Genome-wide association studies (GWAS) have been successful in identifying disease-associated genetic variants. Recently, an increasing number of GWAS summary statistics have been made available to the research community, providing extensive repositories for studies of human complex diseases. In particular, cross-trait associations at the genetic level can be beneficial from large-scale GWAS summary statistics by using genetic variants that are associated with multiple traits. However, direct assessment of cross-trait associations using susceptibility loci has been challenging due to the complex genetic architectures in most diseases, calling for advantageous methods that could integrate functional interpretation and imply biological mechanisms.

Placental development occurs in a low oxygen environment, which stimulates angiogenesis by upregulating vascular endothelial growth factor A (VEGFA), plasminogen activator inhibitor-1 (SERPINE1) and the angiopoietin-2/-1 ratio (ANGPT2/1). At this time, Angiotensin II type 1 receptor (AT1R) is highly expressed. We postulated that the early gestation placental oxygen milieu, by stimulating the angiotensin (Ang) II/AT1R pathway, increases expression of proliferative/angiogenic factors.

Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P1-9R) including a TFR1-targeting peptide coupled to a nine-arginine cell-penetrating peptide (CPP) that facilitates the release of the AON from TFR1 in endosomal vesicles. We demonstrated that the P1-9R/V1 nanocomplex promotes the efficient and prolonged redirection of splicing towards the physiological splice site and subsequent normalization of WT FECH mRNA and protein levels. Finally, the P1-9R/V1 nanocomplex increases WT FECH mRNA production and significantly decreases PPIX accumulation in primary cultures of differentiating erythroid progenitors from an overt EPP-affected individual. P1-9R is a method designed to target erythroid progenitors and represents a potentially powerful tool for the in vivo delivery of therapeutic DNA in many erythroid disorders.

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.

Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).

Morbid obesity, defined as body mass index (BMI) ≥40 kg/m2, affects approximately 8% of United States adults and is a recognized risk factor for chronic kidney disease (CKD). We present the first focused biopsy-based study exploring the range of kidney diseases in this population. Among 3263 native kidney biopsies interpreted at Columbia University in 2017, we identified 248 biopsies from morbidly obese patients. In this cohort with median age of 53.5 years, 56% were female and median BMI was 44.0 kg/m2. Diabetes and hypertension were present in 47% and 81% of patients, respectively. Median estimated glomerular filtration rate (eGFR) was 30 ml/min/1.73 m2, and most patients had nephrotic range proteinuria. Obesity related glomerulopathy (ORG), defined as focal segmental glomerulosclerosis with glomerulomegaly or glomerulomegaly alone, was detected in 73 patients, including 29 with ORG alone and 44 with ORG plus another kidney disease. In contrast, 167 patients had other kidney diseases alone, without ORG, most commonly (in descending order) diabetic nephropathy, acute tubular necrosis, hypertensive nephrosclerosis, IgA nephropathy, membranous nephropathy, and lupus nephritis. In 49% of patients, kidney biopsy yielded a diagnosis predicted to change patient management. The strongest predictor of non-ORG lesions was eGFR <30 ml/min per 1.73 m2, and presentation with nephrotic syndrome or acute kidney injury (with or without background CKD) was more common in non-ORG than ORG. The findings reveal an unexpectedly broad spectrum of kidney pathology beyond metabolic syndrome-associated disorders and highlight the importance of kidney biopsy to guide management and prognosis in the morbidly obese population.

SPRY domain-containing SOCS box protein 1 (SPSB1) is an E3 ligase adaptor protein with unknown functions in cancer cells. In this study, we found that SPSB1 knockdown markedly decreased the viability and migration of ovarian cancer cells, while ectopic SPSB1 overexpression in IL-3-dependent Ba/F3 cells significantly increased their proliferation rate compared with empty vector-transfected cells. SPSB1 knockdown significantly elevated p21 protein and mRNA levels and induced apoptosis in ovarian cancer cells, as evidenced by increased levels of cleaved PARP and decreased levels of Bcl-2. Notably, mechanistic investigations revealed that SPSB1 accelerated p21 destabilization by directly interacting with p21 and promoting its ubiquitin-mediated proteasomal degradation. Taken together, our findings provide novel insights into the role of SPSB1 in ovarian cancer cells.

Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. VIDEO ABSTRACT.

Although pluripotent stem cells can generate various types of differentiated cells, it is unclear why lineage-committed stem/progenitor cells derived from pluripotent stem cells are decelerated and why the differentiation-resistant propensity of embryonic stem cell (ESC)/induced pluripotent stem cell (iPSC)-derived cells is predominant compared with the in vivo equivalents derived from embryonic/adult tissues. In this study, we demonstrated that iPSCs reprogrammed and maintained with three chemical inhibitors of the fibroblast growth factor 4-mitogen-activated protein kinase cascade and GSK3β (3i) could be differentiated into all three germ layers more efficiently than the iPSCs reprogrammed without the 3i chemicals, even though they were maintained with 3i chemicals once they were reprogrammed. Although the iPSCs reprogrammed with 3i had increased numbers of Zscan4-positive cells, the Zscan4-positive cells among iPSCs that were reprogrammed without 3i did not have an accelerated differentiation ability. These observations suggest that 3i exposure during the reprogramming period determines the accelerated differentiation/maturation potentials of iPSCs that are stably maintained at the distinct state.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disease caused by mutations in the NF1 tumor suppressor gene. Plexiform neurofibromas (PNFs) are benign Schwann cell (SC) tumors of the peripheral nerve sheath that develop through NF1 inactivation and can progress toward a malignant soft tissue sarcoma. There is a lack of non-perishable model systems to investigate PNF development. We reprogrammed PNF-derived NF1(-/-) cells, descendants from the tumor originating cell. These NF1(-/-)-induced pluripotent stem cells (iPSCs) captured the genomic status of PNFs and were able to differentiate toward neural crest stem cells and further to SCs. iPSC-derived NF1(-/-) SCs exhibited a continuous high proliferation rate, poor myelination ability, and a tendency to form 3D spheres that expressed the same markers as their PNF-derived primary SC counterparts. They represent a valuable model to study and treat PNFs. PNF-derived iPSC lines were banked for making them available.

Attaining proper organ size during development and regeneration hinges on the activity of mitogenic factors. Here, we performed a large-scale chemical screen in embryonic zebrafish to identify cardiomyocyte mitogens. Although commonly considered anti-proliferative, vitamin D analogs like alfacalcidol had rapid, potent mitogenic effects on embryonic and adult cardiomyocytes in vivo. Moreover, pharmacologic or genetic manipulation of vitamin D signaling controlled proliferation in multiple adult cell types and dictated growth rates in embryonic and juvenile zebrafish. Tissue-specific modulation of vitamin D receptor (VDR) signaling had organ-restricted effects, with cardiac VDR activation causing cardiomegaly. Alfacalcidol enhanced the regenerative response of injured zebrafish hearts, whereas VDR blockade inhibited regeneration. Alfacalcidol activated cardiac expression of genes associated with ErbB2 signaling, while ErbB2 inhibition blunted its effects on cell proliferation. Our findings identify vitamin D as mitogenic for cardiomyocytes and other cell types in zebrafish and indicate a mechanism to regulate organ size and regeneration.

Sleep is regulated by homeostatic process and circadian clock. Light indirectly modulates sleep by entraining the circadian clock to the solar day. Light can also influence sleep independent of photo-entrainment [1]. An acute light exposure could induce sleep, and an acute dark pulse could increase wakefulness in nocturnal animals [1, 2]. The photoreceptors and cell types in the retina that mediate light and dark effects on sleep are well characterized [1-4]. A few studies have explored the brain region involved in acute light induction of sleep. Fos expression and nonspecific lesions suggest that the superior colliculus (SC) may play a role in acute light induction of sleep [2, 5]. In contrast, the brain area and neural circuits mediating acute dark induction of wakefulness are unknown. Here, we demonstrated that retina ganglion cells (RGCs) had direct innervations on the GABAergic neurons in the mouse SC, and the activities of these cells were inhibited by an acute dark pulse, but not influenced by a light pulse. Moreover, ablating SC GABAergic neurons abolished the acute dark induction of wakefulness, but not light induction of sleep. Based on optogenetic and electrophysiological experiments, we found that SC GABAergic neurons formed monosynaptic functional connections with dopaminergic neurons in the ventral tegmental area (VTA). Selective lesions of VTA dopaminergic cells totally abolished acute dark induction of wakefulness without affecting the light induction of sleep. Collectively, our findings uncover a fundamental role for a retinal-SC GABAergic-VTA dopaminergic circuit in acute dark induction of wakefulness and indicate that the dark and light signals affect sleep-wake behaviors through distinct pathways.

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β cells. A comprehensive picture of the changes during T1D development is lacking due to limited sample availability, inability to sample longitudinally, and the paucity of technologies enabling comprehensive tissue profiling. Here, we analyzed 1,581 islets from 12 human donors, including eight with T1D, using imaging mass cytometry (IMC). IMC enabled simultaneous measurement of 35 biomarkers with single-cell and spatial resolution. We performed pseudotime analysis of islets through T1D progression from snapshot data to reconstruct the evolution of β cell loss and insulitis. Our analyses revealed that β cell destruction is preceded by a β cell marker loss and by recruitment of cytotoxic and helper T cells. The approaches described herein demonstrate the value of IMC for improving our understanding of T1D pathogenesis, and our data lay the foundation for hypothesis generation and follow-on experiments.

The interaction between the immune system and endocrine cells in the pancreas is crucial for the initiation and progression of type 1 diabetes (T1D). Imaging mass cytometry (IMC) enables multiplexed assessment of the abundance and localization of more than 30 proteins on the same tissue section at 1-μm resolution. Herein, we have developed a panel of 33 antibodies that allows for the quantification of key cell types including pancreatic exocrine cells, islet cells, immune cells, and stromal components. We employed this panel to analyze 12 pancreata obtained from donors with clinically diagnosed T1D and 6 pancreata from non-diabetic controls. In the pancreata from donors with T1D, we simultaneously visualized significant alterations in islet architecture, endocrine cell composition, and immune cell presentation. Indeed, we demonstrate the utility of IMC to investigate complex events on the cellular level that will provide new insights on the pathophysiology of T1D.

Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.

Histone deacetylase 4 (HDAC4) has been proposed as a target for Amyotrophic Lateral Sclerosis (ALS) because it mediates nerve-skeletal muscle interaction and since its expression in skeletal muscle correlates with the severity of the disease. However, our recent studies on the skeletal muscle response upon long-term denervation highlighted the importance of HDAC4 in maintaining muscle integrity.

1-N-Butyl-3-methylimidazolium hexafluorophosphate, [BMIM][PF6], and its methylated form, 1-N-butyl-2,3-dimethylimidazolium hexafluorophosphate, [BMMIM][PF6], were incorporated into CuBTC to examine the effect of methylation of ionic liquids (ILs) on the gas separation performance of the corresponding IL/metal-organic framework (MOF) composites. Spectroscopic analysis revealed that the interactions of the methylated ILs with CuBTC were weaker compared to those of its non-methylated counterpart. Gas uptake measurements illustrated that this difference in the interactions influences the gas separation performance of the composites. Accordingly, the CO2/N2: 15/85 and CH4/N2: 50/50 selectivities increased by 37% and 60% for [BMMIM][PF6]/CuBTC and 34% and 50% for [BMIM][PF6]/CuBTC, respectively, compared to the corresponding selectivities of pristine CuBTC at 1000 mbar. The results revealed another structural parameter controlling the performance of the IL/MOF composites, a novel type of material with rapidly expanding application areas.

Family socioeconomic status (SES) is an important factor that affects an individual's neural and cognitive development. The two novel aims of this study were to reveal (a) the effects of family SES on mean diffusivity (MD) using diffusion tensor imaging given the characteristic property of MD to reflect neural plasticity and development and (b) the sex differences in SES effects. In a study cohort of 1,216 normal young adults, we failed to find significant main effects of family SES on MD; however, previously observed main effects of family SES on regional gray matter volume and fractional anisotropy (FA) were partly replicated. We found a significant effect of the interaction between sex and family income on MD in the thalamus as well as significant effects of the interaction between sex and parents' educational qualification (year's of education) on MD and FA in the body of the corpus callosum as well as white matter areas between the anterior cingulate cortex and lateral prefrontal cortex. These results suggest the sex-specific associations of family SES with neural and/or cognitive mechanisms particularly in neural tissues in brain areas that play key roles in basic information processing and higher-order cognitive processes in a way females with greater family SES level show imaging outcome measures that have been associated with more neural tissues (such as greater FA and lower MD) and males showed opposite.

Background: The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analog, Beraprost (BPS), ameliorates pulmonary hypertension (PH). Prostaglandins are an important treatment for PH. Mechanisms of their action are not fully elucidated in relation to receptor subtype and effects on O2 sensitive Kv channels. Methods: Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established PH were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid receptor expression and activity of the O2 sensitive Kv channels. Results: Prostacyclin receptor (IP), prostaglandin receptor E3 (EP3) and prostaglandin receptor E4 (EP4) are the main pulmonary artery receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced receptor expression of IP but not of EP4. The effects on IP expression were overcome with BPS. Dilatory responses in PH to BPS were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in pulmonary artery smooth muscle cell from rats with PH and humans with PAH and were also overcome by administration of BPS. Effects of BPS on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 receptor, as well as the IP receptor, in mediating BPS effects. Conclusion: Reduced expression of pulmonary IP receptors and reduced activity of O2 sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, BPS, is able to reverse these changes, partly through binding to the EP4 receptor.

Objective: The present meta-analysis was aimed to systematically evaluate the effectiveness and accuracy of brain natriuretic peptide (BNP), cardiac troponin (cTn), high sensitive C reactive protein (hs-CRP) and CRP for predicting postoperative major adverse cardiovascular events (MACE) in patients undergoing noncardiac surgery. Methods: A total of 26 relevant studies with 7,877 participants were collected from five databases, namely PubMed, Embase, China National Knowledge Infrastructure (CNKI), CQVIP and the Wanfang Database until August 10, 2018. And the Review Manager Version 5.3 and Stata/SE 12 software were used for data syntheses in the meta-analysis. Results: Strong relationships of BNP/NT-proBNP, cTnI/cTnT and hs-CRP with MACE were detected in patients undergoing noncardiac surgery, and the five biomarkers all increased the risk of MACE. Compared to normal levels, elevated BNP/NT-proBNP could increase the MACE risk by almost 4-fold [RR:3.92, 95%CI: 3.23-4.75, P < 0.001]; elevated BNP corresponded to a 4.5-fold risk [RR:4.57, 95%CI: 3.37-6.20, P < 0.001]; elevated NT-proBNP led to a 3-fold higher risk [RR:3.48, 95%CI: 2.71-4.46, P < 0.001]. Comparing with normal levels of cTnI/cTnT, increased cTnI/cTnT was associated with nearly 5-fold more higher risk of MACE [RR:5.52, 95%CI: 4.62-6.58, P < 0.001]; elevated cTnI faced a 5-fold risk [RR:5.21, 95%CI: 3.96-6.86, P < 0.001]; elevated cTnT resulted in nearly 6-fold higher risk [RR:5.73, 95%CI: 4.55-7.22, P < 0.001]. The elevation of hs-CRP was associated with nearly 4-fold higher risk of MACE in comparison with normal concentration [RR:3.73, 95%CI: 2.63-5.30, P < 0.001]. Conclusion: According to the results of our meta-analysis, the elevations of BNP/NT-proBNP, cTnI/cTnT, and hs-CRP, pre-operation or post-operation immediately, can predict much higher risk of postoperative MACE in patients undergoing noncardiac surgery.