Higher temperature sensitivity of retrogressive thaw slump activity in the Arctic compared to the Third Pole.

Climate change exacerbates permafrost thawing, resulting exceptionally intense retrogressive thaw slump (RTS) activity in the Arctic and Third Pole. However, comparative assessments of permafrost characteristics and RTS sensitivity under warming climate at both poles are still lacking. Here, the severity and temperature sensitivity of RTS were presented and compared using Tasselled Cap (TC) trend analysis of time-series Landsat images and Interferometric Synthetic Aperture Radar (InSAR) measurement. RTS has a more severe growth trend in the Arctic cold permafrost region, also with a deformation rate of approximately 70 mm/year and cumulative displacement up to 120 mm. In comparison, the deformation rate in the Third Pole is approximately 50 mm/year. The RTS severity in the Arctic is about 1.5 times higher than in the Third Pole, primarily owing to different sensitivities of cold and warm permafrost under warming climate. The intensification and vulnerability of RTS have global implications on climatological processes, hydrology, carbon release and ground stability, thus calling for attention and effective governance action.

High Comorbidity of Pediatric Cancers in Patients with Birth Defects: Insights from Whole Genome Sequencing Analysis of Copy Number Variations.

BACKGROUND: Patients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions. METHODS: This study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program. RESULTS: 8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 patients including 17 males. Large recurrent P/LP duplications >5MB were detected in 33 patients. CONCLUSIONS: This study revealed that P/LP CNVs were common in a large cohort of BD patients with high rate of pediatric cancers. We present a comprehensive spectrum of P/LP CNVs in patients with BDs and various cancers. Notably, deletions involving E2F target genes and genes implicated in mitotic spindle assembly and G2/M checkpoint were identified, potentially disrupting cell-cycle progression and providing mechanistic insights into the concurrent occurrence of BDs and cancers.

Genomic variants exclusively identified in children with birth defects and concurrent malignant tumors predispose to cancer development.

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3'UTR regions. Exclusive exonic variants, especially synonymous variants, tend to occur in prior exons locus in BD-cancer children. Intronic variants close to splicing site (< 500 bp from exon) have little overlaps in BD-cancer and BD-only patients. Exonic variants in non-coding RNA (ncRNA) tend to occur in different ncRNAs exons regardless of the overlaps. Notably, genes with 5' UTR variants are almost mutually exclusive between the two phenotypes. In conclusion, we conducted the first genomic study to explore the impact of recurrent variants exclusive to the two distinguished clinical phenotypes under study, BD with or without cancer, demonstrating enrichment of selective protein-coding/ncRNAs differentially expressed between these two phenotypes, suggesting that selective genetic factors may underlie the molecular processes of pediatric cancer development in BD children.

Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing.

BACKGROUND: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies may improve our understanding of the underlying molecular mechanisms and provide clues for early cancer detection in children with BD. METHODS: In this study, whole genome sequencing (WGS) data of blood-derived DNA for 1653 individuals without chromosomal anomalies were acquired from the Kids First Data Resource Center (DRC), including 541 BD probands with at least one type of malignant tumors, 767 BD probands without malignant tumor, and 345 healthy family members who are the parents or siblings of the probands. Recurrent variants exclusively seen in cancer patients were selected and mapped to their corresponding genomic regions. The targeted genes/non-coding RNAs were further reduced using random forest and forward feature selection (ffs) models. RESULTS: The filtered genes/non-coding RNAs, including variants in non-coding areas, showed enrichment in cancer-related pathways. To further support the validity of these variants, blood WGS data of additional 40 independent BD probands, including 25 patients with at least one type of cancers from unrelated projects, were acquired. The counts of variants of interest identified in the Kid First data showed clear deviation in the validation dataset between BD patients with cancer and without cancer. Furthermore, a deep learning model was built to assess the predictive abilities in the 40 patients using variants of interest identified in the Kids First cohort as feature vectors. The accuracies are ~ 75%, with the noteworthy observation that variants mapped to non-coding regions provided the highest accuracy (31 out of 40 patients were labeled correctly). CONCLUSION: We present for the first time a panorama of genetic variants that are associated with cancers in non-chromosomal BD patients, implying that our approach may potentially serve for the early detection of malignant tumors in patients with BD.

Paleochannel of the Yellow River within the Zoige Basin and its environmental significance on the NE Tibetan Plateau.

Paleochannel sedimentary sequences can provide abundant information on regional environmental changes. A typical paleochannel (paleo-oxbow lake type) section of the Yellow River was identified within the Zoige Basin on the NE Tibetan Plateau. A multi-index approach was used to accurately identify sediments of different genetic types, such as riverbed deposits of the Yellow River, paleo-oxbow lake deposits, and overbank flood deposits (OFD) in the section. Based on optically stimulated luminescence (OSL) and AMS 14C dates, we examined the environmental evolution recorded by the section. The results show that: (1) The section is a record of environmental change since 4.17 ± 0.49 ka. During 4.17 ± 0.49 to 3.24 ± 0.26 ka, the ancient Yellow River occupied the channel. At 3.24 ± 0.26 ka, the paleochannel experienced a neck cutoff, and the fluvial environment began to change into the oxbow lake environment. After 2.45 ± 0.11 ka, the paleo-oxbow lake gradually disappeared. Subalpine meadow soil has developed at this site since 1.31 ± 0.05 ka. (2) Paleoenvironmental proxies indicate that the Zoige Basin was warmer and wetter before ~3.00 ka, and became drier and colder after ~3.00 ka, which may be mainly related to the weakening of the East Asian summer monsoon (EASM) and the strengthening of the Westerlies. (3) Two episodes of extreme overbank flooding occurred at 2.96 ± 0.24 to 2.87 ± 0.27 ka and 1.84 ± 0.20 to 1.70 ± 0.16 ka, correlated with climate shift period from the mid-Holocene climatic optimum to the late Holocene and the Dark Age Cold Period (DACP), respectively. Due to the relatively cold and dry climate in these periods, glaciers generally advanced on the Tibetan Plateau, and the contribution of snow and ice meltwater weakened. Therefore, the strong rainfall caused by the abnormal atmospheric circulation may be the main cause of these extreme overbank flooding.

Early diagenetic control on the enrichment and fractionation of rare earth elements in deep-sea sediments.

The rare earth elements and yttrium (REY) in bioapatite from deep-sea sediments are potential proxies for reconstructing paleoenvironmental conditions. However, the REY enrichment mechanism and the reliability of this tracer remain elusive because of the lack of key information from ambient pore water. Here, we report high-resolution geochemical data for pore water, bottom water, and bioapatite from deep-sea sites in the western Pacific. Our results reveal that the benthic flux of REY from the deep sea is less substantial than from the shallow marine realm, resulting in REY-rich sediment. The depth distribution of REY in pore water is opposite to that of bioapatite, and REY patterns and neodymium isotopic compositions are not uniformly distributed within bioapatite. These results indicate alteration of REY and neodymium isotopic compositions during early diagenesis. Therefore, we infer that REY from bioapatite are not robust recorders of the deep marine environment through Earth's history.

Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. METHODS: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. RESULTS: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. CONCLUSION: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

A Novel Rat Model with Long Range Optic Nerve Injury to Study Retinal Ganglion Cells Endogenous Regeneration.

In adult mammals, axon regeneration is limited within the lesion site after injury to the optic nerve. Changes in the microenvironment of lesion sites play an important role in retinal ganglion cells (RGCs) axon regeneration along with other intrinsic factors. In this study, the effect of the lesion site on the microenvironment and axon growth was evaluated using a refined optic nerve crush (ONC) injury model, in which the injury range was extended compared to classical injury. The number of regenerated axons labeled anterogradely with cholera toxin B fragment (CTB) was significantly increased in the long-range crush injury (LI) group compared to the ONC group at distances of 500, 1000 and 1500 µm from the initial site of the injury. These data confirmed that RGC axons can regenerate inside the lesion site. Immunofluorescence and proteomic analysis showed that the microenvironment at the lesion site was highly heterogeneous. The levels of myelin-associated inhibitors, chondroitin-sulfate proteoglycans (CSPGs) and other axon growth inhibitors decreased inside the lesion site compared to the posterior segment of the optic nerve lesion site. The expression of multiple lysosome-related enzymes, metabolic inhibitors including cholesterol esterase, cathepsin B, D, Z and arylsulfatase B (ARSB) were significantly increased inside the lesion site for the LI group compared to the normal optic nerves. Our results suggest that the model of long range optic nerve injury is more useful towards understanding the lesion microenvironment and the endogenous regeneration of RGCs. Also, we showed that myelin and neurocan (a CSPG) are differently expressed in the optic nerve between the interior and posterior lesion sites and may explain why axons cannot reach the brain through the lesion site.

Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer and antibacterial agents to induce both autophagy and apoptosis.

Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclometalated iridium(III) complexes (Ir1: [Ir(piq)2L]PF6; Ir2: [Ir(bzq)2L]PF6; Ir3: [Ir(dfppy)2L]PF6; Ir4: [Ir(thpy)2L]PF6; piq = 1-phenylisoquinoline; bzq = benzo[h]quinoline; dfppy = 2-(2,4-difluorophenyl)pyridine;thpy = 2-(2-thienyl)pyridine; L = 1,10-phenanthroline-5-amine) were synthesized and characterized. Cytotoxicity tests show that these complexes have excellent cytotoxicity to cancer cells, and mechanism studies indicatethat these complexes can specifically target mitochondria. Complexes Ir1 and Ir2 can damage the function of mitochondria, subsequently increasing intracellular levels of ROS, decreasing MMP (mitochondrial membrane potential), and interfering with ATP energy production, which leads to autophagy and apoptosis. Furthermore, autophagy induced by Ir1 and Ir2 can promote cell death in coordination with apoptosis. Surprisingly, these four complexes also showed moderate antibacterial activity to S. aureusand P. aeruginosa.

Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA HGB8P were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.

An adherent drug depot for retinal ganglion cell protection and regeneration in rat traumatic optic neuropathy models.

Traumatic optic neuropathy (TON) describes an injury to the optic nerve following either blunt or penetrating trauma, and remains an important cause of vision loss. No generalized treatment of TON has been established so far to restore the injured optic nerve. We developed an adherent drug-encapsulated bi-layered depot (DBP) as a dual drug vehicle for local treatment to protect the residual retinal ganglion cells (RGCs) and regenerate axons following optic nerve damage. The inner layer of the depot was prepared by co-electrospinning poly(d,l-lactide-co-glycolide acid) (PLGA: 75 : 25) and collagen (COL) with the hydrophobic corticosteroid triamcinolone acetonide (TA) loaded. The outer layer was made of PLGA and the hydrophilic neuroprotective agent Fasudil (FA). The DBP showed suitable morphology, hydrophilicity and mechanical properties, and slowly released TA and FA in vitro by undergoing time-dependent degradation and swelling. All depots showed good biocompatibility with L929 mouse fibroblasts, and DBP was helpful in maintaining the morphology of RGCs in vitro. In addition, direct implantation of DBP at the injured optic nerve in a rat model mitigated inflammation and the death of RGCs, and increased the expression of nerve growth-related protein GAP-43. Therefore, DBP maybe a promising local therapy against TON in future.

Mitochondria-targeted Re(I) complexes bearing guanidinium as ligands and their anticancer activity.

As the "powerhouse" of a cell, mitochondria maintain energy homeostasis, synthesize ATP via oxidative phosphorylation, generate ROS signaling molecules, and modulate cell apoptosis. Herein, three Re(I) complexes bearing guanidinium derivatives have been synthesized and characterized. All of these complexes exhibit moderate anticancer activity in HepG2, HeLa, MCF-7, and A549 cancer cells. Mechanism studies indicate that complex 3, [Re(CO)3(L)(Im)](PF6)2, can selectively localize in the mitochondria and induce cancer cell death through mitochondria-associated pathways. In addition, complex 3 can effectively depress the ability of cell migration, cell invasion, and colony formation.

Non-coding structural variation differentially impacts attention-deficit hyperactivity disorder (ADHD) gene networks in African American vs Caucasian children.

Previous studies of attention-deficit hyperactivity disorder (ADHD) have suggested that structural variants (SVs) play an important role but these were mainly studied in subjects of European ancestry and focused on coding regions. In this study, we sought to address the role of SVs in non-European populations and outside of coding regions. To that end, we generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The ADHD cases included 116 African Americans (AA) and 89 of European Ancestry (EA) with SVs in comparison with 408 AA and 262 controls, respectively. Multiple SVs and target genes that associated with ADHD from previous studies were identified or replicated, and novel recurrent ADHD-associated SV loci were discovered. We identified clustering of non-coding SVs around neuroactive ligand-receptor interaction pathways, which are involved in neuronal brain function, and highly relevant to ADHD pathogenesis and regulation of gene expression related to specific ADHD phenotypes. There was little overlap (around 6%) in the genes impacted by SVs between AA and EA. These results suggest that SVs within non-coding regions may play an important role in ADHD development and that WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.

Solidification Crack Evolution in High-Strength Steel Welding Using the Extended Finite Element Method.

High-strength steel suffers from an increasing susceptibility to solidification cracking in welding due to increasing carbon equivalents. However, the cracking mechanism is not fully clear for a confidently completely crack-free welding process. To present a full, direct knowledge of fracture behavior in high-strength steel welding, a three-dimensional (3-D) modeling method is developed using the extended finite element method (XFEM). The XFEM model and fracture loads are linked with the full model and the output of the thermo-mechanical finite element method (TM-FEM), respectively. Solidification cracks in welds are predicted to initiate at the upper tip at the current cross-section, propagate upward to and then through the upper weld surface, thereby propagating the lower crack tip down to the bottom until the final failure. This behavior indicates that solidification cracking is preferred on the upper weld surface, which has higher weld stress introduced by thermal contraction and solidification shrinkage. The modeling results show good agreement with the solidification crack fractography and in situ observations. Further XFEM results show that the initial defects that exhibit higher susceptibility to solidification cracking are those that are vertical to the weld plate plane, open to the current cross-section and concentratedly distributed compared to tilted, closed and dispersedly distributed ones, respectively.

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

A novel path to prepare Fe/Al-layered double hydroxide nanosheets by sacrificial double anodes for the treatment of Cr-containing wastewater.

Many methods used to synthesize efficient reducing agents of Fe and Al-layered double hydroxide (Fe/Al-LDH) nanosheets against oxidizing contaminants often require the use of unstable bivalent iron salts and long aging times at ambient temperatures. Here, we developed an easy-to-operate, environment-friendly, and scaled-up electrochemical engineering method without adding metal salts to synthesize Fe/Al-LDHs via an electrolytic reaction of active metal electrodes (Fe and Al). The process resulted in the growth of thin hexagonal Fe/Al-LDHs with a lateral size of approximately 100 nm and thickness of approximately 32 nm. The crystallization process of Fe/Al-LDHs strongly relied on the crystal nucleus of the first precipitate Al(OH)3 and the Fe chemical valence. The oxidation state of Fe was markedly influenced by hydroxyl ions that formed on the cathode surface and the oxygen evolution reaction at high current density (i). The fast and simple manufacturing technique not only had high yield (approximately 0.2 g of Fe/Al-LDHs was obtained when i was 2 mA/cm2 within 25 min) but also afforded Fe/Al-LDHs with excellent reducibility for the removal of Cr(VI). This study demonstrated an attractive option for the rapid and large-scale synthesis of Fe/Al-LDHs to enhance their application prospects.

Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk.

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma. Here we identify common variants at 11q22.2 within MMP20 that associate with neuroblastoma cases harboring 11q deletion (rs10895322), using GWAS in 113 European-American cases and 5109 ancestry-matched controls. The association is replicated in 44 independent cases and 1902 controls. Our study yields novel insights into the genetic underpinnings of neuroblastoma, demonstrating that the inherited common variants reported contribute to the origin of intra-tumor genetic heterogeneity in neuroblastoma.Chromosomal abnormalities such as 11q deletion are associated with poor prognosis in neuroblastoma. Here, the authors perform a genome-wide association study and identify an association between a variant within a Matrix metalloproteinase (MMP) gene member, MMP20, and 11q-deletion subtype neuroblastoma.

Erratum: A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.

We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.