Observation and quantification of the pseudogap in unitary Fermi gases.

The microscopic origin of high-temperature superconductivity in cuprates remains unknown. It is widely believed that substantial progress could be achieved by better understanding of the pseudogap phase, a normal non-superconducting state of cuprates1,2. In particular, a central issue is whether the pseudogap could originate from strong pairing fluctuations3. Unitary Fermi gases4,5, in which the pseudogap-if it exists-necessarily arises from many-body pairing, offer ideal quantum simulators to address this question. Here we report the observation of a pair-fluctuation-driven pseudogap in homogeneous unitary Fermi gases of lithium-6 atoms, by precisely measuring the fermion spectral function through momentum-resolved microwave spectroscopy and without spurious effects from final-state interactions. The temperature dependence of the pairing gap, inverse pair lifetime and single-particle scattering rate are quantitatively determined by analysing the spectra. We find a large pseudogap above the superfluid transition temperature. The inverse pair lifetime exhibits a thermally activated exponential behaviour, uncovering the microscopic virtual pair breaking and recombination mechanism. The obtained large, temperature-independent single-particle scattering rate is comparable with that set by the Planckian limit6. Our findings quantitatively characterize the pseudogap in strongly interacting Fermi gases and they lend support for the role of preformed pairing as a precursor to superfluidity.

A p21-ATD mouse model for monitoring and eliminating senescent cells and its application in liver regeneration post injury.

Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair.

Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

Comparative proteomic analysis of vancomycin-sensitive and vancomycin-intermediate resistant Staphylococcus aureus.

PURPOSE: The extensive use of vancomycin has led to the development of Staphylococcus aureus strains with varying degrees of resistance to vancomycin. The present study aimed to explore the molecular causes of vancomycin resistance by conducting a proteomics analysis of subcellular fractions isolated from vancomycin-intermediate resistant S. aureus (VISA) and vancomycin-sensitive S. aureus (VSSA) strains. METHODS: We conducted proteomics analysis of subcellular fractions isolated from 2 isogenic S. aureus strains: strain 11 (VSSA) and strain 11Y (VISA). We used an integrated quantitative proteomics approach assisted by bioinformatics analysis, and comprehensively investigated the proteome profile. Intensive bioinformatics analysis, including protein annotation, functional classification, functional enrichment, and functional enrichment-based cluster analysis, was used to annotate quantifiable targets. RESULTS: We identified 128 upregulated proteins and 21 downregulated proteins in strain 11Y as compared to strain 11. The largest group of differentially expressed proteins was composed of enzymatic proteins associated with metabolic and catalytic activity, which accounted for 32.1% and 50% of the total proteins, respectively. Some proteins were indispensable parts of the regulatory networks of S. aureus that were altered with vancomycin treatment, and these proteins were related to cell wall metabolism, cell adhesion, proteolysis, and pressure response. CONCLUSION: Our proteomics study revealed regulatory proteins associated with vancomycin resistance in S. aureus. Some of these proteins were involved in the regulation of cell metabolism and function, which provides potential targets for the development of strategies to manage vancomycin resistance in S. aureus.

Vortex-assisted hydrophobic natural deep eutectic solvent liquid-liquid microextraction for the removal of silver ions from environmental water.

This study presents a novel approach for the quantification of silver ions in environmental water through the utilization of liquid-liquid microextraction, employing natural deep eutectic solvents in conjunction with inductively coupled plasma emission spectroscopy. The extracted solvent was characterized by Fourier transform infrared spectroscopy (FT-IR). The impact of various extractant types, extractant molar ratio, extractant volume, extraction time, and salt concentration on the efficacy of silver ion extraction was investigated. The findings indicate that the optimal extraction efficiency was attained by utilizing a 5-mL aqueous solution volume, containing 1000 µL thymol/lactic acid NADES 1:3, a salt concentration of 1 mg mL-1, a pH value of 4, and a vortex time of 4 min. Upon implementing the optimized experimental conditions, the recovery of target metal ions was from 96.9 to 101.0%. The relative standard deviations were observed to be within the range of 1.5 to 2.7%. The present study demonstrates the reproducibility, accuracy, and reliability of the method for detecting silver ions in environmental water, with linear range of 5~1000 ng mL-1 and limits of detection (LOD) and limits of quantification (LOQ) of 1.52 ng mL-1 and 5.02 ng mL-1, respectively.

Long-Term Outcomes in Older Patients with Sepsis in the ICU: A Retrospective Study.

Objective: The primary objectives of this study were to compare the characteristics of older and younger patients with sepsis and to analyze risk factors associated with 28-day and 90-day mortality in critically ill patients. Our study aimed to explore whether there are significant differences between sepsis patients in different age groups and whether these differences are related to the association between disease severity and mortality. Methods: We conducted a single-center, retrospective study of 5783 critically ill patients over 18 years of age from the Medical Information Mart for Intensive Care III database diagnosed with sepsis and admitted to the intensive care unit between 2008 and 2012. We performed a retrospective analysis, selected the Critical Care Medicine Information Mart III database, and collected data on patients with sepsis. We then collated and analyzed these data to compare differences in characteristics between older and younger patients and identify associated risk factors, which can help understand patient mortality. This approach leverages existing clinical data and avoids new experiments or data collection. Kaplan-Meier survival curve was used to assess 28-day and 90-day mortality, and a Cox proportional hazards regression model was used to evaluate the associated risk factors with 28-day and 90-day mortality. Results: Our study identified significant differences in mortality between older and younger patients with sepsis, finding that older patients had significantly higher mortality than younger patients. Furthermore, we successfully identified risk factors associated with mortality, results that have important implications for optimizing patient care and making clinical decisions. Of 5783 patients with sepsis, 2044 (35.3%) were younger than 60 years, and 3739 (64.7%) were aged 60 years or older. The 28-day mortality rate was 11.8% and 21.2% in the younger and older cohorts, respectively (P < .01). In the age-stratified analysis, the 28-day mortality was the highest in patients aged over 80 years (14.6% vs. 21.2% vs. 26.8%, P < .001). Factors associated with 28-day and 90-day mortality in patients with sepsis included age, weight, the need for mechanical ventilation, congestive heart failure, chronic pulmonary disease, malignancy, and Sequential Organ Failure Assessment score. Higher mortality in older patients with sepsis suggests the need for more aggressive treatment and monitoring. We also identified risk factors associated with mortality, helping to develop individualized treatment strategies. In addition, the different clinical characteristics of patients in different age groups emphasize the need for refined care pathways to meet their special needs. These results will help improve the treatment effect and quality of life of patients with sepsis. Conclusions: Our study fills the knowledge gap on the manifestations of sepsis patients in different age groups and helps medical staff better predict and manage disease progression in these two groups and provide personalized treatment. This lays the foundation for future in-depth research on age-related sepsis factors and is expected to improve patient survival and recovery rates. Older patients with sepsis had higher mortality rates and adverse outcomes. The mortality rate in patients with sepsis gradually increased with age. The importance of these findings is that they can help guide patient care and clinical decision-making, particularly when dealing with older and younger patients with sepsis, to improve treatment outcomes and reduce mortality. We would like to acknowledge that there are several limitations to the study, including the selectivity of the database and the retrospective nature, which preclude inference of causal relationships. In addition, some unconsidered variables may affect the results, and missing information in the data may also have an impact on the study. Future research could further explore these issues.This study highlights the critical role of age in sepsis patient outcomes and provides a strong basis for more sophisticated care and treatment. Our findings will help save more lives and improve patients' chances of recovery, which has profound implications for future research and clinical practice in the field of sepsis.

Higher Risks of Copper Toxicity in Turbid Waters: Quantifying the Bioavailability of Particle-Bound Metals to Set Site-Specific Water Quality Criteria.

In coastal waters, particulate metals constitute a substantial fraction of the total metals; however, the prevalent water quality criteria are primarily based on dissolved metals, seemingly neglecting the contribution of particulate metals. Here we developed a method to quantify the toxicity risk of particulate metals, and proposed a way to calculate modifying factors (MFs) for setting site-specific criteria in turbid waters. Specifically, we used a side-by-side experimental design to study copper (Cu) bioaccumulation and toxicity in an estuarine clam, Potamocorbula laevis, under the exposure to "dissolved only" and "dissolved + particulate" 65Cu. A toxicokinetic-toxicodynamic model (TK-TD) was used to quantify the processes of Cu uptake, ingestion, assimilation, egestion, and elimination, and to relate mortality risk to tissue Cu. We find that particulate Cu contributes 40-67% of the Cu bioaccumulation when the suspended particulate matter (SPM) ranges from 12 to 229 mg L-1. The Cu-bearing SPM also increases the sensitivity of organisms to internalized Cu by decreasing the internal threshold concentration (CIT) from 141 to 76.8 µg g-1. MFs were derived based on the TK-TD model to consider the contribution of particulate Cu (in the studied SPM range) for increasing Cu bioaccumulation (MF = 1.3-2.2) and toxicity (MF = 2.3-3.9). Water quality criteria derived from dissolved metal exposure need to be lowered by dividing by an MF to provide adequate protection. Overall, the method we developed provides a scientifically sound framework to manage the risks of metals in turbid waters.

The potential value of serum GP73 in the ancillary diagnosis and grading of liver cirrhosis.

This study is to evaluate the potential value of serum GP73 in ancillary cirrhosis diagnosis. 150 cirrhotic subjects and healthy subjects were retrospectively analyzed, and the two groups were compared in terms of Child‒Pugh grade. Serum GP73 was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curves were drawn to evaluate the diagnostic value of GP73, and the quantitative relationship between cirrhosis and GP73 was verified by logistic regression. The result showed in regard to serum biomarkers related to cirrhosis, the serum levels of GP73, TBIL, DBIL, and PT were higher and the ALB and PLT were lower in the cirrhosis group than in the control group (p = 0.000), and the area under the ROC curve of GP73 for diagnosing cirrhosis was 0.823 (p = 0.000), the cutoff value was 135 ng/ml, the sensitivity was 60.0%, and the specificity was 88.67%. Logistic regression analysis showed that GP73 > 135 ng/ml had an odds ratio of 11.735 (ß= 2.463, 95% CI: 6.432-21.411, p = 0.000) for diagnosing cirrhosis. Additionally, the Child‒Pugh A, B, and C groups had different levels of GP73 (χ2 =17.840, p = 0.000). A pairwise comparison between the groups showed that there was a significant difference between grades A and B (p = 0.004) and between grades A and C (p = 0.002), but there was no significant difference between grades B and C (p = 1.000). We found serum GP73 levels were elevated in patients with cirrhosis. When the GP73 level was >135 ng/ml, the potential risk of a cirrhosis diagnosis increased approximately 12-fold.

Integrating US-guided FNAB, BRAFV600E mutation, and clinicopathologic characteristics to predict cervical central lymph-node metastasis in preoperative patients with cN0 papillary thyroid carcinoma.

BACKGROUND: The prevalence of cervical central lymph-node metastasis (CLNM) is high in patients with papillary thyroid carcinoma (PTC). There is considerable controversy surrounding the benefits of prophylactic central lymph-node dissection (pCLND) in patients with clinically negative central compartment lymph nodes (cN0). Therefore, it is crucial to accurately predict the likelihood of cervical CLNM before surgery to make informed surgical decisions. METHODS: Date from 214 PTC patients (cN0) who underwent partial or total thyroidectomy and pCLND at the Guizhou Provincial People's Hospital were collected and retrospectively analyzed. They were divided into two groups in accordance with cervical CLNM or not. Their information, including clinical characteristics, ultrasound (US) features, pathological results of fine-needle aspirations biopsy (FNAB), and other characteristics of the groups, was analyzed and compared using univariate and multivariate logistic regression analyses. RESULTS: A total of 214 patients were eligible in this study. Among them, 43.5% (93/214) of PTC patients had cervical CLNM, and 56.5% (121/214) did not. The two groups were compared using a univariate analyses, and there were no significant differences between the two groups in aspect ratio, boundary, morphology, component, and BRAFV600E (P > 0.05), and there were significant differences between gender, age, maximum tumor size, tumor location, capsule contact, microcalcifications, color Doppler flow imaging (CDFI), and Hashimoto's thyroiditis (HT) (P < 0.05). A multivariate logistic regression analysis was performed to further clarify the correlation of these indices. However, only age (OR = 2.455, P = 0.009), maximum tumor size (OR = 2.586, P = 0.010), capsule contact (OR = 3.208, P = 0.001), and CDFI (OR = 2.225, P = 0.022) were independent predictors of cervical CLNM. Combining these four factors, the area under the receiver-operating characteristic (ROC) curve for the joint diagnosis is 0.8160 (95% 0.7596-0.8725). Univariate analysis indicated that capsule contact (P = 0.001) was a possible predictive factor of BRAFV600E mutation. CONCLUSIONS: In conclusion, four independent predictors of cervical CLNM, including age < 45 years, tumor size > 1.0 cm, capsule contact, and rich blood flow, were screened out. Therefore, a comprehensive assessment of these risk factors should be conducted when designing individualized treatment regimens for PTC patients.

House dust mite allergy in Malaysia: review of research gaps in the current scenario and the way forward.

The prevalence of house dust mite (HDM) allergy, especially in Asian countries with rapid urbanization, has been increasing. House dust mites thrive in places with relatively high humidity. With the combination of climate change, naturally high humidity, and urbanization, tropical countries like Malaysia are becoming a hotspot for HDM allergy fast. With a previously reported sensitization rate of between 60 and 80%, it is a worrying trend for Malaysia. However, due to incomplete and out-of-date data, as seen by the limited study coverage in the past, these numbers do not paint a complete picture of the true HDM allergy scene in Malaysia. This review briefly discusses the HDM fauna, the HDM sensitization rate, the common diagnosis and therapeutic tools for HDM allergy in Malaysia, and makes suggestions for possible improvements in the future. This review also highlights the need of more comprehensive population-based prevalence studies to be done in Malaysia, encompassing the three main HDMs-Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Blomia tropicalis-as the lack of up-to-date studies failed to give a clearer picture on the current scenario of HDM allergy in Malaysia. Future studies will be beneficial to the nation in preparing a better blueprint for the management and treatment of HDM allergy.

Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Cross-Coupling Reaction for the Stereoselective Synthesis of Multisubstituted Olefins.

The aryl-to-vinyl nickel 1,4-migration (1,4-Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4-Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.

Functional Divergence of Multiple Duplicated Foxl2 Homeologs and Alleles in a Recurrent Polyploid Fish.

Evolutionary fates of duplicated genes have been widely investigated in many polyploid plants and animals, but research is scarce in recurrent polyploids. In this study, we focused on foxl2, a central player in ovary, and elaborated the functional divergence in gibel carp (Carassius gibelio), a recurrent auto-allo-hexaploid fish. First, we identified three divergent foxl2 homeologs (Cgfoxl2a-B, Cgfoxl2b-A, and Cgfoxl2b-B), each of them possessing three highly conserved alleles and revealed their biased retention/loss. Then, their abundant sexual dimorphism and biased expression were uncovered in hypothalamic-pituitary-gonadal axis. Significantly, granulosa cells and three subpopulations of thecal cells were distinguished by cellular localization of CgFoxl2a and CgFoxl2b, and the functional roles and the involved process were traced in folliculogenesis. Finally, we successfully edited multiple foxl2 homeologs and/or alleles by using CRISPR/Cas9. Cgfoxl2a-B deficiency led to ovary development arrest or complete sex reversal, whereas complete disruption of Cgfoxl2b-A and Cgfoxl2b-B resulted in the depletion of germ cells. Taken together, the detailed cellular localization and functional differences indicate that Cgfoxl2a and Cgfoxl2b have subfunctionalized and cooperated to regulate folliculogenesis and gonad differentiation, and Cgfoxl2b has evolved a new function in oogenesis. Therefore, the current study provides a typical case of homeolog/allele diversification, retention/loss, biased expression, and sub-/neofunctionalization in the evolution of duplicated genes driven by polyploidy and subsequent diploidization from the recurrent polyploid fish.

Explaining the GeV Antiproton Excess, GeV γ-Ray Excess, and W-Boson Mass Anomaly in an Inert Two Higgs Doublet Model.

For the newly discovered W-boson mass anomaly, one of the simplest dark matter (DM) models that can account for the anomaly without violating other astrophysical and experimental constraints is the inert two Higgs doublet model, in which the DM mass (m_{S}) is found to be within ∼54-74 GeV. In this model, the annihilation of DM via SS→bb[over ¯] and SS→WW^{*} would produce antiprotons and gamma rays, and may account for the excesses identified previously in both particles. Motivated by this, we reanalyze the AMS-02 antiproton and Fermi-LAT Galactic center γ-ray data. For the antiproton analysis, the novel treatment is the inclusion of the charge-sign-dependent three-dimensional solar modulation model as constrained by the time-dependent proton data. We find that the excess of antiprotons is more distinct than previous results based on the force-field solar modulation model. The interpretation of this excess as the annihilation of SS→WW^{*} (SS→bb[over ¯]) requires a DM mass of ∼40-80 (40-60) GeV and a velocity-averaged cross section of O(10^{-26}) cm^{3} s^{-1}. As for the γ-ray data analysis, besides adopting the widely used spatial template fitting, we employ an orthogonal approach with a data-driven spectral template analysis. The fitting to the GeV γ-ray excess yields DM model parameters overlapped with those to fit the antiproton excess via the WW^{*} channel. The consistency of the DM particle properties required to account for the W-boson mass anomaly, the GeV antiproton excess, and the GeV γ-ray excess suggests a common origin of them.

Effect evaluation of kangaroo mother care in Liping area, Guizhou province,China.

BACKGROUD: Kangaroo mother care (KMC) refers to the mother and baby after the birth of the early start of continuous skin contact way of a newborn care, which is a simple operation, easy controlled and with low cost, no large or high consumption of equipment.So it is very suitable for developing in areas where medical resources are relatively scarce, such as GuiZhou province where is a relatively poor province in China with many ethnic minorities. METHODS: This study selected the pregnant women who gave birth in Liping County, Guizhou Province, China, as the research object, to explore the impact of kangaroo mother care on the physiologic status of newborns in liping county, Guizhou Province. RESULTS: A total of 347 hospitalized parturient women were divided into the KMC group and the control group. The results showed that the KMC group showed obvious advantages in stabilizing newborn vital signs, health indicators, promoting the success rate of breastfeeding and reducing newborn pain. CONCLUSIONS: Research shows that kangaroo mother care is beneficial to postpartum maternal and infant health, and has advantages suitable for local characteristics, which is worth further promotion in minority areas of Guizhou Province.

Tetrandrine-induced downregulation of lncRNA NEAT1 inhibits rheumatoid arthritis progression through the STAT3/miR-17-5p pathway.

BACKGROUND: The inhibitory effect of Tetrandrine (Tet) on rheumatoid arthritis (RA) is well established. However, its exact molecular mechanism remains unknown. METHODS: RT-qPCR coupled with western blotting was employed to analyze the expression of NEAT1, miR-17-5p, and STAT3 in RA tissues and/or RA-fibroblast-like synoviocytes (RA-FLS) treated with 3 µmol/L of Tet for 48 h. Cell Counting Kit-8 assay and flow cytometry were performed to assess RA-FLS proliferation and apoptosis. Luciferase reporter assays were used to validate the interactions between miR-17-5p and STAT3 or NEAT1. RESULTS: The expression of NEAT1 decreased in a time-dependent manner upon Tet treatment. Tet significantly inhibited RA-FLS proliferation and triggered apoptosis by downregulating NEAT1 expression. Additionally, NEAT1 directly targeted miR-17-5p to upregulate STAT3 expression. Tet-induced low NEAT1 expression impaired RA-FLS growth by targeting miR-17-5p and inhibiting STAT3. CONCLUSION: Tet exerts its inhibitory role in RA progression by regulating the NEAT1/miR-17-5p/STAT3 pathway.

Genome-Wide Characterization of High-Affinity Nitrate Transporter 2 (NRT2) Gene Family in Brassica napus.

Nitrate transporter 2 (NRT2) plays an essential role in Nitrogen (N) uptake, transport, utilization, and stress resistance. In this study, the NRT2 gene family in two sequenced Brassica napus ecotypes were identified, including 31 genes in 'Zhongshuang11' (BnaZSNRT2s) and 19 in 'Darmor-bzh' (BnaDarNRT2s). The candidate genes were divided into three groups (Group I-III) based on phylogenetic analyses, supported by a conserved intron-exon structure in each group. Collinearity analysis revealed that the large expansion of BnaZSNRT2s attributed to allopolyploidization of ancestors Brassica rapa and Brassica oleracea, and small-scale duplication events in B. napus. Transcription factor (TF) binding site prediction, cis-element analysis, and microRNA prediction suggested that the expressions of BnaZSNRT2s are regulated by multiple factors, and the regulatory pattern is relatively conserved in each group and is tightly connected between groups. Expression assay showed the diverse and differentiated spatial-temporal expression profiles of BnaZSNRT2s in Group I, but conserved patterns were observed in Group II/III; and the low nitrogen (LN) stress up-regulated expression profiles were presented in Group I-III, based on RNA-seq data. RT-qPCR analyses confirmed that BnaZSNRT2.5A-1 and BnaZSNRT2.5C-1 in Group II were highly up-regulated under LN stress in B. napus roots. Our results offer valid information and candidates for further functional BnaZSNRT2s studies.

Cancer-associated fibroblasts impact the clinical outcome and treatment response in colorectal cancer via immune system modulation: a comprehensive genome-wide analysis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment are associated with poor prognosis and chemoresistance in multiple solid tumours. However, there is a lack of universal measures of CAFs in colorectal cancer (CRC). The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism. METHODS: The GSE39582 dataset, which includes 316 CRC patients who did not receive adjuvant chemotherapy was used as a discovery cohort to identify the prognostic fibroblast-related genes (FRGs). A total of 1352 CRC patients were divided into one training cohort (GSE39582, n = 461) and two validation cohorts (TCGA, n = 338; meta-validation, n = 553) for the construction of the FRGS and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to explore the underlying mechanism. The ability of the FRGS to predict immunotherapy response was further tested in a clear cell renal cell carcinoma (ccRCC) cohort. RESULTS: An 11-gene signature that had prognostic value for stage II/III CRC patients in both validation cohorts was developed (TCGA cohort: HR = 1.90, 95% CI 1.16-3.12, P < 0.01; meta-validation cohort: HR = 1.95, 95% CI 1.39-2.73, P < 0.001). A high level of CAFs was correlated with worse prognosis in CRC patients who did not receive adjuvant chemotherapy (HR = 3.63, 95% CI 2.24-5.88, P < 0.001). Importantly, patients in the low-risk group were found to be benefit from chemotherapy (P < 0.01), but not in the high CAF group (P > 0.05). Similar results were found in the TCGA cohort. Integrated with clinical characteristics, the FRGS was confirmed to be an independent prognostic factor in the multivariate analysis after adjustment for tumour TNM stage (GSE39582 cohort: HR = 3.19, 95% CI 1.88-5.41, P < 0.001; TCGA cohort: HR = 5.00, 95% CI 1.58-15.85, P = 0.007; meta-validation cohort: HR = 2.99, 95% CI 1.44-6.21, P = 0.003). Furthermore, the enrichment analysis found that the antitumour immune response was suppressed and the infiltration of CD4 T cells and M1 macrophages was depressed in the high CAF group. The FRGS was also found to have value in predicting for immunotherapy response in the ccRCC cohort. CONCLUSIONS: The 11-gene FRGS had independent prognostic value for CRC patients, as well as utility in the prediction of benefit from chemotherapy. CAFs in the tumour microenvironment might have an impact on the prognosis of CRC patients via inhibiting immune response.

Protein-protein interaction analysis reveals a novel cancer stem cell related target TMEM17 in colorectal cancer.

BACKGROUND: Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS: Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS: By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/ß-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION: Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).

Cactus-Inspired Janus Membrane with a Conical Array of Wettability Gradient for Efficient Fog Collection.

Fog collection plays an important role in alleviating the global water shortage. Despite great progress in creating bionic surfaces to collect fog, water droplets still could adhere to the microscale hydrophilic region and reach the thermodynamic stable state before falling, which delays the transport of water and hinders the continuous fog collection. Inspired by lotus leaves and cactuses, we designed a Janus membrane that functions to both collect fog from the air and transport it to a certain region. The Janus membrane with opposite wettability contains conical microcolumns with a wettability gradient and hydrophilic copper mesh surface. The apexes of conical microcolumns are superhydrophobic and the rest are hydrophobic. The fog droplets were deposited, coalesced, and directionally transported to the bottom of the conical microcolumns. Then, the droplets unidirectionally passed through the membrane and flowed into the water film on the surface of the copper mesh. The asymmetric structural and wettability merits endow the Janus membrane with an improved fog collection of ∼7.05 g/cm2/h. The study is valuable for designing and developing fluid control equipment in fog collection, liquid manipulation, and microfluidics.

Genome-wide investigation and comparative analysis of MATE gene family in Rosaceae species and their regulatory role in abiotic stress responses in Chinese pear (Pyrus bretschneideri).

The Multidrug and Toxic Compound Extrusion (MATE) protein belongs to a secondary transporter gene family, which plays a primary role in transporting many kinds of substrates such as organic compounds, secondary metabolites, and phytohormones. MATE protein members exist in both prokaryotes and eukaryotes. However, evolution and comprehensive analysis of the MATE genes has not been performed in Rosaceae species. In the present study, a total of 404 MATEs genes were identified from six Rosaceae genomes (Prunus avium, Pyrus bretschneideri, Prunus persica, Fragaria vesca, Prunus mume, and Malus domestica) and classified into eight main subfamilies (I-VII) based on structural and phylogenetic analysis. Microcollinearity analysis showed that whole-genome duplication events might play a vital role in the expansion of the MATE genes family. The Ka/Ks analysis, chromosomal localization, subcellular localization, and molecular characteristics (length, weight, and pI) were performed using various bioinformatics tools. Furthermore, different subfamilies have different introns-exons structures, cis-acting elements, and conserved motifs analysis, indicating functional divergence in the MATE family. Subsequently, RNA-seq analysis and real-time qRT-PCR were conducted during Chinese pear fruit development. Moreover, PbMATE genes were significantly expressed under hormonal treatments of MeJA (methyl jasmonate), SA (salicylic acid), and ABA (abscisic acid). Overall, our results provide helpful insights into the functions, expansion complexity, and evolutions of the MATE genes in Chinese pear and five Rosaceae species.