bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Effects of Global Warming and Ozone Depletion/Recovery on Southern Hemisphere Atmospheric Circulation and Regional Precipitation
Authors: Mindlin Julia , Shepherd Theodore G. , Vera Carolina , Osman Marisol 
Published: June 2021

AbstractOzone depletion led to a positive trend in the summertime Southern Annular Mode (SAM) during the last decades of the 20th century. During the present century, global warming (GW) is expected to contribute to a positive SAM trend while ozone recovery is expected to act in the opposite direction. Here, Southern Hemisphere (SH) circulation and regional precipitation change are studied with a methodology that separates the effects from GW and ozone depletion/recovery. Our results show that a “tug‐of‐war” between ozone and GW occurs in the summertime stratosphere, propagating to the troposphere where it is manifest in the SAM. However, at the regional scale this “tug‐of‐war” is not as relevant as the combined effects of other remote drivers of circulation change, which force different kinds of precipitation changes in the SH. For regional precipitation changes, the uncertainty in future circulation change is as important as the uncertainty in the GW level.
Reexamining the Indian Summer Monsoon Rainfall–ENSO Relationship From Its Recovery in the 21st Century: Role of the Indian Ocean SST Anomaly Associated With Types of ENSO Evolution
Authors: Yu Shi‐Yun , Fan Lei , Zhang Yu , Zheng Xiao‐Tong , Li Ziguang 
Published: June 2021

AbstractThis study found that the relationship between the Indian Summer Monsoon Rainfall (ISMR) and El Niño‐Southern Oscillation (ENSO) has recovered since 2001, and the relationship strength is closely related to the summer tropical Indian Ocean (TIO) sea surface temperature (SST) anomaly, with the TIO warming (cooling) indicating a stronger (weaker) relationship. Under the same El Niño/La Niña scenario, different signs of the TIO anomaly indicate distinct atmospheric circulation anomalies over the Indian Ocean, thus affecting the ISMR–ENSO relationship. The TIO anomaly is principally associated with different types of ENSO temporal evolution. Strong El Niño events with an early onset, and the transition of El Niño to La Niña, tend to have a warmer TIO and a stronger ISMR–ENSO relationship, in contrast to most of the cases of a decaying La Niña or a La Niña that persists throughout the year. The result brings a prospect for improving the ISMR prediction.
Fossil Versus Nonfossil CO Sources in the US: New Airborne Constraints From ACT‐America and GEM
Authors: Gonzalez Andres , Millet Dylan B. , Yu Xueying , Wells Kelley C. , Griffis Timothy J. , Baier Bianca C. , Campbell Patrick C. , Choi Yonghoon , DiGangi Joshua P. , Gvakharia Alexander , Halliday Hannah S. , Kort Eric A. , McKain Kathryn , Nowak John B. , Plant Genevieve 
Published: June 2021

AbstractCarbon monoxide (CO) is an ozone precursor, oxidant sink, and widely used pollution tracer. The importance of anthropogenic versus other CO sources in the US is uncertain. Here, we interpret extensive airborne measurements with an atmospheric model to constrain US fossil and nonfossil CO sources. Measurements reveal a low bias in the simulated CO background and a 30% overestimate of US fossil CO emissions in the 2016 National Emissions Inventory. After optimization we apply the model for source partitioning. During summer, regional fossil sources account for just 9%–16% of the sampled boundary layer CO, and 32%–38% of the North American enhancement—complicating use of CO as a fossil fuel tracer. The remainder predominantly reflects biogenic hydrocarbon oxidation plus fires. Fossil sources account for less domain‐wide spatial variability at this time than nonfossil and background contributions. The regional fossil contribution rises in other seasons, and drives ambient variability downwind of urban areas.
Oct4 confers stemness and radioresistance to head and neck squamous cell carcinoma by regulating the homologous recombination factors PSMC3IP and RAD54L
Authors: Nathansen Jacqueline , Lukiyanchuk Vasyl , Hein Linda , Stolte Maya-Isabel , Borgmann Kerstin , Löck Steffen , Kurth Ina , Baumann Michael , Krause Mechthild , Linge Annett , Dubrovska Anna 
Published: June 2021

AbstractHead and neck squamous cell carcinoma (HNSCC) is often being diagnosed at an advanced stage, conferring a poor prognosis. The probability of local tumor control after radiotherapy depends on the eradication of cancer stem cells (CSCs) with activated DNA repair. This study provides evidence that the CSC-related transcription factor Oct4 contributes to HNSCC radioresistance by regulating DNA damage response and the CSC phenotype. Knockdown of Oct4 A isoform reduced self-renewal capacity in HNSCC and led to partial tumor cell radiosensitization caused by transcriptional downregulation of the cell cycle checkpoint kinases CHK1 and WEE1 and homologous recombination (HR) repair genes PSMC3IP and RAD54L. Besides, PARP inhibition with Olaparib selectively radiosensitized Oct4 A knockout, but not wild-type HNSCC cells. This finding links Oct4 A to the HR-mediated DNA repair mechanisms. In turn, knockdown of PSMC3IP and RAD54L reduced the HNSCC self-renewal capacity and clonogenic cell survival after irradiation, suggesting the interplay between DNA repair and the CSC phenotype. Similar to the effect of Oct4 knockdown, overexpression of Oct4 also resulted in significant HNSCC radiosensitization and increased DNA damage, suggesting that Oct4-dependent regulation of DNA repair depends on its fine-tuned expression. In line with this observation, HNSCC patients with high and low nuclear Oct4 expression at the invasive tumor front exhibited better loco-regional tumor control after postoperative radio(chemo)therapy compared to the intermediate expression subgroup. Thus, we found that the Oct4-driven transcriptional program plays a critical role in regulating HNSCC radioresistance, and a combination of radiotherapy with PARP inhibitors may induce synthetic lethality in Oct4-deregulated tumors.
Compositional and genetic alterations in Graves’ disease gut microbiome reveal specific diagnostic biomarkers
Authors: Zhu Qiyun , Hou Qiangchuan , Huang Shi , Ou Qianying , Huo Dongxue , Vázquez-Baeza Yoshiki , Cen Chaoping , Cantu Victor , Estaki Mehrbod , Chang Haibo , Belda-Ferre Pedro , Kim Ho-Cheol , Chen Kaining , Knight Rob , Zhang Jiachao 
Published: June 2021

Abstract
Graves’ Disease is the most common organ-specific autoimmune disease and has been linked in small pilot studies to taxonomic markers within the gut microbiome. Important limitations of this work include small sample sizes and low-resolution taxonomic markers. Accordingly, we studied 162 gut microbiomes of mild and severe Graves’ disease (GD) patients and healthy controls. Taxonomic and functional analyses based on metagenome-assembled genomes (MAGs) and MAG-annotated genes, together with predicted metabolic functions and metabolite profiles, revealed a well-defined network of MAGs, genes and clinical indexes separating healthy from GD subjects. A supervised classification model identified a combination of biomarkers including microbial species, MAGs, genes and SNPs, with predictive power superior to models from any single biomarker type (AUC = 0.98). Global, cross-disease multi-cohort analysis of gut microbiomes revealed high specificity of these GD biomarkers, notably discriminating against Parkinson’s Disease, and suggesting that non-invasive stool-based diagnostics will be useful for these diseases.
Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours
Authors: Middleton Mark R. , Dean Emma , Evans Thomas R. J. , Shapiro Geoffrey I. , Pollard John , Hendriks Bart S. , Falk Martin , Diaz-Padilla Ivan , Plummer Ruth 
Published: June 2021

Abstract
Background
Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours.

Methods
We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2.

Results
Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease.

Conclusions
Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.

Clinical trial identifier
NCT02157792.
Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours
Authors: Shapiro Geoffrey I. , Wesolowski Robert , Devoe Craig , Lord Simon , Pollard John , Hendriks Bart S. , Falk Martin , Diaz-Padilla Ivan , Plummer Ruth , Yap Timothy A. 
Published: June 2021

AbstractBackgroundBerzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin.MethodsAdult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W).ResultsThirty-one patients received berzosertib (90–210 mg/m2) and cisplatin (40–75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2(days 2 and 9) and cisplatin 75 mg/m2(day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy.ConclusionsBerzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting.Clinical Trials IdentifierNCT02157792.
MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF
Authors: Wang Xin , Ros Uris , Agrawal Deepti , Keller Eva C. , Slotta-Huspenina Julia , Dill Veronika , Shen Bo , Shi Run , Herold Tobias , Belka Claus , Mishra Ritu , Bassermann Florian , Garcia-Saez Ana J. , Jost Philipp J. 
Published: June 2021

AbstractThe blockade of cellular differentiation represents a hallmark of acute myeloid leukemia (AML), which is largely attributed to the dysfunction of lineage-specific transcription factors controlling cellular differentiation. However, alternative mechanisms of cellular differentiation programs in AML remain largely unexplored. Here we report that mixed lineage kinase domain-like protein (MLKL) contributes to the cellular differentiation of transformed hematopoietic progenitor cells in AML. Using gene-targeted mice, we show that MLKL facilitates the release of granulocyte colony-stimulating factor (G-CSF) by controlling membrane permeabilization in leukemic cells. Mlkl−/− hematopoietic stem and progenitor cells released reduced amounts of G-CSF while retaining their capacity for CSF3 (G-CSF) mRNA expression, G-CSF protein translation, and G-CSF receptor signaling. MLKL associates with early endosomes and controls G-CSF release from intracellular storage by plasma membrane pore formation, whereas cell death remained unaffected by loss of MLKL. Of note, MLKL expression was significantly reduced in AML patients, specifically in those with a poor-risk AML subtype. Our data provide evidence that MLKL controls myeloid differentiation in AML by controlling the release of G-CSF from leukemic progenitor cells.
RNA atlas of human bacterial pathogens uncovers stress dynamics linked to infection
Authors: Avican Kemal , Aldahdooh Jehad , Togninalli Matteo , Mahmud A. K. M. Firoj , Tang Jing , Borgwardt Karsten M. , Rhen Mikael , Fällman Maria 
Published: June 2021

AbstractBacterial processes necessary for adaption to stressful host environments are potential targets for new antimicrobials. Here, we report large-scale transcriptomic analyses of 32 human bacterial pathogens grown under 11 stress conditions mimicking human host environments. The potential relevance of the in vitro stress conditions and responses is supported by comparisons with available in vivo transcriptomes of clinically important pathogens. Calculation of a probability score enables comparative cross-microbial analyses of the stress responses, revealing common and unique regulatory responses to different stresses, as well as overlapping processes participating in different stress responses. We identify conserved and species-specific ‘universal stress responders’, that is, genes showing altered expression in multiple stress conditions. Non-coding RNAs are involved in a substantial proportion of the responses. The data are collected in a freely available, interactive online resource (PATHOgenex).
Through bonds or contacts? Mapping protein vibrational energy transfer using non-canonical amino acids
Authors: Deniz Erhan , Valiño-Borau Luis , Löffler Jan G. , Eberl Katharina B. , Gulzar Adnan , Wolf Steffen , Durkin Patrick M. , Kaml Robert , Budisa Nediljko , Stock Gerhard , Bredenbeck Jens 
Published: June 2021

AbstractVibrational energy transfer (VET) is essential for protein function. It is responsible for efficient energy dissipation in reaction sites, and has been linked to pathways of allosteric communication. While it is understood that VET occurs via backbone as well as via non-covalent contacts, little is known about the competition of these two transport channels, which determines the VET pathways. To tackle this problem, we equipped the β-hairpin fold of a tryptophan zipper with pairs of non-canonical amino acids, one serving as a VET injector and one as a VET sensor in a femtosecond pump probe experiment. Accompanying extensive non-equilibrium molecular dynamics simulations combined with a master equation analysis unravel the VET pathways. Our joint experimental/computational endeavor reveals the efficiency of backbone vs. contact transport, showing that even if cutting short backbone stretches of only 3 to 4 amino acids in a protein, hydrogen bonds are the dominant VET pathway.
UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Authors: Subramanian Manivannan , Hyeon Seung Jae , Das Tanuza , Suh Yoon Seok , Kim Yun Kyung , Lee Jeong-Soo , Song Eun Joo , Ryu Hoon , Yu Kweon 
Published: June 2021

AbstractThe formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer’s disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.
Analysis of the Coptis chinensis genome reveals the diversification of protoberberine-type alkaloids
Authors: Liu Yifei , Wang Bo , Shu Shaohua , Li Zheng , Song Chi , Liu Di , Niu Yan , Liu Jinxin , Zhang Jingjing , Liu Heping , Hu Zhigang , Huang Bisheng , Liu Xiuyu , Liu Wei , Jiang Liping , Alami Mohammad Murtaza , Zhou Yuxin , Ma Yutao , He Xiangxiang , Yang Yicheng , Zhang Tianyuan , Hu Hui , Barker Michael S. , Chen Shilin , Wang Xuekui , Nie Jing 
Published: June 2021

AbstractChinese goldthread (Coptis chinensis Franch.), a member of the Ranunculales, represents an important early-diverging eudicot lineage with diverse medicinal applications. Here, we present a high-quality chromosome-scale genome assembly and annotation of C. chinensis. Phylogenetic and comparative genomic analyses reveal the phylogenetic placement of this species and identify a single round of ancient whole-genome duplication (WGD) shared by the Ranunculaceae. We characterize genes involved in the biosynthesis of protoberberine-type alkaloids in C. chinensis. In particular, local genomic tandem duplications contribute to member amplification of a Ranunculales clade-specific gene family of the cytochrome P450 (CYP) 719. The functional versatility of a key CYP719 gene that encodes the (S)-canadine synthase enzyme involved in the berberine biosynthesis pathway may play critical roles in the diversification of other berberine-related alkaloids in C. chinensis. Our study provides insights into the genomic landscape of early-diverging eudicots and provides a valuable model genome for genetic and applied studies of Ranunculales.
Inactivation and sensitization of Pseudomonas aeruginosa by microplasma jet array for treating otitis media
Authors: Sun Peter P. , Won Jungeun , Choo-Kang Gabrielle , Li Shouyan , Chen Wenyuan , Monroy Guillermo L. , Chaney Eric J. , Boppart Stephen A. , Eden J. Gary , Nguyen Thanh H. 
Published: June 2021

AbstractOtitis media (OM), known as a middle ear infection, is the leading cause of antibiotic prescriptions for children. With wide-spread use of antibiotics in OM, resistance to antibiotics continues to decrease the efficacy of the treatment. Furthermore, as the presence of a middle ear biofilm has contributed to this reduced susceptibility to antimicrobials, effective interventions are necessary. A miniaturized 3D-printed microplasma jet array has been developed to inactivate Pseudomonas aeruginosa, a common bacterial strain associated with OM. The experiments demonstrate the disruption of planktonic and biofilm P. aeruginosa by long-lived molecular species generated by microplasma, as well as the synergy of combining microplasma treatment with antibiotic therapy. In addition, a middle ear phantom model was developed with an excised rat eardrum to investigate the antimicrobial effects of microplasma on bacteria located behind the eardrum, as in a patient-relevant setup. These results suggest the potential for microplasma as a new treatment paradigm for OM.
Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
Authors: Bassenden Angelia V. , Dumalo Linda , Park Jaeok , Blanchet Jonathan , Maiti Krishnagopal , Arya Dev P. , Berghuis Albert M. 
Published: June 2021

AbstractPlazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2′)-Ia from Providencia stuartii. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2′)-Ia from P. stuartii, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2′)-Ia-acetylated plazomicin complex, these structures outline AAC(2′)-Ia’s specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2′)-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.
Mitochondria in epithelial ovarian carcinoma exhibit abnormal phenotypes and blunted associations with biobehavioral factors
Authors: Bindra Snehal , McGill Marlon A. , Triplett Marina K. , Tyagi Anisha , Thaker Premal H. , Dahmoush Laila , Goodheart Michael J. , Ogden R. Todd , Owusu-Ansah Edward , R Karan Kalpita , Cole Steve , Sood Anil K. , Lutgendorf Susan K. , Picard Martin 
Published: June 2021

AbstractMalignant tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and mitochondria in malignant tumors remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign tissue and in high-grade epithelial ovarian carcinoma (EOC) in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n = 1435) showed that gene expression of specific mitochondrial proteins in EOC is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in tissue from 51 patients with benign ovarian masses and 128 patients with high-grade EOC revealed that compared to benign tissue, EOCs exhibit 3.3–8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P < 0.001) but similar mitochondrial DNA (mtDNA) levels (− 3.1%), documenting abnormal mitochondrial phenotypes in EOC. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r = − 0.43 to 0.47). In contrast, serous EOCs showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in EOC and warrant further research on the link between biobehavioral factors and mitochondria in cancer.