Effects of rainfall patterns in dry and rainy seasons on the biomass, ecostoichiometric characteristics, and NSC content of Fraxinus malacophylla seedlings.

With global climate change and rising temperatures, rainfall will change. The impact of global rainfall changes on ecosystems has prompted people to delve deeper into how changes in rainfall affect plant growth; Plant biomass, nutrient element content, and non-structural carbohydrate content are very sensitive to changes in precipitation. Therefore, understanding the impact of rainfall changes on seedlings is crucial. However, it is currently unclear how the seedlings of Fraxinus malacophylla Hemsl in rocky desertification areas respond to changes in rainfall. In this study, the response of biomass, nutrient accumulation, and NSC content of Fraxinus malacophylla Hemsl seedlings to different rainfall intervals and rainfall during the dry and rainy seasons was studied. Use natural rainfall duration of 5 days (T) and extended rainfall duration of 10 days(T+) as rainfall intervals; average monthly rainfall was used as the control (W), with a corresponding 40% increase in rainfall (W+) and a 40% decrease in rainfall (W-) as rainfall treatments. The research results indicate that the biomass of roots, stems, and leaves, as well as the accumulation of C, N, and P in Fraxinus malacophylla Hemsl seedlings increase with the increase of rainfall, while the soluble sugar and starch content show a pattern of first increasing and then decreasing. The biomass and nutrient accumulation of each organ showed root>leaf>stem. Except for the beginning of the dry season, prolonging the duration of rainfall in other periods inhibits the biomass accumulation of Fraxinus malacophylla Hemsl seedlings, and promotes the accumulation of C, N, and P nutrients and an increase in soluble sugar and starch content. There was a significant positive correlation (P<0.05) between the nutrient contents of C, N, and P in various organs, as well as between soluble sugar and starch content; And N: P>16, plant growth is limited by P element. These results indicate that changes in rainfall can affect the growth and development of Fraxinus malacophylla Hemsl seedlings, increasing rainfall can promote biomass and nutrient accumulation of Fraxinus malacophylla Hemsl seedlings, and prolonging rainfall intervals and reducing rainfall have inhibitory effects on them. The exploration of the adaptation of Fraxinus malacophylla Hemsl seedlings to rainfall patterns has promoted a basic understanding of the impact of rainfall changes on the growth of Fraxinus malacophylla Hemsl. This provides a theoretical basis for understanding how Fraxinus malacophylla Hemsl can grow better under rainfall changes and for future management of Fraxinus malacophylla Hemsl artificial forests in rocky desertification areas.

Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

Experience of financial toxicity and coping strategies in young and middle-aged patients with stroke: a qualitative study.

BACKGROUND: While financial toxicity (FT) is prevalent in patients with cancer, young and middle-aged patients with stroke are also affected by FT, which can exacerbate their physical and psychological challenges. Understanding the patient's experience and response measures can further understand the impact of FT on patients with stroke, to help alleviate FT. However, little is known concerning the experience of patients with stroke with FT or their coping strategies. Therefore, this study aimed to describe the experiences of FT in young and middle-aged patients with stroke and their coping strategies. METHODS: A phenomenological method was utilized. Semi-structured interviews were conducted with 21 young and middle-aged stroke patients (aged 18-59) between October 2022 and March 2023. The participants were recruited from a tertiary hospital in Shanghai, China. The research team used NVivo 12.0 software. Giorgi's phenomenological analysis method was used to analyse the interview data. RESULTS: The interview results were divided into two categories in terms of patients' experiences of FT and their coping strategies. Nine subthemes were constructed. The experience category included four subthemes: (1) taking on multifaceted economic pressure, (2) dual choice of treatment, (3) decline in material living standards, and (4) suffering from negative emotions such as anxiety and depression. The coping strategy category included five subthemes: (1) reducing expenses, (2) improving living habits, (3) proactive participation in medical decision-making, (4) making a job position choice, and (5) seeking social support. CONCLUSIONS: FT in young and middle-aged patients with stroke, which affected their physical and mental health, led them to implement strategies for dealing with FT. The Chinese government needs to broaden the reach of health insurance coverage and advance the fairness of healthcare policies. Healthcare professionals must pay active attention to FT in such patients in terms of strengthening their health education and considering their needs and preferences. Patients need to improve their sense of self-efficacy, actively reintegrate into society, and adhere to rehabilitation and treatment. Individuals at a high risk of stroke are recommended to purchase health insurance. Multifaceted efforts are needed to reduce the impact of FT in young and middle-aged patients with stroke.

Single-cell mapping reveals several immune subsets associated with liver metastasis of pancreatic ductal adenocarcinoma.

BACKGROUND: Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive. METHODS: Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry. FINDINGS: High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103+PD-1+CD39+ T cells with cytotoxic and exhausted functional status and an increased proportion of CD73+ macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC. CONCLUSIONS: Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy. FUNDING: This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.

Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression.

Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.

Effects of exogenous calcium on growth, chlorophyll fluorescence characteristics and antioxidant system of Fraxinus malacophylla seedlings.

Karst ecosystems are becoming increasingly problematic, and high calcium is one of the main characteristics of soils in rocky desertification areas. Chlorophyll fluorescence is one of the most important indicators of the extent to which plants are affected by their environment. There are few reports on the effects of changes in exogenous calcium levels on the chlorophyll fluorescence properties of Fraxinus malacophylla seedlings. In the present study, we investigated the growth, chlorophyll fluorescence properties and antioxidant system of Fraxinus malacophylla seedlings in response to exogenous calcium (as the concentrations of 0, 25, 50, 75 mmol L-1). The results showed that Ca2+ concentration (25-50 mmol L-1) treatment mainly promoted the growth, biomass accumulation, root activity, and chlorophyll synthesis and effect on chlorophyll fluorescence in Fraxinus malacophylla; the developed root system became a strong linking hub for calcium adaptation. In addition, the activities of the antioxidant enzymes peroxidase (POD) and catalase (CAT) are upregulated and play an important role in preventing excessive oxidative damage. OJIP test parameters changed significantly with the addition of exogenous calcium, and parameters related to each photosystem II (PSII) reaction centre, such as ABS/RC and DIo/RC, increased significantly in the OJIP test, with enhanced function of the PSII electron donor lateral oxygen evolution complex. In conclusion, the addition of exogenous calcium (25-50 mmol L-1) had an important protective effect on the photosynthetic mechanism of Fraxinus malacophylla, promoting photosynthesis, better growth and better adaptability.

Vermicomposting of Pleurotus eryngii spent mushroom substrates and the possible mechanisms of vermicompost suppressing nematode disease caused by Meloidogyne incognita.

The mushroom industry produces a large amount of spent mushroom substrate (SMS), which requires a large geographical footprint and causes pollution. Vermicomposting is a low-cost technology for its value in recycling of organic wastes and production of beneficial organic fertilizers. In this study, the changes of physicochemical properties was characterized during vermicomposting of Pleurotus eryngii SMS with cow dung (CD) as amendment. The efficiency and possible mechanisms of vermicompost suppressing disease induced by Meloidogyne incognita was also investigated. Six combinations with different ratios of SMS and cow dung (CD) was included in the vermicomposting using Eisenia fetida. Effect of vermicompost against disease induced by M. incognita on tobacco was conducted under greenhouse condition. And the possible mechanisms of vermicompost suppressing M. incognita was investigated by evaluated the species diversity of nematode-trapping fungi (NTF) in soil, and the defense response enzymes in tobacco. The combination of 65% SMS +35% CD was more suitable for vermicomposting, in which the highest vermicompost production (57%) and earthworm biomass increment (268%) were achieved. Additionally, the reduction in pH, total organic carbon, carbon: nitrogen ratio, and the pronounced elevation in four overall nutrient status were also observed. Soil amended with vermicompost (100:1 w/w) showed 61% control efficiency against nematode disease caused by M. incognita on tobacco, which significantly higher than that of the normal compost (24%). Comparing to the normal compost, the potential mechanism of vermicompost suppressing M. incognita could be rely on promoting species diversity of NTF in soil and enhancing the activities of the defense response enzymes in tobacco plant. Our findings indicate that vermicomposting is a promising technology for recycling of P. eryngii SMS, and the resulting vermicompost as organic fertilizer can be sued for management of the diseases caused by root-knot nematodes. This study establish a sustainable avenue for P. eryngii SMS disposal and a practical manner for controlling pathogens.

Characteristics of the cancer stem cell niche and therapeutic strategies.

Distinct regions harboring cancer stem cells (CSCs) have been identified within the microenvironment of various tumors, and as in the case of their healthy counterparts, these anatomical regions are termed "niche." Thus far, a large volume of studies have shown that CSC niches take part in the maintenance, regulation of renewal, differentiation and plasticity of CSCs. In this review, we summarize and discuss the latest findings regarding CSC niche morphology, physical terrain, main signaling pathways and interactions within them. The cellular and molecular components of CSCs also involve genetic and epigenetic modulations that mediate and support their maintenance, ultimately leading to cancer progression. It suggests that the crosstalk between CSCs and their niche plays an important role regarding therapy resistance and recurrence. In addition, we updated diverse therapeutic strategies in different cancers in basic research and clinical trials in this review. Understanding the complex heterogeneity of CSC niches is a necessary pre-requisite for designing superior therapeutic strategies to target CSC-specific factors and/or components of the CSC niche.

The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models. METHODS: We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC. RESULTS: The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8+ T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+ T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8+ T cells and exerted a significant synergistic effect on HCC. CONCLUSION: These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC.

Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma.

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.

Driver mutations of intrahepatic cholangiocarcinoma shape clinically relevant genomic clusters with distinct molecular features and therapeutic vulnerabilities.

Purpose: To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC). Methods: The genomic data of 1481 ICCs from diverse populations was analyzed to investigate the pair-wise co-occurrences or mutual exclusivities among recurrent driver mutations. Clinicopathological features and outcomes were compared among different clusters. Gene expression and DNA methylation profiling datasets were analyzed to investigate the molecular distinctions among mutational clusters. ICC cell lines with different gene mutation backgrounds were used to evaluate the cluster specific biological behaviors and drug sensitivities. Results: Statistically significant mutation-pairs were identified across 21 combinations of genes. Seven most recurrent driver mutations (TP53, KRAS, SMAD4, IDH1/2, FGFR2-fus and BAP1) showed pair-wise co-occurrences or mutual exclusivities and could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction of KRAS, TP53 and SMAD4 mutations, exhibited large bile duct histological phenotype with high CA19-9 level and dismal prognosis; Cluster2: co-association of IDH/BAP1 or FGFR2-fus/BAP1 mutation, was characterized by small bile duct phenotype, low CA19-9 level and optimal prognosis; Cluster3: mutation-free ICC cases with intermediate clinicopathological features. These clusters showed distinct molecular traits, biological behaviors and responses to therapeutic drugs. Finally, we identified S100P and KRT17 as "cluster-specific", "lineage-dictating" and "prognosis-related" biomarkers, which in combination with CA19-9 could well stratify Cluster3 ICCs into two biologically and clinically distinct subtypes. Conclusions: This clinically applicable clustering system can be instructive to ICC prognostic stratification, molecular classification, and therapeutic optimization.

Association of Alcohol Use and Physical Activity with Body Mass Index in Mexican-Origin Adults.

BACKGROUND: Studies across racial/ethnic groups indicate that physical activity (PA) and alcohol consumption are positively associated, and that alcohol consumption is negatively associated with body mass index (BMI), but this relationship is less often evaluated in Hispanics. The purpose of this study was to assess the relationships between alcohol consumption, PA, and BMI in Hispanic adults. METHODS: In this secondary data analysis of a Mexican-American cohort, we collected self-reported PA, alcohol consumption, and demographics, and measured height and weight. Linear regression assessed the association between PA and alcohol consumption with BMI, controlling for covariates. Total sample for analyses was n = 3897. RESULTS: We found an inverse relationship between high PA and BMI in the full sample (adjusted estimate = - 0.03, 95% CI - 0.07, - 0.01) and in females, but not males. We also found an inverse relationship between current alcohol use and BMI in the full sample (adjusted estimate = - 0.05, 95% CI - 0.09, - 0.01) and both sexes. There was no significant interaction between PA and alcohol use on BMI. CONCLUSIONS: In this study of Mexican-origin adults, current alcohol use and high PA were associated with lower BMIs, but there was no interaction between PA and alcohol use. These results can be used to inform multiple behavior change interventions in Mexican-origin adults.

Morphological and Phylogenetic Evidence for Recognition of Two New Species of Phanerochaete from East Asia.

Two new corticioid fungal species, Phanerochaete pruinosa and P. rhizomorpha spp. nov. are proposed based on a combination of morphological features and molecular evidence. Phanerochaete pruinosa is characterized by the resupinate basidiomata with the pruinose hymenial surface, a monomitic hyphal system with simple-septate generative hyphae and subcylindrical basidiospores measuring as 3.5-6.7 × 1.5-2.7 µm. Phanerochaete rhizomorpha is characterized by having a smooth hymenophore covered by orange hymenial surface, the presence of rhizomorphs, subulate cystidia, and narrower ellipsoid to ellipsoid basidiospores. Sequences of ITS+nLSU nrRNA gene regions of the studied specimens were generated and phylogenetic analyses were performed with maximum likelihood, maximum parsimony, and Bayesian inference methods. These phylogenetic analyses showed that two new species clustered into genus Phanerochaete, in which P. pruinosa was sister to P. yunnanensis with high supports (100% BS, 100% BT, 1.00 BPP); morphologically differing by a pale orange to greyish orange and densely cracked hymenial surface. Another species P. rhizomorpha was closely grouped with P. citrinosanguinea with lower supports; morphologically having yellow to reddish yellow hymenial surface, and smaller cystidia measuring as 31-48 × 2.3-4.8 µm.

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives.

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

The complete chloroplast genome of Solanum betacea (Solanaceae, Solaneae).

Solanum betacea is a sub-tropical tree, and the fruit has high nutritional value, unique flavor and color. It is used as a functional ingredient in health care, food, cosmetic and pharmaceutical applications. The complete chloroplast(Cp) genome of S. betacea has been assembled and annotated in this paper. Its length was 155,937 bp, containing a large single-copy region of 86,731 bp, a small single-copy region of 18,450 bp, and a pair of IR regions of 25,378 bp in each. The complete chloroplast genome of S. betacea contained 134 genes, including 90 protein-coding genes, 36 transfer RNA genes (tRNAs), and 8 ribosome RNA genes (rRNAs). The overall GC content was 37.7% and the GC contents of the LSC, SSC, and IR regions were 35.7%, 31.8%, and 43.1%, respectively. Phylogenetic analysis with the reported chloroplast genomes revealed that S. betacea has been most closely related to Solanum torvum. These findings will provide useful information for further investigation of chloroplast genome evolution in Solanum betacea.

CD4+CD25+ Regulatory T Cells in Intracranial Thrombi Are Inversely Correlated with Hemorrhagic Transformation after Thrombectomy: A Clinical-Immunohistochemical Analysis of Acute Ischemic Stroke.

Mechanical thrombectomy is not only effective for managing patients with acute ischemic stroke (AIS), but it also enables a valuable histological analysis of thrombi. Previous studies indicated that regulatory T cells (Treg) adoptive transfer might alleviate the hemorrhagic transformation. However, whether Treg in intracranial thrombi correlates with hemorrhagic transformation after mechanical thrombectomy remains unclear. This study mainly analyzed the colocation of Treg markers in serial thrombus sections stained serially for CD4 and CD25 in groups of hemorrhagic or nonhemorrhagic transformation. Second, to investigate whether these immunohistochemical parameters could provide any additional information beyond hemorrhagic transformation, we compared the overlap between Treg markers among other groups, such as functional outcomes, stroke subtypes, and gender. Our results showed that the number of CD4+CD25+ Treg cells was lower in the hemorrhagic transformation thrombi than in the nonhemorrhagic group (p < 0.001) but there were no significant differences otherwise. The present finding of CD4+CD25+ Treg cell reductions in thrombi associated with hemorrhagic transformation provides the histological evidence supporting that thromboinflammation might involve in the pathological process of an acute stroke after mechanical thrombectomy.

Nomogram to Predict Cognitive Dysfunction After a Minor Ischemic Stroke in Hospitalized-Population.

An easily scoring system to predict the risk of cognitive impairment after minor ischemic stroke has not been available. We aimed to develop and externally validate a nomogram for predicting the probability of post-stroke cognitive impairment (PSCI) among hospitalized population with minor stroke. Moreover, the association of Trimethylamine N-oxide (TMAO) with PSCI is also investigated. We prospectively conducted a developed cohort on collected data in stroke center from June 2017 to February 2018, as well as an external validation cohort between June 2018 and February 2019. The main outcome is cognitive impairment defined as <22 Montreal Cognition Assessment (MoCA) score points 6 - 12 months following a minor stroke onset. Based on multivariate logistic models, the nomogram model was generated. Plasma TMAO levels were assessed at admission using liquid chromatography tandem mass spectrometry. A total of 228 participants completed the follow-up data for generating the nomogram. After multivariate logistic regression, seven variables remained independent predictors of PSCI to compose the nomogram included age, female, Fazekas score, educational level, number of intracranial atherosclerotic stenosis (ICAS), HbA1c, and cortical infarction. The area under the receiver-operating characteristic (AUC-ROC) curve of model was 0.829, C index was good (0.810), and the AUC-ROC of the model applied in validation cohort was 0.812. Plasma TMAO levels were higher in patients with cognitive impairment than in them without cognitive dysfunction (median 4.56 vs. 3.22 µmol/L; p ≤ 0.001). In conclusion, this scoring system is the first nomogram developed and validated in a stroke center cohort for individualized prediction of cognitive impairment after minor stroke. Higher plasma TMAO level at admission suggests a potential marker of PSCI.

Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer.

Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.

The complete chloroplast genome of Crateva unilocularis (Capparaceae).

Crateva unilocularis is naturally distributed in Southern China, which is an elite natural tree with high edible and medicinal value. In this study, whole chloroplast (cp) genome of Crateva unilocularis was assembled and characterized on the basis of Illumina pair-end sequencing data. The complete cp genome was 156,417 bp in length, containing a large single-copy region (LSC) of 85,607 bp and a small single-copy region (SSC) of 18,164 bp, which were separated by a pair of 26,323 bp inverted repeat regions (IRs). The genome contained 128 genes, including 85 protein-coding genes, 35 tRNA genes, and 8 rRNA genes. The overall GC content is 36.32%, while the corresponding values of the LSC, SSC, and IR regions were 33.98, 29.45, and 42.48%, respectively. The maximum-likelihood phylogenetic analysis showed a strong sister relationship with Crateva tapia. These findings provide a foundation for further investigation of cp genome evolution in Crateva unilocularis and other higher plants.

IFN-α facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) and how they are activated play critical roles in tumor progression and metastasis, and in hepatocellular carcinoma (HCC), they are associated with sorafenib resistance. Reprogramming of TAMs into M1-like macrophages has been proposed as an approach to stimulate tumor regression. Here we studied the collective effects of interferon-alpha (IFN-α) and sorafenib on HCC. We found that IFN-α delayed tumor growth and inhibited pulmonary metastasis in an orthotopic HCC implantation model. Via in vitro studies, we found that IFN-α treatment could reprogram M2-like RAW264.7 and THP-1 macrophage cells toward M1-like cells. In addition, we also found that IFN-α combined with a low dose of sorafenib has a synergistic inhibitory effect on HCC tumor growth and pulmonary metastasis without obvious toxicity in an in vivo mice model. Moreover, IFN-α increased sorafenib's therapeutic efficacy by shifting TAM polarization to an M1-like phenotype, increasing and activating intratumoral CD8+ T cells in HCCs. In conclusion, a combination of IFN-α and sorafenib have synergistic inhibitory effects on HCC growth and metastasis resulting from a shift in TAM polarization rather than their depletion. Our study supports the future clinical use of a combination of IFN-α and sorafenib for the treatment of advanced HCC.