adult patients with a body mass index (BMI) of ≥ 24 kg/m2 and T2DM. Beinaglutide was administered for three months. Changes in body weight, fasting plasma glucose (FPG) level, 2 h postprandial plasma glucose (2h-PG) level, glycosylated hemoglobin (HbA1c) level, BMI and visceral and subcutaneous fat areas were measured at baseline and after three months of treatment. In addition, relevant inflammation/obesity cytokines and biomarkers were measured. Results: After three months, beinaglutide treatment led to significant changes, including in body weight, BMI, FPG level, HbA1c level, visceral and subcutaneous fat areas. In addition, serpin E1, leptin, C-reaction protein (CRP) and tumor necrosis factor-α (TNF-α) also decreased significantly. The plasma protein concentrations of CRP (Log2 transformed) were found to be positively correlated with the percentage of weight loss (R = 0.514 and p-value = 0.021). Conclusion: Beinaglutide treatment resulted in weight loss, plasma glucose control and anti-inflammatory effects in patients with T2DM and overweight/obesity.