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OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Objectives To evaluate inter- and intra- scan mode and scanner repeatability and reproducibility of radiomics features within and between single-energy CT (SECT) and dual-energy CT (DECT). Methods A standardized phantom with sixteen rods of clinical-relevant densities was scanned on seven DECT-capable scanners and three SECT-only scanners. The acquisition parameters were selected to present typical abdomen-pelvic examinations with the same voxel size. Images of SECT at 120 kVp and corresponding 120 kVp-like virtual monochromatic images (VMIs) in DECT which were generated according to scanners were analyzed. Regions of interest were drawn with rigid registrations to avoid variations due to segmentation. Radiomics features were extracted via Pyradiomics platform. Test-retest repeatability was evaluated by Bland-Altman analysis for repeated scans. Intra-scanner reproducibility for different scan modes was tested by intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC). Inter-scanner reproducibility among different scanners for same scan mode was assessed by coefficient of variation (CV) and quartile coefficient of dispersion (QCD). Results The test-retest analysis presented that 92.91% and 87.02% of the 94 assessed features were repeatable for SECT 120kVp and DECT 120 kVp-like VMIs, respectively. The intra-scanner analysis for SECT 120kVp vs DECT 120 kVp-like VMIs demonstrated that 10.76% and 10.28% of features were with ICC > 0.90 and CCC > 0.90, respectively. The inter-scanner analysis showed that 17.09% and 27.73% of features for SECT 120kVp were with CV < 10% and QCD < 10%, and 15.16% and 32.78% for DECT 120 kVp-like VMIs, respectively. Conclusions The majority of radiomics features were non-reproducible within and between SECT and DECT. Key Points • Although the test-retest analysis showed high repeatability for radiomics features, the overall reproducibility of radiomics features within and between SECT and DECT was low. • Only about one-tenth of radiomics features extracted from SECT images and corresponding DECT images did match each other, even their average photon energy levels were considered alike, indicating that the scan mode potentially altered the radiomics features. • Less than one-fifth of radiomics features were reproducible among multiple SECT and DECT scanners, regardless of their fixed acquisition and reconstruction parameters, suggesting the necessity of scanning protocol adjustment and post-scan harmonization process.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.

The presence of actinic keratoses (AKs) increases a patient’s risk of developing squamous cell carcinoma by greater than six-fold. We evaluated the effect of topical treatment with imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment with imiquimod 3.75%. Biopsies were collected prospectively from 21 patients and examined histologically. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay. Imiquimod decreased number of AKs by study endpoint at week 14 (p p p p

Aims: To investigate the prognostic relevance of platelet volume indices for survival in laryngeal cancer. Patients & methods: The study included 640 patients with laryngeal cancer. We analyzed the optimal cutoff values through receiver operating characteristic analysis, then analyzed the univariate factor and multivariate variables. Kaplan–Meier curves and log-rank tests were conducted to compare the overall survival (OS) and recurrence-free survival rates between the groups. Results: In multivariate analysis, elevated platelet distribution width (PDW) and PDW/platelet count ratio were significantly correlated with poor prognosis for OS; however, elevated mean platelet volume (MPV) and MPV/platelet count ratio suggested a notable correlation with favorable prognosis for OS. Meanwhile, elevated PDW and decreased MPV were significantly correlated with poor prognosis for recurrence-free survival. Conclusions: Our findings indicate that elevated PDW and decreased MPV could serve as independent biomarkers for worse survival in laryngeal cancer.

This survey aimed to describe the health-related quality of life (HRQoL) and to explore the relationship between chronic diseases and HRQoL among urban residents in Shanghai, China. A cross-sectional study of 9 426 adults was conducted in Xuhui District of Shanghai, China in 2015. The EuroQol five-dimension three-level (EQ-5D-3 L) was used to measure HRQoL. The average age of subjects was 55.6 ± 17.4 years and 53% were female. Their mean values of utility and visual analogue scale (VAS) were 0.974 ± 0.099 and 80.00 ± 12.36, respectively, which were above the Chinese norm values. Women had lower scores compared with men. The utility value decreased with age, which accelerated after the age of 55 years. Chronic conditions including diabetes, tumor, cardiovascular disease, and respiratory disease, were significantly related to HRQoL, and the reported proportions of problems in the five dimensions increased with the number of chronic diseases (p 0.05). Chronic diseases except for respiratory disease had a negative effect on HRQoL utility value and VAS score after the adjustment for covariates (p 0.05). Chronic diseases had a negative impact on both EQ-5D-3 L utility and VAS scores, although the health-related quality of life for the study was above the national average.

Inspired by the dynamic morphology control of molecular assemblies in biological systems, we have developed pH‐responsive transformable peptide‐based nanoparticles for photodynamic therapy (PDT) with prolonged tumor retention times. The self‐assembled peptide–porphyrin nanoparticles transformed into nanofibers when exposed to the acidic tumor microenvironment, which was mainly driven by enhanced intermolecular hydrogen bond formation between the protonated molecules. The nanoparticle transformation into fibrils improved their singlet oxygen generation ability and enabled high accumulation and long‐term retention at tumor sites. Strong fluorescent signals of these nanomaterials were detected in tumor tissue up to 7 days after administration. Moreover, the peptide assemblies exhibited excellent anti‐tumor efficacy via PDT in vivo. This in situ fibrillar transformation strategy could be utilized to design effective stimuli‐responsive biomaterials for long‐term imaging and therapy., Fibrillar‐transformable peptide‐porphyrin (PWG) nanoparticles activated by the acidic inter‐ and intracellular tumor microenvironment were developed for photodynamic therapy (PDT). The transformation of nanoparticles into nanofibers improved their singlet oxygen generation ability and enabled high accumulation and long‐term retention at tumor sites, resulting in excellent anti‐tumor efficacy via PDT in vivo.

Inspired by the diverse protein-based structures and materials in organisms, proteins have been expected as promising biological components for constructing nanomaterials toward various applications. In numerous studies protein-based nanomaterials have been constructed with the merits of abundant bioactivity and good biocompatibility. However, self-assembly of proteins as a dominant approach in constructing anticancer nanodrugs has not been reviewed. Here, we provide a comprehensive account of the role of protein self-assembly in fabrication, regulation, and application of anticancer nanodrugs. The supramolecular strategies, building blocks, and molecular interactions of protein self-assembly as well as the properties, functions, and applications of the resulting nanodrugs are discussed. The applications in chemotherapy, radiotherapy, photodynamic therapy, photothermal therapy, gene therapy, and combination therapy are included. Especially, manipulation of molecular interactions for realizing cancer-specific response and cancer theranostics are emphasized. By expounding the impact of molecular interactions on therapeutic activity, rational design of highly efficient protein-based nanodrugs for precision anticancer therapy can be envisioned. Also, the challenges and perspectives in constructing nanodrugs based on protein self-assembly are presented to advance clinical translation of protein-based nanodrugs and next-generation nanomedicine.

Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine., Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.

Background Our research was designed to decide whether the application of C2 pars screws is an alternative choice for patients with OPLL involving the C2 segment. Methods A total of 40 patients who underwent cervical laminectomy with fusion (LF) from C2 to C6 for OPLL were reviewed. Among them, C2 pedicle screws were placed in 23 patients, who were the pedicle group, and C2 pars screws were placed in 17 patients, who were the pars group. The screw placement and vertebral artery (VA) anatomy presented by standard CT. General clinical characteristics and health-related outcomes were evaluated and compared preoperatively and during the follow-up period. Results The Pars group tended to have a shorter operation duration and less blood loss than the pedicle group (operation time: 115.29 ± 28.75 vs 133.48 ± 26.22, p = 0.044; blood loss: 383.53 ± 116.19 vs 457.83 ± 145.45, p = 0.039). Operation time and blood loss were both independently related to the pars group (operation time: OR = 0.966, p = 0.021; blood loss: OR = 0.993, p = 0.046). The idealization and acceptability of C2 screws in the pars group exceeded those in the pedicle group (100% vs 91.3%). However, no statistically obvious variation in the included complications or health-related outcomes between the pedicle and pars groups was observed. Conclusion In the treatment of patients with OPLL involving the C2 segment, the application of C2 pars screws is an alternative choice, which is not only safer but also reduces the amount of blood loss, shortens the operation time and obtains a more ideal screw placement.

FTO (fat mass and obesity associated) is a recently discovered gene related to obesity and expressed in various tissues of the human body, especially with high expression in the brain. Earlier studies have found that FTO is involved in several biological processes, including brain development and function. In particular, recent studies have found that FTO is a demethylase of N6-methyladenosine (m6A) and it can affect neurological function through the m6A modification of mRNA. At present, a number of studies have shown that FTO is associated with many neuropsychiatric disorders. This paper reviews the discovery, structure, function, and tissue expression of FTO followed by discussing the relationship between FTO and neuropsychiatric diseases. In addition, the potential roles of FTO gene in drug addiction, major depression (MDD), and schizophrenia (SCZ) through regulating m6A modification of dopamine related genes were also highlighted.

Combinational photoimmunotherapy (PIT) is considered to be an ideal strategy for the treatment of malignant cancer, because it can ablate the primary tumor and induce the host immune response to control tumor growth and distal metastasis.

This study was aimed at investigating the diagnostic value of MRI based on K-space data reconstruction algorithm for anterior cruciate ligament (ACL) injury of knee joint and the influencing factors of ligament injury. 96 patients with ACL injury of knee joint were selected, and they were randomly divided into two groups: group A (arthroscopy) and group B (MRI examination), and another 96 healthy volunteers in the same period were selected as the control group. The test results of each indicator were compared. The results showed that the signal-to-noise ratio (SNR) of SMASH algorithm was higher than that of sum of squares (SOS) algorithm. In group A, there were 66 positive and 30 negative tests, and in group B, there were 56 positive and 40 negative tests ( P < 0.05 ). The intercondylar fossa width, the intercondylar fossa width index, and the ratio of tibial intercondylar eminence width to intercondylar fossa width in group B were lower than those in the control group ( P < 0.05 ). Compared with the traditional SOS algorithm, SMASH algorithm can improve the image quality, reduce the impact of damage data on the final synthesis image, and improve the image SNR. In clinical work, the ratio of the width of tibial intercondylar eminence to the width of femoral intercondylar fossa can be measured by imaging data to evaluate the matching between tibial intercondylar eminence and femoral intercondylar fossa, so as to evaluate the risk of ACL rupture.

Recent studies revealed that circular RNAs (circRNAs) are important in numerous biological process and involved in autoimmune diseases. However, their role in Vogt–Koyanagi–Harada (VKH) disease, a classical autoimmune disease, is not yet known. This research aimed to study the expression profile of mRNAs, microRNAs (miRNAs) and circRNAs and investigate the influence of circRNAs on the pathogenesis of VKH disease. We identified circRNAs, miRNAs, and mRNAs expression profiles in CD4+ T cells between 4 VKH patients and 3 healthy controls using the whole-transcriptome sequencing (RNA-seq) technique. We discovered that a total of 5088 mRNAs, 451 circRNAs and 433 miRNAs were differently expressed. The GO and KEGG pathway enrichment analyses were performed for significantly differentially expressed circRNAs and mRNAs. GSEA was conducted for all mRNAs. The functional enrichment suggested that the inflammatory response, the adaptive immune response, NF-kappa B signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation and T cell receptor signaling pathway were associated with VKH disease. In addition, based on the immune-related genes we screened, the circRNA-miRNA-mRNA ceRNA network was analyzed and constructed. Ten differently expressed mRNAs (LAT, ZAP70, ITK, ICOS, RASGRP1, PAG1, PLCG1, PRKCQ, LCK, CARD11) and 5 differently expressed circRNAs (hsa_circ_0033144, hsa_circ_0000233, hsa_circ_0000396, hsa_circ_0001924, hsa_circ_0001320) were selected to be validated by Real-time qPCR (RT-qPCR). The results of RT-qPCR turned out to be consistent with RNA-seq data. Further analysis showed that hsa_circ_0001320 and hsa_circ_0001924 may serve as crucial candidate marker genes of VKH disease. These results reveal that circRNAs may have a crucial immunomodulatory function in the pathophysiological process of VKH disease.

A thymoma is a type of thymic tumor which is rarely malignant that is frequently reported in adult patients. A number of thymoma‐related immune disorders are observed including autoimmune diseases, which suggests a strong connection between thymoma development and immunological mechanisms. Characterized by association with humoral and cellular immunodeficiency, thymoma patients are susceptible to opportunistic infections by environmental factors. Recent reports have suggested that viral infection may play a role in the etiological mechanisms of thymoma development associated with dysregulated immunity. In this review, we summarize the case reports and studies related to viral infection, such as CMV, EBV and HSV, that probably play a part in the pathogenesis of thymoma and related diseases. Furthermore, we demonstrate the underlying mechanisms by which viruses may induce the occurrence of thymoma with autoimmune diseases. Lastly, we discuss the potential application of antiviral therapy in the treatment of thymic diseases.

Objective To culturally adapt the VISA-A into a simplified Chinese version (VISA-A-CHN) and test its measurement properties. Design Methodological study; Setting Hospital and university laboratory. Participants 240 subjects were divided into the healthy (n = 80), at-risk (n = 80), and tendinopathy groups (n = 80). Main outcomes measures The internal consistency, test-retest reliability, construct validity, and the floor and ceiling effect of the VISA-A-CHN. Results The VISA-A-CHN showed adequate internal consistency (Cronbach's α = 0.73, 95% CI 0.63 to 0.81), excellent test-retest reliability (ICC3A,1 = 0.97, 95%CI = 0.95 to 0.98), standard error of measurement of 2.2 points, minimum detectable change of 6.0 points, with no floor and ceiling effects. Two factors (pain/symptoms and physical function/activity) were extracted in exploratory factor analysis. There were moderate associations of VISA-A-CHN score with scores of Lower Extremity Functional Scale and SF-36 physical components (rs = 0.53–0.74, P 0.05). VISA-A-CHN mean score of Achilles tendinopathy group was significantly lower than those of healthy and at-risk groups (P Conclusions The VISA-A-CHN is equivalent to the original version in terms of language and measurement properties. It can be used as the outcome measure for Chinese patients with Achilles tendinopathy.

In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.

In diverse biological systems, the oxidation of tyrosine to melanin or dityrosine is crucial for the formation of crosslinked proteins and thus for the realization of their structural, biological, and photoactive functionalities; however, the predominant factor in determining the pathways of this chemical evolution has not been revealed. Herein, we demonstrate for tyrosine-containing amino acid derivatives, peptides, and proteins that the selective oxidation of tyrosine to produce melanin or dityrosine can be readily realized by manipulating the oxygen concentration in the reaction system. This oxygen-dependent pathway selection reflects the selective chemical evolution of tyrosine to dityrosine and melanin in anaerobic and aerobic microorganisms, respectively. The resulting melanin- and dityrosine-containing nanomaterials reproduce key functions of their natural counterparts with respect to their photothermal and photoluminescent characteristics, respectively. This work reveals the plausible role of oxygen in the chemical evolution of tyrosine derivatives and provides a versatile strategy for the rational design of tyrosine-based multifunctional biomaterials.

The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer., Tumor cell-microenvironment interactions generate heterogeneity and promote progression. Here, Ma et al. show that the E3 ligase SIAH2 degrades NRF1 in response to hypoxia to enhance pro-tumor metabolic and environmental effects, whereas NRF1 stabilization sensitizes tumor cells to apoptosis.

Management activities such as law enforcement and community outreach are thought to affect conservation outcomes in protected areas, but their importance relative to intrinsic environmental characteristics of the parks and extrinsic human pressures surrounding the parks have not been explored. Furthermore, it is not clear which is more related to conservation outcomes-the management itself or local people's perceptions of the management. We measured objective (reports by park staff) and subjective (reports by local people) levels of community outreach and law enforcement based on responses to 374 questionnaires. We estimated mammal abundance and diversity of 6 protected areas based on data from 115 camera traps in Xishuangbanna, southwest China, a biodiversity hotspot with high hunting and land-conversion pressures. We then examined correlations among them and found that local people's perception of law enforcement was positively related to the local abundance of 2 large, hunted species, wild boar (Sus scrofa) (β = 15.22) and muntjac (Muntiacus vaginalis) (β = 14.82), but not related to the abundance of smaller mammals or to objective levels of enforcement. The subjective frequency of outreach by park staff to local communities (β = 3.42) and park size (β = 3.28) were significantly and positively related to mammal species richness, whereas elevation, human population density, and subjective frequency of law enforcement were not. We could not conclude that community outreach and law enforcement were directly causing increased mammal abundance and diversity. Nevertheless, the patterns we detected are some of the first empirical evidence consistent with the idea that biodiversity in protected areas may be more positively and strongly related to local perceptions of the intensity of park management than to either intrinsic (e.g., elevation, park size) or extrinsic (e.g., human population density) environmental factors.Efectos de la Aplicación de la Ley y la Participación de la Comunidad sobre la Diversidad de Mamíferos en un Punto Caliente de Biodiversidad Resumen Las actividades de manejo como la aplicación de la ley y la participación de la comunidad afectan los resultados de conservación dentro de las áreas protegidas, pero su importancia en relación con las características ambientales intrínsecas de los parques y las presiones humanas extrínsecas que rodean a los parques no han sido exploradas. Además, no está claro cuál está más relacionado con los resultados de conservación - el manejo en sí o las percepciones que las personas locales tienen sobre el manejo. Medimos los niveles objetivos (reportes dados por el personal del parque) y subjetivos (reportes dados por los locales) de la participación de la comunidad y la aplicación de la ley con base en las respuestas a 347 cuestionarios. Estimamos la abundancia y diversidad de mamíferos de seis áreas protegidas con base en datos de 115 cámaras trampa en Xishuangbann, al suroeste de China, un punto caliente de biodiversidad con altas presiones causadas por la caza y la conversión del uso de suelo. Después examinamos la correlación entre ellos y encontramos que la percepción que los locales tienen sobre la aplicación de la ley estuvo relacionada positivamente con la abundancia local de dos grandes especies que son cazadas, el jabalí (Sus scrofa) (β = 15.22) y el muntíaco (Muntiacus vaginalis) (β = 14.82), pero no estuvo relacionada con la abundancia de mamíferos más pequeños o con los niveles objetivos de la aplicación de la ley. La frecuencia subjetiva del alcance del personal del parque hacia las comunidades locales (β = 3.42) y el tamaño del parque and (β = 3.28) estuvieron relacionadas significativa y positivamente con la riqueza de las especies de mamíferos, mientras que la elevación, la densidad de la población humana, y la frecuencia subjetiva de la aplicación de la ley no lo estuvieron. No pudimos concluir que la participación de la comunidad y la aplicación de la ley estuvieran causando directamente una abundancia y diversidad aumentada de mamíferos. Sin embargo, los patrones que detectamos son de las primeras evidencias empíricas consistentes con la idea de que la biodiversidad en las áreas protegidas podría estar relacionada positiva y fuertemente con la percepción que tienen los locales de la intensidad del manejo del parque y no con los factores ambientales intrínsecos (p. ej.: elevación, tamaño del parque) o extrínsecos (p.ej.: densidad de la población humana).保护区执法 和社区宣传 等管理活动被认为会影响保护区的保护成果, 但其相对于保护区内在环境特征因素以及保护区周边的外在人类活动因素的重要性尚未得到探索。此外, 尚不清楚哪个与保护结果更相关 - 管理本身或当地人对管理行为的感知。我们通过 374 份问卷测量了客观 (由保护区工作人员报告的) 和主观 (由当地人报告的) 执法和社区宣传水平。我们通过 115 个相机陷阱估算了西双版纳的 6 个保护区的哺乳动物丰度和多样性, 西双版纳是一个具有高狩猎压力和土地流转压力的生物多样性热点地区。我们接下来验证了管理活动和生物多样性指标的相关性, 发现当地居民对执法行为的感知与 2 种大型猎物, 野猪 (Sus scrofa) (β = 15.22) 和赤麂 (Muntiacus vaginalis) (β = 14.82) 的相对多度呈正相关, 但与较小的哺乳动物的相对多度无相关性关, 且客观的执法水平猎物丰富度也无相关性。当地居民感知的保护区宣传频率 (β = 3.42) 和保护区面积 (β = 3.28) 与哺乳动物物种丰富度显著正相关, 而与海拔, 保护区周边人口密度和保护区汇报的宣传频率无相关性。虽然, 相关性不等于因果关系, 我们无法得出是保护区执法和社区宣传直接导致了保护区哺乳动物多度和多样性地增加。不过, 我们发现的结果可能是第一个与平时推测相一致的实验性证据:保护区周边居民对保护区管理的感知与保护区内的生物多样性的相关性高于保护区内在环境特征 (例如保护区海拔和面积) 以及保护区周边的外在人类活动因素 (例如保护区周边的人口密度) 与保护区内的生物多样性的相关性。.

Background To explore the relationship between spino cranial angle (SCA) and loss of cervical lordosis (LOCL), and to determine whether SCA has the ability to predict LOCL for patients with cervical myelopathy. Methods A total of 68 consecutive patients with cervical myelopathy who received laminoplasty (LAMP) were selected to the current study. C2–C7 lordosis was defined as a representation of the cervical alignment. Alignment change > 0° was considered LOCL. Multiple linear regression analysis was applied to evaluate the association between LOCL and various sagittal parameters at preoperative, such as SCA, CL, T1s and cSVA. Linear regression analysis was applied to evaluate the relationships between LOCL and preoperative SCA in each subgroup. Results Patients were assigned to three groups depending on the quartile of preoperative SCA. The first quarter of patients were defined as the low SCA group, the last quarter were defined as the high SCA group and the middle half were defined as the middle SCA group. There was no statistically significant difference in age, sex and the type of OPLL among the three groups. Patients in the low SCA group showed more cervical lordosis before surgery and more LOCL after LAMP (p r = − 0.857, p r = − 0.515, p = 0.034). However, there was no significant correlation between preoperative SCA and LOCL in the middle SCA group (r = 0.027, p = 0.881). Conclusions Patients with lower SCA had more lordosis preoperatively and performed more LOCL after LAMP at 2 years of follow-up. Both too high or low preoperative SCA were negatively correlated with the degree of LOCL, while when the SCA fluctuates in a suitable range, it is easier to compensate for the changes of cervical sagittal alignment.

Perforin, a pore-forming glycoprotein, has been demonstrated to play key roles in clearing virus-infected cells and tumour cells due to its ability of forming 'pores' on the cell membranes. Additionally, perforin is also found to be associated with human diseases such as tumours, virus infections, immune rejection and some autoimmune diseases. Until now, plenty of perforin genes have been identified in vertebrates, especially the mammals and teleost fish. Conversely, vertebrate homologue of perforin gene was not identified in the invertebrates. Although recently there have been several reviews focusing on perforin and granzymes in mammals, no one highlighted the current advances of perforin in the other vertebrates. Here, in addition to mammalian perforin, the structure, evolution, tissue distribution and function of perforin in bony fish are summarized, respectively, which will allow us to gain more insights into the perforin in lower animals and the evolution of this important pore-forming protein across vertebrates.

To investigate aqueous metabolic profiles in Vogt-Koyanagi-Harada (VKH) and Behcet’s disease (BD), we applied ultra-high-performance liquid chromatography equipped with quadrupole time-of flight mass spectrometry in aqueous humor samples collected from these patients and controls. Metabolite levels in these three groups were analyzed by univariate logistic regression. The differential metabolites were subjected to subsequent pathway analysis by MetaboAnalyst. The results showed that both partial-least squares discrimination analysis and hierarchical clustering analysis showed specific aqueous metabolite profiles when comparing VKH, BD, and controls. There were 28 differential metabolites in VKH compared to controls and 29 differential metabolites in BD compared to controls. Amino acids and fatty acids were the two most abundant categories of differential metabolites. Furthermore, pathway enrichment analysis identified several perturbed pathways, including pantothenate and CoA biosynthesis when comparing VKH with the control group, and D-arginine and D-ornithine metabolism and phenylalanine metabolism when comparing BD with the control group. Aminoacyl-tRNA biosynthesis was altered in both VKH and BD when compared to controls. Our findings suggest that amino acids metabolism as well as two fatty acids, palmitic acid and oleic acid, may be involved in the pathogenesis of BD and VKH.

Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan–Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51–11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms.

A fever clinic within a hospital plays a vital role in pandemic control because it serves as an outpost for pandemic discovery, monitoring and handling. As the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan was gradually brought under control, the fever clinic in the West Campus of Wuhan Union Hospital introduced a new model for construction and management of temporary mobile isolation wards. A traditional battlefield hospital model was combined with pandemic control regulations, to build a complex of mobile isolation wards that used adaptive design and construction for medical operational, medical waste management and water drainage systems. The mobile isolation wards allowed for the sharing of medical resources with the fever clinic. This increased the capacity and efficiency of receiving, screening, triaging and isolation and observation of patients with fever. The innovative mobile isolation wards also controlled new sudden outbreaks of COVID-19. We document the adaptive design and construction model of the novel complex of mobile isolation wards and explain its characteristics, functions and use.

Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP–Epac–CREB signaling pathway to upregulate FGF21 expression in hepatocytes.

Insulin resistance (IR) precedes the development of type 2 diabetes (T2D) and increases cardiovascular disease risk. Although genome wide association studies (GWAS) have uncovered new loci associated with T2D, their contribution to explain the mechanisms leading to decreased insulin sensitivity has been very limited. Thus, new approaches are necessary to explore the genetic architecture of insulin resistance. To that end, we generated an iPSC library across the spectrum of insulin sensitivity in humans. RNA-seq based analysis of 310 induced pluripotent stem cell (iPSC) clones derived from 100 individuals allowed us to identify differentially expressed genes between insulin resistant and sensitive iPSC lines. Analysis of the co-expression architecture uncovered several insulin sensitivity-relevant gene sub-networks, and predictive network modeling identified a set of key driver genes that regulate these co-expression modules. Functional validation in human adipocytes and skeletal muscle cells (SKMCs) confirmed the relevance of the key driver candidate genes for insulin responsiveness., Author summary Insulin resistance is characterized by a defective response (“resistance”) to normal insulin concentrations to uptake the glucose present in the blood, and is the underlying condition that leads to type 2 diabetes (T2D) and increases the risk of cardiovascular disease. It is estimated that 25–33% of the US population are insulin resistant enough to be at risk of serious clinical consequences. For more than a decade, large population studies have tried to discover the genes that participate in the development of insulin resistance, but without much success. It is now increasingly clear that the complex genetic nature of insulin resistance requires novel approaches centered in patient specific cellular models. To fill this gap, we have generated an induced pluripotent stem cell (iPSC) library from individuals with accurate measurements of insulin sensitivity, and performed gene expression and key driver analyses. Our work demonstrates that iPSCs can be used as a revolutionary technology to model insulin resistance and to discover key genetic drivers. Moreover, they can develop our basic knowledge of the disease, and are ultimately expected to increase the therapeutic targets to treat insulin resistance and type 2 diabetes.

Background Dai, Hani, and Yao people, in the trans-boundary region between China, Laos, and Vietnam, have gathered plentiful traditional knowledge about wild edible plants during their long history of understanding and using natural resources. The ecologically rich environment and the multi-ethnic integration provide a valuable foundation and driving force for high biodiversity and cultural diversity in this region. However, little study has uncovered this unique and attractive culture to the world. Methods We conducted ethnobotanical survey in 20 villages of Jiangcheng County from 2016 to 2020. Altogether 109 local Dai, Hani, and Yao people were interviewed, and their traditional knowledge about wild edible plants was recorded. Voucher specimens were identified by the authors and deposited in the herbarium of Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences (HITBC). The use value was used as a quantitative index to evaluate the consumption frequency and relative importance of the wild edible plants. The Jaccard index was calculated to assess the usage similarity of different areas. The relationship of age and recognized wild edible plants by different ethnic people was performed by R. Results A total of 211 wild edible plants, belonging to 71 families and 151 genera, were recorded. These plants were consumed as wild edible vegetables, seasonal fruits, salads, spices, sour condiments, tonic soups, tea substitutes, liquor brewing, or dyeing materials. The use value (UV), current cultivation, market availability, and the quantitative traditional knowledge inheritance situation of these wild edible plants among different generations, were analyzed. Based on the data from the threatened species list of China’s higher plants and the IUCN Red List, the food plant list for Asia Elephant, the Subject Database of China Plant, and the calculated UV score, the top 30 most important wild edible plants were selected for further cultivation in some local villages. Conclusion Traditional knowledge of wild edible plants, owned by Dai, Hani, and Yao people in Jiangcheng County, is rich but at risk of being lost among the young generation. Diversified cultivation of wild edible plants by the local communities could be a solution for the sustainable use of natural resources and to conserve the endangered species in this trans-boundary region.

Scope Milk fat globule membrane (MFGM), which contains abundant polar lipids and glycoproteins, can narrow the gap in growth and development between breast-fed and infant-formula-fed babies. The objective of this study is to evaluate the effect of MFGM supplementation in infant formula on intestinal epithelium maturation, tight junctions, and gut colonization in rat pups. Methods and results Sprague Dawley rat pups consume one of the five diets from postnatal day 8, including rat breastfeeding (BF), infant formula (IF), and infant formula containing MFGM at 260 mg kg-1 body weight (BW), 520 mg kg-1 BW, or 1040 mg kg-1 BW. Results show that MFGM supplementation in infant formula can facilitate intestinal mucosal barrier maturation via promoting intestinal proliferation and differentiation, and increasing tight junction proteins. In addition, compared with that of the IF pups, the intestinal flora composition of MFGM-supplemented pups is more similar to that of BF pups. Conclusion MFGM supplementation in infant formula can restore the intestinal development in infant-formula-fed pups, which suggests that the supplementation of MFGM in infant formula can better mimic breast milk.

Combination of corticosteroids (CS) with cyclosporin A (CsA) is widely used in the treatment of autoimmune diseases, autoinflammatory diseases and transplantation rejection. However, some patients fail to respond or develop resistance to the combination regimen. In Vogt-Koyanagi-Harada (VKH) disease model, we performed RNA sequencing (RNA-seq) based transcriptomics, isobaric tags for relative and absolute quantification (iTRAQ) based proteomics and assays in vitro to screen and validate potential resistant molecules. We found that a total of 1697 differentially expressed genes (DEGs) and 21 differentially expressed proteins (DEPs) in CD4(+) T cells between CsA & CS-resistant and -sensitive VKH patients. Ribosomal Protein S4, Y-Linked 1 (RPS4Y1) was verified to regulate the resistance of CD4(+) T cells from male VKH patients to CsA & CS. Importantly, we showed that chlorambucil (CLB) could reverse the resistance by RPS4Y1 suppression. Taken together, we identify RPS4Y1 as an important CsA & CS resistance gene in VKH disease. Researchers should consider validating the resistant effect of RPS4Y1 in other autoimmune diseases or organ transplantation.

Vogt-Koyanagi-Harada (VKH) disease is a common type of uveitis in China, but the diagnosis criteria of VKH disease is controversial. The aim of this study was to investigate potential diagnostic plasma biomarkers for VKH disease. A case-control study including 55 VKH patients (28 active patients and 27 inactive VKH patients) and 30 healthy controls in a tertiary referral center was performed. The metabolic phenotype of VKH patients showed a significant difference compared to healthy controls. Fifteen differentially expressed metabolites (DEMs) were identified between active VKH patients and healthy controls and nine DEMs were found between inactive VKH patients and healthy controls after controlling variable importance in the projection (VIP) value > 1 and false discovery rate (FDR) < 0.05. D-mannose, stearic acid and L-lysine were shown to be potential diagnostic biomarkers which can discriminate active VKH patients from healthy controls with a diagnostic performance with AUC = 0.965, 0.936 and 0.910 respectively in independent diagnosis and an AUC = 0.999 when combined. Sarcosine was recognized as an independent potential biomarker which could distinguish inactive VKH patients from healthy controls. This study reveals a significant difference of plasma metabolic phenotype and identifies diagnostic biomarkers for VKH disease. Changes in the metabolic profile may provide clues towards the pathophysiology of VKH disease.

BackgroundTo investigate the clinical efficacy and outcomes of skin stretch suturing with self-locking sliding Nice knots in the treatment of small- or medium-sized wounds.MethodsFrom June 2015 to May 2018, 26 patients with small- or medium-sized wounds were included in the present study. Skin stretch suturing with self-locking slide Nice knots was performed to gradually close the soft-tissue defects in these patients. The time of wound closure and healing was recorded. The color and blood supply of the skin, cutaneous sensation, the stretch of skin, and the hair growth situation of the skin wound were observed and recorded.ResultsThere were 17 males and 9 females with an average age of 30.65 years (range, 15–48 years). The areas of the soft-tissue defects were between 3.2 × 7.1 cm and 8.0 × 15.2 cm. All patients underwent stretch suturing with self-locking slide Nice knots to close the soft-tissue defects. All wounds were successfully closed and healed. The mean time of wound closure was 10.69 days (range, 5–20 days), and the mean time of wound healing was 16.85 days (range, 10–24 days). The cutaneous sensation of skin wound recovered normally, and the color of the skin wounds was the same as that of normal skin at the last follow-up. The hair growth situation of the skin wounds also returned to normal.ConclusionsThis study revealed that Nice knots yielded an accepted clinical result as a new method to close small- or medium-sized wounds that was simple and less minimally invasive, resulted in progressive tension, did not return to previous results, and partially replace flaps or free skin grafts.

Age-related macular degeneration and Alzheimer's disease are closely related complex diseases that may share overlapping pathogenesis in gene networks. This study was conducted to investigate the genetic factors shared by both diseases. We analyzed genome-wide association studies' summary statistics from both diseases using a new platform known as functional mapping and annotation (FUMA) and a co-localization analysis. We obtained disease-related gene expression profile data from the Gene Expression Omnibus and analyzed these data using weighted gene co-expression network analysis. FUMA analysis and Bayesian co-localization analysis showed that ten genes on chromosome 7, one pathway (complement and coagulation cascade), and forty-two biological processes were common for both diseases. Among these ten genes, two protein-coding genes, two pseudogenes, and two RNA genes were, for the first time, identified to be associated with both diseases. Weighted gene co-expression network analysis identified 19 age-related macular degeneration hub genes and 19 Alzheimer's disease hub genes and revealed that these two diseases shared nine pathways and 63 biological processes. Using FUMA, co-localization analysis, and weighted gene co-expression network analysis, 10 genes on chromosome 7, 10 pathways, and 105 biological processes were found to be associated with the two degenerative diseases. This suggests that these10 genes and the hub genes of these modules associated with the shared pathways are potential diagnostic markers for both diseases.

To investigate aqueous cytokine profiles in acute anterior uveitis (AAU), Fuchs' syndrome, Vogt-Koyanagi-Harada (VKH) disease and Behcet's disease (BD), we assayed the concentrations of 17 cytokines by multiplex immunoassay in aqueous humor (AqH) collected during cataract surgery from 24 AAU, 29 Fuchs' syndrome, 29 VKH disease, 30 BD and 30 senile cataract control patients. Aqueous cytokine levels were compared between the five groups and analysed by logistic regression. Cytokine levels were then compared between uveitis patients who underwent cataract surgery within 3 months and those who underwent this surgery more than 3 months after complete control of intraocular inflammation. The results showed that aqueous levels of interferon (IFN)-gamma, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1 beta and tumour necrosis factor (TNF)-alpha levels in AqH from patients with Fuchs' syndrome were significantly higher than those in the other four groups. Using multivariate analysis, MIP-1 beta was found to be significantly associated with Fuchs' syndrome. There was no difference in aqueous cytokine levels between cases having cataract surgery within 3 months compared to those after 3 months of complete control of their intraocular inflammation. The current study shows that Chinese patients with Fuchs' syndrome appear to have a specific cytokine profile. MIP-1 beta is an important chemokine in the intraocular environment of Fuchs' syndrome. Aqueous cytokine profiles support the performance of cataract surgery in uveitis within 3 months after intraocular inflammation control.

Photothermal nanomedicine based on self-assembly of biological components, with excellent biosafety and customized performance, is vital significance for precision cancer therapy. However, the programmable design of photothermal nanomedicine remains extremely challenging due to the vulnerability and variability of noncovalent interactions governing supramolecular self-assembly. Herein, it is reported that amino acid encoding is a facile and potent means to design and construct supramolecular photothermal nanodrugs with controlled therapeutic activities. It is found that the amount and type of amino acid dominates the assembled nanostructures, structural stability, energy-conversion pathway, and therapeutic mechanism of the resulting nanodrugs. Two optimized nanodrugs are endowed with robust structural integrity against disassembly along with high photothermal conversion efficiency, efficient cellular internalization, and enhanced tumor accumulation, which result in more efficient tumor ablation. This work demonstrates that design based on amino acid encoding offers an unprecedented opportunity for the construction of remarkable photoactive nanomedicines toward cancer diagnostics and therapeutics.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP. Electronic supplementary material The online version of this article (10.1007/s00401-018-1900-5) contains supplementary material, which is available to authorized users.

Mercury (Hg) is a globally-distributed pollutant, toxic to humans and animals. Emissions are particularly high in Asia, and the source of exposure for humans there may also be different from other regions, including rice as well as fish consumption, particularly in contaminated areas. Yet the threats Asian wildlife face in rice-based ecosystems are as yet unclear. We sought to understand how Hg flows through rice-based food webs in historic mining and non-mining regions of Guizhou, China. We measured total Hg (THg) and methylmercury (MeHg) in soil, rice, 38 animal species (27 for MeHg) spanning multiple trophic levels, and examined the relationship between stable isotopes and Hg concentrations. Our results confirm biomagnification of THg/MeHg, with a high trophic magnification slope. Invertivorous songbirds had concentrations of THg in their feathers that were 15x and 3x the concentration reported to significantly impair reproduction, at mining and non-mining sites, respectively. High concentrations in specialist rice consumers and in granivorous birds, the later as high as in piscivorous birds, suggest rice is a primary source of exposure. Spiders had the highest THg concentrations among invertebrates and may represent a vector through which Hg is passed to vertebrates, especially songbirds. Our findings suggest there could be significant population level health effects and consequent biodiversity loss in sensitive ecosystems, like agricultural wetlands, across Asia, and invertivorous songbirds would be good subjects for further studies investigating this possibility.

AimTo elucidate the role of microRNA-20a-5p (miR-20a-5p) in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.MethodsQuantitative real-time PCR was used to quantify miR-20a-5p expression in CD4+ T cells from patients with active VKH and normal controls. The promoter methylation status of miR-20a-5p was detected by bisulfite sequencing PCR. Targets were evaluated by a luciferase reporter assay. The functional effects of miR-20a-5p on CD4+ T cells from patients with active VKH were assessed by upregulation or downregulation of its expression using liposomes.ResultsThe miR-20a-5p level was significantly decreased in CD4+ T cells from patients with active VKH as compared with normal controls. The two genes, oncostatin M (OSM) and C-C motif chemokine ligand 1 (CCL1), were identified as targets of miR-20a-5p. The upregulation of miR-20a-5p significantly suppressed interleukin 17 (IL-17) production in CD4+ T cells from patients with active VKH, whereas downregulation of miR-20a-5p exhibited an inverse effect. In addition, overexpression of OSM and CCL1 could rescue the effect of the upregulation of miR-20a-5p. Moreover, the level of miR-20a-5p was reduced in response to hypermethylation of the promoter. Further study showed that miR-20a-5p suppressed the activity of the phosphoinositide 3-kinase-AKT pathway.ConclusionsOur findings indicate that downregulation of miR-20a-5p is caused by promoter hypermethylation. MiR-20a-5p could also suppress the production of IL-17 by targeting OSM and CCL1 production in CD4+ T cells in patients with active VKH.

Brown adipose tissue is important for maintaining energy homeostasis and adaptive thermogenesis in rodents and humans. As disorders arising from dysregulated energy metabolism, such as obesity and metabolic diseases, have increased, so has interest in the molecular mechanisms of adipocyte biology. Using a functional screen, we identified cyclin C (CycC), a conserved subunit of the Mediator complex, as a novel regulator for brown adipocyte formation. siRNA-mediated CycC knockdown (KD) in brown preadipocytes impaired the early transcriptional program of differentiation, and genetic KO of CycC completely blocked the differentiation process. RNA sequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα in white adipogenesis, CycC-KD also inhibited differentiation of 3T3-L1 cells into white adipocytes. Together, these data indicate that CycC activates adipogenesis in part by stimulating the transcriptional activity of C/EBPα.

Supramolecular peptide materials have attracted increasing attention due to their natural biological origin and versatile applications. However, it is often challenging to control and modulate the self-assembly of peptides (especially short peptides) for constructing hydrogels with tunable mechanical properties and adaptive injectability toward biomedical applications. Here, we report a supramolecular strategy for forming robust and injectable hydrogels based on the self-assembly of a rationally designed bola-dipeptide. The self-assembled hydrogels exhibit versatile functionalities, including flow under shear stress, good recovery properties, and easy encapsulation of hydrophilic prodrugs. The prodrug-loaded hydrogels show sustained release profiles, inhibited nontargeted leakage, and enhanced localized prodrug conversion, leading to highly efficient photodynamic tumor ablation. Hence, the supramolecular strategy is promising for the rational construction of injectable hydrogels toward targeted and sustained prodrug conversion and tumor therapy.

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination- and heating-enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.

Mitochondria are highly dynamic organelles and respond to stress by changing their fission-fusion cycle, undergoing mitophagy, or releasing apoptotic proteins to initiate cell death. The molecular mechanisms that sense different stresses and coordinate distinct effectors still await full characterization. Here, we show that PGAM5, which exists in an equilibrium between dimeric and multimeric states, dephosphorylates BCL-xL to inhibit apoptosis or FUNDC1 to activate mitofission and mitophagy in response to distinct stresses. In vinblastine-treated cells, PGAM5 dephosphorylates BCL-xL at Ser62 to restore BCL-xL sequestration of BAX and BAK and thereby resistance to apoptosis. Selenite-induced oxidative stress increases the multimerization of PGAM5, resulting in its dissociation from BCL-xL, which causes increased BCL-xL phosphorylation and apoptosis. Once freed, the more multimeric and active PGAM5 dephosphorylates FUNDC1 to initiate mitofission and mitophagy. The reciprocal interaction of PGAM5 with FUNDC1 and BCL-xL, controlled by PGAM5 multimerization, serves as a molecular switch between mitofission/mitophagy and apoptosis.

Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an IFN-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTL) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary with metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR− macrophages. The HLA-DR− subset coexpressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy. Significance: These findings provide a deeper understanding of the tumor immune microenvironment by combining multiple modalities to stratify patients into risk groups, a critical step to improving the management of patients with melanoma.

Cyclic dipeptides (CDPs), the smallest naturally occurring cyclic peptides, have attracted tremendous attention due to their exceptional biological and pharmacological activities such as antitumor, antimicrobial, and immune regulation. However, controlled fabrication of CDPs nanostructures to address the problem of poor aqueous solubility and low bioavailability existing in therapeutic application is still in challenging, due to their remarkable structural rigidity and superior hydrogen-bonding-forming capability. Herein, a simple but robust and universal strategy for the construction of CDP nanoribbons based on the amphiphilic dye-mediated hydrophobic self-assembly is presented. The amphiphilic dyes not only provide the robust hydrophobic interaction for the formation of CDP nanoribbons but also offer enough electrostatic repulsion forces to stabilize the formed assemblies. Moreover, the introduction of functional dyes endows the assembled CDP nanoribbons multiple benign therapeutic features, including adjustable shape and size, improved bioavailability, as well as preferable cellular uptake and biodistribution, thereby enhanced chemotherapy efficacy in vitro and in vivo. The strategy developed based on the dye-mediated self-assembly provides a promising way to rationally design water-insoluble bioactive CDPs for therapeutic applications.

Photothermal nanomaterials that integrate multimodal imaging and therapeutic functions provide promising opportunities for noninvasive and targeted diagnosis and treatment in precision medicine. However, the clinical translation of existing photothermal nanoagents is severely hindered by their unclear physiological metabolism, which makes them a strong concern for biosafety. Here, the utilization of biliverdin (BV), an endogenic near-infrared (NIR)-absorbing pigment with well-studied metabolic pathways, to develop photothermal nanoagents with the aim of providing efficient and metabolizable candidates for tumor diagnosis and therapy, is demonstrated. It is shown that BV nanoagents with intense NIR absorption, long-term photostability and colloidal stability, and high photothermal conversion efficiency can be readily constructed by the supramolecular multicomponent self-assembly of BV, metal-binding short peptides, and metal ions through the reciprocity and synergy of coordination and multiple noncovalent interactions. In vivo data reveal that the BV nanoagents selectively accumulate in tumors, locally elevate tumor temperature under mild NIR irradiation, and consequently induce efficient photothermal tumor ablation with promising biocompatibility. Furthermore, the BV nanoagents can serve as a multimodal contrast for tumor visualization through both photoacoustic and magnetic resonance imaging. BV has no biosafety concerns, and thereby offers a great potential in precision medicine by integrating multiple theranostic functions.

Purpose: Biomarkers are needed to stratify patients with stage II–III melanoma for clinical trials of adjuvant therapy because, while immunotherapy is protective, it also confers the risk of severe toxicity. We previously defined and validated a 53-immune gene melanoma immune profile (MIP) predictive both of distant metastatic recurrence and of disease-specific survival (DSS). Here, we test MIP on a third independent population. Experimental Design: A retrospective cohort of 78 patients with stage II–III primary melanoma was analyzed using the NanoString assay to measure expression of 53 target genes, and MIP score was calculated. Statistical analysis correlating MIP with DSS, overall survival, distant metastatic recurrence, and distant metastasis-free interval was performed using ROC curves, Kaplan–Meier curves, and standard univariable and multivariable Cox proportional hazards models. Results: MIP significantly distinguished patients with distant metastatic recurrence from those without distant metastatic recurrence using ROC curve analysis (AUC = 0.695; P = 0.008). We defined high- and low-risk groups based on the cutoff defined by this ROC curve and find that MIP correlates with both DSS and overall survival by ROC curve analysis (AUC = 0.719; P = 0.004 and AUC = 0.698; P = 0.004, respectively). Univariable Cox regression reveals that a high-risk MIP score correlates with DSS (P = 0.015; HR = 3.2). Conclusions: MIP identifies patients with low risk of death from melanoma and may constitute a clinical tool to stratify patients with stage II–III melanoma for enrollment in clinical trials.

Although the contact calls of birds have been studied for their acoustic properties, limited research has investigated their repetitive nature. The rate of contact calls could be related to movement, with recruiting birds signalling their location, or it could help maintaining spacing between group mates, or give information about the environment where both signaller and receiver are located. If maintaining spacing, higher call rates would be expected in denser vegetation; alternatively, if birds gain information about predation risk from the cessation of contact calling, then open areas might elicit higher call rate. We studied how contact call rate in groups of Swinhoe’s White-eyes (Zosterops simplex) was influenced by vegetation, collecting a total of 800 recordings. After statistically controlling for group size, the vegetation effect was weak and inconsistent. However, flying individuals produced a distinct flight call consisting of repeated notes similar to contact calls, and group-level contact call rate increased before flights, particularly when birds flew into the group. Therefore, we believe that contact call rate indicates information about individual or group movements, and could function as a continuous signal about the need for recruitment. We encourage further studies investigating how habitat, risk and audience influence contact call rate.

Objective— Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress. Approach and Results— In angiotensin II–induced ApoE − /− mouse and CaCl 2 -induced C57BL/6J mouse model of AAA, IMD 1− 53 significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff–van Gieson staining showed that IMD 1− 53 significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl 2 . Mechanistically, IMD 1− 53 attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD 1− 53 inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II–treated mouse aortas and was markedly decreased by IMD 1− 53 . In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II–induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD 17− 47 and protein kinase A inhibitor H89 inhibited the effect of IMD 1–53 , reducing Nox4 protein levels. Conclusions— IMD 1− 53 could have a protective effect on AAA by inhibiting oxidative stress.