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Diatomic catalysts, particularly those with heteronuclear active sites, have recently attracted considerable attention for their advantages over single-atom catalysts in reactions involving multielectron transfers. Herein, we report bimetallic iridium−iron diatomic catalysts (IrFe−N−C) derived from metal−organic frameworks in a facile wet chemical synthesis followed by postpyrolysis. We use various advanced characterization techniques to comprehensively confirm the atomic dispersion of Ir and Fe on the nitrogen-doped carbon support and the presence of atomic pairs. The asobtained IrFe−N−C shows substantially higher electrocatalytic performance for both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) when compared to the single-atom counterparts (i.e., Ir−N−C and Fe−N−C), revealing favorable bifunctionality. Consequently, IrFe−N−C is used as an air cathode in zinc− air batteries, which display much better performance than the batteries containing commercial Pt/C + RuO2 benchmark catalysts. Our synchrotron-based X-ray absorption spectroscopy experiments and density functional theory (DFT) calculations suggest that the IrFe dual atoms presumably exist in an IrFeN6 configuration where both Ir and Fe coordinates with four N atoms and two N atoms are shared by the IrN4 and FeN4 moieties. Furthermore, the Fe site contributes mainly to the ORR, while the Ir site plays a more important role in the OER. The dual-atom sites work synergistically, reducing the energy barrier of the rate-determining step and eventually boosting the reversible oxygen electrocatalysis. The IrFe−N−C catalysts hold great potential for use in various electrochemical energy storage and conversion devices.

Background Parkinson‘s disease (PD) is known to be associated with non-genetic factors. To infer causality, Mendelian randomization (MR) studies are increasingly used. Here, genetic variants are used as instrumental variables for the risk factor but have no direct effect on PD themselves. Methods We performed a systematic literature review on MR studies for PD. Studies were identified searching the PubMed database. Upon data extraction, we evaluated the methodological quality and summarized the evidence. Results Twelve articles were included. Most studies showed “good” methodological quality, but most did not report proper power estimations. Twelve analyses yielded nominally significant effects. Conclusions Our systematic review shows that most MR studies were well performed and allow to identify causal exposures, which may inform further studies on the prevention and early intervention of PD.

Since their first appearance in the context of schizophrenia and bipolar disorder in 2009, polygenic risk scores (PRSs) have been described for a large number of common complex diseases. However, the clinical utility of PRSs in disease risk assessment or therapeutic decision making is likely limited because PRSs usually only account for the heritable component of a trait and ignore the etiological role of environment and lifestyle. We surveyed the current state of PRSs for various diseases, including breast cancer, diabetes, prostate cancer, coronary artery disease, and Parkinson disease, with an extra focus upon the potential improvement of clinical scores by their combination with PRSs. We observed that the diagnostic and prognostic performance of PRSs alone is consistently low, as expected. Moreover, combining a PRS with a clinical score at best led to moderate improvement of the power of either risk marker. Despite the large number of PRSs reported in the scientific literature, prospective studies of their clinical utility, particularly of the PRS-associated improvement of standard screening or therapeutic procedures, are still rare. In conclusion, the benefit to individual patients or the health care system in general of PRS-based extensions of existing diagnostic or treatment regimens is still difficult to judge.

In this study, Palladium (Pd) nanoparticles (NPs) are decorated on the multi-walled carbon nanotubes (MWCNTs) using the chemical reduction method. In situ extended x-ray absorption fine structure (EXAFS) spectroscopy of Pd NPs decorated on MWCNTs is carried out in different temperatures from 77 K up to 540 K to investigate the local structure around the absorber atom Pd, under molecular hydrogen, H2, pressure, and in a vacuum. The Pd K-edge EXAFS gives a deeper insight into the structural properties of Pd-MWCNT compounds under in-situ H2 treatment at various temperatures. EXAFS data show three mechanisms of the interaction of H2 with Pd: the first mechanism involves physical absorption of H2 at low temperatures from 110 to 190 K, the second mechanism includes the formation of PdHx compound at 300 K, and the third mechanism is attributed to the decomposition of PdHx compound at above 400 K. Furthermore, X-ray photoelectron spectroscopy (XPS) results verify the reduction of the palladium oxide after interaction of the sample with molecular hydrogen and the stability of the catalyst under several cycles of annealing and cooling in hydrogen.

The proceeding developments in next generation sequencing (NGS) technologies enable increasing discrimination power for short tandem repeat (STR) analyses and provide new possibilities for human identification. Therefore, the growing relevance and demand in forensic casework display the need for reliable validation studies and experiences with challenging DNA samples. The presented validation of the MiSeq FGx system and the ForenSeq™ DNA Signature Prep Kit (1) investigated sensitivity, repeatability, reproducibility, concordance, pooling variations, DNA extraction method variances, DNA mixtures, degraded, and casework samples and (2) optimized the sequencing workflow for challenging samples from human corpses by testing additional PCR purification, pooling adjustments, and adapter volume reductions. Overall results indicate the system's reliability in concordance to traditional capillary electrophoresis (CE)-based genotyping and reproducibility of sequencing data. Genotyping success rates of 100% were obtained down to 62.5 pg DNA input concentrations. Autosomal STR (aSTR) profiles of artificially degraded samples revealed significantly lower numbers of locus and allelic dropouts than CE. However, it was observed that the system still exposed drawbacks when sequencing highly degraded and inhibited samples from human remains. Due to the lack of studies evaluating the sequencing success of samples from decomposed or skeletonised corpses, the presented optimisation studies provide valuable recommendations such as an additional PCR purification, an increase in library pooling volumes, and a reduction of adapter volumes for samples with concentrations ≥31.2 pg. Thus, this research highlights the importance of all-encompassing validation studies for implementing novel technologies in forensic casework and presents recommendations for challenging samples.

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified. Polish National Science Centre [UMO-2016/22/E/NZ5/00270]; Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [SP1532/3-1, SP1532/4-1, SP1532/5-1]; Max Planck FoundationFoundation CELLEX; Deutsches Zentrum fur Luft-und Raumfahrt (DLR)Helmholtz AssociationGerman Aerospace Centre (DLR) [01GM1925]; Projekt DEAL Open Access funding enabled and organized by Projekt DEAL. A.J. was supported by the grant from the Polish National Science Centre UMO-2016/22/E/NZ5/00270. M.S. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SP1532/31, SP1532/4-1 and SP1532/5-1), the Max Planck Foundation and the Deutsches Zentrum fur Luft-und Raumfahrt (DLR 01GM1925).

Myocardial deformation can be assessed from routine cardiac magnetic resonance (MR) images using two-dimensional feature tracking (2D-FT). Although reference values are essential for implementation of strain imaging in clinical practice, data for the healthy pediatric age group are limited.To provide pediatric MR reference values for strain and strain rate for all four heart chambers.Retrospective.One hundred and fifty-seven healthy children from two institutions (102 male, age 4.7-18 years).1.5 T; balanced steady-state free precession sequence.Left ventricular (LV) global and regional longitudinal, circumferential, and radial strain and strain rate as well as right ventricular (RV) and atrial global and regional longitudinal strain and strain rate were measured in two-, three-, and four-chamber views and the short axis stack. The relationships between strain parameters and age, height, weight, and gender were investigated. Age- and height-specific centile curves and tables were created for LV strain and strain rate. For all other global strain parameters, the mean was calculated as a reference.Lambda-mu-sigma (LMS)-method of Cole and Green, univariable, and multivariable linear regression models. A P value0.05 was considered to be statistically significant.Age, height and weight had a significant influence on LV global strain values. These parameters also showed an influence on RV strain but only in boys (girls P = 0.12) and none of the variables had a significant influence on atrial strain (P = 0.19-0.49). Gender differences were only found for RV strain values.Pediatric potential reference values for myocardial deformation parameters of both ventricles and atria are provided. The values may serve as a reference in future studies and clinical practice.3 TECHNICAL EFFICACY: Stage 5.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1–3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6–8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic, and behavioral functions, and is involved in various conditions including androgen-insensitivity-syndrome (AIS) or prostate cancer. Here we identified functional AIS-patient mutations in the formin and actin nucleator DAAM2. DAAM2 localized to the nucleus and colocalized with the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2-AR-droplets ranged from 0.02 to 0.06 µm3 in size and associated with active RNA polymerase II. DAAM2 polymerizes actin directly at the AR to promote droplet fusion in a highly dynamic manner and actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

The objective of our study was to investigate the impact of the mitochondrial polygenic score (MGS) and lifestyle/environmental data on age at onset in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic Parkinson’s disease (iPD).In this study, we included N=486 patients withLRRK2-PD and N=9259 patients with iPD from AMP-PD, Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data was utilized to perform the MGS analysis, using 14 Single Nucleotide Polymorphisms (SNPs) from genes causally associated with mitochondrial function and PD risk. Additionally, lifestyle and environmental data were obtained from the PD risk factor questionnaire (PD-RFQ). Correlation analyses and linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.We observed that higher MGS was associated with earlier AAO in patients withLRRK2-PD (p=4.0×10−4, β=-0.18) but not in patients with iPD. A correlation between MGS and AAO was visibly stronger in European ancestryLRRK2-PD patients (p=0.01, r=-0.16) than in Tunisian Arab-Berber patients (p=0.44, r=-0.05). We found that the MGS interacted with coffee (p=0.03, β=-0.38) and caffeinated soda consumption (p=0.03, β=-0.37) inLRRK2-PD and with caffeine soda consumption (p=0.047, β=-0.22) and pesticide exposure (p=0.02, β=-0.37) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeine or were exposed to pesticides.The MGS related to mitochondrial function was associated with AAO inLRRK2-PD but not iPD with an ethnic-specific effect. Caffeine consumption or pesticide exposure interacted with MGS to predict PD AAO. Our study suggests gene-environment interactions as modifiers of AAO inLRRK2-PD.

The recent characterization of a group of non-MYC rearranged aggressive B-cell lymphomas, resembling Burkitt lymphoma (BL), characteristically harboring a telomeric 11q loss or combined 11q proximal gains/loss pattern has led to the introduction of the provisional entity of Burkitt-like lymphoma with 11q aberration (BLL-11q). Prompted by the discovery of a telomeric 11q loss in an HIV+ high-grade B-cell lymphoma patient, we investigated an extended cohort of aggressive B-cell lymphomas, enriched for cases with histopathological features intermediate between DLBCL and BL, including double- and triple-hit lymphomas (n = 47), for 11q loss/combined 11q proximal gains/loss pattern by fluorescence in situ hybridization. We provide first evidence that 11q aberrations can be found in both BLL in the context of an underlying HIV infection as well as in high-grade B-cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements. We therefore propose that the clinicopathological spectrum of malignancies carrying this aberration may be broader than previously assumed.