bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time‐Domain Reflectometry Measurements and Modeling of Firn Meltwater Infiltration at DYE‐2, Greenland
Authors: Samimi S. , Marshall S. J. , Vandecrux B. , MacFerrin M. 
Published: September 2021

AbstractSurface meltwater can be retained in an ice sheet if it infiltrates the firn and refreezes. This is an important mass balance process for the Greenland Ice Sheet, reducing meltwater runoff and associated sea‐level rise. The processes of meltwater infiltration and refreezing are not fully understood, however, and remain difficult to monitor remotely. We deployed vertical arrays of thermistors and time‐domain reflectometry (TDR) probes to 4‐m depth in the firn to continuously monitor meltwater infiltration and refreezing processes at DYE‐2, Greenland. The observations provide a detailed picture of the coupled thermal and hydrological evolution of the firn through the 2016 melt season, including estimates of firn water content. The thaw and wetting fronts reached a maximum depth of 1.8 m, with meltwater infiltration concentrated in four main pulses of melting and subsurface warming that reached progressively deeper into the firn. The observations were used to constrain a coupled model of firn thermodynamics and hydrology, which was then run over the period 1950–2020, driven by meteorological forcing from GC‐Net station data and ERA5 climate reanalyses. Model results suggest that decadal‐scale firn evolution at DYE‐2 is strongly influenced by extreme melt seasons such as those of 1968, 2012, and 2019, when meltwater infiltration reached depths of 6–7 m. Extreme melt years drive increases in firn temperature, ice content, and density, reducing firn meltwater retention capacity. Such processes are likely to govern future meltwater retention as the percolation zone extends to higher elevations in Greenland in the coming decades.
Active Faulting and Deep‐Seated Gravitational Slope Deformation in Carbonate Rocks (Central Apennines, Italy): A New “Close‐Up” View
Authors: Del Rio Luca , Moro Marco , Fondriest Michele , Saroli Michele , Gori Stefano , Falcucci Emanuela , Cavallo Andrea , Doumaz Fawzi , Di Toro Giulio 
Published: September 2021

AbstractActive faulting and deep‐seated gravitational slope deformation (DGSD) are common geological hazards in mountain belts worldwide. In the Italian central Apennines, kilometer‐thick carbonate sedimentary sequences are cut by major active normal faults that shape the landscape, generating intermontane basins. Geomorphological observations suggest that the DGSDs are commonly located in fault footwalls. We selected five mountain slopes affected by DGSD and exposing the footwall of active seismogenic normal faults exhumed from 2 to 0.5 km depth. Field structural analysis of the slopes shows that DGSDs exploit preexisting surfaces formed both at depth and near the ground surface by tectonic faulting and, locally, by gravitational collapse. Furthermore, the exposure of sharp scarps along mountain slopes in the central Apennines can be enhanced either by surface seismic rupturing or gravitational movements (e.g., DGSD) or by a combination of the two. At the microscale, DGSDs accommodate deformation mechanisms similar to those associated with tectonic faulting. The widespread compaction of micro‐grains (e.g., clast indentation), observed in the matrix of both normal faults and DGSD slip zones, is consistent with clast fragmentation, fluid‐infiltration, and congruent pressure‐solution active at low ambient temperatures (<60°C) and lithostatic pressures (<80 MPa). Although clast comminution is more intense in the slip zones of normal faults because of the larger displacement accommodated, we are not able to find microstructural markers that allow us to uniquely distinguish faults from DGSDs.
Microglial-expressed genetic risk variants, cognitive function and brain volume in patients with schizophrenia and healthy controls
Authors: Corley Emma , Holleran Laurena , Fahey Laura , Corvin Aiden , Morris Derek W. , Donohoe Gary 
Published: September 2021

AbstractChanges in immune function are associated with variance in cognitive functioning in schizophrenia. Given that microglia are the primary innate immune cells in the brain, we examined whether schizophrenia risk-associated microglial genes (measured via polygenic score analysis) explained variation in cognition in patients with schizophrenia and controls (n = 1,238) and tested whether grey matter mediated this association. We further sought to replicate these associations in an independent sample of UK Biobank participants (n = 134,827). We then compared the strength of these microglial associations to that of neuronal and astroglial (i.e., other brain-expressed genes) polygenic scores, and used MAGMA to test for enrichment of these gene-sets with schizophrenia risk. Increased microglial schizophrenia polygenic risk was associated with significantly lower performance across several measures of cognitive functioning in both samples; associations which were then found to be mediated via total grey matter volume in the UK Biobank. Unlike neuronal genes which did show evidence of enrichment, the microglial gene-set was not significantly enriched for schizophrenia, suggesting that the relevance of microglia may be for neurodevelopmental processes related more generally to cognition. Further, the microglial polygenic score was associated with performance on a range of cognitive measures in a manner comparable to the neuronal schizophrenia polygenic score, with fewer cognitive associations observed for the astroglial score. In conclusion, our study supports the growing evidence of the importance of immune processes to understanding cognition and brain structure in both patients and in the healthy population.
Inhibition of Notch activity promotes pancreatic cytokeratin 5-positive cell differentiation to beta cells and improves glucose homeostasis following acute pancreatitis
Authors: Zhang Xiaoyi , Tao Jing , Yu Jia , Hu Ning , Zhang Xuanzhe , Wang Guirong , Feng Jiarui , Xiong Xingcheng , Li Man , Chai Dongqi , Li Hanjun , Rong Yuping , Tang Zhigang , Wang Weixing , Peng Zhiyong , Shi Qiao 
Published: September 2021

AbstractSome individuals develop prediabetes and/or diabetes following acute pancreatitis (AP). AP-induced beta-cell injury and the limited regenerative capacity of beta cells might account for pancreatic endocrine insufficiency. Previously, we found that only a few pancreatic cytokeratin 5 positive (Krt5+) cells differentiated into beta cells in the murine AP model, which was insufficient to maintain glucose homeostasis. Notch signaling determines pancreatic progenitor differentiation in pancreas development. This study aimed to examine whether Notch signaling inhibition could promote pancreatic Krt5+ cell differentiation into beta cells and improve glucose homeostasis following AP. Pancreatic tissues from patients with acute necrotizing pancreatitis (ANP) were used to evaluate beta-cell injury, Krt5+ cell activation and differentiation, and Notch activity. The murine AP model was induced by cerulein, and the effect of Notch inhibition on Krt5+ cell differentiation was evaluated both in vivo and in vitro. The results demonstrated beta-cell loss in ANP patients and AP mice. Krt5+ cells were activated in ANP pancreases along with persistently elevated Notch activity, which resulted in the formation of massive duct-like structures. AP mice that received Notch inhibitor showed that impaired glucose tolerance was reversed 7 and 15 days following AP, and increased numbers of newborn small islets due to increased differentiation of Krt5+ cells to beta cells to some extent. In addition, Krt5+ cells isolated from AP mice showed increased differentiation to beta cells by Notch inhibition. Collectively, these findings suggest that beta-cell loss contributes to pancreatic endocrine insufficiency following AP, and inhibition of Notch activity promotes pancreatic Krt5+ cell differentiation to beta cells and improves glucose homeostasis. The findings from this study may shed light on the potential treatment of prediabetes/diabetes following AP.
Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
Authors: Perzel Mandell Kira A. , Eagles Nicholas J. , Wilton Richard , Price Amanda J. , Semick Stephen A. , Collado-Torres Leonardo , Ulrich William S. , Tao Ran , Han Shizhong , Szalay Alexander S. , Hyde Thomas M. , Kleinman Joel E. , Weinberger Daniel R. , Jaffe Andrew E. 
Published: September 2021

AbstractDNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction. Using whole-genome bisulfite sequencing, we have surveyed DNAm in 344 samples of human postmortem brain tissue from neurotypical subjects and individuals with schizophrenia. We identify genetic influence on local methylation levels throughout the genome, both at CpG sites and CpH sites, with 86% of SNPs and 55% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting the genes and regions with which these loci are epigenetically associated. These findings can be used to better characterize schizophrenia GWAS-identified variants as epigenetic risk variants. Regions differentially methylated by schizophrenia risk-SNPs explain much of the heritability associated with risk loci, despite covering only a fraction of the genomic space. We provide a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain.
Peroxisome inspired hybrid enzyme nanogels for chemodynamic and photodynamic therapy
Authors: Qin Xing , Wu Chu , Niu Dechao , Qin Limei , Wang Xia , Wang Qigang , Li Yongsheng 
Published: September 2021

AbstractPeroxisome, a special cytoplasmic organelle, possesses one or more kinds of oxidases for hydrogen peroxide (H2O2) production and catalase for H2O2 degradation, which serves as an intracellular H2O2 regulator to degrade toxic peroxides to water. Inspired by this biochemical pathway, we demonstrate the reactive oxygen species (ROS) induced tumor therapy by integrating lactate oxidase (LOx) and catalase (CAT) into Fe3O4 nanoparticle/indocyanine green (ICG) co-loaded hybrid nanogels (designated as FIGs-LC). Based on the O2 redistribution and H2O2 activation by cascading LOx and CAT catalytic metabolic regulation, hydroxyl radical (·OH) and singlet oxygen (1O2) production can be modulated for glutathione (GSH)-activated chemodynamic therapy (CDT) and NIR-triggered photodynamic therapy (PDT), by manipulating the ratio of LOx and CAT to catalyze endogenous lactate to produce H2O2 and further cascade decomposing H2O2 into O2. The regulation reactions of FIGs-LC significantly elevate the intracellular ROS level and cause fatal damage to cancer cells inducing the effective inhibition of tumor growth. Such enzyme complex loaded hybrid nanogel present potential for biomedical ROS regulation, especially for the tumors with different redox state, size, and subcutaneous depth.
Synthetic exploration of sulfinyl radicals using sulfinyl sulfones
Authors: Wang Zikun , Zhang Zhansong , Zhao Wanjun , Sivaguru Paramasivam , Zanoni Giuseppe , Wang Yingying , Anderson Edward A. , Bi Xihe 
Published: September 2021

AbstractSulfinyl radicals – one of the fundamental classes of S-centered radicals – have eluded synthetic application in organic chemistry for over 60 years, despite their potential to assemble valuable sulfoxide compounds. Here we report the successful generation and use of sulfinyl radicals in a dual radical addition/radical coupling with unsaturated hydrocarbons, where readily-accessed sulfinyl sulfones serve as the sulfinyl radical precursor. The strategy provides an entry to a variety of previously inaccessible linear and cyclic disulfurized adducts in a single step, and demonstrates tolerance to an extensive range of hydrocarbons and functional groups. Experimental and theoretical mechanistic investigations suggest that these reactions proceed through sequential sulfonyl and sulfinyl radical addition.
A comprehensive map of alternative polyadenylation in African American and European American lung cancer patients
Authors: Zingone Adriana , Sinha Sanju , Ante Michael , Nguyen Cu , Daujotyte Dalia , Bowman Elise D. , Sinha Neelam , Mitchell Khadijah A. , Chen Qingrong , Yan Chunhua , Loher Phillipe , Meerzaman Daoud , Ruppin Eytan , Ryan Bríd M. 
Published: September 2021

AbstractDeciphering the post-transcriptional mechanisms (PTM) regulating gene expression is critical to understand the dynamics underlying transcriptomic regulation in cancer. Alternative polyadenylation (APA)—regulation of mRNA 3′UTR length by alternating poly(A) site usage—is a key PTM mechanism whose comprehensive analysis in cancer remains an important open challenge. Here we use a method and analysis pipeline that sequences 3′end-enriched RNA directly to overcome the saturation limitation of traditional 5′–3′ based sequencing. We comprehensively map the APA landscape in lung cancer in a cohort of 98 tumor/non-involved tissues derived from European American and African American patients. We identify a global shortening of 3′UTR transcripts in lung cancer, with notable functional implications on the expression of both coding and noncoding genes. We find that APA of non-coding RNA transcripts (long non-coding RNAs and microRNAs) is a recurrent event in lung cancer and discover that the selection of alternative polyA sites is a form of non-coding RNA expression control. Our results indicate that mRNA transcripts from EAs are two times more likely than AAs to undergo APA in lung cancer. Taken together, our findings comprehensively map and identify the important functional role of alternative polyadenylation in determining transcriptomic heterogeneity in lung cancer.
Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach
Authors: Huang Jonathan Yinhao , Cai Shirong , Huang Zhongwei , Tint Mya Thway , Yuan Wen Lun , Aris Izzuddin M. , Godfrey Keith M. , Karnani Neerja , Lee Yung Seng , Chan Jerry Kok Yen , Chong Yap Seng , Eriksson Johan Gunnar , Chan Shiao-Yng 
Published: September 2021

AbstractAssisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (−0.5 SD [95% CI: −0.7, −0.2]), lighter (−0.6 SD [−0.9, −0.3]) and have lower skinfold thicknesses (e.g. −14% [−24%, −3%] suprailiac), and blood pressure (−3 mmHg [−6, −0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.
Field-free topological behavior in the magnetic domain wall of ferrimagnetic GdFeCo
Authors: Li Zhuolin , Su Jian , Lin Shi-Zeng , Liu Dan , Gao Yang , Wang Shouguo , Wei Hongxiang , Zhao Tongyun , Zhang Ying , Cai Jianwang , Shen Baogen 
Published: September 2021

AbstractExploring and controlling topological textures such as merons and skyrmions has attracted enormous interests from the perspective of fundamental research and spintronic applications. It has been predicted theoretically and proved experimentally that the lattice form of topological meron-skyrmion transformation can be realized with the requirement of external magnetic fields in chiral ferromagnets. However, such topological transition behavior has yet to be verified in other materials. Here, we report real-space observation of magnetic topology transformation between meron pairs and skyrmions in the localized domain wall of ferrimagnetic GdFeCo films without the need of magnetic fields. The topological transformation in the domain wall of ferrimagnet is introduced by temperature-induced spin reorientation transition (SRT) and the underlying mechanism is revealed by micromagnetic simulations. The convenient electric-controlling topology transformation and driving motion along the confined domain wall is further anticipated, which will enable advanced application in magnetic devices.
Generation of a more efficient prime editor 2 by addition of the Rad51 DNA-binding domain
Authors: Song Myungjae , Lim Jung Min , Min Seonwoo , Oh Jeong-Seok , Kim Dong Young , Woo Jae-Sung , Nishimasu Hiroshi , Cho Sung-Rae , Yoon Sungroh , Kim Hyongbum Henry 
Published: September 2021

AbstractAlthough prime editing is a promising genome editing method, the efficiency of prime editor 2 (PE2) is often insufficient. Here we generate a more efficient variant of PE2, named hyPE2, by adding the Rad51 DNA-binding domain. When tested at endogenous sites, hyPE2 shows a median of 1.5- or 1.4- fold (range, 0.99- to 2.6-fold) higher efficiencies than PE2; furthermore, at sites where PE2-induced prime editing is very inefficient (efficiency < 1%), hyPE2 enables prime editing with efficiencies ranging from 1.1% to 2.9% at up to 34% of target sequences, potentially facilitating prime editing applications.
A blueprint of the topology and mechanics of the human ovary for next-generation bioengineering and diagnosis
Authors: Ouni Emna , Peaucelle Alexis , Haas Kalina T. , Van Kerk Olivier , Dolmans Marie-Madeleine , Tuuri Timo , Otala Marjut , Amorim Christiani A. 
Published: September 2021

AbstractAlthough the first dissection of the human ovary dates back to the 17th century, the biophysical characteristics of the ovarian cell microenvironment are still poorly understood. However, this information is vital to deciphering cellular processes such as proliferation, morphology and differentiation, as well as pathologies like tumor progression, as demonstrated in other biological tissues. Here, we provide the first readout of human ovarian fiber morphology, interstitial and perifollicular fiber orientation, pore geometry, topography and surface roughness, and elastic and viscoelastic properties. By determining differences between healthy prepubertal, reproductive-age, and menopausal ovarian tissue, we unravel and elucidate a unique biophysical phenotype of reproductive-age tissue, bridging biophysics and female fertility. While these data enable to design of more biomimetic scaffolds for the tissue-engineered ovary, our analysis pipeline is applicable for the characterization of other organs in physiological or pathological states to reveal their biophysical markers or design their bioinspired analogs.
Berberine is an insulin secretagogue targeting the KCNH6 potassium channel
Authors: Zhao Miao-Miao , Lu Jing , Li Sen , Wang Hao , Cao Xi , Li Qi , Shi Ting-Ting , Matsunaga Kohichi , Chen Chen , Huang Haixia , Izumi Tetsuro , Yang Jin-Kui 
Published: September 2021

AbstractCoptis chinensisis an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specificKcnh6knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.
Periodontitis associates with species-specific gene expression of the oral microbiota
Authors: Belstrøm Daniel , Constancias Florentin , Drautz-Moses Daniela I. , Schuster Stephan C. , Veleba Mark , Mahé Frédéric , Givskov Michael 
Published: September 2021

AbstractThe purpose of the present investigation was to characterize species-specific bacterial activity of the oral microbiota in periodontitis. We tested the hypotheses that chronic inflammation, i.e., periodontitis, associates with bacterial gene expression of the oral microbiota. Oral microbial samples were collected from three oral sites—subgingival plaque, tongue, and saliva from patients with periodontitis and healthy controls. Paired metagenomics and metatranscriptomics were used to perform concomitant characterization of taxonomic composition and to determine species-specific bacterial activity as expressed by the ratio of specific messenger RNA reads to their corresponding genomic DNA reads. Here, we show the association of periodontitis with bacterial gene expression of the oral microbiota. While oral site was the main determinant of taxonomic composition as well as bacterial gene expression, periodontitis was significantly associated with a reduction of carbohydrate metabolism of the oral microbiota at three oral sites (subgingival plaque, tongue, and saliva). Data from the present study revealed the association of periodontitis with bacterial gene expression of the oral microbiota. Conditions of periodontitis was associated with bacterial activity of local subgingival plaque, but also on tongue and the salivary microbiota. Collectively, data suggest that periodontitis associates with impaired carbohydrate metabolism of the oral microbiota. Future longitudinal and interventional studies are warranted to evaluate the potential pathogenic role of impaired bacterial carbohydrate metabolism not only in periodontitis but also in other diseases with low-grade inflammation, such as type 2 diabetes mellitus.