bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression
Authors: Shao Tihong , Leung Patrick S. C. , Zhang Weici , Tsuneyama Koichi , Ridgway William M. , Young Howard A. , Shuai Zongwen , Ansari Aftab A. , Gershwin M. Eric 
Published: August 2022

AbstractThe interferon (IFN) signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity. We have generated a unique murine model named ARE-Del, with chronic overexpression of IFNγ, by altering IFNγ metabolism. Importantly, these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis, including high titers of autoantibodies and portal inflammation. We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis. To study this hypothesis, ARE-Del+/− mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied. JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage, associated with a significant reduction in splenic and hepatic CD4+ T cells and CD8+ T cells. Functionally, ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγ and TNF from splenic CD4+ T cells. Additionally, ruxolitinib treatment also decreased the frequencies of germinal center B (GC B) cells and T follicular helper (Tfh) cells and led to lower serological AMA levels. Of note, liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment. Mechanistically, ruxolitinib inhibited the secretion of IL-6, TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro, indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway. Our data highlight the significance, both immunologically and clinically, of the JAK/STAT signaling pathway in autoimmune cholangitis.
Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes
Authors: Halford Jennifer L. , Morrill Valerie N. , Choi Seung Hoan , Jurgens Sean J. , Melloni Giorgio , Marston Nicholas A. , Weng Lu-Chen , Nauffal Victor , Hall Amelia W. , Gunn Sophia , Austin-Tse Christina A. , Pirruccello James P. , Khurshid Shaan , Rehm Heidi L. , Benjamin Emelia J. , Boerwinkle Eric , Brody Jennifer A. , Correa Adolfo , Fornwalt Brandon K. , Gupta Namrata , Haggerty Christopher M. , Harris Stephanie , Heckbert Susan R. , Hong Charles C. , Kooperberg Charles , Lin Henry J. , Loos Ruth J. F. , Mitchell Braxton D. , Morrison Alanna C. , Post Wendy , Psaty Bruce M. , Redline Susan , Rice Kenneth M. , Rich Stephen S. , Rotter Jerome I. , Schnatz Peter F. , Soliman Elsayed Z. , Sotoodehnia Nona , Wong Eugene K. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Sabatine Marc S. , Ruff Christian T. , Lunetta Kathryn L. , Ellinor Patrick T. , Lubitz Steven A. 
Published: August 2022

AbstractAccurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.
Synthesizing theories of human language with Bayesian program induction
Authors: Ellis Kevin , Albright Adam , Solar-Lezama Armando , Tenenbaum Joshua B. , O’Donnell Timothy J. 
Published: August 2022

AbstractAutomated, data-driven construction and evaluation of scientific models and theories is a long-standing challenge in artificial intelligence. We present a framework for algorithmically synthesizing models of a basic part of human language: morpho-phonology, the system that builds word forms from sounds. We integrate Bayesian inference with program synthesis and representations inspired by linguistic theory and cognitive models of learning and discovery. Across 70 datasets from 58 diverse languages, our system synthesizes human-interpretable models for core aspects of each language’s morpho-phonology, sometimes approaching models posited by human linguists. Joint inference across all 70 data sets automatically synthesizes a meta-model encoding interpretable cross-language typological tendencies. Finally, the same algorithm captures few-shot learning dynamics, acquiring new morphophonological rules from just one or a few examples. These results suggest routes to more powerful machine-enabled discovery of interpretable models in linguistics and other scientific domains.
Organic phosphorescent nanoscintillator for low-dose X-ray-induced photodynamic therapy
Authors: Wang Xiao , Sun Wenjing , Shi Huifang , Ma Huili , Niu Guowei , Li Yuxin , Zhi Jiahuan , Yao Xiaokang , Song Zhicheng , Chen Lei , Li Shi , Yang Guohui , Zhou Zixing , He Yixiao , Qu Shuli , Wu Min , Zhao Zhu , Yin Chengzhu , Lin Chongyang , Gao Jia , Li Qiuying , Zhen Xu , Li Lin , Chen Xiaoyuan , Liu Xiaogang , An Zhongfu , Chen Hongmin , Huang Wei 
Published: August 2022

AbstractX-ray-induced photodynamic therapy utilizes penetrating X-rays to activate reactive oxygen species in deep tissues for cancer treatment, which combines the advantages of photodynamic therapy and radiotherapy. Conventional therapy usually requires heavy-metal-containing inorganic scintillators and organic photosensitizers to generate singlet oxygen. Here, we report a more convenient strategy for X-ray-induced photodynamic therapy based on a class of organic phosphorescence nanoscintillators, that act in a dual capacity as scintillators and photosensitizers. The resulting low dose of 0.4 Gy and negligible adverse effects demonstrate the great potential for the treatment of deep tumours. These findings provide an optional route that leverages the optical properties of purely organic scintillators for deep-tissue photodynamic therapy. Furthermore, these organic nanoscintillators offer an opportunity to expand applications in the fields of biomaterials and nanobiotechnology.
Land use change and carbon emissions of a transformation to timber cities
Authors: Mishra Abhijeet , Humpenöder Florian , Churkina Galina , Reyer Christopher P. O. , Beier Felicitas , Bodirsky Benjamin Leon , Schellnhuber Hans Joachim , Lotze-Campen Hermann , Popp Alexander 
Published: August 2022

AbstractUsing engineered wood for construction has been discussed for climate change mitigation. It remains unclear where and in which way the additional demand for wooden construction material shall be fulfilled. Here we assess the global and regional impacts of increased demand for engineered wood on land use and associated CO2emissions until 2100 using an open-source land system model. We show that if 90% of the new urban population would be housed in newly built urban mid-rise buildings with wooden constructions, 106 Gt of additional CO2could be saved by 2100. Forest plantations would need to expand by up to 149 Mha by 2100 and harvests from unprotected natural forests would increase. Our results indicate that expansion of timber plantations for wooden buildings is possible without major repercussions on agricultural production. Strong governance and careful planning are required to ensure a sustainable transition to timber cities even if frontier forests and biodiversity hotspots are protected.
Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis
Authors: Merker Matthias , Rasigade Jean-Philippe , Barbier Maxime , Cox Helen , Feuerriegel Silke , Kohl Thomas A. , Shitikov Egor , Klaos Kadri , Gaudin Cyril , Antoine Rudy , Diel Roland , Borrell Sonia , Gagneux Sebastien , Nikolayevskyy Vladyslav , Andres Sönke , Crudu Valeriu , Supply Philip , Niemann Stefan , Wirth Thierry 
Published: August 2022

AbstractTransmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.
A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity
Authors: Kedor Claudia , Freitag Helma , Meyer-Arndt Lil , Wittke Kirsten , Hanitsch Leif G. , Zoller Thomas , Steinbeis Fridolin , Haffke Milan , Rudolf Gordon , Heidecker Bettina , Bobbert Thomas , Spranger Joachim , Volk Hans-Dieter , Skurk Carsten , Konietschke Frank , Paul Friedemann , Behrends Uta , Bellmann-Strobl Judith , Scheibenbogen Carmen 
Published: August 2022

AbstractA subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.
Precursor engineering of hydrotalcite-derived redox sorbents for reversible and stable thermochemical oxygen storage
Authors: High Michael , Patzschke Clemens F. , Zheng Liya , Zeng Dewang , Gavalda-Diaz Oriol , Ding Nan , Chien Ka Ho Horace , Zhang Zili , Wilson George E. , Berenov Andrey V. , Skinner Stephen J. , Sedransk Campbell Kyra L. , Xiao Rui , Fennell Paul S. , Song Qilei 
Published: August 2022

AbstractChemical looping processes based on multiple-step reduction and oxidation of metal oxides hold great promise for a variety of energy applications, such as CO2 capture and conversion, gas separation, energy storage, and redox catalytic processes. Copper-based mixed oxides are one of the most promising candidate materials with a high oxygen storage capacity. However, the structural deterioration and sintering at high temperatures is one key scientific challenge. Herein, we report a precursor engineering approach to prepare durable copper-based redox sorbents for use in thermochemical looping processes for combustion and gas purification. Calcination of the CuMgAl hydrotalcite precursors formed mixed metal oxides consisting of CuO nanoparticles dispersed in the Mg-Al oxide support which inhibited the formation of copper aluminates during redox cycling. The copper-based redox sorbents demonstrated enhanced reaction rates, stable O2 storage capacity over 500 redox cycles at 900 °C, and efficient gas purification over a broad temperature range. We expect that our materials design strategy has broad implications on synthesis and engineering of mixed metal oxides for a range of thermochemical processes and redox catalytic applications.
Structure of a nucleosome-bound MuvB transcription factor complex reveals DNA remodelling
Authors: Koliopoulos Marios G. , Muhammad Reyhan , Roumeliotis Theodoros I. , Beuron Fabienne , Choudhary Jyoti S. , Alfieri Claudio 
Published: August 2022

AbstractGenes encoding the core cell cycle machinery are transcriptionally regulated by the MuvB family of protein complexes in a cell cycle-specific manner. Complexes of MuvB with the transcription factors B-MYB and FOXM1 activate mitotic genes during cell proliferation. The mechanisms of transcriptional regulation by these complexes are still poorly characterised. Here, we combine biochemical analysis and in vitro reconstitution, with structural analysis by cryo-electron microscopy and cross-linking mass spectrometry, to functionally examine these complexes. We find that the MuvB:B-MYB complex binds and remodels nucleosomes, thereby exposing nucleosomal DNA. This remodelling activity is supported by B-MYB which directly binds the remodelled DNA. Given the remodelling activity on the nucleosome, we propose that the MuvB:B-MYB complex functions as a pioneer transcription factor complex. In this work, we rationalise prior biochemical and cellular studies and provide a molecular framework of interactions on a protein complex that is key for cell cycle regulation.
Integrated cognitive and physical fitness training enhances attention abilities in older adults
Authors: Anguera Joaquin A. , Volponi Joshua J. , Simon Alexander J. , Gallen Courtney L. , Rolle Camarin E. , Anguera-Singla Roger , Pitsch Erica A. , Thompson Christian J. , Gazzaley Adam 
Published: August 2022

AbstractPreserving attention abilities is of great concern to older adults who are motivated to maintain their quality of life. Both cognitive and physical fitness interventions have been utilized in intervention studies to assess maintenance and enhancement of attention abilities in seniors, and a coupling of these approaches is a compelling strategy to buttress both cognitive and physical health in a time- and resource-effective manner. With this perspective, we created a closed-loop, motion-capture video game (Body-Brain Trainer: BBT) that adapts a player’s cognitive and physical demands in an integrated approach, thus creating a personalized and cohesive experience across both domains. Older adults who engaged in two months of BBT improved on both physical fitness (measures of blood pressure and balance) and attention (behavioral and neural metrics of attention on a continuous performance task) outcome measures beyond that of an expectancy matched, active, placebo control group, with maintenance of improved attention performance evidenced 1 year later. Following training, the BBT group’s improvement on the attention outcome measure exceeded performance levels attained by an untrained group of 20-year olds, and showed age-equilibration of a neural signature of attention shown to decline with age: midline frontal theta power. These findings highlight the potential benefits of an integrated, cognitive-physical, closed-loop training platform as a powerful tool for both cognitive and physical enhancement in older adults.
Superconductivity and topological aspects of two-dimensional transition-metal monohalides
Authors: Dong Wen-Han , Zhang Yu-Yang , Zhang Yan-Fang , Sun Jia-Tao , Liu Feng , Du Shixuan 
Published: August 2022

AbstractTwo-dimensional (2D) superconducting states have attracted much recent interest, especially when they coexist with nontrivial band topology which affords a promising approach towards Majorana fermions. Using first-principles calculations, we predict van der Waals monolayered transition-metal monohalides MX (M = Zr, Mo; X = F, Cl) as a class of 2D superconductors with remarkable transition temperature (5.9–12.4 K). Anisotropic Migdal-Eliashberg theory reveals that ZrCl have a single superconducting gap ∆ ~ 2.14 meV, while MoCl is a two-gap superconductor with ∆ ~ 1.96 and 1.37 meV. The Z2 band topology of 2D MX is further demonstrated that MoF and MoCl are candidates for realizing topological superconductivity. Moreover, the Dirac phonons of ZrCl and MoCl contribute w-shape phononic edge states, which are potential for an edge-enhanced electron-phonon coupling. These findings demonstrate that 2D MX offers an attractive platform for exploring the interplay between superconductivity, nontrivial electronic and phononic topology.
Superconductivity in the crystallogenide LaFeSiO1−δ with squeezed FeSi layers
Authors: Hansen M. F. , Vaney J.-B. , Lepoittevin C. , Bernardini F. , Gaudin E. , Nassif V. , Méasson M.-A. , Sulpice A. , Mayaffre H. , Julien M.-H. , Tencé S. , Cano A. , Toulemonde P. 
Published: August 2022

AbstractPnictogens and chalcogens are both viable anions for promoting Fe-based superconductivity, and intense research activity in the related families has established a systematic correlation between the Fe-anion height and the superconducting critical temperature Tc, with an optimum Fe-anion height of ~1.38 Å. Here, we report the discovery of superconductivity in the compound LaFeSiO1−δ that incorporates a crystallogen element, Si, and challenges the above picture: considering the strongly squeezed Fe–Si height of 0.94 Å, the superconducting transition at Tc = 10 K is unusually high. In the normal state, the resistivity displays non-Fermi-liquid behavior while NMR experiments evidence weak antiferromagnetic fluctuations. According to first-principles calculations, the Fermi surface of this material is dominated by hole pockets without nesting properties, which explains the strongly suppressed tendency toward magnetic order and suggests that the emergence of superconductivity materializes in a distinct set-up, as compared to the standard s±- and d-wave electron-pocket-based situations. These properties and its simple-to-implement synthesis make LaFeSiO1−δ a particularly promising platform to study the interplay between structure, electron correlations, and superconductivity.
The antibody landscapes following AS03 and MF59 adjuvanted H5N1 vaccination
Authors: Goll Johannes B. , Jain Aarti , Jensen Travis L. , Assis Rafael , Nakajima Rie , Jasinskas Algis , Coughlan Lynda , Cherikh Sami R. , Gelber Casey E. , Khan S. , Huw Davies D. , Meade Philip , Stadlbauer Daniel , Strohmeier Shirin , Krammer Florian , Chen Wilbur H. , Felgner Philip L. 
Published: August 2022

AbstractCurrent seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays (NCT01317758 and NCT01317745). The arrays were designed to reflect both full-length and globular head HA derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and heterosubtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. The adjuvanted vaccine was also associated with the elicitation of stalk-directed antibody. We established good correlation of the array antibody responses to H5 antigens with standard HA inhibition and microneutralization titers.
Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity
Authors: Choi Minee L. , Chappard Alexandre , Singh Bhanu P. , Maclachlan Catherine , Rodrigues Margarida , Fedotova Evgeniya I. , Berezhnov Alexey V. , De Suman , Peddie Christopher J. , Athauda Dilan , Virdi Gurvir S. , Zhang Weijia , Evans James R. , Wernick Anna I. , Zanjani Zeinab Shadman , Angelova Plamena R. , Esteras Noemi , Vinokurov Andrey Y. , Morris Katie , Jeacock Kiani , Tosatto Laura , Little Daniel , Gissen Paul , Clarke David J. , Kunath Tilo , Collinson Lucy , Klenerman David , Abramov Andrey Y. , Horrocks Mathew H. , Gandhi Sonia 
Published: August 2022

AbstractAggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)–derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.