Microsatellite instability (MSI) has been approved as a pan-cancer biomarker for immune checkpoint blockade (ICB) therapy. However, current MSI identification methods are not available for all ...patients. We proposed an ensemble multiple instance deep learning model to predict microsatellite status based on histopathology images, and interpreted the pathomics-based model with multi-omics correlation. Methods: Two cohorts of patients were collected, including 429 from The Cancer Genome Atlas (TCGA-COAD) and 785 from an Asian colorectal cancer (CRC) cohort (Asian-CRC). We established the pathomics model, named Ensembled Patch Likelihood Aggregation (EPLA), based on two consecutive stages: patch-level prediction and WSI-level prediction. The initial model was developed and validated in TCGA-COAD, and then generalized in Asian-CRC through transfer learning. The pathological signatures extracted from the model were analyzed with genomic and transcriptomic profiles for model interpretation. Results: The EPLA model achieved an area-under-the-curve (AUC) of 0.8848 (95% CI: 0.8185-0.9512) in the TCGA-COAD test set and an AUC of 0.8504 (95% CI: 0.7591-0.9323) in the external validation set Asian-CRC after transfer learning. Notably, EPLA captured the relationship between pathological phenotype of poor differentiation and MSI (P < 0.001). Furthermore, the five pathological imaging signatures identified from the EPLA model were associated with mutation burden and DNA damage repair related genotype in the genomic profiles, and antitumor immunity activated pathway in the transcriptomic profiles. Conclusions: Our pathomics-based deep learning model can effectively predict MSI from histopathology images and is transferable to a new patient cohort. The interpretability of our model by association with pathological, genomic and transcriptomic phenotypes lays the foundation for prospective clinical trials of the application of this artificial intelligence (AI) platform in ICB therapy.
•Effects of specimen size of PET FRP-confined concrete in square stub columns are first ever studied.•Existing models on PET FRP-confined concrete in square stub columns are first ever assessed.•The ...minimum confinement stiffness ratio for a sufficient confinement is 0.0036.•Increasing PET FRP thickness and corner radius ratio shorten transition segment and enhance ultimate stress.•Specimen size has insignificant effect for small- and medium-sized stub columns with similar confinement level.
As an environmental-friendly material with high rupture strain capacity, polyethylene terephthalate (PET) fiber reinforced polymer (FRP) has promising industry applications. Previous studies mainly focused on the application of PET FRP-confined concrete in circular columns, while investigations on PET FRP-confined concrete in square columns are rather limited. The purpose of this study is to fundamentally understand the confinement mechanism of PET FRP-confinede concrete in square stub columns by conducting axial compression tests. Particularly, the influences of confinement thickness, corner radius and specimen size were investigated. Test results reveal that the specimen size is not significant for small- and medium-sized stub columns with a similar confinement level. The minimum confinement stiffness ratio and modified confinement ratio for achieving a sufficient confinement are 0.0036 and 0.13 respectively. Additionally, assessments of existing confinement models for PET FRP-confined concrete are conducted.
Heat sensation and tolerance are crucial for determining species' survival and distribution range of small mammals. As a member of the transmembrane proteins, transient receptor potential vanniloid 1 ...(TRPV1) is involved in the sensation and thermoregulation of heat stimuli; however, the associations between animal's heat sensitivity and TRPV1 in wild rodents are less studied. Here, we found that Mongolian gerbils (
), a rodent species living in Mongolia grassland, showed an attenuated sensitivity to heat compared with sympatrically distributed mid-day gerbils (
) based on a temperature preference test. To explain this phenotypical difference, we measured the TRPV1 mRNA expression of two gerbil species in the hypothalamus, brown adipose tissue, and liver, and no statistical difference was detected between two species. However, according to the bioinformatics analysis of TRPV1 gene, we identified two single amino acid mutations on two TRPV1 orthologs in these two species. Further Swiss-model analyses of two TRPV1 protein sequences indicated the disparate conformations at amino acid mutation sites. Additionally, we confirmed the haplotype diversity of TRPV1 in both species by expressing TRPV1 genes ectopicly in
system. Taken together, our findings supplemented genetic cues to the association between the discrepancy of heat sensitivity and the functional differentiation of TRPV1 using two wild congener gerbils, promoting the comprehension of the evolutionary mechanisms of the TRPV1 gene for heat sensitivity in small mammals.
Apicomplexan parasite growth and replication relies on nutrient acquisition from host cells, in which intracellular multiplication occurs, yet the mechanisms that underlie the nutrient salvage remain ...elusive. Numerous ultrastructural studies have documented a plasma membrane invagination with a dense neck, termed the micropore, on the surface of intracellular parasites. However, the function of this structure remains unknown. Here we validate the micropore as an essential organelle for endocytosis of nutrients from the host cell cytosol and Golgi in the model apicomplexan Toxoplasma gondii. Detailed analyses demonstrated that Kelch13 is localized at the dense neck of the organelle and functions as a protein hub at the micropore for endocytic uptake. Intriguingly, maximal activity of the micropore requires the ceramide de novo synthesis pathway in the parasite. Thus, this study provides insights into the machinery underlying acquisition of host cell-derived nutrients by apicomplexan parasites that are otherwise sequestered from host cell compartments.
Summary Human angiostrongyliasis caused by Angiostrongylus cantonensis , a rat lungworm, has been reported globally. Human infections are acquired by ingestion of raw or undercooked snails or slugs, ...paratenic hosts such as prawns, or contaminated vegetables that contain the infective larvae of the worm. So far, at least 2827 cases of the disease have been documented worldwide. During the past few years, several outbreaks of human angiostrongyliasis have been reported in mainland China, Taiwan, and the USA. Additionally, sporadic cases in travellers who have returned from endemic areas have been reported. We review the clinical features, diagnosis, and treatment of human angiostrongyliasis, and describe the geographical distribution and prevalence of A cantonensis . Educating the public about the dangers of eating raw or undercooked intermediate and paratenic hosts in endemic areas is essential for the prevention and control of this foodborne zoonotic disease.
Although the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ), Numerical Pain Rating Scale (NPRS), Oswestry Disability Index (ODI), Roland Morris Disability Questionnaire ...(RMDQ), and Short Form 36 Health Survey (SF-36) has shown a preferable psychometric properties in patients with low back pain (LBP), but no study has yet determined these in conservative treatment of patients with lumbar disc herniation (LDH). Thus the current study aimed to compare those scales in LDH patients receiving conservative treatment to select the better option to assess the severity of disease. LDH patients were invited to complete the JOABPEQ, NPRS, ODI, RMDQ, and SF-36 twice. The internal consistency was evaluated by the Cronbach's alpha. Test-retest reliability was tested by the intraclass correlation coefficient (ICC). The relationships of these scales were evaluated by the Pearson correlation coefficients (r). The responsiveness was operationalised using the receiver operating characteristic (ROC) curve, as well as the comparison of smallest detectable change (SDC), minimum important change (MIC). A total of 353 LDH patients were enrolled. Four subscales of the Chinese JOABPEQ were over 0.70, then the ICCs for the test-retest reliability were over 0.75. For functional status, remarked negative correlations could be seen between JOABPEQ Q2-Q4 and ODI, as well as RMDQ (r = - 0.634 to - 0.752). For general health status, remarkable positive correlations could also be seen between Q5 Mental health and SF-36 PCS (r = 0.724) as well as SF-36 MCS (r = 0.736). Besides, the area under of the curves (AUC) of the JOABPEQ ranged from 0.743 to 0.827, indicating acceptale responsiveness, as well as the NPRS, ODI, and RMDQ. NPRS, and ODI or RMDQ is recommended in studies related to LDH patients, while if the quality of life also is needed to observe, the NPRS, and JOABPEQ would be more appropriate rather than SF-36.
•A pilot study on rectangular double-tube concrete columns (DTCCs) is presented.•The post-yield strength of the high strength steel can be effectively utilized in rectangular DTCCs.•The axial ...load-axial strain curves of rectangular DTCCs feature approximately bilinear behavior.•The inner steel tube offers additional lateral confinement to core concrete so that the majority of the concrete in a DTCC is effectively confined by the steel tube and the FRP tube.•The predicted ultimate axial stresses and strains based on a theoretical model are in agreement with the experimental results.
This paper presents a novel form of rectangular fiber-reinforced polymer (FRP)-concrete-high strength steel (HSS) hybrid columns referred to as rectangular double-tube concrete columns (DTCCs). These columns consist of a rectangular FRP tube filled with concrete and an elliptical HSS tube as internal reinforcement. The inner elliptical steel tube encloses most of the concrete in the rectangular section and therefore most of the concrete in the section is effectively confined. The high susceptibility of the HSS elliptical tube to local buckling is expected to be suppressed by the confined concrete, leading to full utilization of the high strength of HSS. This paper demonstrates the excellent performance of the new columns due to the above beneficial interactions between different components in the column through an experimental study. In the experimental study, twelve rectangular DTCCs covering different FRP tube thicknesses and aspect ratios were tested under axial compression. Finally, an existing stress–strain model for FRP-confined concrete in rectangular columns is modified to be applicable to the concrete in the new column by accounting for the confinement effect from the inner elliptical HSS tube. It is found that the modified model provides more accurate predictions on the stress–strain curves of confined concrete in the rectangular DTCCs than the original model.
Ambient temperatures have great impacts on thermoregulation of small mammals. Brown adipose tissue (BAT), an obligative thermogenic tissue for small mammals, is localized not only in the ...interscapular depot (iBAT), but also in supraclavicular, infra/subscapular, cervical, paravertebral, and periaortic depots. The iBAT is known for its cold-induced thermogenesis, however, less has been paid attention to the function of BAT at other sites. Here, we investigated the function of BAT at different sites of the body during cold acclimation in a small rodent species. As expected, Brandt's voles (Lasiopodomys brandtii) consumed more food and reduced the body mass gain when they were exposed to cold. The voles increased resting metabolic rate and maintained a relatively lower body temperature in the cold (36.5 ± 0.27 °C) compared to those in the warm condition (37.1 ± 0.36 °C). During cold acclimation, the uncoupling protein 1 (UCP1) increased in aBAT (axillary), cBAT (anterior cervical), iBAT (interscapular), nBAT (supraclavicular), and sBAT (suprascapular). The levels of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, were higher in cBAT and iBAT in the cold than in the warm group. The pAMPK/AMPK and pCREB/CREB were increased in cBAT and iBAT during cold acclimation, respectively. These data indicate that these different sites of BAT play the cold-induced thermogenic function for small mammals.
The schematic diagram illustrates cold-stimulated BAT thermogenesis at different sites of the body in Brandt's voles (Lasiopodomys brandtii). During cold acclimation, the levels of UCP1, PCNA, and pCREB/CREB increased in iBAT; UCP1, PGC1α, and pAMPK/AMPK increased in cBAT; UCP1 and PCNA increased in aBAT; UCP1 increased in nBAT and sBAT; and PGC1α increased in chBAT. These data indicate that these different sites of BAT play the cold-induced thermogenic function. As a result, the voles increased the metabolic rate and food intake, but reduced body temperature and body mass gain to defense cold.
aBAT, axillary brown adipose tissue; cBAT, anterior cervical BAT; chBAT, cheek BAT; iBAT, interscapular BAT; nBAT, supraclavicular BAT; sBAT, supraspinal BAT; PCNA, proliferating cell nuclear antigen; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1α; pAMPK/AMPK, phosphorylated AMP-activated protein kinase/AMP-activated protein kinase; pCREB/CREB, phosphorylated cAMP response element-binding brotein/cAMP response element-binding protein; UCP1, uncoupling protein 1. Display omitted
•The uncoupling protein 1 (UCP1) increased in brown adipose tissue (BAT) at different sites of body during cold acclimation.•Cell proliferation increased in anterior cervical BAT (cBAT) and interscapular BAT (iBAT) during cold acclimation.•The AMPK and PKA signaling pathways were activated in cBAT and iBAT during cold acclimation•The different sites of BAT play the cold-induced thermogenic function.
Clonorchiasis: a key foodborne zoonosis in China Lun, Zhao-Rong; Gasser, Robin B; Lai, De-Hua ...
The Lancet infectious diseases,
January 2005, 2005, 2005-Jan, 2005-01-00, 20050101, Letnik:
5, Številka:
1
Journal Article
Recenzirano
The oriental liverfluke, Clonorchis sinensis, is of major socioeconomic importance in parts of Asia, including China, Japan, Korea, Taiwan, and Vietnam. The parasite is transmitted via snails to ...freshwater fish, and then to human beings and other piscivorous mammals, and causes substantial clinical or subclinical disease, known as clonorchiasis. There is considerable evidence for an aetiological relation between clonorchiasis and cholangiocarcinoma in human beings. It is estimated that about 35 million people are infected globally, of whom approximately 15 million are in China. Although very little information from China has been published in the English language, recent analyses of epidemiological data sets suggest that clonorchiasis is having an increased human-health impact due to the greater consumption of raw freshwater fish. To gain an improved insight into clonorchiasis in China, this review provides a background on the parasite and its life cycle, summarises key aspects regarding the pathogenesis, diagnosis, and treatment of clonorchiasis, describes the geographic distribution and prevalence of clonorchiasis, and makes some recommendations for future research and the control of this important disease.
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