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The emerging SARS-CoV-2 variants, commonly with many mutations in S1 subunit of spike (S) protein are weakening the efficacy of the current vaccines and antibody therapeutics. This calls for the variant-proof SARS-CoV-2 vaccines targeting the more conserved regions in S protein. Here, we designed a recombinant subunit vaccine, HR121, targeting the conserved HR1 domain in S2 subunit of S protein. HR121 consisting of HR1–linker1–HR2–linker2–HR1, is conformationally and functionally analogous to the HR1 domain present in the fusion intermediate conformation of S2 subunit. Immunization with HR121 in rabbits and rhesus macaques elicited highly potent cross-neutralizing antibodies against SARS-CoV-2 and its variants, particularly Omicron sublineages. Vaccination with HR121 achieved near-full protections against prototype SARS-CoV-2 infection in hACE2 transgenic mice, Syrian golden hamsters and rhesus macaques, and effective protection against Omicron BA.2 infection in Syrian golden hamsters. This study demonstrates that HR121 is a promising candidate of variant-proof SARS-CoV-2 vaccine with a novel conserved target in the S2 subunit for application against current and future SARS-CoV-2 variants.

To investigate the epidemiological features in children after the coronavirus disease 2019 (COVID-19) pandemic.This study collected throat swabs and serum samples from hospitalized pediatric patients of Renmin Hospital of Wuhan University, Wuhan, Hubei province, China before and after the COVID-19 pandemic. Respiratory infected pathogens [adenovirus (ADV), influenza virus A/B (Flu A/B), parainfluenza virus 1/2/3 (PIV1/2/3), respiratory syncytial virus (RSV), Mycoplasma pneumoniae (MP), and Chlamydia pneumoniae (CP)] were detected. The pathogens, age, and gender were used to analyze the epidemiological features in children after the COVID-19 pandemic.The pathogen detection rate was significantly higher in females than in males (P0.05), and the infection of PIV1 and MP was mainly manifested. After the COVID-19 pandemic, PIV1, PIV3, RSV, and MP had statistically different detection rates among the age groups (P0.05), and was mainly detected in patients aged 0-6 years, 0-3 years, 0-3 years, and 1-6 years, respectively. When comparing before the COVID-19 pandemic, the total detection rate of common respiratory pathogens was lower (P0.05). Except for the increase in the detection rate of PIV1 and CP, the infection rate of other pathogens had almost decreased.The prevention and control measures for the COVID-19 pandemic effectively changed the epidemiological features of common respiratory tract infectious diseases in pediatric children.

Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) belongs to the G protein-coupled receptor family, and it exhibits up-regulated expression in various types of human cancer. However, there are few reports of LGR6 contributing to gastric cancer (GC). Herein, we investigated the function of LGR6 and associated tumorigenic mechanisms in GC. LGR6 expression in GC was analyzed in the cancer genome atlas (TCGA) dataset and further confirmed in GC cell lines and fifteen paired tissue samples via quantitative real-time polymerase chain reaction (qRT-PCR). LGR6 expression was knocked down via small interfering RNA (siRNA), after which the impacts of silencing LGR6 on cell function were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), cell colony formation, wound-healing, and cell cycle assays. Western blot was performed to explore signaling pathways and regulatory mechanisms associated with LGR6 function. In this study, we showed that LGR6 was at higher levels in GC cell lines and gastric adenocarcinoma tissues. We found that silencing LGR6 in MKN-45 and BGC-823 cells inhibited cell proliferation and migration ability, which accompanied with an obvious regulation of MMP-9, β-catenin, CCNA2, CDK-2, and ERK1/2. In conclusion, this study demonstrated that LGR6 could act as an oncogene and may be a therapeutic target in GC.

In this work, we developed a ferroptosis self-catalyst, PTAF, exhibiting self-catalyzed ferroptosis for enhanced cancer therapy. Briefly, synergistic actions of self-catalyzed ˙OH accumulation and GPX4 indirect inactivation based on the establishment of the ROS self-catalytic loop effectively induced tumor ferroptosis, which provided a novel approach for enhanced tumor therapy.

Quantification of steroids possesses a crucial clinical value in early diagnosis and prognosis evaluation of various endocrine diseases. However, it is still challenging to realize feasible analysis of estrogens, androgens, progestogens, and corticoids within one single workflow. In this study, two derivatization reactions were newly designed for improvement: (1) acylation of phenolic hydroxyl on estrogens with isonicotinoyl chloride (INC) under the catalysis of 4-dimethylaminopyridine and (2) post-modification of oxime hydroxyl on hydroxylamine-pretreated ketosteroids with INC. Both reactions could conduct instantaneously at room temperature under aqueous conditions. Moreover, the resulting phenolic-INC and oxime-INC esters exhibited favorable MS responses. Through integrating these derivatization strategies with cold-induced phase separation technology, a feasible LC-MS/MS method was developed for simultaneous quantification of 15 multiclass steroids with proper sample consumption (50 μL serum), satisfying sensitivity (lower limit of quantitation at 0.01-5.00 ng/mL) and high throughput (40 min for sample-preparation). The practical applicability was tested by detecting 30 real samples from pregnant and non-pregnant women. The obtained results showed a good agreement with a previous validated methodology.

Subcellular organelle targeted imaging and therapy are of enormous interest in cancer theranostics. However, the lack of tumor-selective organelle targeting has compromised their efficacy and safety. In this work, we found that the near-infrared (NIR) fluorophore hemicyanine (CyNH2) can selectively target mitochondria with strong cytotoxicity through decreasing the mitochondrial membrane potential and increasing the intracellular reactive oxygen species (ROS) levels. A macrotheranostic probe (denoted as PLCy) based on conjugating CyNH2 with an acetylated lysine group was developed with masked fluorescence and cytotoxicity, which could both be unmasked through sequential activation by cancer cells overexpressing histone deacetylases (HDACs) and cathepsin L (CTSL) enzymes for selective cancer cell mitochondria-targeted imaging and therapy. In vitro and in vivo studies confirmed that the specific fluorescence turn-on and toxicity were restored in cancer cells and efficiently inhibited tumor growth. This macrotheranostic probe with sequential enzyme activation and mitochondrial targeting is expected to have promising applications in imaging-guided cancer therapy with high specificity and efficiency. Statement of significance To improve the targeting efficiency and enhance the anti-cancer activities of macrotheranostic probe. We designed macrotheranostic probe PLCy that can be activated via sequential enzymes for selective tumor mitochondria targeting. More importantly, the activated CyNH2 can decrease the mitochondrial membrane potential and elevate the reactive oxygen species level in cancer cells without light irradiation, which can further induce apoptosis of tumor cells for chemotherapy. Therefore, the use of sequential enzyme activation and mitochondria targeting strategies in the context of enzymatic activation may provide a general strategy for organelle-targeted imaging and therapy with high specificity and efficiency.

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease caused by various pathogenic factors, including hypoxia. Hypoxia stimulates the production of the extracellular matrix to promote fibrosis. However, the integrated function and the underlying mechanism of hypoxia in SSc are unclear.MethodsIn the present study, we used Agilent SurePrint G3 Human Gene Expression v3 for the transcriptional sequencing of fibroblasts with and without hypoxia to detect differentially expressed genes (DEGs) in hypoxia. We analyzed the results with the transcriptome data of SSc lesions (GSE95065) to select the co-DEGs. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on the basis of the co-DEGs using the R package ClusterProfiler, which showed that hypoxia and cross talk of hypoxia with other pathogenic factors are involved in the pathogenesis of SSc. Furthermore, we constructed a protein–protein interaction (PPI) network of co-DEGs and screened two significant functional expression modules.ResultsWe identified nine hub genes (ALDH1A1, EGF, NOX4, LYN, DNTT, PTGS2, TKT, ACAA2, and ALDH3A1). These genes affect the pentose phosphate pathway, oxidative stress, and lipolysis.ConclusionOur study provides insights into the mechanisms underlying the effects of hypoxia on SSc pathogenesis, which will help to better understand SSc pathogenesis and develop new therapeutic strategies for SSc.

The use of polyprodrugs, which bind drugs to polymer chains through responsive linkers, is a potential technique for cancer therapy; however, a lack of endogenous triggering factors limits drug activation in tumor tissue. Herein, we rationally created a reactive oxygen species (ROS)-sensitive polyprodrug (TS

Background To understand the prevalence of diabetic retinopathy (DR) in Shenzhen and to analyze the risk factors for the occurrence and development of DR. Based on the comprehensive information system for diabetes prevention and control in the communities of Shenzhen in 2019, six community health service centers in Shenzhen were used as research sites to carry out multicenter, cross-sectional screening studies. Methods Cluster random sampling was used to collect data from 904 patients with diabetes in Shenzhen. The occurrence of DR and vision-threatening diabetic retinopathy (VTDR) was analyzed, and multivariate logistic regression was performed to analyze the risk factors for DR and VTDR. EpiData version 3.1 (EpiData Association, Odense, Denmark) statistical software was used to build a database, and Statistical Package for the Social Sciences (SPSS) version 25.0 (IBM Corp., Armonk, N.Y., USA) was used to sort up and analyze the data. Results The prevalence of DR among diabetic patients in Shenzhen was 18.58% [95% confidence interval (CI): 16.13-21.3%], and the prevalence of VTDR was 2.43% (95% CI: 1.57-1.2%). The prevalence of DR and VTDR was higher in males than in females. Logistic regression analysis showed that age, disease duration, medication mode, and the occurrence of diabetic peripheral neuropathy (DPN) were associated with the incidence of DR in diabetic patients, and that disease duration, the occurrence of DPN, and diabetic nephropathy were associated with the occurrence of VTDR. Conclusions The prevalence of DR in the communities of Shenzhen is high. Age, disease duration, medications, and DPN are the major risk factors for the occurrence of DR.

DNA methylation is an important epigenetics, which occurs in the early stages of tumor formation. And it also is of great significance to find the relationship between DNA methylation and cancer. This paper proposes a novel model, iCancer-Pred, to identify cancer and classify its types further. The datasets of DNA methylation information of 7 cancer types have been collected from The Cancer Genome Atlas (TCGA). The coefficient of variation firstly is used to reduce the number of features, and then the elastic network is applied to select important features. Finally, a fully connected neural network is constructed with these selected features. In predicting seven types of cancers, iCancer-Pred has achieved an overall accuracy of over 97% accuracy with 5-fold cross-validation. For the convenience of the application, a user-friendly web server: http://bioinfo.jcu.edu.cn/cancer or http://121.36.221.79/cancer/ is available. And the source codes are freely available for download at https://github.com/Huerhu/iCancer-Pred.

Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes, and a common cause of blindness in working‑age individuals. Mesenchymal stem cell (MSC) transplantation has been considered a promising intervention therapy for DR, wherein the differentiation of MSCs into nerve cells plays an essential role. However, research into the role of MSCs in DR treatment remains incomplete, and the mechanisms of retinal repair at the molecular level have yet to be clarified. In the present study, all‑trans retinoic acid (ATRA) was used to promote the proliferation of rat umbilical cord (UC)‑derived MSCs and their differentiation into nerve cells. Furthermore, the effects and mechanisms of UC‑MSCs with or without ATRA treatment were investigated in rats subjected to streptozocin (STZ)‑induced DR. The results demonstrated that the transplantation of UC‑MSCs treated with or without ATRA attenuated DR in rats, and alleviated retinal tissue damage and apoptosis. In addition, the transplantation of UC‑MSCs treated with or without ATRA attenuated angiogenesis and inflammation in the retina by regulating the levels of relevant cytokines. UC‑MSCs treated with ATRA exerted a more prominent therapeutic effect than the untreated UC‑MSCs. On the whole, these findings indicate that UC‑MSCs alleviate STZ‑induced DR in rats by regulating angiogenesis and the inflammatory response at the molecular level. Thus, the findings of the present study may provide a theoretical basis for the application of MSCs in the treatment of DR.

A cell contains numerous protein molecules. One of the fundamental goals in molecular cell biology is to determine their subcellular locations since this information is extremely important to both basic research and drug development. In this paper, we report a novel and very powerful predictor called "pLoc_bal-mHum" for predicting the subcellular localization of human proteins based on their sequence information alone. Cross-validation tests on exactly the same experiment-confirmed dataset have indicated that the new predictor is remarkably superior to the existing state-of-the-art predictor in identifying the subcellular localization of human proteins. To maximize the convenience for the majority of experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mHum/, by which users can easily get their desired results without the need to go through the detailed mathematics.

In drug development, unexpected side effects are the main reason for the failure of candidate drug trials. Discovering potential side effects of drugsin silicocan improve the success rate of drug screening. However, most previous works extracted and utilized an effective representation of drugs from a single perspective. These methods merely considered the topological information of drug in the biological entity network, or combined the association information (e.g. knowledge graph KG) between drug and other biomarkers, or only used the chemical structure or sequence information of drug. Consequently, to jointly learn drug features from both the macroscopic biological network and the microscopic drug molecules. We propose a hybrid embedding graph neural network model named idse-HE, which integrates graph embedding module and node embedding module. idse-HE can fuse the drug chemical structure information, the drug substructure sequence information and the drug network topology information. Our model deems the final representation of drugs and side effects as two implicit factors to reconstruct the original matrix and predicts the potential side effects of drugs. In the robustness experiment, idse-HE shows stable performance in all indicators. We reproduce the baselines under the same conditions, and the experimental results indicate that idse-HE is superior to other advanced methods. Finally, we also collect evidence to confirm several real drug side effect pairs in the predicted results, which were previously regarded as negative samples. More detailed information, scientific researchers can access the user-friendly web-server of idse-HE at http://bioinfo.jcu.edu.cn/idse-HE. In this server, users can obtain the original data and source code, and will be guided to reproduce the model results.

Although stimuli-responsive polymers have emerged as promising strategies for intelligent cancer therapy, limited polymer degradation and insufficient drug release remain a challenge. Here, we report a novel reactive oxygen species (ROS)-awakened self-amplifying degradable cinnamaldehyde (CA)-based poly(thioacetal) polymer. The polymer consists of ROS responsive thioacetal (TA) group and CA as the ROS generation agent. The self-amplified polymer degradation process is triggered by endogenous ROS-induced cleavage of the TA group to release CA. The CA released then promotes the generation of more ROS through mitochondrial dysfunction, resulting in amplified polymer degradation. More importantly, poly(thioacetal) itself can trigger immunogenic cell death (ICD) of the tumor cells and its side chains can be conjugated with indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor to reverse the immunosuppressive tumor microenvironment for synergistic cancer immunotherapy. The self-amplified degradable poly(thioacetal) developed in this work provides insights into the development of novel stimulus-responsive polymers for enhanced cancer immunotherapy.

Reactive oxygen species (ROS)-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the inability to release sufficient drugs at tumor sites due to the paucity of ROS, which is required for prodrug activation usually limits the antitumor potency. Herein, a delivery nanosystem with self-amplifiable drug release pattern is constructed by encapsulating a tumor specificity ROS inducer NAD(P)H: quinone oxidoreductase-1 (NQO1)-responsive hemicyanine fluorescent dye (NCyNHsub2/sub) in a ROS-responsive self-immolative polyprodrug nanoparticle for orchestrated oxidation-chemotherapy. In response to ROS stimulation, the self-immolative polyprodrug can degrade and release doxorubicin (DOX) through a domino-like fragmentation, which can impart advanced attributes of this nanosystem such as minimum cleavage events required and maximum cleavage speed for disintegration. Thus, the NCyNHsub2/sub-loaded self-immolative polyprodrug nanoparticle (SIPN) could be dissociated in response to endogenous ROS, triggering the release of DOX and NCyNHsub2/sub. Subsequently, the NCyNHsub2/subcould be activated by intratumoral overexpressed NQO1 to generate additional ROS, which further induces the amplifiable degradation of self-immolative polyprodrug to release sufficient drugs. The in vitro and in vivo studies consistently demonstrate that SIPN amplifies the drug release efficiency of ROS-responsive polyprodrug by specifically upregulating intratumoral ROS levels, resulting in significant antitumor efficacy with minimal side effects.

Colon cancer (CC) is a prevalent malignancy worldwide and is one of the most easily altered cancers by dietary regulation. Petunidin 3-O-[rhamnopyranosyl-(trans-p-coumaroyl)]-5-O-(β-D-glucopyranoside) (Pt3R5G) isolated and purified from Lycium ruthenicum Murray, which exhibits highly efficient antioxidant activity and specific anticancer effects, is the flavonoids compound. We aimed to study the effect of Pt3R5G on CC cells and elucidate the potential underlying mechanisms.Cell proliferation was measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. Cell cycle, cell apoptosis and reactive oxygen species (ROS) analysis were performed by flow cytometry. RNA-sequencing was performed to elucidate the potential underlying mechanisms. The lipid peroxidation level of cells was detected by malondialdehyde (MDA) assay. The mitochondrial morphology of cells was inspected using a transmission electron microscope. Additionally, we overexpressed SLC7A11 to perform rescue experiments. In vivo, xenograft mice assay was performed to verify the effect of Pt3R5G on the growth of colon cancer.Pt3R5G reduced the cell activity by blocking the cell cycle in G0/G1 phase, inducing the apoptosis and ferroptosis in RKO cells. The overexpressed of SLC7A11, a significantly down-regulated expression gene caused by Pt3R5G, rescued the cell proliferation inhibition and ferroptosis process. Furthermore, Pt3R5G inhibited tumor growth in nude mice. Our study suggests that Pt3R5G inhibits RKO cell proliferation through mainly reducing ferroptosis by down-regulated SLC7A11.As a potential therapeutic drug, Pt3R5G showed efficient anticancer activity through a variety of pathways.

Background: Hereditary retinal degeneration (HRD) is an irreversible eye disease that results in blindness in severe cases. It is most commonly caused by variants in the ABCA4 gene. HRD presents a high degree of clinical and genetic heterogeneity. We determined genotypic and phenotypic correlations, in the natural course of clinical observation, of unrelated progenitors of HRD associated with ABCA4. Objective: To analyze the relationship between the phenotypes and genotypes of ABCA4 variants. Methods: A retrospective clinical study of five cases from the ophthalmology department of the People’s Hospital of Wuhan University from January 2019 to October 2020 was conducted. We tested for ABCA4 variants in the probands. We performed eye tests, including the best-corrected visual acuity, super-wide fundus photography and spontaneous fluorescence photography, optical coherence tomography, and electrophysiological examination. Results: Disease-causing variants were identified in the ABCA4 genes of all patients. Among these, seven ABCA4 variants were novel. All patients were sporadic cases; only one patient had parents who were relatives, and the other four patients were offspring of unrelated parents. Two patients presented with Stargardt disease, mainly with macular lesions, two presented with retinitis pigmentosa (cone-rod type), and one presented with cone dystrophy. The visual acuity and visual field of the five patients showed varying degrees of deterioration and impairment. Conclusions: The same ABCA4 mutation can lead to different clinical phenotypes, and there is variation in the degree of damage to vision, visual field, and electrophysiology among different clinical phenotypes. Clinicians must differentiate between and diagnose pathologies resulting from this mutation.

Pyroptosis is an inflammatory form of programmed cell death that can effectively eliminate malignant cells and boost anticancer immunity. However, most of the current pyroptosis inducers lack cell selectivity, which may cause severe side effects for cancer therapy. In this work, for the first time, we discovered that the commonly used near-infrared (NIR) fluorogenic hemicyanine (CyNH2) induces pyrolysis to kill cancer cells and boost antitumor immunity. Cancer cells overexpressing the NAD(P)H: quinone oxidoreductase isozyme 1 (NQO1)-responsive theranostic (NCyNH2) were designed for selective cell pyroptosis and were nonfluorescent with low toxicity before activation. In the presence of NQO1, the fluorescence of CyNH2 was restored and could selectively initiate pyroptosis of cancer cells and further lead to systemic antitumor immunity activation for solid tumor therapy. Thus, this fluorogenic NIR dye may represent a novel theranostic agent for the selective initiation of tumor pyroptosis.

Currently, stimulus-responsive nanomedicines are usually activated by a single cancer-associated biomarker and utilize different image/therapeutic agents for cancer imaging/therapy, which restricts the specificity of nanomedicine and complicates their design. Herein, we report a novel dual-locking theranostic nanoprobe (DL-P) based on near-infrared (NIR) hemicyanine CyNH2 with two orthogonal stimuli of cancer cell lysosomal pH (first "lock")- and lysosome-overexpressed cathepsin B (CTB, second "lock")-triggered NIR fluorescence turn-on and drug activation to improve the specificity of cancer imaging and therapy. The fluorescence of CyNH2 was initially quenched due to intramolecular charge transfer (ICT) but could be selectively activated under the dual-key stimulation of lysosomal pH and CTB to liberate CyNH2, resulting in strong NIR fluorescence turn-on for cancer imaging. Moreover, CyNH2 caused mitochondrial dysfunction to inhibit cancer cell proliferation in the absence of laser irradiation, which can be used in cancer therapy. Compared with previously reported probes that respond to a single stimulus, this dual-locking nanoprobe that is responsive to two orthogonal stimuli triggers with integrated imaging and therapy function in a single agent exhibits increased selectivity and specificity, which provides a prospective strategy for precise cancer imaging and therapy.

Atherosclerosis (AS), a chronic arterial disease, is characterized by endothelial dysfunction, inflammatory reactions and lipid accumulation in parallel with aberrant angiogenesis and vascular smooth muscle cell (VSMC) proliferation. Adipose tissue has been suggested to have an integral influence on metabolism and endocrine secretion, while there have been increasing concerns about the possible involvement of adipokines in cardiovascular diseases, including AS. Here, we focused on chemerin, an adipokine highly expressed in adipose tissue, with strong evidence of an association with inflammation, endothelial dysfunction, metabolic disorder, aberrant angiogenesis, VSMC proliferation and calcification. In this review, we discuss chemerin and its receptors in the pathogenesis of AS. However, the existing data assign various, even contradictory, roles to chemerin in atherosclerosis, such as inhibiting vascular calcification and impairing endothelial function. Current studies focusing on its anti- and pro-atherogenic effects have pinpointed its distinct role in specific cell types and contexts in the pathogenesis of atherosclerosis. Therefore, the gaps in current knowledge regarding the specific role played by chemerin in the etiology of AS require additional future studies. It seems reasonable to suggest that targeted chemerin therapy can be developed as an innovative approach for treating AS.

To analyze the rules of acupoint selection in the treatment of gastroesophageal reflux disease in China using data mining technology.The published literature of treating gastroesophageal reflux disease with acupuncture was retrieved from electronic databases from January 1, 1983 to December 1, 2019, including SinoMed, CNKI, Wanfang and VIP database. Acupuncture prescription database was established, and the rules of acupoint selection were explored by statistical software SPSS 20.0 and SPSS Modeler 18.0.A total of 92 articles were included into this analysis, involving 92 acupuncture prescriptions, 76 acupoints. The total frequency of using these acupoints reached 549 times. Zhongwan (CV 12) was the most frequently used acupoint; the often selected meridians were conception vessel, stomach meridian, governor vessel, bladder meridian; the acupoints located at the abdomen, lower limbs and back were commonly selected; crossing points in the specific acupoints were commonly selected; the most frequently used group was Zusanli (ST 36)-Zhongwan (CV 12) and Neiguan (PC 6).Treating gastroesophageal reflux disease by acupuncture in China is dominated by

Background Population-based screening was essential for glaucoma management. Although various studies have investigated the cost-effectiveness of glaucoma screening, policymakers facing with uncontrollably growing total health expenses were deeply concerned about the potential financial consequences of glaucoma screening. This present study was aimed to explore the impact of glaucoma screening with artificial intelligence (AI) automated diagnosis from a budgetary standpoint in Changjiang county, China. Methods A Markov model based on health care system’s perspective was adapted from previously published studies to predict disease progression and healthcare costs. A cohort of 19,395 individuals aged 65 and above were simulated over a 15-year timeframe. Fur illustrative purpose, we only considered primary angle-closure glaucoma (PACG) in this study. Prevalence, disease progression risks between stages, compliance rates were obtained from publish studies. We did a meta-analysis to estimate diagnostic performance of AI automated diagnosis system from fundus image. Screening costs were provided by the Changjiang screening programme, whereas treatment costs were derived from electronic medical records from two county hospitals. Main outcomes included the number of PACG patients and health care costs. Cost-offset analysis was employed to compare projected health outcomes and medical care costs under the screening with what they would have been without screening. One-way sensitivity analysis was conducted to quantify uncertainties around model results. Results Among people aged 65 and above in Changjiang county, it was predicted that there were 1940 PACG patients under the AI-assisted screening scenario, compared with 2104 patients without screening in 15 years’ time. Specifically, the screening would reduce patients with primary angle closure suspect by 7.7%, primary angle closure by 8.8%, PACG by 16.7%, and visual blindness by 33.3%. Due to early diagnosis and treatment under the screening, healthcare costs surged dramatically to $107,761.4 dollar in the first year and then were constantly declining over time, while without screening costs grew from $14,759.8 in the second year until peaking at $17,900.9 in the 9th year. However, cost-offset analysis revealed that additional healthcare costs resulted from the screening could not be offset by decreased disease progression. The 5-, 10-, and 15-year accumulated incremental costs of screening versus no screening were estimated to be $396,362.8, $424,907.9, and $434,903.2, respectively. As a result, the incremental cost per PACG of any stages prevented was $1464.3. Conclusions This study represented the first attempt to address decision-maker’s budgetary concerns when adopting glaucoma screening by developing a Markov prediction model to project health outcomes and costs. Population screening combined with AI automated diagnosis for PACG in China were able to reduce disease progression risks. However, the excess costs of screening could never be offset by reduction in disease progression. Further studies examining the cost-effectiveness or cost-utility of AI-assisted glaucoma screening were needed.

Discovering new strategies to overcome multidrug resistance (MDR) is still urgently needed. MDR is associated with the overexpression of transmembrane efflux pumps, and adenosine triphosphate (ATP) is indispensable for its function. Herein, we developed a pH- and glutathione (GSH)-responsive amphiphilic poly(disulfide acetal) (PCS) containing cinnamaldehyde (CA) and disulfide groups that amplify oxidative stress for anticancer drug delivery and simultaneously overcome drug resistance in cancer cells. Reactive oxygen species (ROS)-generating CA and the disulfide groups to deplete GSH and synergize to amplify oxidative stress in cancer cells by oxidizing nicotinamide adenine dinucleotide with hydrogen (NADH) to nicotinamide adenine dinucleotide (NAD+). The production of ATP is preferentially inhibited, leading to the malfunction of efflux pumps due to the lack of ATP and making resistant cells more impressionable to anticancer drugs. The in vitro and in vivo experiments confirmed that PCS could induce amplified oxidative stress and efficiently overcome MDR in cancer cells. We believe that the polymer with amplified oxidative stress in cancer cells holds great promise in developing polymer-based drug delivery systems to reverse MDR for cancer therapy.

Vascular calcification (VC), which is closely associated with significant mortality in cardiovascular disease, chronic kidney disease (CKD), and/or diabetes mellitus, is characterized by abnormal deposits of hydroxyapatite minerals in the arterial wall. The impact of oxidative stress (OS) on the onset and progression of VC has not been well described. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, myeloperoxidase (MPO), nitric oxide synthases (NOSs), superoxide dismutase (SOD) and paraoxonases (PONs) are relevant factors that influence the production of reactive oxygen species (ROS). Furthermore, excess ROS-induced OS has emerged as a critical mediator promoting VC through several mechanisms, including phosphate balance, differentiation of vascular smooth muscle cells (VSMCs), inflammation, DNA damage, and extracellular matrix remodeling. Because OS is a significant regulator of VC, antioxidants may be considered as novel treatment options.

Adipose tissue (AT), a critical endocrine gland, is capable of producing and secreting abundant adipokines. Adipokines act on distant or adjacent organ tissues via paracrine, autocrine, and endocrine mechanism, which play attractive roles in the regulation of glycolipid metabolism and inflammatory response. Increasing evidence shows that adipokines can connect obesity with cardiovascular diseases by serving as promoters or inhibitors in vascular calcification. The chronic hypoxia in AT, caused by the adipocyte hypertrophy, is able to trigger imbalanced adipokine generation, which leads to apoptosis, osteogenic differentiation of vascular smooth muscle cells (VSMCs), vascular inflammation, and abnormal deposition of calcium and phosphorus in the vessel wall. The objectives of this review aim at providing a brief summary of the crucial influence of major adipokines on the formation and development of vascular calcification, which may contribute to better understanding these adipokines for establishing the appropriate therapeutic strategies to counteract obesity-associated vascular calcification.

Atherosclerosis is one of the chronic progressive diseases, which is caused by vascular injury and promoted by the interaction of various inflammatory factors and inflammatory cells. In recent years, kruppel-like factor 4 (KLF4), a significant transcription factor that participated in cell growth, differentiation and proliferation, has been proved to cause substantial impacts on regulating cardiovascular disease. This paper will give a comprehensive summary to highlight KLF4 as a crucial regulator of foam cell formation, vascular smooth muscle cells (VSMCs) phenotypic transformation, macrophage polarization, endothelial cells inflammation, lymphocyte differentiation and cell proliferation in the process of atherosclerosis. Recent studies show that KLF4 may be an important "molecular switch" in the process of improving vascular injury and inflammation under harmful stimulation, suggesting that KLF4 is a latent disease biomarker for the therapeutic target of atherosclerosis and vascular disease.

Atherosclerosis (AS) is the pathophysiologic basis of many cardiovascular diseases. A number of studies have shown that post-translational modification (PTM) contributes to the initiation and progression of AS. For example, recent studies found that SUMOylation, ie, small ubiquitin-like modifier (SUMO) conjugation to target substrate proteins, was involved in AS. This PTM appears related to endothelial cell dysfunction (ECD), dyslipidemia and vascular smooth muscle cell (VSMC) proliferation. This review focuses on the molecular effects of SUMOylation in the initiation and progression of AS, including ECD, dyslipidemia and VSMC proliferation to better understand this pathologic process.

Oral submucous fibrosis (OSF) is an insidious chronic oral and oropharyngeal potentially malignant disorder. Our previously studies reported that DNA image cytometry (ICM) using brushing added in the diagnosis of high-grade dysplasia and staging of oral leukoplakia (OLK). This preliminary study aimed to investigate the abnormal rate of DNA content in 30 cases of OSF including three cases of OSF concomitant OLK and evaluate their the diagnostic and clinical implications with special emphasis on the OSF concomitant OLK. Brushing and biopsy sample form each patient was processed by DNA-ICM and histological examination, respectively. The results of DNA-ICM analysis showed that all the lesions from the 27 patients with OSF only were identified as normal DNA content. Strikingly, two of three cases of OSF concomitant OLK were identified as abnormal DNA content, and one case of whom progressed to early oral squamous cell carcinoma at the follow-up of 31 months. Collectively, this preliminary evaluation revealed that DNA content abnormality was hardly observed in OSF only; however, it may be usually observed in OSF concomitant OLK, whom should be monitored on a priority basis for early detection of carcinoma. Multicenter large studies are needed to validate the findings of the current study.

The normoxic and hypoxic microenvironments in solid tumors cause cancer cells to show different sensitivities to various treatments. Therefore, it is essential to develop different therapeutic modalities based on the tumor microenvironment. In this study, we designed size-switchable nanoparticles with self-destruction and tumor penetration characteristics for site-specific phototherapy of cancer. This was achieved by photodynamic therapy in the perivascular normoxic microenvironment due to high local oxygen concentrations and photothermal therapy (PTT) in the hypoxic microenvironment, which are not in proximity to blood vessels due to a lack of effective approaches for heat transfer. In brief, a poly(amidoamine) dendrimer with photothermal agent indocyanine green (PAMAM-ICG) was conjugated to the amphiphilic polymer through a singlet oxygen-responsive thioketal linker and then loaded with photosensitizer chlorin e6 (Ce6) to construct a nanotherapy platform (denoted as SNPICG/Ce6). After intravenous injection, SNPICG/Ce6 was accumulated at the perivascular sites of the tumor. The singlet oxygen produced by Ce6 can ablate the tumor cells in the normoxic microenvironment and simultaneously cleave the thioketal linker, allowing the release of small PAMAM-ICGs with improved tumor penetration for PTT in the hypoxic microenvironment. This tailored site-specific phototherapy in normoxic and hypoxic microenvironments provides an effective strategy for cancer therapy.

Anticoagulants have exhibited a critical role in the prevention and/or treatment of thrombotic diseases. Up to now, kinds of novel oral anticoagulants, inhibiting plasma serine proteases in the coagulation cascade, have been developed to overcome the clinical limitations of classical anticoagulants (like warfarin and heparins). Some of them, such as Apixaban, Rivaroxaban, Edoxaban, and Dabigatran, have been approved by FDA in recent years. This review summarizes the discovery and optimization of representative novel oral anticoagulants with the aim to improve selectivity and bioavailability of compounds. The impact of different targets in the cascade on bleeding risk also is discussed. We hope some more effective, selective, and safer anticoagulants can be developed in the future on the basis of these design experiences.

Polo-like kinase 2 (Plk2) is a potential target for the treatment of cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among Plk1, Plk2 and Plk3, and structure-based drug design strategies, two novel series of selective Plk2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of Plk2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human cancer cell lines. All efforts led to the identification of the most potent compounds C2 (3.40 nM against Plk2) and C21 (4.88 nM against Plk2) from the first and second series of selective Plk2 inhibitors respectively. Additionally, the selectivity of C21 over Plk1/3 was significantly increased with the selectivity indexes of 12.57 and 910.06. Moreover, most of our compounds exhibited antitumor activity in the nanomolar range in the MTT assay, indicating that our compounds, especially C2 and C21 could be promising Plk2 inhibitors for further anticancer research.

Theranostic prodrugs that can precisely monitor drug activation with synergistic therapeutic effects are highly desirable for personalized medicine. In this study, a theranostic heterodimeric prodrug, CyNH-SS-DOX, with synchronous and independent dual-channel fluorescence turn-on and dual-prodrug activation for synergistic cancer therapy is developed. A hemicyanine fluorescent drug, CyNH2 , with good therapeutic effects found in this work, is conjugated to doxorubicin (DOX) through a disulfide linker to form CyNH-SS-DOX. Before activation, both the fluorescence of DOX and CyNH2 are in the off state and the toxicity is low. In the presence of intracellular glutathione, both the fluorescence of DOX and CyNH2 at different channels are turned on. Meanwhile, DOX and CyNH2 are activated in a synergistic anticancer effect. It is believed that CyNH-SS-DOX is promising for monitoring prodrug activation in dual-fluorescence channels and for enhancing therapeutic efficacy with few side effects.

Motivation For in-depth understanding the functions of proteins in a cell, the knowledge of their subcellular localization is indispensable. The current study is focused on human protein subcellular location prediction based on the sequence information alone. Although considerable efforts have been made in this regard, the problem is far from being solved yet. Most existing methods can be used to deal with single-location proteins only. Actually, proteins with multi-locations may have some special biological functions that are particularly important for both basic research and drug design. Results Using the multi-label theory, we present a new predictor called ‘pLoc-mHum’ by extracting the crucial GO (Gene Ontology) information into the general PseAAC (Pseudo Amino Acid Composition). Rigorous cross-validations on a same stringent benchmark dataset have indicated that the proposed pLoc-mHum predictor is remarkably superior to iLoc-Hum, the state-of-the-art method in predicting the human protein subcellular localization. Availability and implementation To maximize the convenience of most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc-mHum/, by which users can easily get their desired results without the need to go through the complicated mathematics involved. Supplementary information Supplementary data are available at Bioinformatics online.

Atherosclerosis is an arterial disease associated with dyslipidemia, abnormal arterial calcification and oxidative stress. It has been shown that a continued chronic inflammatory state of the arterial wall contributes to the development of atherosclerosis. The inflammatory stimulation, recruitment of inflammatory cells and production of pro-inflammatory cytokines enhances vascular inflammation. Some members of the S100 proteins family bind with their receptors, such as advanced glycation end products (RAGE), scavenger receptors (CD36) and toll-like receptor 4 (TLR-4), contributing to the cellular response in atherosclerotic progression. This review summarizes the roles of S100 proteins (S100A8, S100A9 and S100A12) in the vascular inflammation, vascular calcification and vascular oxidative stress. S100 proteins are released from monocytes, smooth muscle cells and endothelial cells in response to cellular stress stimuli, and then the binding of S100 proteins to RAGE activate downstream signaling such as transcription factor kappa B (NF-κB) translocation and reactive oxygen species (ROS) production, which act as a positive feedback loop for inducing pro-inflammatory phenotype in a wide variety of cell types including endothelial cells, vascular smooth muscle cells and leukocytes. Thus, it suggests that the inhibition of S100 proteins-mediated RAGE and TLR4 activation appears to be a promising approach to treat atherosclerosis. In addition, recent study showed that serum S100A12 can predict future cardiovascular events, highlighting that S100A12 is likely to be a potential biomarker of therapeutic efficacy and disease progression in coronary heart disease. Future studies of patients with coronary heart disease may provide more evidences supporting that S100 proteins is promising drug target in the prevention and therapy of atherosclerosis.

The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been debated in recent decades. Here, we established an intestinal barrier dysfunction model in mice and Caco2 cell line by Lipopolysaccharide (LPS), and evaluated the fatty acid uptake capacity of the intestine. We found that LPS stimulation restricted the absorption of long chain fatty acid (LCFA), while Cathelicidin-WA (CWA) pretreatment facilitated this physiological process. At the molecular level, our results demonstrated that the stimulatory effects of CWA on intestinal lipid absorption were dependent on cluster determinant 36 and fatty acid transport protein 4, but not fatty acid–binding protein. Further, an enhanced intestinal barrier was observed in vivo and in vitro when CWA alleviated the fatty acid absorption disorder induced by LPS stimulation. Mechanistically, peroxisome proliferator-activated receptor (PPAR-γ) signaling was considered as a key pathway for CWA to enhance LCFA absorption and barrier function. Treatment with a PPAR-γ inhibitor led to impaired intestinal barrier function and suppressed LCFA uptake. Moreover, once PPAR-γ signaling was blocked, CWA pretreatment could not maintain the stability of the intestinal epithelial cell barrier or LCFA uptake after LPS stimulation. Collectively, these findings suggested that PPAR-γ may serve as a target for specific therapies aimed at alleviating fatty acid uptake disorder, and CWA showed considerable potential as a new PPAR-γ agonist to strengthen intestinal barrier function against fatty acid malabsorption.

Purpose To determine possible impacts on retinal microvasculature in healthy young adults during exercise with a face mask, using optical coherence tomography angiography (OCTA). Methods Twenty-three healthy participants (23 eyes, 17 women and 6 men) performed the incremental continuous running test (ICRT) with different masks. OCTA of the macula and optic nerve head were performed before and after ICRT to detect changes in retinal vessel density (VD). All participants were in groups A, B, and C (before ICRT) and groups A′, B′, and C′ (after ICRT), which comprised data from volunteers without a mask, with a surgical mask, and with an N95 mask, respectively. Results Before ICRT, group C showed significantly reduced VD in the superficial plexus (SP), except foveal VD, compared with group A (P < 0.05). After ICRT, groups B′ and C′ showed significantly shorter maximum running time, lower oxygen saturation, and lower perifoveal VD of SP compared with group A′ (P < 0.05). Conclusions Use of an N95 mask reduced VD in SP even under quiescent conditions, which might have clinical implications for protecting healthy workers and indoor manual labor workers from potential risks of retinal damage due to long-term mask use. Moreover, mask use while exercising might lead to attenuated exercise ability and lower VD in SP, which should be investigated in additional studies. Translational Relevance Retina vascular perfusion dynamics could be monitored in vivo by OCTA, which would be valuable to study physiologic retinal blood flow redistribution and potential impacts on retinal vascular perfusion during exercise with face masks.

Motivation: Post-translational modification, abbreviated as PTM, refers to the change of the amino acid side chains of a protein after its biosynthesis. Owing to its significance for in-depth understanding various biological processes and developing effective drugs, prediction of PTM sites in proteins have currently become a hot topic in bioinformatics. Although many computational methods were established to identify various single-label PTM types and their occurrence sites in proteins, no method has ever been developed for multi-label PTM types. As one of the most frequently observed PTMs, the K-PTM, namely, the modification occurring at lysine (K), can be usually accommodated with many different types, such as ‘acetylation’, ‘crotonylation’, ‘methylation’ and ‘succinylation’. Now we are facing an interesting challenge: given an uncharacterized protein sequence containing many K residues, which ones can accommodate two or more types of PTM, which ones only one, and which ones none? Results: To address this problem, a multi-label predictor called iPTM-mLys has been developed. It represents the first multi-label PTM predictor ever established. The novel predictor is featured by incorporating the sequence-coupled effects into the general PseAAC, and by fusing an array of basic random forest classifiers into an ensemble system. Rigorous cross-validations via a set of multi-label metrics indicate that the first multi-label PTM predictor is very promising and encouraging. Availability and Implementation: For the convenience of most experimental scientists, a user-friendly web-server for iPTM-mLys has been established at http://www.jci-bioinfo.cn/iPTM-mLys, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved. Contact: wqiu@gordonlifescience.org, xxiao@gordonlifescience.org, kcchou@gordonlifescience.org Supplementary information: Supplementary data are available at Bioinformatics online.

// Wang-Ren Qiu 1, 2 , Bi-Qian Sun 1 , Xuan Xiao 1, 3 , Zhao-Chun Xu 1 , Kuo-Chen Chou 3, 4, 5 1 Computer Department, Jingdezhen Ceramic Institute, Jingdezhen, China 2 Department of Computer Science and Bond Life Science Center, University of Missouri, Columbia, MO, USA 3 Gordon Life Science Institute, Boston, MA, USA 4 Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia 5 Center of Bioinformatics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China Correspondence to: Xuan Xiao, email: xxiao@gordonlifescience.org Keywords: PTMs, hydroxyproline, hydroxylysine, sequence-coupling model, general PseAAC Received: April 20, 2016 Accepted: May 29, 2016 Published: June 14, 2016 ABSTRACT Protein hydroxylation is a posttranslational modification (PTM), in which a CH group in Pro (P) or Lys (K) residue has been converted into a COH group, or a hydroxyl group (-OH) is converted into an organic compound. Closely associated with cellular signaling activities, this type of PTM is also involved in some major diseases, such as stomach cancer and lung cancer. Therefore, from the angles of both basic research and drug development, we are facing a challenging problem: for an uncharacterized protein sequence containing many residues of P or K, which ones can be hydroxylated, and which ones cannot? With the explosive growth of protein sequences in the post-genomic age, the problem has become even more urgent. To address such a problem, we have developed a predictor called iHyd-PseCp by incorporating the sequence-coupled information into the general pseudo amino acid composition (PseAAC) and introducing the “Random Forest” algorithm to operate the calculation. Rigorous jackknife tests indicated that the new predictor remarkably outperformed the existing state-of-the-art prediction method for the same purpose. For the convenience of most experimental scientists, a user-friendly web-server for iHyd-PseCp has been established at http://www.jci-bioinfo.cn/iHyd-PseCp , by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved.

// Wang-Ren Qiu 1, 2 , Xuan Xiao 1, 3 , Zhao-Chun Xu 1 , Kuo-Chen Chou 3, 4, 5 1 Computer Department, Jingdezhen Ceramic Institute, Jingdezhen, China 2 Department of Computer Science and Bond Life Science Center, University of Missouri, Columbia, MO, USA 3 Gordon Life Science Institute, Boston, MA, USA 4 Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia 5 Center of Bioinformatics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China Correspondence to: Wang-Ren Qiu, email: qiuone@163.com Xuan Xiao, email: xxiao@gordonlifescience.org Kuo-Chen Chou, email: kcchou@gordonlifescience.org Keywords: protein phosphorylation, pseudo components, random forests, ensemble classifier Received: April 05, 2016 Accepted: May 23, 2016 Published: June 13, 2016 ABSTRACT Protein phosphorylation is a posttranslational modification (PTM or PTLM), where a phosphoryl group is added to the residue(s) of a protein molecule. The most commonly phosphorylated amino acids occur at serine (S), threonine (T), and tyrosine (Y). Protein phosphorylation plays a significant role in a wide range of cellular processes; meanwhile its dysregulation is also involved with many diseases. Therefore, from the angles of both basic research and drug development, we are facing a challenging problem: for an uncharacterized protein sequence containing many residues of S, T, or Y, which ones can be phosphorylated, and which ones cannot? To address this problem, we have developed a predictor called iPhos-PseEn by fusing four different pseudo component approaches (amino acids’ disorder scores, nearest neighbor scores, occurrence frequencies, and position weights) into an ensemble classifier via a voting system. Rigorous cross-validations indicated that the proposed predictor remarkably outperformed its existing counterparts. For the convenience of most experimental scientists, a user-friendly web-server for iPhos-PseEn has been established at http://www.jci-bioinfo.cn/iPhos-PseEn , by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved.

// Xuan Xiao 1, 2, 5 , Han-Xiao Ye 1 , Zi Liu 3 , Jian-Hua Jia 1 , Kuo-Chen Chou 4, 5 1 Computer Department, Jing-De-Zhen Ceramic Institute, Jing-De-Zhen, 333403, China 2 Information School, ZheJiang Textile and Fashion College, NingBo, 315211, China 3 School of Computer Science and Engineering, Nanjing University of Science and Technology, Nanjing, 210094, China 4 Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, 21589, Saudi Arabia 5 Gordon Life Science Institute, Boston, Massachusetts, 02478, USA Correspondence to: Xuan Xiao, email: xxiao@gordonlifescience.org , jdzxiaoxuan@163.com Keywords: origin of replication, position-specific dinucleotide propensity, general pseudo nucleotide composition, random forest, iROS-gPseKNC Received: March 02, 2016 Accepted: April 09, 2016 Published: April 27, 2016 ABSTRACT DNA replication, occurring in all living organisms and being the basis for biological inheritance, is the process of producing two identical replicas from one original DNA molecule. To in-depth understand such an important biological process and use it for developing new strategy against genetics diseases, the knowledge of duplication origin sites in DNA is indispensible. With the explosive growth of DNA sequences emerging in the postgenomic age, it is highly desired to develop high throughput tools to identify these regions purely based on the sequence information alone. In this paper, by incorporating the dinucleotide position-specific propensity information into the general pseudo nucleotide composition and using the random forest classifier, a new predictor called iROS-gPseKNC was proposed. Rigorously cross–validations have indicated that the proposed predictor is significantly better than the best existing method in sensitivity, specificity, overall accuracy, and stability. Furthermore, a user-friendly web-server for iROS-gPseKNC has been established at http://www.jci-bioinfo.cn/iROS-gPseKNC , by which users can easily get their desired results without the need to bother the complicated mathematics, which were presented just for the integrity of the methodology itself.

Succinylation is a posttranslational modification (PTM) where a succinyl group is added to a Lys (K) residue of a protein molecule. Lysine succinylation plays an important role in orchestrating various biological processes, but it is also associated with some diseases. Therefore, we are challenged by the following problem from both basic research and drug development: given an uncharacterized protein sequence containing many Lys residues, which one of them can be succinylated, and which one cannot? With the avalanche of protein sequences generated in the postgenomic age, the answer to the problem has become even more urgent. Fortunately, the statistical significance experimental data for succinylated sites in proteins have become available very recently, an indispensable prerequisite for developing a computational method to address this problem. By incorporating the sequence-coupling effects into the general pseudo amino acid composition and using KNNC (K-nearest neighbors cleaning) treatment and IHTS (inserting hypothetical training samples) treatment to optimize the training dataset, a predictor called iSuc-PseOpt has been developed. Rigorous cross-validations indicated that it remarkably outperformed the existing method. A user-friendly web-server for iSuc-PseOpt has been established at http://www.jci-bioinfo.cn/iSuc-PseOpt, where users can easily get their desired results without needing to go through the complicated mathematical equations involved.

To investigate the effect of progressive early bed physical activity on blood flow in lower limb of patients on mechanical ventilation in intensive care unit (ICU).Adult patients with mechanical ventilation ≥ 72 hours admitted to ICU of the Affiliated Hospital of Zunyi Medical University from February 22nd to November 30th, 2016 were enrolled. The patients were randomly divided into experimental group and control group by random number table method. Patients in the two groups were given the same basic treatment, including antibiotics, analgesia and sedation, mechanical ventilation, nutritional support, and routine ICU activities such as maintaining functional position of limbs and raising of bed head. On the basis of those, the experimental group was given early bed physical activity with gradual enhancement of grades I-III according to the nerve, circulation and respiration situations, such as passive/active exercise of the bicycle, straight leg lifting exercise, etc. The exercise intensity was evaluated with target heart rate, and the exercise was performed for 15-30 minutes at a time, twice a day. The control group was given intermittent pneumatic compression (IPC), 30 minutes in each time, twice a day. Mean blood flow and blood volume were measured before and immediately, 5, 10 and 15 minutes after intervention on the 3rd day. Heart rate and blood pressure were measured at 5 minutes before intervention, during 5 minutes, and 5, 10, 15, 30 minutes after intervention on the 3rd day.214 adult patients were selected, after excluding the patients who died during the intervention or gave up treatment, 160 patients were included in the data analysis, with 81 in the experimental group and 79 in the control group. The mean blood flow velocity and blood volume were increased in both groups, and the mean blood flow velocity and blood flow volume in the experimental group were significantly increased and lasted longer than those in the control group [mean blood flow velocity (mm/s) of the experimental group were 11.92±1.06, 18.19±0.17, 17.24±0.14, 15.48±0.12, 12.68±0.16, and that of the control group were 12.01±1.41, 15.65±0.18, 12.91±0.14, 12.13±0.12, 11.59±0.16, respectively, the time effect was F = 1 043.101, P = 0.000, the intervention effect was F = 151.001, P = 0.000, and the interaction effect between intervention and time was F = 224.830, P = 0.001; the blood volume (mL/min) of the experimental group were 3.39±0.96, 5.59±0.11, 5.16±0.12, 4.19±0.10. 3.35±0.09, and that of the control group were 3.28±0.82, 4.04±0.11, 3.40±0.12, 3.02±0.10, 3.00±0.10, respectively, the time effect was F = 680.405, P = 0.000, the intervention effect was F = 125.359, P = 0.000, and the interaction effect between intervention and time was F = 79.631, P = 0.012]. The heart rate and blood pressure of the two groups of patients in the course of intervention were increased first, then decreased and then slowly recovered to the change trend before intervention, but the index of the experimental group fluctuated greatly [heart rate (bpm) of the experimental group were 97.64±1.50, 113.91±1.36, 105.96±1.34, 98.52±1.48, 97.84±1.46, 97.54±1.48, and that of the control group were 97.03±1.57, 105.39±1.38, 96.76±1.35, 96.54±1.50, 97.22±1.48, 96.53±1.49, respectively, the time effect was F = 235.030, P = 0.000, the intervention effect was F = 39.473, P = 0.000, and the interaction effect between intervention and time was F = 3.494, P = 0.063; the systolic blood pressure (mmHg, 1 mmHg = 0.133 kPa) of the experimental group were 118.57±1.06, 133.05±1.01, 120.44±1.10, 117.78±1.07, 117.65±1.01, 118.14±1.00, and that of the control group were 118.10±1.08, 126.68±1.02, 118.23±1.11, 117.48±1.08, 118.04±1.03, 118.90±1.10, respectively, the time effect was F = 336.604, P = 0.000, the intervention effect was F = 26.350, P = 0.000, and the interaction effect between intervention and time was F = 0.948, P = 0.332; the diastolic blood pressure (mmHg) of the experimental group were 68.07±0.72, 72.79±0.73, 70.68±0.74, 69.30±0.72, 68.73±0.74, 67.80±0.73, and that of the control group were 68.51±0.73, 72.03±0.74, 70.05±0.75, 69.10±0.73, 68.41±0.75, 67.85±0.74, respectively, the time effect was F = 286.390, P = 0.000, the intervention effect was F = 4.812, P = 0.000, and the interactive effect between intervention and time was F = 0.055, P = 0.815].The effects of progressive early bed physical activity on the mean blood flow velocity and blood volume of lower limbs in ICU patients with mechanical ventilation are better than those of IPC. Although the fluctuation of heart rate and blood pressure is large, it does not cause any harm to the patients.

Knowledge of protein subcellular localization is vitally important for both basic research and drug development. With the avalanche of protein sequences emerging in the post-genomic age, it is highly desired to develop computational tools for timely and effectively identifying their subcellular localization based on the sequence information alone. Recently, a predictor called “pLoc-mPlant” was developed for identifying the subcellular localization of plant proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with multi-label systems in which some proteins, called “multiplex proteins”, may simultaneously occur in two or more subcellular locations. Although it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mPlant was trained by an extremely skewed dataset in which some subsets (i.e., the protein numbers for some subcellular locations) were more than 10 times larger than the others. Accordingly, it cannot avoid the biased consequence caused by such an uneven training dataset. To overcome such biased consequence, we have developed a new and bias-free predictor called pLoc_bal-mPlant by balancing the training dataset. Cross-validation tests on exactly the same experimentconfirmed dataset have indicated that the proposed new predictor is remarkably superior to pLoc-mPlant, the existing state-of-the-art predictor in identifying the subcellular localization of plant proteins. To maximize the convenience for the majority of experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mPlant/, by which users can easily get their desired results without the need to go through the detailed mathematics.

To understand the measures and effects of schistosomiasis elimination in Wujin District, Changzhou City, so as to provide the reference for other similar areas.The data of schistosomiasis prevention and control were collected and analyzed in Wujin District, Changzhou City from 1995 to 2015.From 1995 to 2015, the accumulated area for investigatingIn Wujin District, the aim of schistosomiasis elimination has been performed through the active control measures. However, there are still social and natural risk factors of re-endemic of schistosomiasis, and therefore, the schistosomiasis monitoring work still should be strengthened.

To determine the effect of the posterior condylar offset (PCO) on clinical results after total knee arthroplasty (TKA) using a high-flex posterior-stabilized (PS) fixed-bearing prosthesis.We prospectively studied the clinical and radiographic materials of 89 consecutive female patients (89 knees), who had undergone primary TKAs for end-stage osteoarthritis. All operations were performed by a single senior surgeon or under his supervision using the same operative technique. Based on the corrected PCO change, we divided all cases into two groups: group A (corrected PCO change ≥0 mm, 58 knees) and group B (corrected PCO change0 mm, 31 knees). One-year postoperatively, clinical and radiographic variables from the two groups were compared by independent t-test. The associations between the corrected PCO changes and the improvements of clinical variables in all patients were analyzed by Pearson linear correlation.One-year postoperatively, the Knee Society Scores, the Western Ontario and McMaster Universities Osteoarthritis Index, non-weight-bearing active and passive range of knee flexion, flexion contracture, extensor lag, and their improvements had no statistical differences between the two groups (all p0.05). The corrected PCO change was not significantly correlated with the improvement of any clinical variable (all p0.05). Group A demonstrated greater flexion than group B during active weight bearing (p0.05).Restoration of PCO plays an important role in the optimization of active knee flexion during weight-bearing conditions after posterior-stabilized TKA, while it has no benefit to non-weight-bearing knee flexion or any other clinical result.

Summary Background Oral leukoplakia (OL) is the best-known potentially malignant disorder of oral cancer. The hypothesis was tested that DNA content abnormality may contribute to risk prediction of malignant potential of OL. Methods All OLs were staged according to a clinicopathologic classification and OL-staging system. DNA content status was investigated in a blinded prospective series of OL using brush biopsy with image cytometry, and examined the correlation of DNA content with the clinicopathologic features and OL-staging system in this preliminary study. Results Among 65 patients with OL, 27 (41.5%) was identified as DNA content abnormality. The frequency (77.8%) of DNA content abnormality in tongue was higher than that (22.2%) in other oral sites (χ2 test, P = 0.038), and moderate or severe dysplasia had a higher frequency (63.0%) of DNA content abnormality than that (37.0%) of no or mild dysplasia (χ2 test, P = 0.022). Moreover, the odds ratio of DNA content abnormality in high-risk patient group was 5.74-fold (95% confidence interval, 1.81–18.20; P = 0.003) increase compared with low-risk patient group. Importantly, the positive correlation between OL-staging system and DNA content status was significant (P = 0.018, correlation coefficient = 0.292). Conclusion Our findings showed that DNA content status correlated with OL-staging system, suggesting that DNA content abnormality in OL as detected by image cytometry was an early event in oral carcinogenesis. The further large-scale prospective studies with clinical endpoints are warranted to validate the value of DNA image cytometry.

Objective: Being a kind of post-transcriptional modification (PTCM) in RNA, the 2′-O-methylation modification occurs in the processes of life development and disease formation as well. Accordingly, from the angles of both basic research and drug development, we are facing a challenging problem: given an uncharacterized RNA sequence formed by many nucleotides of A (adenine), C (cytosine), G (guanine), and U (uracil), which one can be of 2-O-methylation modification, and which one cannot? Unfortunately, so far no computational method whatsoever has been developed to address such a problem. Method: To fill this empty area, we propose a predictor called iRNA-2methyl. It is formed by incorporating a series of sequence-coupled factors into the general PseKNC (pseudo nucleotide composition), followed by fusing 12 basic random forest classifier into four ensemble predictors, with each aimed to identify the cases of A, C, G, and U along the RNA sequence concerned, respectively. Results: Rigorous jackknife cross-validations have indicated that the success rates are very high (>93%). For the convenience of most experimental scientists, a user-friendly web-server for iRNA-2mthyl has been established at http://www.jci-bioinfo.cn/iRNA-2methyl, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved. Conclusion: The proposed predictor iRNA-2mthyl will become a very useful bioinformatics tool for medicinal chemistry, helping to design effective drugs against the diseases related to the 2′-O-methylation modification.

Hawk tea (Litsea coreana Lévl. var. Lanuginosa (Migo) Yen C. Yang & P.H. Huang), a very popular herbal tea material, has attracted more and more attention due to its high antioxidant properties and possible therapeutic effect on type II diabetes mellitus. The raw materials of Hawk tea are usually divided into three kinds: bud tea (BT), primary leaf tea (PLT) and mature leaf tea (MLT). In this study, the DPPH radical scavenging activity and the antimicrobial properties of these three kinds of Hawk tea from different regions were comparatively investigated, and a ultra-high performance liquid chromatographic coupled with a photodiode array detector (UPLC-DAD) method was employed for comparison of the three major flavonoid constituents, including hyperoside, isoquercitrin and astragalin, in different samples of Hawk tea. At the same time, the effect of methanol extract (ME) of PLT on the mouse postprandial blood glucose and the effect of ME and its different fractions (petroleum ether fraction (PE), ethyl acetate fraction (EA), n-butanol fraction (n-BuOH), and water fraction (WF)) on the activity of α-glucosidase were studied. The results showed that Hawk BT and Hawk PLT possessed the higher radicals scavenging activity than Hawk MLT, while the antibacterial activity against P. vulgaris of PLT and MLT was higher than Hawk BT. The contents of the three major flavonoid constituents in samples of Hawk PLT are higher than Hawk BT and Hawk MLT. The mouse postprandial blood glucose levels of the middle dose (0.5 g/kg) group and the high dose (1 g/kg) group with oral administration of the ME of PLT were significantly lower than the control group. What’s more, the inhibitory effect of ME of PLT and its EA and n-BuOH fractions on α-glucosidase was significantly higher than that of acarbose. Rapid ultra-high performance liquid chromatography/quadrupole time-of-flight-mass spectrometry (UPLC-ESI-QTOF-MS) was used to identify the flavonoids in Hawk PLT, and a total of 20 flavonoids were identified or tentatively identified by comparing their retention times and accurate mass measurements with reference compounds or literature data. The bioactive flavonoid composition and DPPH radical scavenging activities present in different Hawk tea raw materials are quite different due to the different ontogenesis of these raw materials. Further studies on PLT showed that the substances in PLT ME could reduce the level of mouse postprandial blood glucose through inhibiting the activity of α-glucosidase.

Lysine crotonylation (Kcr) is an evolution-conserved histone posttranslational modification (PTM), occurring in both human somatic and mouse male germ cell genomes. It is important for male germ cell differentiation. Information of Kcr sites in proteins is very useful for both basic research and drug development. But it is time-consuming and expensive to determine them by experiments alone. Here, we report a novel predictor called iKcr-PseEns that is established by incorporating five tiers of amino acid pairwise couplings into the general pseudo amino acid composition. It has been observed via rigorous cross-validations that the new predictor's sensitivity (Sn), specificity (Sp), accuracy (Acc), and stability (MCC) are 90.53%, 95.27%, 94.49%, and 0.826, respectively. For the convenience of most experimental scientists, a user-friendly web-server for iKcr-PseEns has been established at http://www.jci-bioinfo.cn/iKcr-PseEns, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved.