bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Changing Arctic Sea Ice Extent, Sea Ice Age, and Snow Depth on Sea Salt Aerosol From Blowing Snow and the Open Ocean for 1980–2017
Authors: Confer K. L. , Jaeglé L. , Liston G. E. , Sharma S. , Nandan V. , Yackel J. , Ewert M. , Horowitz H. M.
Published: January 2023

We evaluate the effects of rapidly changing Arctic sea ice conditions on sea salt aerosols (SSA) produced by oceanic wave‐breaking and the sublimation of wind‐lofted salty blowing snow on sea ice. We use the GEOS‐Chem chemical transport model to assess the influence of changing extent of the open ocean, multi‐year sea ice (MYI), first‐year sea ice (FYI), and snow depths on SSA emissions for 1980–2017. We combine snow depths from the Lagrangian snow‐evolution model (SnowModel‐LG) together with an empirically‐derived snow salinity function of snow depth to derive spatially and temporally varying snow surface salinity over Arctic FYI. We find that pan‐Arctic SSA surface mass concentrations have increased by 6%–12% decade−1 during the cold season (November–April) and by 7%–11% decade−1 during the warm season (May–October). The cold season trend is due to increasing blowing snow SSA originating from FYI: as MYI is replaced by FYI with thinning snow depths, snow surface salinity increases by more than 11% decade−1. During the warm season, rapid sea ice loss and thus increasing open ocean SSA are the cause of modeled SSA trends. Observations of SSA mass concentrations at Alert, Canada display positive trends during the cold season (10%–12% decade−1), consistent with our pan‐Arctic simulations. During fall, Alert observations show a negative trend (−18% decade−1), due to locally decreasing wind speeds and thus lower open ocean emissions. These significant changes in SSA concentrations could potentially affect past and future bromine explosions and Arctic climate feedbacks.
Hydroclimate Variability in the Equatorial Western Indian Ocean for the Last 250,000 Years
Authors: Windler Grace , Tierney Jessica E. , deMenocal Peter B.
Published: January 2023

Indian Ocean sea surface temperatures impact precipitation across the basin through coupled ocean‐atmosphere responses to changes in climate. To understand the hydroclimate response over the western Indian Ocean and equatorial east Africa to different forcing mechanisms, we present four new proxy reconstructions from core VM19‐193 (2.98°N, 51.47°E) that span the last 250 ky. Sub‐surface water temperatures (Sub‐T; TEX86) show strong precessional (23 ky) variability that is primarily influenced by maximum incoming solar radiation (insolation) during the Northern Hemisphere spring season, likely indicating that local insolation dominates the upper water column at this tropical location over time. Leaf waxes, on the other hand, reflect two different precipitation signals: δ13Cwax (in phase with boreal fall insolation) is likely reflecting vegetation changes in response to local rainfall over east Africa, whereas δDprecip (primarily driven by boreal summer insolation) represents changes in regional circulation associated with the summer monsoon. Glacial‐interglacial changes in ocean temperatures support glacial shelf exposure over the Maritime Continent in the eastern Indian Ocean and the subsequent weakening of the Indian Walker Circulation as a mechanism driving 100 ky climate variability across the tropical Indo‐Pacific. Additionally, the 100 ky spectral power in δDprecip supports a basin‐wide weakening of summer monsoon circulation in response to glacial climates. Overall, the proxy records from VM19‐193 indicate that both precession and glacial‐interglacial cycles exert control over hydroclimate at this tropical location.
Geodynamics of the Central Tethyan Belt Revisited: Inferences From Crustal Magnetization in the Anatolia‐Caucasus‐Black Sea Region
Authors: Teknik V. , Artemieva I. M. , Thybo H.
Published: January 2023

We calculate the depth to magnetic basement and the average crustal magnetic susceptibility, which is sensitive to the presence of iron‐rich minerals, to interpret the present structure and the tecto‐magmatic evolution in the Central Tethyan belt. Our results demonstrate exceptional variability of crustal magnetization with smooth, small‐amplitude anomalies in the Gondwana realm and short‐wavelength high‐amplitude variations in the Laurentia realm. Poor correlation between known ophiolites and magnetization anomalies indicates that Tethyan ophiolites are relatively poorly magnetized, which we explain by demagnetization during recent magmatism. We analyze regional magnetic characteristics for mapping previously unknown oceanic fragments and mafic intrusions, hidden beneath sedimentary sequences or overprinted by tectono‐magmatic events. By the style of crustal magnetization, we distinguish three types of basins and demonstrate that many small‐size basins host large volumes of magmatic rocks within or below the sedimentary cover. We map the width of magmatic arcs to estimate paleo‐subduction dip angle and find no systematic variation between the Neo‐Tethys and Paleo‐Tethys subduction systems, while the Pontides magmatic arc has shallow (∼15°) dip in the east and steep (∼50°–55°) dip in the west. We recognize an unknown, buried 450 km‐long magmatic arc along the western margin of the Kırşehir massif formed above steep (55°) subduction. We propose that lithosphere fragmentation associated with Neo‐Tethys subduction systems may explain high‐amplitude, high‐gradient crustal magnetization in the Caucasus Large Igneous Province. Our results challenge conventional regional geological models, such as Neo‐Tethyan subduction below the Greater Caucasus, and call for reevaluation of the regional paleotectonics.
Obstructive sleep apnea (OSA) is associated with the impairment of beta-cell response to glucose in children and adolescents with obesity
Authors: Umano Giuseppina Rosaria , Galderisi Alfonso , Aiello Francesca , Martino Mariangela , Camponesco Ornella , Di Sessa Anna , Marzuillo Pierluigi , Alfonso Papparella , Miraglia del Giudice Emanuele
Published: January 2023

Background

The main purpose of the study is to assess the association between obstructive sleep apnea (OSA) and insulin secretion in children with obesity.

Methods

We enrolled children and adolescents who attended our pediatric clinic because of obesity and OSA. Glucose homeostasis was assessed through standard 2-h oral glucose tolerance test (OGTT). Nocturnal cardio-respiratory polygraphy was performed for OSA diagnosis. Twenty-two patients underwent a 3-h OGTT to investigate insulin secretion and sensitivity through the oral-minimal model.

Results

seventy-seven children and adolescents were included in the study. Based on OSA severity, the cohort was divided into three groups (29 mild, 29 moderate, and 19 severe OSA). The group with mild OSA showed lower levels of 30-min glucose (p = 0.01) and 60-min glucose (p = 0.03), and lower prevalence of elevated 1-h glucose (10.4% versus 44.8% in moderate and 31.6% in severe OSA, p = 0.01). The odds for elevated 1-h plasma glucose was 6.2-fold (95%CI 1.6–23.4) higher in subjects with moderate and severe OSA compared to mild OSA (p = 0.007) independent of confounders. Spearman correlation test revealed a positive correlation between 30-min plasma glucose and apnea-hypopnea index (AHI, r = 0.31, p = 0.01), oxygen desaturation index (ODI, r = 0.31, p = 0.009), and mean desaturation (r = 0.25, p = 0.04). The 3-h OGTT study included 22 participants (7 mild, 9 moderate, and 6 severe OSA). The group with mild OSA showed a higher dynamic, static, and total insulin secretion compared to those with moderate and severe OSA (p < 0.0001, p = 0.007, p = 0.007, respectively). AHI was significantly correlated to dynamic insulin secretion (r = −0.48, p = 0.02).

Conclusions

OSA might impair beta-cell function reducing the pool of promptly releasable insulin in children and adolescents with obesity, in the absence of an effect on insulin sensitivity.
Cell differentiation modifies the p53 transcriptional program through a combination of gene silencing and constitutive transactivation
Authors: Tatavosian Roubina , Donovan Micah G. , Galbraith Matthew D. , Duc Huy N. , Szwarc Maria M. , Joshi Molishree U. , Frieman Amy , Bilousova Ganna , Cao Yingqiong , Smith Keith P. , Song Kunhua , Rachubinski Angela L. , Andrysik Zdenek , Espinosa Joaquin M.
Published: January 2023

The p53 transcription factor is a master regulator of cellular responses to stress that is commonly inactivated in diverse cancer types. Despite decades of research, the mechanisms by which p53 impedes tumorigenesis across vastly different cellular contexts requires further investigation. The bulk of research has been completed using in vitro studies of cancer cell lines or in vivo studies in mouse models, but much less is known about p53 action in diverse non-transformed human tissues. Here, we investigated how different cellular states modify the p53 transcriptional program in human cells through a combination of computational analyses of publicly available large-scale datasets and in vitro studies using an isogenic system consisting of induced pluripotent stem cells (iPSCs) and two derived lineages. Analysis of publicly available mRNA expression and genetic dependency data demonstrated wide variation in terms of expression and function of a core p53 transcriptional program across various tissues and lineages. To monitor the impact of cell differentiation on the p53 transcriptome within an isogenic cell culture system, we activated p53 by pharmacological inhibition of its negative regulator MDM2. Using cell phenotyping assays and genome wide transcriptome analyses, we demonstrated that cell differentiation confines and modifies the p53 transcriptional network in a lineage-specific fashion. Although hundreds of p53 target genes are transactivated in iPSCs, only a small fraction is transactivated in each of the differentiated lineages. Mechanistic studies using small molecule inhibitors and genetic knockdowns revealed the presence of two major regulatory mechanisms contributing to this massive heterogeneity across cellular states: gene silencing by epigenetic regulatory complexes and constitutive transactivation by lineage-specific transcription factors. Altogether, these results illuminate the impact of cell differentiation on the p53 program, thus advancing our understanding of how this tumor suppressor functions in different contexts.
Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway
Authors: Yuan Baoshi , Shi Kexin , Zha Juanmin , Cai Yujia , Gu Yue , Huang Kai , Yue Wenchang , Zhai Qiaocheng , Ding Ning , Ren Wenyan , He Weiqi , Xu Ying , Wang Tao
Published: January 2023

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.
Longitudinal efficacy and toxicity of SARS-CoV-2 vaccination in cancer patients treated with immunotherapy
Authors: Spiliopoulou Pavlina , Janse van Rensburg Helena J. , Avery Lisa , Kulasingam Vathany , Razak Albiruni , Bedard Philippe , Hansen Aaron , Chruscinski Andrzej , Wang Ben , Kulikova Maria , Chen Rachel , Speers Vanessa , Nguyen Alisa , Lee Jasmine , Coburn Bryan , Spreafico Anna , Siu Lillian L.
Published: January 2023

Despite more than 2 years having elapsed since the onset of SARS-CoV-2 pandemic, a level of hesitation around increased SARS-CoV-2 vaccine toxicity in cancer patients receiving immunotherapy (IO) remains. This hesitation stems from the idea that IO agents could elicit an overwhelming immune stimulation post vaccination and therefore increase the risk of vaccine-related toxicity. The aim of our study was to explore serological responses to SARS-CoV-2 vaccination in patients treated with IO and describe the level of immune stimulation using parameters such as blood cytokines, autoantibody levels and immune related adverse events (irAEs) post vaccination. Fifty-one evaluable patients were enrolled in this longitudinal study. Absolute levels and neutralization potential of anti-SARS-CoV-2 antibodies were not significantly different in the IO group compared to non-IO. Chemotherapy adversely affected seroconversion when compared to IO and/or targeted treatment. Following vaccination, the prevalence of grade ≥2 irAEs in patients treated with IO was not higher than the usual reported IO toxicity. We report, for the first time, that anti-SARS-CoV-2 vaccination, elicited the generation of five autoantibodies. The significantly increased autoantibodies were IgM autoantibodies against beta-2 glycoprotein (p = 0.02), myeloperoxidase (p = 0.03), nucleosome (p = 0.041), SPLUNC2 (p < 0.001) and IgG autoantibody against Myosin Heavy Chain 6 (MYH6) (p < 0.001). Overall, comprehensive analysis of a small cohort showed that co-administration of SARS-CoV-2 vaccine and IO is not associated with increased irAEs. Nevertheless, the detection of autoantibodies post anti-SARS-CoV-2 vaccination warrants further investigation (NCT03702309).
BACH1-induced ferroptosis drives lymphatic metastasis by repressing the biosynthesis of monounsaturated fatty acids
Authors: Xie Xiufeng , Tian Lusong , Zhao Yan , Liu Fang , Dai Shuyang , Gu Xinglu , Ye Yuxin , Zhou Lanping , Liu Xinmiao , Sun Yulin , Zhao Xiaohang
Published: January 2023

Esophageal squamous cell carcinoma (ESCC) is one of the fatal malignancies worldwide. It has an increased propensity to metastasize via lymphogenous routes in an early stage. The prognosis of patients with lymph node metastases (LNM) is often worse than that of patients without metastases. Although several factors have been found to influence metastasis, the mechanisms of preference for specific metastatic routes remain poorly understood. Herein, we provide evidence that the intrinsic hypersensitivity of tumor cells to ferroptosis may proactively drive lymphatic metastasis. Serum autoantibodies associated with LNM of early ESCC were screened using a whole-proteome protein array containing 19 394 human recombinant proteins, and an anti-BACH1 autoantibody was first identified. Pan-cancer analysis of ferroptosis-related genes with preferential lymphatic metastasis and preferential hematogenous metastasis based on The Cancer Genome Atlas data was performed. Only BACH1 showed significant overexpression in tumors with preferential lymphatic metastasis, whereas it was downregulated in most tumors with preferential nonlymphatic metastasis. In addition, it was found that the serum levels of autoantibodies against BACH1 were elevated in early-stage patients with LNM. Interestingly, BACH1 overexpression and ferroptosis induction promoted LNM but inhibited hematogenous metastasis in mouse models. Transcriptomic and lipidomic analyses found that BACH1 repressed SCD1-mediated biosynthesis of monounsaturated fatty acids, especially oleic acid (OA). OA significantly attenuated the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. OA addition significantly rescued the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. Importantly, the concentration gradient of OA between primary lesions and the lymph resulted in the chemoattraction of tumor cells to promote invasion, thus facilitating lymphatic metastasis. BACH1-induced ferroptosis drives lymphatic metastasis via the BACH1-SCD1-OA axis. More importantly, this study confirms that ferroptosis is a double-edged sword in tumorigenesis and tumor progression. The clinical application of ferroptosis-associated agents requires a great caution.
Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer
Authors: Su Yong-Han , Wu Yi-Zhen , Ann David K. , Chen Jenny Ling-Yu , Kuo Ching-Ying
Published: January 2023

Obesity is a risk factor in various types of cancer, including breast cancer. The disturbance of adipose tissue in obesity highly correlates with cancer progression and resistance to standard treatments such as chemo- and radio-therapies. In this study, in a syngeneic mouse model of triple-negative breast cancer (TNBC), diet-induced obesity (DIO) not only promoted tumor growth, but also reduced tumor response to radiotherapy. Serpine1 (Pai-1) was elevated in the circulation of obese mice and was enriched within tumor microenvironment. In vitro co-culture of human white adipocytes-conditioned medium (hAd-CM) with TNBC cells potentiated the aggressive phenotypes and radioresistance of TNBC cells. Moreover, inhibition of both cancer cell autonomous and non-autonomous SERPINE1 by either genetic or pharmacological strategy markedly dampened the aggressive phenotypes and radioresistance of TNBC cells. Mechanistically, we uncovered a previously unrecognized role of SERPINE1 in DNA damage response. Ionizing radiation-induced DNA double-strand breaks (DSBs) increased the expression of SERPINE1 in cancer cells in an ATM/ATR-dependent manner, and promoted nuclear localization of SERPINE1 to facilitate DSB repair. By analyzing public clinical datasets, higher SERPINE1 expression in TNBC correlated with patients’ BMI as well as poor outcomes. Elevated SERPINE1 expression and nuclear localization were also observed in radioresistant breast cancer cells. Collectively, we reveal a link between obesity and radioresistance in TNBC and identify SERPINE1 to be a crucial factor mediating obesity-associated tumor radioresistance.
Crocetin antagonizes parthanatos in ischemic stroke via inhibiting NOX2 and preserving mitochondrial hexokinase-I
Authors: Wu Hao , Li Ying , Zhang Qian , Wang Hanxun , Xiu Wenyu , Xu Pu , Deng Yujie , Huang Wanxu , Wang Dan Ohtan
Published: January 2023

Parthanatos is one of the major pathways of programmed cell death in ischemic stroke characterized by DNA damage, poly (ADP-ribose) polymerases (PARP) activation, and poly (ADP-ribose) (PAR) formation. Here we demonstrate that crocetin, a natural potent antioxidant compound from Crocus sativus, antagonizes parthanatos in ischemic stroke. We reveal that mechanistically, crocetin inhibits NADPH oxidase 2 (NOX2) activation to reduce reactive oxygen species (ROS) and PAR production at the early stage of parthanatos. Meanwhile we demonstrate that PARylated hexokinase-I (HK-I) is a novel substrate of E3 ligase RNF146 and that crocetin interacts with HK-I to suppress RNF146-mediated HK-I degradation at the later stage of parthanatos, preventing mitochondrial dysfunction and DNA damage that ultimately trigger the irreversible cell death. Our study supports further development of crocetin as a potential drug candidate for preventing and/or treating ischemic stroke.
miR-150-5p in neutrophil-derived extracellular vesicles associated with sepsis-induced cardiomyopathy in septic patients
Authors: Ye Rongzong , Lin Qiuyun , Xiao Wenkai , Mao Lixia , Zhang Pengfei , Zhou Lingshan , Wu Xiaoxia , Jiang Nannan , Zhang Xihe , Zhang Yinhua , Ma Daqing , Huang Jiahao , Wang Xiaoyan , Deng Liehua
Published: January 2023

Introduction

Early diagnosis and potential therapeutic targets of sepsis-induced cardiomyopathy (SIC) remain challenges clinically. Circulating extracellular vesicles from immune cells carrying crucial injurious mediators, including miRNAs in sepsis. However, the impacts of neutrophil-derived extracellular vesicles and their miRNAs in the SIC development are unknown.

Objectives

The present study focused on the in-depth miRNA expression profiles of neutrophil-derived extracellular vesicles and explored the potential molecular biomarkers during the process of SIC.

Methods

Neutrophil-derived extracellular vesicles were isolated from the blood samples in three sepsis patients with or without cardiomyopathy on day 1 and day 3 after ICU admission in comparison with three healthy controls. miRNAs were determined by RNA sequencing. The closely related differentially expressed miRNAs with SIC were further validated through qRT-PCR in the other cohorts of sepsis patients with (30 patients) or without cardiomyopathy (20 patients) and the association between miRNAs and the occurrence or disease severity of septic cardiomyopathy were stratified with logistic regression analysis.

Results

Sixty-eight miRNAs from neutrophil-derived extracellular vesicles were changed significantly between healthy controls and without septic cardiomyopathy patients (61 miRNAs upregulated and seven downregulated). Thirty-eight miRNAs were differentially expressed in the septic cardiomyopathy patients. 27 common differentially expressed miRNAs were found in both groups with similar kinetics (23 miRNAs upregulated and four downregulated). The enriched cellular signaling pathway mediated by miRNAs from sepsis to septic cardiomyopathy was the HIF-1 signaling system modulated septic inflammation. Using multivariate logistic regression analysis, miR-150-5p coupled with NT-pro BNP, LVEF, and SOFA score (AUC = 0.941) were found to be the independent predictors of septic cardiomyopathy.

Conclusion

miRNAs derived from neutrophil-derived extracellular vesicles play an important role in septic disease severity development towards cardiomyopathy. miR-150-5p may be a predictor of sepsis severity development but warrants further study.
Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease
Authors: Diener Caroline , Hart Martin , Kehl Tim , Becker-Dorison Anouck , Tänzer Tanja , Schub David , Krammes Lena , Sester Martina , Keller Andreas , Unger Marcus , Walch-Rückheim Barbara , Lenhof Hans-Peter , Meese Eckart
Published: January 2023

Parkinson’s disease (PD) emerges as a complex, multifactorial disease. While there is increasing evidence that dysregulated T cells play a central role in PD pathogenesis, elucidation of the pathomechanical changes in related signaling is still in its beginnings. We employed time-resolved RNA expression upon the activation of peripheral CD4+ T cells to track and functionally relate changes on cellular signaling in representative cases of patients at different stages of PD. While only few miRNAs showed time-course related expression changes in PD, we identified groups of genes with significantly altered expression for each different time window. Towards a further understanding of the functional consequences, we highlighted pathways with decreased or increased activity in PD, including the most prominent altered IL-17 pathway. Flow cytometric analyses showed not only an increased prevalence of Th17 cells but also a specific subtype of IL-17 producing γδ-T cells, indicating a previously unknown role in PD pathogenesis.
Epigenomic charting and functional annotation of risk loci in renal cell carcinoma
Authors: Nassar Amin H. , Abou Alaiwi Sarah , Baca Sylvan C. , Adib Elio , Corona Rosario I. , Seo Ji-Heui , Fonseca Marcos A. S. , Spisak Sandor , El Zarif Talal , Tisza Viktoria , Braun David A. , Du Heng , He Monica , Flaifel Abdallah , Alchoueiry Michel , Denize Thomas , Matar Sayed G. , Acosta Andres , Shukla Sachet , Hou Yue , Steinharter John , Bouchard Gabrielle , Berchuck Jacob E. , O’Connor Edward , Bell Connor , Nuzzo Pier Vitale , Mary Lee Gwo-Shu , Signoretti Sabina , Hirsch Michelle S. , Pomerantz Mark , Henske Elizabeth , Gusev Alexander , Lawrenson Kate , Choueiri Toni K. , Kwiatkowski David J. , Freedman Matthew L.
Published: January 2023

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.
Surface charge as activity descriptors for electrochemical CO2 reduction to multi-carbon products on organic-functionalised Cu
Authors: Lim Carina Yi Jing , Yilmaz Meltem , Arce-Ramos Juan Manuel , Handoko Albertus D. , Teh Wei Jie , Zheng Yuangang , Khoo Zi Hui Jonathan , Lin Ming , Isaacs Mark , Tam Teck Lip Dexter , Bai Yang , Ng Chee Koon , Yeo Boon Siang , Sankar Gopinathan , Parkin Ivan P. , Hippalgaonkar Kedar , Sullivan Michael B. , Zhang Jia , Lim Yee-Fun
Published: January 2023

Intensive research in electrochemical CO2 reduction reaction has resulted in the discovery of numerous high-performance catalysts selective to multi-carbon products, with most of these catalysts still being purely transition metal based. Herein, we present high and stable multi-carbon products selectivity of up to 76.6% across a wide potential range of 1 V on histidine-functionalised Cu. In-situ Raman and density functional theory calculations revealed alternative reaction pathways that involve direct interactions between adsorbed histidine and CO2 reduction intermediates at more cathodic potentials. Strikingly, we found that the yield of multi-carbon products is closely correlated to the surface charge on the catalyst surface, quantified by a pulsed voltammetry-based technique which proved reliable even at very cathodic potentials. We ascribe the surface charge to the population density of adsorbed species on the catalyst surface, which may be exploited as a powerful tool to explain CO2 reduction activity and as a proxy for future catalyst discovery, including organic-inorganic hybrids.
Dynamic rhenium dopant boosts ruthenium oxide for durable oxygen evolution
Authors: Jin Huanyu , Liu Xinyan , An Pengfei , Tang Cheng , Yu Huimin , Zhang Qinghua , Peng Hong-Jie , Gu Lin , Zheng Yao , Song Taeseup , Davey Kenneth , Paik Ungyu , Dong Juncai , Qiao Shi-Zhang
Published: January 2023

Heteroatom-doping is a practical means to boost RuO2 for acidic oxygen evolution reaction (OER). However, a major drawback is conventional dopants have static electron redistribution. Here, we report that Re dopants in Re0.06Ru0.94O2 undergo a dynamic electron accepting-donating that adaptively boosts activity and stability, which is different from conventional dopants with static dopant electron redistribution. We show Re dopants during OER, (1) accept electrons at the on-site potential to activate Ru site, and (2) donate electrons back at large overpotential and prevent Ru dissolution. We confirm via in situ characterizations and first-principle computation that the dynamic electron-interaction between Re and Ru facilitates the adsorbate evolution mechanism and lowers adsorption energies for oxygen intermediates to boost activity and stability of Re0.06Ru0.94O2. We demonstrate a high mass activity of 500 A gcata.−1 (7811 A gRe-Ru−1) and a high stability number of S-number = 4.0 × 106 noxygen nRu−1 to outperform most electrocatalysts. We conclude that dynamic dopants can be used to boost activity and stability of active sites and therefore guide the design of adaptive electrocatalysts for clean energy conversions.
Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development
Authors: Xu Xiaochan , Seymour Philip Allan , Sneppen Kim , Trusina Ala , Egeskov-Madsen Anuska la Rosa , Jørgensen Mette Christine , Jensen Mogens Høgh , Serup Palle
Published: January 2023

The Notch ligands Jag1 and Dll1 guide differentiation of multipotent pancreatic progenitor cells (MPCs) into unipotent pro-acinar cells (PACs) and bipotent duct/endocrine progenitors (BPs). Ligand-mediated trans-activation of Notch receptors induces oscillating expression of the transcription factor Hes1, while ligand-receptor cis-interaction indirectly represses Hes1 activation. Despite Dll1 and Jag1 both displaying cis- and trans-interactions, the two mutants have different phenotypes for reasons not fully understood. Here, we present a mathematical model that recapitulates the spatiotemporal differentiation of MPCs into PACs and BPs. The model correctly captures cell fate changes in Notch pathway knockout mice and small molecule inhibitor studies, and a requirement for oscillatory Hes1 expression to maintain the multipotent state. Crucially, the model entails cell-autonomous attenuation of Notch signaling by Jag1-mediated cis-inhibition in MPC differentiation. The model sheds light on the underlying mechanisms, suggesting that cis-interaction is crucial for exiting the multipotent state, while trans-interaction is required for adopting the bipotent fate.
Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing
Authors: Legier Thomas , Rattier Diane , Llewellyn Jack , Vannier Thomas , Sorre Benoit , Maina Flavio , Dono Rosanna
Published: January 2023

The processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between tissue organization and morphogens by using human induced pluripotent stem cells (hiPSCs) downregulated for the morphogen regulator GLYPICAN-4, in which defects in tight junctions result in areas of disrupted epithelial integrity. Remarkably, this phenotype does not affect hiPSC stemness, but impacts on cell fate acquisition. Strikingly, cells within disrupted areas become competent to perceive the gastrulation signals BMP4 and ACTIVIN A, an in vitro surrogate for NODAL, and thus differentiate into mesendoderm. Yet, disruption of epithelial integrity sustains activation of BMP4 and ACTIVIN A downstream effectors and correlates with enhanced hiPSC endoderm/mesoderm differentiation. Altogether, our results disclose epithelial integrity as a key determinant of TGF-β activity and highlight an additional mechanism guiding morphogen sensing and spatial cell fate change within an epithelium.
Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity
Authors: Liu Yue , Yang Yue , Xu Chenying , Liu Jianxing , Chen Jiale , Li Guoqing , Huang Bin , Pan Yi , Zhang Yanfeng , Wei Qiong , Pandol Stephen J. , Zhang Fangfang , Li Ling , Jin Liang
Published: January 2023

Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.
Mapping nucleolus-associated chromatin interactions using nucleolus Hi-C reveals pattern of heterochromatin interactions
Authors: Peng Ting , Hou Yingping , Meng Haowei , Cao Yong , Wang Xiaotian , Jia Lumeng , Chen Qing , Zheng Yang , Sun Yujie , Chen Hebing , Li Tingting , Li Cheng
Published: January 2023

As the largest substructures in the nucleus, nucleoli are the sites of ribosome biogenesis. Increasing evidence indicates that nucleoli play a key role in the organization of 3D genome architecture, but systematic studies of nucleolus-associated chromatin interactions are lacking. Here, we developed a nucleolus Hi-C (nHi-C) experimental technique to enrich nucleolus-associated chromatin interactions. Using the nHi-C experiment, we identify 264 high-confidence nucleolus-associated domains (hNADs) that form strong heterochromatin interactions associated with the nucleolus and consist of 24% of the whole genome in HeLa cells. Based on the global hNAD inter-chromosomal interactions, we find five nucleolar organizer region (NOR)-bearing chromosomes formed into two clusters that show different interaction patterns, which is concordant with their epigenetic states and gene expression levels. hNADs can be divided into three groups that display distinct cis/trans interaction signals, interaction frequencies associated with nucleoli, distance from the centromeres, and overlap percentage with lamina-associated domains (LADs). Nucleolus disassembly caused by Actinomycin D (ActD) significantly decreases the strength of hNADs and affects compartment/TAD strength genome-wide. In summary, our results provide a global view of heterochromatin interactions organized around nucleoli and demonstrate that nucleoli act as an inactive inter-chromosomal hub to shape both compartments and TADs.
Closing the gap to effective gene drive in Aedes aegypti by exploiting germline regulatory elements
Authors: Anderson Michelle A. E. , Gonzalez Estela , Ang Joshua X. D. , Shackleford Lewis , Nevard Katherine , Verkuijl Sebald A. N. , Edgington Matthew P. , Harvey-Samuel Tim , Alphey Luke
Published: January 2023

CRISPR/Cas9-based homing gene drives have emerged as a potential new approach to mosquito control. While attempts have been made to develop such systems in Aedes aegypti, none have been able to match the high drive efficiency observed in Anopheles species. Here we generate Ae. aegypti transgenic lines expressing Cas9 using germline-specific regulatory elements and assess their ability to bias inheritance of an sgRNA-expressing element (kmosgRNAs). Four shu-Cas9 and one sds3-Cas9 isolines can significantly bias the inheritance of kmosgRNAs, with sds3G1-Cas9 causing the highest average inheritance of ~86% and ~94% from males and females carrying both elements outcrossed to wild-type, respectively. Our mathematical model demonstrates that sds3G1-Cas9 could enable the spread of the kmosgRNAs element to either reach a higher (by ~15 percentage point) maximum carrier frequency or to achieve similar maximum carrier frequency faster (by 12 generations) when compared to two other established split drive systems.
Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins
Authors: Hou Xiaodong , Xu Huibin , Yuan Zhenbo , Deng Zhiwei , Fu Kai , Gao Yue , Liu Changmei , Zhang Yan , Rao Yijian
Published: January 2023

Asymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for asymmetric reduction is identified. We firstly solve crystal structures of CbAR and CbAR-Emodin complex. It reveals that Tyr210 is critical for emodin recognition and binding, as it forms a hydrogen-bond interaction with His162 and π-π stacking interactions with emodin. This ensures the correct orientation for the stereoselectivity. Then, through structure-guided engineering, variant CbAR-H162F can convert various 2,2-disubstituted 1,3-cyclodiketones and α-haloacetophenones to optically pure (2S, 3S)-ketols and (R)-β-halohydrins, respectively. More importantly, their stereoselectivity mechanisms are also well explained by the respective crystal structures of CbAR-H162F-substrate complex. Therefore, this study demonstrates that an in-depth understanding of catalytic mechanism is valuable for exploiting the promiscuity of anthrol reductases to prepare diverse enantiopure chiral alcohols.
Antimicrobial potential of known and novel probiotics on in vitro periodontitis biofilms
Authors: Van Holm Wannes , Carvalho Rita , Delanghe Lize , Eilers Tom , Zayed Naiera , Mermans Fabian , Bernaerts Kristel , Boon Nico , Claes Ingmar , Lebeer Sarah , Teughels Wim
Published: January 2023

Several oral diseases are characterized by a shift within the oral microbiome towards a pathogenic, dysbiotic composition. Broad-spectrum antimicrobials are often part of patient care. However, because of the rising antibiotic resistance, alternatives are increasingly desirable. Alternatively, supplying beneficial species through probiotics is increasingly showing favorable results. Unfortunately, these probiotics are rarely evaluated comparatively. In this study, the in vitro effects of three known and three novel Lactobacillus strains, together with four novel Streptococcus salivarius strains were comparatively evaluated for antagonistic effects on proximal agar growth, antimicrobial properties of probiotic supernatant and the probiotic’s effects on in vitro periodontal biofilms. Strain-specific effects were observed as differences in efficacy between genera and differences within genera. While some of the Lactobacillus candidates were able to reduce the periodontal pathobiont A. actinomycetemcomitans, the S. salivarius strains were not. However, the S. salivarius strains were more effective against periodontal pathobionts P. intermedia, P. gingivalis, and F. nucleatum. Vexingly, most of the Lactobacillus strains also negatively affected the prevalence of commensal species within the biofilms, while this was lower for S. salivarius strains. Both within lactobacilli and streptococci, some strains showed significantly more inhibition of the pathobionts, indicating the importance of proper strain selection. Additionally, some species showed reductions in non-target species, which can result in unexpected and unexplored effects on the whole microbiome.
Excited state calculations using variational quantum eigensolver with spin-restricted ansätze and automatically-adjusted constraints
Authors: Gocho Shigeki , Nakamura Hajime , Kanno Shu , Gao Qi , Kobayashi Takao , Inagaki Taichi , Hatanaka Miho
Published: January 2023

The ground and excited state calculations at key geometries, such as the Frank–Condon (FC) and the conical intersection (CI) geometries, are essential for understanding photophysical properties. To compute these geometries on noisy intermediate-scale quantum devices, we proposed a strategy that combined a chemistry-inspired spin-restricted ansatz and a new excited state calculation method called the variational quantum eigensolver under automatically-adjusted constraints (VQE/AC). Unlike the conventional excited state calculation method, called the variational quantum deflation, the VQE/AC does not require the pre-determination of constraint weights and has the potential to describe smooth potential energy surfaces. To validate this strategy, we performed the excited state calculations at the FC and CI geometries of ethylene and phenol blue at the complete active space self-consistent field (CASSCF) level of theory, and found that the energy errors were at most 2 kcal mol−1 even on the ibm_kawasaki device.
Enhancement of exogenous riboflavin on microbiologically influenced corrosion of nickel by electroactive Desulfovibrio vulgaris biofilm
Authors: Pu Yanan , Tian Yuan , Hou Su , Dou Wenwen , Chen Shougang
Published: January 2023

Riboflavin, a soluble redox mediator for electron transfer, is involved in various redox processes in biogeochemical systems. This work gives some insights into the MIC mechanism of pure nickel (Ni) caused by Desulfovibrio vulgaris. Compared with pure copper (Cu) metabolite (M)-MIC, Ni MIC by D. vulgaris exhibits distinctly different corrosion behavior. 20 ppm (w/w) riboflavin dramatically enhances the corrosion rate of Ni (59% increase in weight loss), while it has no impact on Cu MIC. Furthermore, headspace H2 detection reveals that neither proton nor H2S corrosion occurs in Ni MIC (Cu MIC caused by biogenic H2S produces large amounts of H2, whereas Ni MIC does not). The thermodynamic analysis and experimental results indicate that Ni D. vulgaris MIC is caused by trapping extracellular electrons from Ni oxidation for energy, which belongs to extracellular electron transfer (EET)-MIC.
Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson’s disease
Authors: Trabjerg Michael Sloth , Andersen Dennis Christian , Huntjens Pam , Mørk Kasper , Warming Nikolaj , Kullab Ulla Bismark , Skjønnemand Marie-Louise Nibelius , Oklinski Michal Krystian , Oklinski Kirsten Egelund , Bolther Luise , Kroese Lona J. , Pritchard Colin E. J. , Huijbers Ivo J. , Corthals Angelique , Søndergaard Mads Toft , Kjeldal Henrik Bech , Pedersen Cecilie Fjord Morre , Nieland John Dirk Vestergaard
Published: January 2023

Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.
Metabolic modelling of the human gut microbiome in type 2 diabetes patients in response to metformin treatment
Authors: Ezzamouri Bouchra , Rosario Dorines , Bidkhori Gholamreza , Lee Sunjae , Uhlen Mathias , Shoaie Saeed
Published: January 2023

The human gut microbiome has been associated with several metabolic disorders including type 2 diabetes mellitus. Understanding metabolic changes in the gut microbiome is important to elucidate the role of gut bacteria in regulating host metabolism. Here, we used available metagenomics data from a metformin study, together with genome-scale metabolic modelling of the key bacteria in individual and community-level to investigate the mechanistic role of the gut microbiome in response to metformin. Individual modelling predicted that species that are increased after metformin treatment have higher growth rates in comparison to species that are decreased after metformin treatment. Gut microbial enrichment analysis showed prior to metformin treatment pathways related to the hypoglycemic effect were enriched. Our observations highlight how the key bacterial species after metformin treatment have commensal and competing behavior, and how their cellular metabolism changes due to different nutritional environment. Integrating different diets showed there were specific microbial alterations between different diets. These results show the importance of the nutritional environment and how dietary guidelines may improve drug efficiency through the gut microbiota.
CLIMBra - Climate Change Dataset for Brazil
Authors: Ballarin André Simões , Sone Jullian Souza , Gesualdo Gabriela Chiquito , Schwamback Dimaghi , Reis Alan , Almagro André , Wendland Edson Cezar
Published: January 2023

General Circulation and Earth System Models are the most advanced tools for investigating climate responses to future scenarios of greenhouse gas emissions, playing the role of projecting the climate throughout the century. Nevertheless, climate projections are model-dependent and may show systematic biases, requiring a bias correction for any further application. Here, we provide a dataset based on an ensemble of 19 bias-corrected CMIP6 climate models projections for the Brazilian territory based on the SSP2-4.5 and SSP5-8.5 scenarios. We used the Quantile Delta Mapping approach to bias-correct daily time-series of precipitation, maximum and minimum temperature, solar net radiation, near-surface wind speed, and relative humidity. The bias-corrected dataset is available for both historical (1980–2013) and future (2015–2100) simulations at a 0.25° × 0.25° spatial resolution. Besides the gridded product, we provide area-averaged projections for 735 catchments included in the Catchments Attributes for Brazil (CABra) dataset. The dataset provides important variables commonly used in environmental and hydroclimatological studies, paving the way for the development of high-quality research on climate change impacts in Brazil.
Exercising is good for the brain but exercising outside is potentially better
Authors: Boere Katherine , Lloyd Kelsey , Binsted Gordon , Krigolson Olave E.
Published: January 2023

It is well known that exercise increases cognitive function. However, the environment in which the exercise is performed may be just as important as the exercise itself. Time spent in natural outdoor environments has been found to lead to increases in cognition similar to those resulting from acute exercise. Therefore, the benefits of both exercise and nature exposure suggest an additive impact on brain function when both factors are combined. This raises the question: what is the interaction between acute exercise and environment on cognition? We answered this question using electroencephalography to probe cognitive function using the oddball task before and after brief indoor and outdoor walks on 30 participants (average 21 years old, 95% CI [20, 22]). Our results demonstrate improved performance and an increase in the amplitude of the P300, an event-related neural response commonly associated with attention and working memory, following a 15-min walk outside; a result not seen following a 15-min walk inside. Importantly, this finding indicates that the environment may play a more substantial role in increasing cognitive function such as attention than exercise, at least in terms of acute exercise (i.e., a brief walk). With the world’s growing urbanization and the associated increase in sedentary time indoors, a deeper understanding of how these factors interact and influence cognition may be critical to combat adverse health effects.