The unity and diversity of verbal and visuospatial creativity: Dynamic changes in hemispheric lateralisation.

The investigation of similarities and differences in the mechanisms of verbal and visuospatial creative thinking has long been a controversial topic. Prior studies found that visuospatial creativity was primarily supported by the right hemisphere, whereas verbal creativity relied on the interaction between both hemispheres. However, creative thinking also involves abundant dynamic features that may have been ignored in the previous static view. Recently, a new method has been developed that measures hemispheric laterality from a dynamic perspective, providing new insight into the exploration of creative thinking. In the present study, dynamic lateralisation index was calculated with resting-state fMRI data. We combined the dynamic lateralisation index with sparse canonical correlation analysis to examine similarities and differences in the mechanisms of verbal and visuospatial creativity. Our results showed that the laterality reversal of the default mode network, fronto-parietal network, cingulo-opercular network and visual network contributed significantly to both verbal and visuospatial creativity and consequently could be considered the common neural mechanisms shared by these creative modes. In addition, we found that verbal creativity relied more on the language network, while visuospatial creativity relied more on the somatomotor network, which can be considered a difference in their mechanism. Collectively, these findings indicated that verbal and visuospatial creativity may have similar mechanisms to support the basic creative thinking process and different mechanisms to adapt to the specific task conditions. These findings may have significant implications for our understanding of the neural mechanisms of different types of creative thinking.

Relationship between birth weight and chronic kidney disease: evidence from systematics review and two-sample Mendelian randomization analysis.

Observational studies showed an inverse association between birth weight and chronic kidney disease (CKD) in adulthood existed. However, whether such an association is causal remains fully elusive. Moreover, none of prior studies distinguished the direct fetal effect from the indirect maternal effect. Herein, we aimed to investigate the causal relationship between birth weight and CKD and to understand the relative fetal and maternal contributions. Meta-analysis (n = ~22 million) showed that low birth weight led to ~83% (95% confidence interval [CI] 37-146%) higher risk of CKD in late life. With summary statistics from large scale GWASs (n = ~300 000 for birth weight and ~481 000 for CKD), linkage disequilibrium score regression demonstrated birth weight had a negative maternal, but not fetal, genetic correlation with CKD and several other kidney-function related phenotypes. Furthermore, with multiple instruments of birth weight, Mendelian randomization showed there existed a negative fetal casual association (OR = 1.10, 95% CI 1.01-1.16) between birth weight and CKD; a negative but non-significant maternal casual association (OR = 1.09, 95% CI 0.98-1.21) was also identified. Those associations were robust against various sensitivity analyses. However, no maternal/fetal casual effects of birth weight were significant for other kidney-function related phenotypes. Overall, our study confirmed the inverse association between birth weight and CKD observed in prior studies, and further revealed the shared maternal genetic foundation between low birth weight and CKD, and the direct fetal and indirect maternal causal effects of birth weight may commonly drive this negative relationship.

MoIug4 is a novel secreted effector promoting rice blast by counteracting host OsAHL1-regulated ethylene gene transcription.

Magnaporthe oryzae secretes several effectors that modulate and hijack rice processes to colonize host cells, but the underlying mechanisms remain unclear. We report on a novel cytoplasmic effector MoIug4 that targets the rice ethylene pathway as a transcription repressor to subvert host immunity. We found that MoIug4 binds to the promoter of the host OsEIN2 gene that encodes a central signal transducer in the ethylene-signaling pathway. We also identified a MoIug4 interacting protein, OsAHL1, which acts as an AT-hook motif-containing protein binding to the A/T-rich promoter regions. Our knockout and overexpression studies showed that OsAHL1 positively regulates plant immunity in response to M. oryzae infection. OsAHL1 exhibits transcriptional regulatory activities by binding the OsEIN2 promoter region, similar to MoIug4. Intriguingly, we found that MoIug4 exhibits a higher binding affinity than OsAHL1 to the OsEIN2 promoter, suggesting differential regulatory specificities. These results revealed a counter-defense strategy by which the pathogen effector suppresses the activation of host defense genes by interfering with host transcription activator functions.

Climatic suitability projection for deciduous fruit tree cultivation in main producing regions of northern China under climate warming.

China is the largest fruit producer and consumer market in the world. Understanding the growing conditions responses to climate change is the key to predict future site suitability of main cultivation areas for certain deciduous fruit trees. In this study, we used dynamic and growing degree day models driven by downscaled daily temperatures from 22 global climate models to project the effects of climate change on growing conditions for deciduous fruit trees under two representative concentration pathway (RCP) 4.5 and RCP8.5 scenarios over 2 future time periods (represented by central years 2050s and 2085s) in northern China. The results showed a general increase of available winter chill for all sites under RCP4.5 scenario, and the most dramatic increase in chill accumulation could reach up to 36.8% in northeast regions for RCP8.5. However, the forecasted chill will decrease by 6.4% in southeast stations under RCP8.5 by 2085s. Additionally, the increase rate of growing season heat showed spatially consistency, and the most pronounced increase was found in the RCP8.5 by 2085s. For the southwest station, median heat accumulation increased by 20.8% in the 2050s and 37.1% in the 2085s under RCP8.5. Similar increasing range could be found in the northeast station; the median growing season heat increased by 19.8% and 38.8% in the 2050s and 2085s under RCP8.5, respectively. Moreover, the date of last spring frost was expected to advance and the frequency of frost occurrences was projected to decline in the study area compared to the past. Overall, the present study improves understanding regarding site-specific characteristics of climatic suitability for deciduous fruit tree cultivation in main producing regions of northern China. The results could provide growers and decision-makers with theoretical evidence to take adaptive measure to ensure fruit production in future.

The clinical characteristics of patients with acute leukemia or stem cell transplantation exhibiting immune based platelet refractoriness.

BACKGROUND: To investigate the related factors influencing immune platelet transfusion refractoriness (PTR) in acute leukemia (AL) from induction to consolidation and compare management for immune PTR, so as to improve the Platelet increment in AL. METHODS: The primary analysis included 890 patients with AL, 225 of whom were the immune PTR (25 %).They are patients in our center from induction to consolidation or transplantation in the past 10 years. Flow cytometry, karyotype characteristics and other basic information were compared between the immune PTR vs control (no-PTR) groups. We analyzed the treatment outcomes of immune PTR including matched platelets, intravenous immunoglobulin (IVIG), increasing apheresis platelet does. RESULTS: Immune PTR is more likely to occur in patients with poor prognosis in acute lymphoblastic leukemia (ALL) (P = 0.01).There is a relation between NPM1 mutation and occurrence of immune PTR (P = 0.029).The incidence of PTR at 35-59Y was higher than that at <35Y(OR = 0.68, 95 % CI = 0.48-0.96) and ≥60Y(OR = 0.49,95 % CI = 0.28-0.83), and the difference was statistically significant(P = 0.03, P = 0.01).The Platelet increment with 1 unit (u) was 47.12 %, 2 u increased to 71.14 %, and the matched 2 u (75.11 %) had the best effect. IVIG improved the Platelet increment, but there was no difference between 0.4 g/kg IVIG and 1 g/kg IVIG. Immune PTR is more likely to occur in the ages of 35-60 years. CONCLUSION: There are specific AL patient characteristics which predispose to the phenomenon of immune based PTR. Meanwhile, increasing the IVIG dose could not improve Platelet increment obviously.

The adenylate cyclase UvAc1 and phosphodiesterase UvPdeH control the intracellular cAMP level, development, and pathogenicity of the rice false smut fungus Ustilaginoidea virens.

The cyclic adenosine monophosphate (cAMP) signaling pathway plays pleiotropic roles in regulating development and pathogenicity in eukaryotes. cAMP is a second messenger that is important for the activation of downstream pathways. The intracellular cAMP level is modulated mainly by its biosynthesis, which is catalyzed by adenylate cyclases (ACs), and hydrolysis by phosphodiesterases (PDEs). Here, we identified the AC UvAc1 and the cAMP high-affinity PDE UvPdeH in the rice false smut fungus Ustilaginoidea virens; these enzymes are homologs of MoMac1 and MoPdeH in Magnaporthe oryzae (rice blast fungus). A heterogenous complementation assay revealed that UvAc1 and UvPdeH partially or completely rescued the defects in ΔMomac1 and ΔMopdeH mutant M. oryzae. UvAc1 and UvPdeH play important roles in the development and virulence of U. virens. ΔUvac1 and ΔUvpdeH mutant fungi showed defects in conidial production, morphology, and germination; reduced toxicity against germinating rice seeds; and reduced virulence on rice panicles. ΔUvac1 exhibited increased sensitivity to Calcofluor White (CFW) and sodium chloride (NaCl), and decreased sensitivity to Congo Red (CR), while ΔUvpdeH showed increased sensitivity to sodium dodecyl sulfate, CR, sorbitol, and hydrogen peroxide, and decreased sensitivity to CFW and NaCl. High-performance liquid chromatography revealed that the intracellular cAMP level was significantly increased in ΔUvpdeH and decreased in ΔUvac1. Taken together, our results demonstrate that UvAc1 and UvPdeH are conservative components of the cAMP pathway that are important for conidiogenesis, stress responses, virulence, and regulation of the intracellular cAMP level in U. virens.

Aberrant Phenotype and Function of Dendritic Cells in Adult B Lineage Acute Lymphoblastic Leukemia.

Dendritic cells (DCs) play a major role in regulating immune responses, but the aberrant phenotype and function of defective DCs in adult acute lymphoblastic leukemia (ALL) remain unclear. Here, B lineage ALL (B-ALL) patients were divided into groups according to different standards. By course of disease: newly diagnosed (ND), complete remission (CR), consolidation (CONS). By stratification: high risk (HR), standard risk (SR). By minimal residual disease (MRD): MRD positive(MRD+), MRD negative (MRD-). The proportion of plasmacytoid DC(pDC) and myeloid DC(mDC) were compared within these standards. The costimulatory molecule levels of pDC, mDC in ND and CR were measured and the function of peripheral blood monocyte-derived DC(MoDC)s were examined. We found proportions of pDC and mDC in ND were both lower compared to control group and gradually increased after CR. In HR and MRD+, the proportions were also lower compared to SR and MRD- at CR stage, respectively; but there were no difference between these comparisons when newly diagnosed. In ND, both CD80, CD86 levels in pDC, mDC were higher while the levels in activated MoDCs were lower when compared to control and CR group, respectively. The dextran uptake of MoDCs, T cell proliferation promoting ability, IL-12, BAFF, INF-α levels in supernatant and their mRNA relative expression in activated MoDCs in ND were also lower than those in control and CR group. So, DCs in B-ALL display suppressed status in phenotype and function，which would be gradually restored after effective chemotherapy. pDC and mDC could respond to patient condition, DCs proportion may be useful for monitoring disease progression.

Construction and Validation of a MRI­Based Radiomic Nomogram to Predict Overall Survival in Patients with Local Advanced Cervical Cancer: A Multicenter Study.

BACKGROUND: Cervical cancer is the fourth most common cancer among women. Radiomics has emerged as a new approach providing valuable information for cancer management. The aim of this study was to construct a radiomics nomogram to accurately predict survival outcomes in patients with locally advanced cervical cancer. METHODS: This retrospective study enrolled a total of 582 locally advanced cervical cancer patients from three center (training cohort: n = 228; internal validation cohort: n = 98; external validation cohort: n = 256). Radiomic features were extracted from pretreatment MRI images. Least absolute shrinkage and selection operator logistic regression were applied to select radiomic features and calculated the radiomic scores. Univariate and multivariate Cox proportional hazards regression analyses were used to identify the independent prognostic clinic-radiological factors for cervical cancer, which were incorporated into the nomogram. RESULTS: A total of six radiomic features were found to be associated with overall survival (OS) of locally advanced cervical cancer patients. The AUC of radiomic scores in the training cohort was 0.634-0.708 for the training cohort, 0.725-0.762 for internal validation cohort and 0.788-0.881 for the external validation cohort. Age, parametrial invasion, and radiomic score were the independent prognostic indicators for cervical cancer patients (Age: HR=1.041, 95% CI=1.012-1.071, p = 0.006; Parametrial invasion: HR=4.755, 95% CI=1.493-15.144, p = 0.008; HR=2.324, 95% CI=1.050-5.143, p = 0.037). The nomogram model incorporating these factors showed favorable discrimination in predicting the overall survival rates of cervical cancer patients, with the AUC values of 0.809, 0.808, and 0.862 for 1-, 2-, and 3-year predictions. The decision curve analysis (DCA) indicated that the nomogram model achieved the highest clinical net benefit across the entire range of reasonable threshold probabilities. CONCLUSION: The nomogram, incorporating clinicopathological factors and radiomic features derived from MRI images, showed satisfactory discrimination in predicting the OS rates of locally advanced cervical cancer patients.

Neural basis underlying the association between thought control ability and happiness: The moderating role of the amygdala.

Thought control ability (TCA) plays an important role in individuals' health and happiness. Previous studies demonstrated that TCA was closely conceptually associated with happiness. However, empirical research supporting this relationship was limited. In addition, the neural basis underlying TCA and how this neural basis influences the relationship between TCA and happiness remain unexplored. In the present study, the voxel-based morphometry (VBM) method was adopted to investigate the neuroanatomical basis of TCA in 314 healthy subjects. The behavioral results revealed a significant positive association between TCA and happiness. On the neural level, there was a significant negative correlation between TCA and the gray matter density (GMD) of the bilateral amygdala. Split-half validation analysis revealed similar results, further confirming the stability of the VBM analysis findings. Furthermore, gray matter covariance network and graph theoretical analyses showed positive association between TCA and both the node degree and node strength of the amygdala. Moderation analysis revealed that the GMD of the amygdala moderated the relationship between TCA and happiness. Specifically, the positive association between TCA and self-perceived happiness was stronger in subjects with a lower GMD of the amygdala. The present study indicated the neural basis underlying the association between TCA and happiness and offered a method of improving individual well-being.

Perinatal bisphenol S exposure exacerbates the oxidative burden and apoptosis in neonatal ovaries by suppressing the mTOR/autophagy axis.

Bisphenol S (BPS) is an emerging environmental endocrine disruptor capable of crossing the placental barrier, resulting in widespread exposure to pregnant women due to its extensive usage. However, the impact of perinatal maternal exposure to BPS on reproductive health in offspring and the underlying molecular mechanism remain underexplored. In this study, gestational ICR mice were provided with drinking water containing 3.33 mg/L BPS to mimic possible human exposure in some countries. Results demonstrated that BPS accelerated the breakdown of germ-cell cysts and the assembly of primordial follicles in neonates, leading to oocyte over-loss. Furthermore, the expression levels of folliculogenesis-related genes (Kit, Nobox, Gdf9, Sohlh2, Kitl, Bmp15, Lhx8, Figla, and Tgfb1) decreased, thus compromising oocyte quality and disrupting early folliculogenesis dynamics. BPS also disrupted other aspects of offspring reproduction, including advancing puberty onset, disrupting the estrus cycle, and impairing fertility. Further investigation found that BPS exposure inhibited the activities and expression levels of antioxidant-related enzymes in neonatal ovaries, leading to the substantial accumulation of MDA and ROS. The increased oxidative burden exacerbated the intracellular apoptotic signaling, manifested by increased expression levels of pro-apoptotic markers (Bax, Caspase 3, and Caspase 9) and decreased expression levels of anti-apoptotic marker (Bcl2). Concurrently, BPS inhibited autophagy by increasing p-mTOR/mTOR and decreasing p-ULK1/ULK1, subsequently down-regulating autophagy flux-related biomarkers (LC3b/LC3a and Beclin-1) and impeding the degradation of autophagy substrate p62. However, the imbalanced crosstalk between autophagy, apoptosis and oxidative stress homeostasis was restored after rapamycin treatment. Collectively, the findings demonstrated that BPS exposure induced reproductive disorders in offspring by perturbing the mTOR/autophagy axis, and such autophagic dysfunction exacerbated redox imbalance and promoted excessive apoptosis. These results provide novel mechanistic insights into the role of autophagy in mitigating BPS-induced intergenerational reproductive dysfunction.

Distinct roles of TREM2 in central nervous system cancers and peripheral cancers.

Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.

Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming.

Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t6A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.

Concentration-Regulated Fibrillation of Soy Protein: Structure and In Vitro Digestion.

The impact of protein types, heating temperatures, and times on protein fibrillation has been widely studied. However, there is little understanding of the influence of protein concentration (PC) on the protein fibril assembly. In this work, the structure and in vitro digestibility of soy protein amyloid fibrils (SAFs) were investigated at pH 2.0 and different PCs. Significant increases in fibril conversion rate and parallel ß-sheets proportion were observed in SAFs upon increasing the PC from 2 to 8% (w/v). The AFM images showed that curly fibrils were prone to form at 2-6% PCs, while rigid, straight fibrils developed at higher PCs (≥8%). As evidenced in XRD results, increasing PC led to a more stable structure of SAFs with enhanced thermal stability and lower digestibility. Moreover, positive correlations among PC, ß-sheet content, persistence length, enthalpy, and total hydrolysis were established. These findings would provide valuable insights into concentration-regulated protein fibrillation.

Connectome-based modeling reveals a resting-state functional network that mediates the relationship between social rejection and rumination.

Background: Rumination impedes problem solving and is one of the most important factors in the onset and maintenance of multiple psychiatric disorders. The current study aims to investigate the impact of social rejection on rumination and explore the underlying neural mechanisms involved in this process. Methods: We utilized psychological questionnaire and resting-state brain imaging data from a sample of 560 individuals. The predictive model for rumination scores was constructed using resting-state functional connectivity data through connectome-based predictive modeling. Additionally, a mediation analysis was conducted to investigate the mediating role of the prediction network in the relationship between social rejection and rumination. Results: A positive correlation between social rejection and rumination was found. We obtained the prediction model of rumination and found that the strongest contributions came from the intra- and internetwork connectivity within the default mode network (DMN), dorsal attention network (DAN), frontoparietal control network (FPCN), and sensorimotor networks (SMN). Analysis of node strength revealed the significance of the supramarginal gyrus (SMG) and angular gyrus (AG) as key nodes in the prediction model. In addition, mediation analysis showed that the strength of the prediction network mediated the relationship between social rejection and rumination. Conclusion: The findings highlight the crucial role of functional connections among the DMN, DAN, FPCN, and SMN in linking social rejection and rumination, particular in brain regions implicated in social cognition and emotion, namely the SMG and AG regions. These results enhance our understanding of the consequences of social rejection and provide insights for novel intervention strategies targeting rumination.

Strigolactones modulate stem length and diameter of cherry rootstocks through interaction with other hormone signaling pathways.

Stem growth and development has considerable effects on plant architecture and yield performance. Strigolactones (SLs) modulate shoot branching and root architecture in plants. However, the molecular mechanisms underlying SLs regulate cherry rootstocks stem growth and development remain unclear. Our studies showed that the synthetic SL analog rac-GR24 and the biosynthetic inhibitor TIS108 affected stem length and diameter, aboveground weight, and chlorophyll content. The stem length of cherry rootstocks following TIS108 treatment reached a maximum value of 6.97 cm, which was much higher than that following rac-GR24 treatments at 30 days after treatment. Stem paraffin section showed that SLs affected cell size. A total of 1936, 743, and 1656 differentially expressed genes (DEGs) were observed in stems treated with 10 µM rac-GR24, 0.1 µM rac-GR24, and 10 µM TIS108, respectively. RNA-seq results highlighted several DEGs, including CKX, LOG, YUCCA, AUX, and EXP, which play vital roles in stem growth and development. UPLC-3Q-MS analysis revealed that SL analogs and inhibitors affected the levels of several hormones in the stems. The endogenous GA3 content of stems increased significantly with 0.1 µM rac-GR24 or 10 µM TIS108 treatment, which is consistent with changes in the stem length following the same treatments. This study demonstrated that SLs affected stem growth of cherry rootstocks by changing other endogenous hormone levels. These results provide a solid theoretical basis for using SLs to modulate plant height and achieve sweet cherry dwarfing and high-density cultivation.

Upstream open reading frame-encoded MP31 disrupts the mitochondrial quality control process and inhibits tumorigenesis in glioblastoma.

BACKGROUND: Mitochondrial hyperpolarization achieved by the elevation of mitochondrial quality control (MQC) activity is a hallmark of glioblastoma (GBM). Therefore, targeting the MQC process to disrupt mitochondrial homeostasis should be a promising approach for GBM therapy. METHODS: We used 2-photon fluorescence microscopy, Fluorescence-Activated Cell Sorting, and confocal microscopy with specific fluorescent dyes to detect the mitochondrial membrane potential (MMP) and mitochondrial structures. Mitophagic flux was measured with mKeima. RESULTS: MP31, a phosphatase and tensin homolog (PTEN) uORF-translated and mitochondria-localized micropeptide, disrupted the MQC process and inhibited GBM tumorigenesis. Re-expression of MP31 in patient-derived GBM cells induced MMP loss to trigger mitochondrial fission but blocked mitophagic flux, leading to the accumulation of damaged mitochondria in cells, followed by reactive oxygen species production and DNA damage. Mechanistically, MP31 inhibited lysosome function and blocked lysosome fusion with mitophagosomes by competing with V-ATPase A1 for lactate dehydrogenase B (LDHB) binding to induce lysosomal alkalinization. Furthermore, MP31 enhanced the sensitivity of GBM cells to TMZ by suppressing protective mitophay in vitro and in vivo, but showed no side effects on normal human astrocytes or microglia cells (MG). CONCLUSIONS: MP31 disrupts cancerous mitochondrial homeostasis and sensitizes GBM cells to current chemotherapy, without inducing toxicity in normal human astrocytes and MG. MP31 is a promising candidate for GBM treatment.

Circular RNA encoded MET variant promotes glioblastoma tumorigenesis.

Activated by its single ligand, hepatocyte growth factor (HGF), the receptor tyrosine kinase MET is pivotal in promoting glioblastoma (GBM) stem cell self-renewal, invasiveness and tumorigenicity. Nevertheless, HGF/MET-targeted therapy has shown limited clinical benefits in GBM patients, suggesting hidden mechanisms of MET signalling in GBM. Here, we show that circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) facilitated by the N6-methyladenosine (m6A) reader YTHDF2. Genetic ablation of circMET inhibits MET404 expression in mice and attenuates MET signalling. Conversely, MET404 knock-in (KI) plus P53 knock-out (KO) in mouse astrocytes initiates GBM tumorigenesis and shortens the overall survival. MET404 directly interacts with the MET ß subunit and forms a constitutively activated MET receptor whose activity does not require HGF stimulation. High MET404 expression predicts poor prognosis in GBM patients, indicating its clinical relevance. Targeting MET404 through a neutralizing antibody or genetic ablation reduces GBM tumorigenicity in vitro and in vivo, and combinatorial benefits are obtained with the addition of a traditional MET inhibitor. Overall, we identify a MET variant that promotes GBM tumorigenicity, offering a potential therapeutic strategy for GBM patients, especially those with MET hyperactivation.

Instrumental Heterogeneity in Sex-Specific Two-Sample Mendelian Randomization: Empirical Results From the Relationship Between Anthropometric Traits and Breast/Prostate Cancer.

BACKGROUND: In two-sample Mendelian randomization (MR) studies, sex instrumental heterogeneity is an important problem needed to address carefully, which however is often overlooked and may lead to misleading causal inference. METHODS: We first employed cross-trait linkage disequilibrium score regression (LDSC), Pearson's correlation analysis, and the Cochran's Q test to examine sex genetic similarity and heterogeneity in instrumental variables (IVs) of exposures. Simulation was further performed to explore the influence of sex instrumental heterogeneity on causal effect estimation in sex-specific two-sample MR analyses. Furthermore, we chose breast/prostate cancer as outcome and four anthropometric traits as exposures as an illustrative example to illustrate the importance of taking sex heterogeneity of instruments into account in MR studies. RESULTS: The simulation definitively demonstrated that sex-combined IVs can lead to biased causal effect estimates in sex-specific two-sample MR studies. In our real applications, both LDSC and Pearson's correlation analyses showed high genetic correlation between sex-combined and sex-specific IVs of the four anthropometric traits, while nearly all the correlation coefficients were larger than zero but less than one. The Cochran's Q test also displayed sex heterogeneity for some instruments. When applying sex-specific instruments, significant discrepancies in the magnitude of estimated causal effects were detected for body mass index (BMI) on breast cancer (P = 1.63E-6), for hip circumference (HIP) on breast cancer (P = 1.25E-20), and for waist circumference (WC) on prostate cancer (P = 0.007) compared with those generated with sex-combined instruments. CONCLUSION: Our study reveals that the sex instrumental heterogeneity has non-ignorable impact on sex-specific two-sample MR studies and the causal effects of anthropometric traits on breast/prostate cancer would be biased if sex-combined IVs are incorrectly employed.

Transcriptional signatures of human peripheral blood mononuclear cells can identify the risk of tuberculosis progression from latent infection among individuals with silicosis.

CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02430259).

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis.

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.