Consistent with recent reports indicating that neurons differentiated in vitro from human-induced pluripotent stem cells (hiPSCs) are immature relative to those in the human brain, gene expression ...comparisons of our hiPSC-derived neurons to the Allen BrainSpan Atlas indicate that they most resemble fetal brain tissue. This finding suggests that, rather than modeling the late features of schizophrenia (SZ), hiPSC-based models may be better suited for the study of disease predisposition. We now report that a significant fraction of the gene signature of SZ hiPSC-derived neurons is conserved in SZ hiPSC neural progenitor cells (NPCs). We used two independent discovery-based approaches-microarray gene expression and stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomic mass spectrometry analyses-to identify cellular phenotypes in SZ hiPSC NPCs from four SZ patients. From our findings that SZ hiPSC NPCs show abnormal gene expression and protein levels related to cytoskeletal remodeling and oxidative stress, we predicted, and subsequently observed, aberrant migration and increased oxidative stress in SZ hiPSC NPCs. These reproducible NPC phenotypes were identified through scalable assays that can be applied to expanded cohorts of SZ patients, making them a potentially valuable tool with which to study the developmental mechanisms contributing to SZ.
MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian ...cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n=176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3'-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals.
•Although UHP-FRC panels have thicker insulation layers with higher R-value compared with the conventional panels, they do not necessarily result in building energy reduction; the energy savings of ...using UHP-FRC panels depend on the building type and climate condition.•Energy savings of using UHP-FRC panels rather than conventional panels are higher in colder climates (e.g., Fairbanks) than those in temperate climates (e.g., San Francisco).•Buildings that are dominated by internal loads seem to benefit the least from UHP-FRC.
Majority of building energy consumption is used to heat and cool enclosed spaces. An innovative ultra-high-performance fiber-reinforced concrete (UHP-FRC) façade system could potentially reduce this energy consumption by utilizing UHP-FRC's high structural strength and ductility hence more space for insulation. The energy performance assessment of innovative façade systems such as UHP-FRC panels could be misleading if the effect of building types and climate contexts on building energy consumption is not considered. Moreover, thermal bridging and hygrothermal analyses of UHP-FRC panels are needed to investigate the heat and moisture transfer within the panels in details. The objective of this paper is to investigate the combined effect of different building types and climate conditions on these panels’ energy performance and analyze the heat and moisture behavior within the panels in a detailed assembly scale. Numerical heat and moisture transfer simulations were conducted to evaluate the amount of risk of thermal bridging and risk of mold growth within innovative UHP-FRC façade systems. A probabilistic simulation-based building energy performance analysis was conducted to investigate the combined effect of different building types and climate conditions on the energy performance of UHP-FRC panel systems. The analysis was conducted for fourteen U.S. Department of Energy prototype buildings in fifteen climate zones (210 scenarios). The results of thermal bridging analysis showed that the UHP-FRC panel assembly provides unique thermal properties with higher thermal resistance compared with the conventional panel assembly. The UHP-FRC panel assembly minimizes the thermal bridging by eliminating the structural rebars. However, the energy savings of using UHP-FRC panels depend on the building type and climate condition. On average, energy savings are higher in colder climates (e.g., Fairbanks) than those in temperate climates (e.g., San Francisco). Also, buildings dominated by internal loads seem to benefit the least from UHP-FRC. The hygrothermal analysis also showed that the UHP-FRC panel assembly's performance is superior than the conventional panel in terms of moisture transfer and the risk of mold growth.
Heathcare Workers (HCWs) recognize their responsibility to support the bereaved loved ones of our patients, but we also must attend to our own professional and personal grief in the COVID-19 ...pandemic. COVID-19 grief is occurring in the setting of incomplete grief, disenfranchised grief, fractured US governmental leadership, and evidence of great mistrust, systemic racism, and social injustice. In the intensity and pervasiveness of COVID-19, HCW fears for themselves, their colleagues, and their own loved ones are often in conflict with professional commitments. Even at the dawn of promising national and global vaccination programs, significant HCW morbidity and mortality in COVID-19 has already become clear, will continue to grow, and these effects likely will last far into the future. Given the risks of complicated grief for HCWs in the setting of COVID-19 deaths, individual HCWs must put every effort into their own preparation for these deaths as well as into their own healthy grieving. Equally importantly, our healthcare systems have a primary responsibility both to prepare HCWs and to support them in their anticipatory and realized grief. Special attention must be paid to our HCW trainees, who may have not yet developed personal or professional grief management strategies and are coming into healthcare practice during a time of great disruption to both teaching and clinical care.
Interest in wisdom in the cognitive sciences, psychology, and education has been paralleled by conceptual confusions about its nature and assessment. To clarify these issues and promote consensus in ...the field, wisdom researchers met in Toronto in July of 2019, resolving disputes through discussion. Guided by a survey of scientists who study wisdom-related constructs, we established a common wisdom model, observing that empirical approaches to wisdom converge on the morally-grounded application of metacognition to reasoning and problem-solving. After outlining the function of relevant metacognitive and moral processes, we critically evaluate existing empirical approaches to measurement and offer recommendations for best practices. In the subsequent sections, we use the common wisdom model to selectively review evidence about the role of individual differences for development and manifestation of wisdom, approaches to wisdom development and training, as well as cultural, subcultural, and social-contextual differences. We conclude by discussing wisdom's conceptual overlap with a host of other constructs and outline unresolved conceptual and methodological challenges.
Understanding individual susceptibility to drug-induced cardiotoxicity is key to improving patient safety and preventing drug attrition. Human induced pluripotent stem cells (hiPSCs) enable the study ...of pharmacological and toxicological responses in patient-specific cardiomyocytes (CMs) and may serve as preclinical platforms for precision medicine. Transcriptome profiling in hiPSC-CMs from seven individuals lacking known cardiovascular disease-associated mutations and in three isogenic human heart tissue and hiPSC-CM pairs showed greater inter-patient variation than intra-patient variation, verifying that reprogramming and differentiation preserve patient-specific gene expression, particularly in metabolic and stress-response genes. Transcriptome-based toxicology analysis predicted and risk-stratified patient-specific susceptibility to cardiotoxicity, and functional assays in hiPSC-CMs using tacrolimus and rosiglitazone, drugs targeting pathways predicted to produce cardiotoxicity, validated inter-patient differential responses. CRISPR/Cas9-mediated pathway correction prevented drug-induced cardiotoxicity. Our data suggest that hiPSC-CMs can be used in vitro to predict and validate patient-specific drug safety and efficacy, potentially enabling future clinical approaches to precision medicine.
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•Reprogramming and cardiac differentiation preserve patient-specific gene expression•Metabolic and stress genes account for inter-patient transcriptome variation•Bioinformatics analysis predicts patient-specific drug-induced cardiotoxicity•Drug-induced cardiotoxicity can be functionally evaluated in vitro using hiPSC-CMs
hiPSC-CM transcriptome profiling showed greater inter-patient than intra-patient variation. Toxicology analysis predicted and functionally validated individualized drug responsiveness, suggesting that hiPSC-CMs could serve as preclinical readout platforms for precision medicine.
Reliable reference selection for the accurate quantification of gene expression under various experimental conditions is a crucial step in qRT-PCR normalization. To date, only a few housekeeping ...genes have been identified and used as reference genes in tea plant. The validity of those reference genes are not clear since their expression stabilities have not been rigorously examined. To identify more appropriate reference genes for qRT-PCR studies on tea plant, we examined the expression stability of 11 candidate reference genes from three different sources: the orthologs of Arabidopsis traditional reference genes and stably expressed genes identified from whole-genome GeneChip studies, together with three housekeeping gene commonly used in tea plant research. We evaluated the transcript levels of these genes in 94 experimental samples. The expression stabilities of these 11 genes were ranked using four different computation programs including geNorm, Normfinder, BestKeeper, and the comparative ∆CT method. Results showed that the three commonly used housekeeping genes of CsTUBULIN1, CsACINT1 and Cs18S rRNA1 together with CsUBQ1 were the most unstable genes in all sample ranking order. However, CsPTB1, CsEF1, CsSAND1, CsCLATHRIN1 and CsUBC1 were the top five appropriate reference genes for qRT-PCR analysis in complex experimental conditions.
Key message
Wheat cultivar Madsen has a new gene on the short arm of chromosome 1A and two QTL for all-stage resistance and three QTL for high-temperature adult-plant resistance that in combination ...confer high-level, durable resistance to stripe rust.
Wheat cultivar Madsen has maintained a high-level resistance to stripe rust over 30 years. To map quantitative trait loci (QTL) underlying the high-level, durable resistance, 156 recombinant inbred lines (RILs) developed from cross Avocet S × Madsen were phenotyped with selected races of
Puccinia striiformis
f. sp.
tritici
in the greenhouse seedling tests, and in naturally infected fields during 2015–2017. The RILs were genotyped by SSR and SNP markers from genotyping by sequencing and the 90 K wheat SNP chip. Three QTL for all-stage resistance were mapped on chromosomes 1AS, 1BS and 2AS, and two QTL for high-temperature adult-plant (HTAP) resistance were mapped on 3BS and 6BS. The most effective QTL on 2AS, explaining 8.97–23.10% of the phenotypic variation in seedling tests and 8.60–71.23% in field tests, contained
Yr17
for all-stage resistance and an additional gene for HTAP resistance. The 6BS QTL, detected in all field tests, was identified as
Yr78
. The 1AS QTL, conferring all-stage resistance, was identified as a new gene, which explained 20.45 and 30.23% of variation in resistance to races PSTv-37 and PSTv-40, respectively, and contributed significantly to field resistance at Pullman in 2015-2017, but was not detected at Mount Vernon. The interactions among QTL were mostly additive, and RILs with all five QTL had the highest level of resistance in the field, similar to Madsen. Genotyping 148 US Pacific Northwest wheat cultivars with markers for the 1AS, 2AS and 6BS QTL validated the genes and markers, and indicated their usefulness for marker-assisted selection.
Faithful DNA replication is a cornerstone of genomic integrity. PTEN plays multiple roles in genome protection and tumour suppression. Here we report on the importance of PTEN in DNA replication. ...PTEN depletion leads to impairment of replication progression and stalled fork recovery, indicating an elevation of endogenous replication stress. Exogenous replication inhibition aggravates replication-originated DNA lesions without inducing S phase arrest in cells lacking PTEN, representing replication stress tolerance. iPOND analysis reveals the physical association of PTEN with DNA replication forks and PTEN-dependent recruitment of Rad51. PTEN deletion results in Rad51 dissociation from replication forks. Stalled replication forks in Pten-null cells can be reactivated by ectopic Rad51 or PTEN, the latter facilitating chromatin loading of Rad51. These data highlight the interplay of PTEN with Rad51 in promoting stalled fork restart. We propose that loss of PTEN may initiate a replication stress cascade that progressively deteriorates through the cell cycle.
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