Genetically Encoded Lizard Color Divergence for Camouflage and Thermoregulation.

Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration.

Proteome Landscapes of Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

Liver cancer is among the top leading causes of cancer mortality worldwide. Particularly, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) have been extensively investigated from the aspect of tumor biology. However, a comprehensive and systematic understanding of the molecular characteristics of HCC and CCA remains absent. Here, we characterized the proteome landscapes of HCC and CCA using the data-independent acquisition (DIA) mass spectrometry (MS) method. By comparing the quantitative proteomes of HCC and CCA, we found several differences between the two cancer types. In particular, we found an abnormal lipid metabolism in HCC and activated extracellular matrix-related pathways in CCA. We next developed a three-protein classifier to distinguish CCA from HCC, achieving an area under the curve (AUC) of 0.92, and an accuracy of 90% in an independent validation cohort of 51 patients. The distinct molecular characteristics of HCC and CCA presented in this study provide new insights into the tumor biology of these two major important primary liver cancers. Our findings may help develop more efficient diagnostic approaches and new targeted drug treatments.

Distinct responses and range shifts of lizard populations across an elevational gradient under climate change.

Ongoing climate change has profoundly affected global biodiversity, but its impacts on populations across elevations remain understudied. Using mechanistic niche models incorporating species traits, we predicted ecophysiological responses (activity times, oxygen consumption and evaporative water loss) for lizard populations at high-elevation (<3600 m asl) and extra-high-elevation (≥3600 m asl) under recent (1970-2000) and future (2081-2100) climates. Compared with their high-elevation counterparts, lizards from extra-high-elevation are predicted to experience a greater increase in activity time and oxygen consumption. By integrating these ecophysiological responses into hybrid species distribution models (HSDMs), we were able to make the following predictions under two warming scenarios (SSP1-2.6, SSP5-8.5). By 2081-2100, we predict that lizards at both high- and extra-high-elevation will shift upslope; lizards at extra-high-elevation will gain more and lose less habitat than will their high-elevation congeners. We therefore advocate the conservation of high-elevation species in the context of climate change, especially for those populations living close to their lower elevational range limits. In addition, by comparing the results from HSDMs and traditional species distribution models, we highlight the importance of considering intraspecific variation and local adaptation in physiological traits along elevational gradients when forecasting species' future distributions under climate change.

Simultaneous Quantification of Ampicillin and Kanamycin in Water Samples Based on Lateral Flow Aptasensor Strip with an Internal Line.

In this work, a simple and rapid method based on the lateral flow assay (LFA) has been developed for the detection of dual antibiotics. To achieve the quantitative assay and to reduce the non-specific adsorption, an internal system has been developed. A non-specific DNA was exploited as an internal standard and could be recognized by the DNA marker that was coated at the internal line. Two different kinds of aptamers were applied to recognize ampicillin (AMP) and kanamycin (KAM), and the distance between the detection line and conjugate pad was then optimized. Under the optimum conditions, the quantitative assays of AMP (R2 = 0.984) and KAM (R2 = 0.990) were achieved with dynamic ranges of 0.50 to 500.0 ng/L, and of 0.50 to 1000.0 ng/L, respectively. The LOQs of AMP and KAM were 0.06 ng/L and 0.015 ng/L, respectively. Finally, the proposed method has been successfully applied to analyze aquaculture water, tap water, and lake water, and hospital wastewater, indicating the established method could be used to monitor the environment.

Quantitative proteomics reveals differential biological processes in healthy neonatal cord neutrophils and adult neutrophils.

Neonatal neutrophils are characterized by the immaturity of bactericidal mechanisms that contributes largely to neonatal mortality. However, underlying molecular mechanism associated with the immaturity remains incompletely understood. In this study, we performed comparative proteomic analysis on neonatal neutrophils derived from human cord blood and adult peripheral neutrophils. A total of 1332 proteins were identified and quantified, and 127 proteins were characterized as differentially expressed between adult and cord neutrophils. The differentially expressed proteins are mapped in KEGG pathways into five clusters and indicated impaired functions of neonatal neutrophils in proteasome, lysosome, phagosome, and leukocyte transendothelial migration. In particular, many proteins associated with NETosis, a critical mechanism for antimicrobial process and auto-clearance, were also found to be downregulated in cord neutrophils. This study represents a first comparative proteome profiling of neonatal and adult neutrophils, and provides a global view of differentially expressed proteome for enhancing our understanding of their various functional difference.

Prognostic value and association of the age-adjusted Charlson Comorbidity Index with sarcopenia within patients with gastric cancer after radical resection.

PURPOSE: The association between the age-adjusted Charlson Comorbidity Index (ACCI) and sarcopenia in patients with gastric cancer (GC) remains ambiguous. This study aimed to investigate the association between the ACCI and sarcopenia and the prognostic value in patients with GC after radical resection. In addition, this study aimed to develop a novel prognostic scoring system based on these factors. METHODS: Univariate and multivariate Cox regression analyses were used to determine prognostic factors in patients undergoing radical GC resection. Based on the ACCI and sarcopenia, a new prognostic score (age-adjusted Charlson Comorbidity Index and Sarcopenia [ACCIS]) was established, and its prognostic value was assessed. RESULTS: This study included 1068 patients with GC. Multivariate analysis revealed that the ACCI and sarcopenia were independent risk factors during the prognosis of GC (P = 0.001 and P < 0.001, respectively). A higher ACCI score independently predicted sarcopenia (P = 0.014). A high ACCIS score was associated with a greater American Society of Anesthesiologists score, higher pathologic TNM (pTNM) stage, and larger tumor size (all P < 0.05). Multivariate analysis demonstrated that the ACCIS independently predicted the prognosis for patients with GC (P < 0.001). By incorporating the ACCIS score into a prognostic model with sex, pTNM stage, tumor size, and tumor differentiation, we constructed a nomogram to predict the prognosis accurately (concordance index of 0.741). CONCLUSION: The ACCI score and sarcopenia are significantly correlated in patients with GC. The integration of the ACCI score and sarcopenia markedly enhances the accuracy of prognostic predictions in patients with GC.

Analysis of resting status reveals distinct elevational variation in metabolisms of lizards.

Animals spend a considerable proportion of their life span at rest. However, resting status has often been overlooked when investigating how species respond to environmental conditions. This may induce a large bias in understanding the local adaptation of species across environmental gradients and their vulnerability to potential environmental change. Here, we conducted an empirical study on montane agamid lizards, combined with mechanistic modeling, to compare elevational variations in body temperature and metabolisms (cumulative digestion and maintenance cost) between resting and active status. Our study on three populations of an agamid lizard along an elevational gradient revealed a trend of decreasing body temperature toward higher elevations, the main contributor of which was resting status of the lizards. Using population-specific reaction norms, we predicted greater elevational variation in hourly and cumulative digestion for resting lizards than for active lizards. Climate-change impacts, estimated as the change in cumulative digestion, also show greater elevational variation when resting status is factored into the analysis. Further, our global analysis of 98 agamid species revealed that in about half of their combined distributional range, the contribution of resting status in determining the elevational variation in cumulative digestion and maintenance cost of lizards was greater than the contribution made by a lizard's active status. Our study highlights the importance of considering resting status when investigating how species respond to environmental conditions, especially for those distributed over tropical and subtropical mountain areas.

Comparison of microRNA expression profiles in HCC-derived microvesicles and the parental cells and evaluation of their roles in HCC.

To determine whether the microRNAs (miRNAs) contained in cancer-derived microvesicles (MVs) mirror those of the parental tumor cells, we compared the miRNA expression profiles of MVs derived from their parental hepatocellular carcinoma (HCC) cells. The presence and levels of 888 miRNAs from SMMC-7721 cells and MVs were detected by Agilent miRNA microarray analysis. Four selected miRNAs were verified by real time qRT-PCR. Furthermore, the genes of the miRNAs were bioinformatically identified to explore potential roles of the miRNAs in HCC microenvironment. Our results showed that miRNAs expression profiles of MVs derived from HCC were significantly changed. Of all the miRNAs tested, 148 miRNAs were co-expressed in MVs and SMMC-7721 cells, only 121 and 15 miRNAs were detected in MVs and SMMC-7721 cells, respectively. Among the 148 co-expressing miRNAs, 48 miRNAs had the similar expression level and 6 of them were supposed to be oncogenic or suppressive miRNAs. According to the target prediction by Quantile Algorithm method, these miRNAs may regulate 3831 genes which were closely related to cell cycle, apoptosis and oncogenesis, and 78 were known tumor suppressors or oncogenes. Gene ontology (GO) analysis indicated that 3831 genes were mainly associated with nucleic acid binding, cell death, cell adhesion. MVs containing miRNAs, released into the HCC microenvironment, bear the characteristic miRNAs of the original cells and might participate in cancer progression.

Using Bayesian Neural Networks to Select Features and Compute Credible Intervals for Personalized Survival Prediction.

An Individual Survival Distribution (ISD) models a patient's personalized survival probability at all future time points. Previously, ISD models have been shown to produce accurate and personalized survival estimates (for example, time to relapse or to death) in several clinical applications. However, off-the-shelf neural-network-based ISD models are usually opaque models due to their limited support for meaningful feature selection and uncertainty estimation, which hinders their wide clinical adoption. Here, we introduce a Bayesian-neural-network-based ISD (BNN-ISD) model that produces accurate survival estimates but also quantifies the uncertainty in model's parameter estimation, which can be used to (1) rank the importance of the input features to support feature selection and (2) compute credible intervals around ISDs for clinicians to assess the model's confidence in its prediction. Our BNN-ISD model utilized sparsity-inducing priors to learn a sparse set of weights to enable feature selection. We provide empirical evidence, on 2 synthetic and 3 real-world clinical datasets, that BNN-ISD system can effectively select meaningful features and compute trustworthy credible intervals of the survival distribution for each patient. We observed that our approach accurately recovers feature importance in the synthetic datasets and selects meaningful features for the real-world clinical data as well, while also achieving state-of-the-art survival prediction performance. We also show that these credible regions can aid in clinical decision-making by providing a gauge of the uncertainty of the estimated ISD curves.

Learning accurate personalized survival models for predicting hospital discharge and mortality of COVID-19 patients.

Since it emerged in December of 2019, COVID-19 has placed a huge burden on medical care in countries throughout the world, as it led to a huge number of hospitalizations and mortalities. Many medical centers were overloaded, as their intensive care units and auxiliary protection resources proved insufficient, which made the effective allocation of medical resources an urgent matter. This study describes learned survival prediction models that could help medical professionals make effective decisions regarding patient triage and resource allocation. We created multiple data subsets from a publicly available COVID-19 epidemiological dataset to evaluate the effectiveness of various combinations of covariates-age, sex, geographic location, and chronic disease status-in learning survival models (here, "Individual Survival Distributions"; ISDs) for hospital discharge and also for death events. We then supplemented our datasets with demographic and economic information to obtain potentially more accurate survival models. Our extensive experiments compared several ISD models, using various measures. These results show that the "gradient boosting Cox machine" algorithm outperformed the competing techniques, in terms of these performance evaluation metrics, for predicting both an individual's likelihood of hospital discharge and COVID-19 mortality. Our curated datasets and code base are available at our Github repository for reproducing the results reported in this paper and for supporting future research.

Personalized breast cancer onset prediction from lifestyle and health history information.

We propose a method to predict when a woman will develop breast cancer (BCa) from her lifestyle and health history features. To address this objective, we use data from the Alberta's Tomorrow Project of 18,288 women to train Individual Survival Distribution (ISD) models to predict an individual's Breast-Cancer-Onset (BCaO) probability curve. We show that our three-step approach-(1) filling missing data with multiple imputations by chained equations, followed by (2) feature selection with the multivariate Cox method, and finally, (3) using MTLR to learn an ISD model-produced the model with the smallest L1-Hinge loss among all calibrated models with comparable C-index. We also identified 7 actionable lifestyle features that a woman can modify and illustrate how this model can predict the quantitative effects of those changes-suggesting how much each will potentially extend her BCa-free time. We anticipate this approach could be used to identify appropriate interventions for individuals with a higher likelihood of developing BCa in their lifetime.

Catalytic Asymmetric Amino Acid and Its Derivatives by Chiral Aldehyde Catalysis.

Amine acid transformation is an important chemical process in biological systems. As a well-developed and acknowledged tool, chiral aldehyde catalysis provides good catalytic activation and stereoselective control abilities in the asymmetric reaction of N-unprotected amino acid esters and amino acid esters analogs, in which the key to success is the design of the catalysts derived from chiral BINOL aldehyde, which is based on the face control of enolate intermediates. In this review, one of the co-catalytic systems that combined with a transition metal to form a multiplex catalytic system and the well-established multiplex stereocenters of chiral aldehyde catalysis have been reviewed. Finally, a novel organocatalysis is prospected.

High-resolution metabolomic biomarkers for lung cancer diagnosis and prognosis.

Lung cancer is the leading cause of human cancer mortality due to the lack of early diagnosis technology. The low-dose computed tomography scan (LDCT) is one of the main techniques to screen cancers. However, LDCT still has a risk of radiation exposure and it is not suitable for the general public. In this study, plasma metabolic profiles of lung cancer were performed using a comprehensive metabolomic method with different liquid chromatography methods coupled with a Q-Exactive high-resolution mass spectrometer. Metabolites with different polarities (amino acids, fatty acids, and acylcarnitines) can be detected and identified as differential metabolites of lung cancer in small volumes of plasma. Logistic regression models were further developed to identify cancer stages and types using those significant biomarkers. Using the Variable Importance in Projection (VIP) and the area under the curve (AUC) scores, we have successfully identified the top 5, 10, and 20 metabolites that can be used to differentiate lung cancer stages and types. The discrimination accuracy and AUC score can be as high as 0.829 and 0.869 using the five most significant metabolites. This study demonstrated that using 5 + metabolites (Palmitic acid, Heptadecanoic acid, 4-Oxoproline, Tridecanoic acid, Ornithine, and etc.) has the potential for early lung cancer screening. This finding is useful for transferring the diagnostic technology onto a point-of-care device for lung cancer diagnosis and prognosis.

Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells.

AIM: To investigate the effects of trans-cinnamaldehyde (TCA) on the human leukemia K562 cell line and the cytotoxicity of cytokine-induced killer (CIK) cells against K562 cells. METHODS: Apoptosis, Fas expression, and mitochondrial transmembrane potential in K652 cells were analyzed using flow cytometry. K562 cells were labeled with CFSE. The cytotoxic effect of expanded CIK cells on CFSE-labeled K562 cells was determined by FACS flow cytometry. RESULTS: Treatment with TCA 180 micromol/L for 9 h induced apoptosis in 8.9%+/-1.23% of K562 cells. Treatment with 120 or 180 micromol/L TCA for 24 h significantly increased the apoptotic cells to 18.63%+/-1.42 % and 38.98%+/-2.74%, respectively. TCA significantly upregulates Fas expression and decreases mitochondrial transmembrane potential in K562 cells. TCA treatment at 120 and 180 micromol/L for 9 h enhanced the percentage of lysis of K562 cells by expanded CIK cells from 34.84%+/-2.13% to 48.21%+/-2.22 % and 64.81%+/-3.22% at the E:F ratio of 25:1 and from 49.26%+/-3.22% to 57.81%+/-5.13% and 73.36%+/-5.98% at E:F ratio of 50:1. CONCLUSION: TCA exerts cytotoxic effects on human leukemia K562 cells by inducing apoptosis and synergizing the cytotoxicity of CIK cells against K562 cells. These properties of TCA are beneficial to the treatment of leukemia, even in the patients who have received hematopoietic stem cells transplantation (HSCT).

Identification of Protein Abundance Changes in Hepatocellular Carcinoma Tissues Using PCT-SWATH.

PURPOSE: To rapidly identify protein abundance changes in biopsy-level fresh-frozen hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: The pressure-cycling technology (PCT) is applied and sequential window acquisition of all theoretical mass spectra (SWATH-MS) workflow is optimized to analyze 38 biopsy-level tissue samples from 19 HCC patients. Each proteome is analyzed with 45 min LC gradient. MCM7 is validated using immunohistochemistry (IHC). RESULTS: A total of 11 787 proteotypic peptides from 2579 SwissProt proteins are quantified with high confidence. The coefficient of variation (CV) of peptide yield using PCT is 32.9%, and the R2 of peptide quantification is 0.9729. Five hundred forty-one proteins showed significant abundance change between the tumor area and its adjacent benign area. From 24 upregulated pathways and 13 suppressed ones, enhanced biomolecule synthesis and suppressed small molecular metabolism in liver tumor tissues are observed. Protein changes based on α-fetoprotein expression and hepatitis B virus infection are further analyzed. The data altogether highlight 16 promising tumor marker candidates. The upregulation of minichromosome maintenance complex component 7 (MCM7) is further observed in multiple HCC tumor tissues by IHC. CONCLUSIONS AND CLINICAL RELEVANCE: The practicality of rapid proteomic analysis of biopsy-level fresh-frozen HCC tissue samples with PCT-SWATH has been demonstrated and promising tumor marker candidates including MCM7 are identified.

CD4+CD25high regulatory cells in peripheral blood of cancer patients.

AIM: Regulatory T cells (Treg) that prevent autoimmune diseases by suppression of self-reactive T cells may also suppress the immune response against cancer. Experimental tumor models in mice revealed that Tregs are potent inhibitors of an antitumor immune response. The purpose of the study was to identify a CD4+ population of regulatory T cells expressing high levels of CD25(CD4+CD25 high) in the peripheral blood of cancer patients and provide the opportunity to determine whether cancer patients exhibit an expanded CD4+CD25high pool. METHODS: The frequency of CD4+CD25high in the peripheral blood of 62 cancer patients and 15 healthy donors was determined by flow cytometry. RESULTS: Compared with healthy donors, cancer patients have an increasing prevalence of CD4+CD25high T cells in the peripheral blood with characteristics of Tregs, i.e. they are CD45-RA(), CD69(-). Among patients, those with higher percentages of CD4+CD25high T cells had a poor prognosis than did those with lower percentages. CONCLUSION: We provide evidence of an increased pool of CD4+CD25high in the peripheral blood of cancer patients, which may be related to immunosuppression and tumor progress in cancer patients. This finding suggests that the use of immunomodulatory therapy to treat cancer patients may be an effective strategy.

[Correlation between FoxP3(+) regulatory T cells and chronic obstructive pulmonary disease].

OBJECTIVE: To investigate whether FoxP3(+) regulatory T cells (Treg) are present in the acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the correlation between Treg and COPD. METHODS: Peripheral blood samples were collected from 21 patients of AECOPD, 20 males and 1 female, aged (70 +/- 9) (52-85). Lymphocytes were isolated by three-color labeled three colors monoclonal antibodies flow cytometry to examine the quantities and percentages of CD4(+)CD25(+), CD4(+)CD25(+)FoxP3(+) (CD4(+)Treg), CD8(+)CD25(+), and CD8(+)CD25(+)FoxP3(+) (CD8(+)Treg). ELISA was used to detect the expression of transforming growth factor beta1 (TGF-beta1), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-alpha). Middle correlation coefficient r> or = 0.3 was analysed and discussed. RESULTS: The percentages of CD4(+)CD25(+), CD4(+)Treg, CD8(+)CD25(+), and CD8(+)Treg in AECOPD were (18 +/- 6)%, (19 +/- 13)%, (5 +/- 4)%, and (12 +/- 10)% respectively. Linear correlation analysis indicated that the quantity and percentage of Treg were significantly correlated with age, course of disease, smoking index, quantity of white cells, and blood pH, and there were complex causal relations between the immunity of patients and these factors. However, TGF-beta1 and IL-10 showed no correlation with Treg. CONCLUSION: CD4(+)Treg and CD8(+)Treg are expressed in the peripheral blood of AECOPD patients and contribute to the immune suppression of these patients, so they can be used as new markers of immunity of these patients.

Aqueous-Solution-Based Approach Towards Carbon-Free Sb2 S3 Films for High Efficiency Solar Cells.

Sb2 S3 is a new kind of photovoltaic material that is promising for practical application in solar cells owing to its suitable bandgap, earth-abundant elements, and excellent stability. Here, we report on an aqueous-solution-based approach for the synthesis of Sb2 S3 films from easily accessible Sb2 O3 as antimony source. In this reaction, 3-mercaptopropionic acid was applied as both solvent and sulfur precursor, aqueous ammonia was employed as a solvent. After simple annealing at a temperature as low as 270 °C, the spin-coated precursor solution can generate compact, flat, uniform, and well-crystallized Sb2 S3 film. Mechanistic study showed that the formation of Sb-complex with ammonium carboxylates leads to the successful dissolution of Sb2 O3 powder. A suitable annealing process was able to generate carbon-free Sb2 S3 films. Planar heterojunction solar cell based on the as-prepared Sb2 S3 film delivered a power conversion efficiency of 5.57 %, which is the highest efficiency of solution-processed planar heterojunction Sb2 S3 solar cells and a high value in all kinds of Sb2 S3 solar cells. This research provides a convenient approach for the fabrication of device-quality Sb2 S3 films, and highlights solution processing of carbon-free metal chalcogenide thin films as a suitable process for application in optoelectronic devices.

Expression and functional role of HERG1, K+ channels in leukemic cells and leukemic stem cells.

In order to investigate the expression and functional role of HERG1 K+ channels in leukemic cells and leukemic stem cells (LSCs), RT-PCR was used to detect the HERG1 K+ channels expression in leukemic cells and LSCs. The functional role of HERG1 K+ channels in leukemic cell proliferation was measured by MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. The results showed that herg mRNA was expressed in CD34+/CD38-, CD123+ LSCs but not in circulating CD34+ cells. Herg mRNA was also up-regulated in leukemia cell lines K562 and HL60 as well as almost all the primary leukemic cells while not in normal peripheral blood mononuclear cells (PBMNCs) and the expression of herg mRNA was not associated with the clinical and cytogenetic features of leukemia. In addition, leukemic cell proliferation was dramatically inhibited by HERG K+ channel special inhibitor E-4031. Moreover, E-4031 suppressed the cell growth by inducing a specific block at the G1/S transition phase of the cell cycle but had no effect on apoptosis in leukemic cells. The results suggested that HERG1 K+ channels could regulate leukemic cells proliferation and were necessary for leukemic cells to proceed with the cell cycle. HERG1 K+ channels may also have oncogenic potential and may be a biomarker for diagnosis of leukemia and a novel potential pharmacological target for leukemia therapy.