bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct observation of autoubiquitination for an integral membrane ubiquitin ligase in ERAD
Authors: Moochickal Assainar Basila , Ragunathan Kaushik , Baldridge Ryan D. 
Published: February 2024

AbstractThe endoplasmic reticulum associated degradation (ERAD) pathway regulates protein quality control at the endoplasmic reticulum. ERAD of lumenal and membrane proteins requires a conserved E3 ubiquitin ligase, called Hrd1. We do not understand the molecular configurations of Hrd1 that enable autoubiquitination and the subsequent retrotranslocation of misfolded protein substrates from the ER to the cytosol. Here, we have established a generalizable, single-molecule platform that enables high-efficiency labeling, stoichiometry determination, and functional assays for any integral membrane protein. Using this approach, we directly count Hrd1 proteins reconstituted into individual proteoliposomes. We report that Hrd1 assembles in different oligomeric configurations with mostly monomers and dimers detected at limiting dilution. By correlating oligomeric states with ubiquitination in vitro, we conclude that Hrd1 monomers are inefficient in autoubiquitination while dimers efficiently assemble polyubiquitin chains. Therefore, our results reveal the minimal composition of a Hrd1 oligomer that is capable of autoubiquitination. Our methods are broadly applicable to studying other complex membrane protein functions using reconstituted bilayer systems.
The effect of echoes interference on phonon attenuation in a nanophononic membrane
Authors: Hadi Mohammad , Luo Haoming , Pailhès Stéphane , Tanguy Anne , Gravouil Anthony , Capotondi Flavio , De Angelis Dario , Fainozzi Danny , Foglia Laura , Mincigrucci Riccardo , Paltanin Ettore , Pedersoli Emanuele , Pelli-Cresi Jacopo S. , Bencivenga Filippo , Giordano Valentina M. 
Published: February 2024

AbstractNanophononic materials are characterized by a periodic nanostructuration, which may lead to coherent scattering of phonons, enabling interference and resulting in modified phonon dispersions. We have used the extreme ultraviolet transient grating technique to measure phonon frequencies and lifetimes in a low-roughness nanoporous phononic membrane of SiN at wavelengths between 50 and 100 nm, comparable to the nanostructure lengthscale. Surprisingly, phonon frequencies are only slightly modified upon nanostructuration, while phonon lifetime is strongly reduced. Finite element calculations indicate that this is due to coherent phonon interference, which becomes dominant for wavelengths between ~ half and twice the inter-pores distance. Despite this, vibrational energy transport is ensured through an energy flow among the coherent modes created by reflections. This interference of phonon echos from periodic interfaces is likely another aspect of the mutual coherence effects recently highlighted in amorphous and complex crystalline materials and, in this context, could be used to tailor transport properties of nanostructured materials.
TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes
Authors: Mine Keiichiro , Nagafuchi Seiho , Akazawa Satoru , Abiru Norio , Mori Hitoe , Kurisaki Hironori , Shimoda Kazuya , Yoshikai Yasunobu , Takahashi Hirokazu , Anzai Keizo 
Published: February 2024

AbstractTyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.
A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria
Authors: Espaillat Akbar , Alvarez Laura , Torrens Gabriel , ter Beek Josy , Miguel-Ruano Vega , Irazoki Oihane , Gago Federico , Hermoso Juan A. , Berntsson Ronnie P-A. , Cava Felipe 
Published: February 2024

AbstractThe bacterial cell-wall peptidoglycan is made of glycan strands crosslinked by short peptide stems. Crosslinks are catalyzed by DD-transpeptidases (4,3-crosslinks) and LD-transpeptidases (3,3-crosslinks). However, recent research on non-model species has revealed novel crosslink types, suggesting the existence of uncharacterized enzymes. Here, we identify an LD-transpeptidase, LDTGo, that generates 1,3-crosslinks in the acetic-acid bacterium Gluconobacter oxydans. LDTGo-like proteins are found in Alpha- and Betaproteobacteria lacking LD3,3-transpeptidases. In contrast with the strict specificity of typical LD- and DD-transpeptidases, LDTGo can use non-terminal amino acid moieties for crosslinking. A high-resolution crystal structure of LDTGo reveals unique features when compared to LD3,3-transpeptidases, including a proline-rich region that appears to limit substrate access, and a cavity accommodating both glycan chain and peptide stem from donor muropeptides. Finally, we show that DD-crosslink turnover is involved in supplying the necessary substrate for LD1,3-transpeptidation. This phenomenon underscores the interplay between distinct crosslinking mechanisms in maintaining cell wall integrity in G. oxydans.
Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway
Authors: Zhang Yanan , Tu Shuyu , Ji Xingwei , Wu Jianan , Meng Jinxin , Gao Jinsong , Shao Xian , Shi Shuai , Wang Gan , Qiu Jingjing , Zhang Zhuobiao , Hua Chengang , Zhang Ziyi , Chen Shuxian , Zhang Li , Zhu Shu Jeffrey 
Published: February 2024

AbstractCommensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment in the intestinal tract remains obscure. Here, we demonstrate that an understudied murine commensal bacterium, Dubosiella newyorkensis, and its human homologue Clostridium innocuum, have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated and germ-free mouse models. We identify an important role for the D. newyorkensis in rebalancing Treg/Th17 responses and ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate and L-Lysine (Lys). We further show that Lys induces the immune tolerance ability of dendritic cells (DCs) by enhancing Trp catabolism towards the kynurenine (Kyn) pathway through activation of the metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) in an aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies a previously unrecognized metabolic communication by which Lys-producing commensal bacteria exert their immunoregulatory capacity to establish a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in DCs. This metabolic circuit represents a potential therapeutic target for the treatment of inflammatory bowel diseases.
Plant invasion and naturalization are influenced by genome size, ecology and economic use globally
Authors: Guo Kun , Pyšek Petr , van Kleunen Mark , Kinlock Nicole L. , Lučanová Magdalena , Leitch Ilia J. , Pierce Simon , Dawson Wayne , Essl Franz , Kreft Holger , Lenzner Bernd , Pergl Jan , Weigelt Patrick , Guo Wen-Yong 
Published: February 2024

AbstractHuman factors and plant characteristics are important drivers of plant invasions, which threaten ecosystem integrity, biodiversity and human well-being. However, while previous studies often examined a limited number of factors or focused on a specific invasion stage (e.g., naturalization) for specific regions, a multi-factor and multi-stage analysis at the global scale is lacking. Here, we employ a multi-level framework to investigate the interplay between plant characteristics (genome size, Grime’s adaptive CSR-strategies and native range size) and economic use and how these factors collectively affect plant naturalization and invasion success worldwide. While our findings derived from structural equation models highlight the substantial contribution of human assistance in both the naturalization and spread of invasive plants, we also uncovered the pivotal role of species’ adaptive strategies among the factors studied, and the significantly varying influence of these factors across invasion stages. We further revealed that the effects of genome size on plant invasions were partially mediated by species adaptive strategies and native range size. Our study provides insights into the complex and dynamic process of plant invasions and identifies its key drivers worldwide.
Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor
Authors: Jones Andrew J. Y. , Harman Thomas H. , Harris Matthew , Lewis Oliver E. , Ladds Graham , Nietlispach Daniel 
Published: February 2024

AbstractG protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13C methyl methionine and 19F NMR, we investigate the agonist-bound active state of β1AR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from β1AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of β1AR for Gs results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.
Sediment discharge from Greenland’s marine-terminating glaciers is linked with surface melt
Authors: Andresen Camilla S. , Karlsson Nanna B. , Straneo Fiammetta , Schmidt Sabine , Andersen Thorbjørn J. , Eidam Emily F. , Bjørk Anders A. , Dartiguemalle Nicolas , Dyke Laurence M. , Vermassen Flor , Gundel Ida E. 
Published: February 2024

AbstractSediment discharged from the Greenland Ice Sheet delivers nutrients to marine ecosystems around Greenland and shapes seafloor habitats. Current estimates of the total sediment flux are constrained by observations from land-terminating glaciers only. Addressing this gap, our study presents a budget derived from observations at 30 marine-margin locations. Analyzing sediment cores from nine glaciated fjords, we assess spatial deposition since 1950. A significant correlation is established between mass accumulation rates, normalized by surface runoff, and distance down-fjord. This enables calculating annual sediment flux at any fjord point based on nearby marine-terminating outlet glacier melt data. Findings reveal a total annual sediment flux of 1.324 + /− 0.79 Gt yr-1 over the period 2010-2020 from all marine-terminating glaciers to the fjords. These estimates are valuable for studies aiming to understand the basal ice sheet conditions and for studies predicting ecosystem changes in Greenland’s fjords and offshore areas as the ice sheet melts and sediment discharge increase.
Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
Authors: Chen Yurou , Qiang Yulong , Fan Jiachen , Zheng Qian , Yan Leilei , Fan Guanlan , Song Xiaofei , Zhang Nan , Lv Qiongying , Xiong Jiaqiang , Wang Jingtao , Cao Jing , Liu Yanyan , Xiong Jie , Zhang Wei , Li Feng 
Published: February 2024

AbstractAggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1high ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1high ovarian cancer.
HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression
Authors: Zhang Yi , Wang Mingjie , Ye Ling , Shen Shengqi , Zhang Yuxi , Qian Xiaoyu , Zhang Tong , Yuan Mengqiu , Ye Zijian , Cai Jin , Meng Xiang , Qiu Shiqiao , Liu Shengzhi , Liu Rui , Jia Weidong , Yang Xianzhu , Zhang Huafeng , Zhong Xiuying , Gao Ping 
Published: February 2024

AbstractImmune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune checkpoint inhibitor therapy because of immune evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate immune cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes tumor immune evasion in a CD8+ T cell-dependent manner by activating STAT1/PD-L1 in tumor cells. Mechanistically, HKDC1 binds to and presents cytosolic STAT1 to IFNGR1 on the plasma membrane following IFNγ-stimulation by associating with cytoskeleton protein ACTA2, resulting in STAT1 phosphorylation and nuclear translocation. HKDC1 inhibition in combination with anti-PD-1/PD-L1 enhances in vivo T cell antitumor response in liver cancer models in male mice. Clinical sample analysis indicates a correlation among HKDC1 expression, STAT1 phosphorylation, and survival in patients with hepatocellular carcinoma treated with atezolizumab (anti-PD-L1). These findings reveal a role for HKDC1 in regulating immune evasion by coupling cytoskeleton with STAT1 activation, providing a potential combination strategy to enhance antitumor immune responses.
Rapid single-shot parity spin readout in a silicon double quantum dot with fidelity exceeding 99%
Authors: Takeda Kenta , Noiri Akito , Nakajima Takashi , Camenzind Leon C. , Kobayashi Takashi , Sammak Amir , Scappucci Giordano , Tarucha Seigo 
Published: February 2024

AbstractSilicon-based spin qubits offer a potential pathway toward realizing a scalable quantum computer owing to their compatibility with semiconductor manufacturing technologies. Recent experiments in this system have demonstrated crucial technologies, including high-fidelity quantum gates and multiqubit operation. However, the realization of a fault-tolerant quantum computer requires a high-fidelity spin measurement faster than decoherence. To address this challenge, we characterize and optimize the initialization and measurement procedures using the parity-mode Pauli spin blockade technique. Here, we demonstrate a rapid (with a duration of a few μs) and accurate (with >99% fidelity) parity spin measurement in a silicon double quantum dot. These results represent a significant step forward toward implementing measurement-based quantum error correction in silicon.
Fin whale song characteristics and potential subpopulation identity in the New York Bight
Authors: King-Nolan Carissa D. , Rekdahl Melinda L. , Murray Anita , Strindberg Samantha , Baumgartner Mark F. , Rosenbaum Howard C. 
Published: February 2024

AbstractFin whale (Balaenoptera physalus) song can follow a highly consistent pattern, and regional differences in song patterns can be a valuable indicator of subpopulation identity and distribution. In the Northwest Atlantic, endangered fin whales are currently managed as a single stock despite previous identification of different regional song patterns, which indicates potential subpopulation structuring and vulnerability to anthropogenic disturbance if not managed accordingly. Here we document fin whale song in the New York Bight (NYB) from 2017 to 2020 using passive acoustic data to identify monthly and yearly trends in song patterns and to explore potential subpopulation structuring. The predominant song pattern observed was highly consistent with the pattern documented almost a decade prior in the NYB, with short inter-note intervals (INI) from fall–winter and long-INIs in the spring. However, in one song year the majority of songs were composed of long-INIs. This change in song pattern could be due to a shift in fin whale behavior or possibly multiple fin whale subpopulations using the NYB. Fin whales in the NYB may be particularly vulnerable to disturbance given the increasing anthropogenic pressures in this region, and further research into subpopulation structuring is needed to ensure adequate management of these endangered whales.
Rehabilitation effect of standing bed combined with early anti-gravity running table training on ankle fracture
Authors: Chen JiaWei , Wu TianYu , Liu Shuigen , Guo Ying 
Published: February 2024

AbstractTo explore the clinical effect of standing bed combined with early anti-gravity running table training in the healing and functional recovery of anterior rotation external rotation ankle fractures. Fifty-two patients with ankle fractures of degree III or degree IV of PER admitted to Pingle Orthopaedic and Traumatology Hospital of Shenzhen City between September 2021 and January 2023 were selected for observation, and they were divided into 26 cases in each group according to the method of randomised numerical table into the control group and the observation group. The patients in the control group started the routine rehabilitation treatment on the 1st day after operation, and in the 0–2 weeks after operation, the affected limb was elevated and ankle pump training was carried out; in the 3–6 weeks after operation, joint mobility training, strength training and soft tissue release were carried out; and in the 6–8 weeks after operation, weight-bearing training was increased. The observation group added standing bed training on the 7th postoperative day and anti-gravity running table training on the 28th postoperative day on the basis of the treatment protocol of the control group. Bone density, ankle mobility and American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scores, pain, ankle mobility and swelling evaluations were compared between the 2 groups before and after 8 weeks of treatment, and the quality scores of bone scabs were compared between the 2 groups after 4 weeks of treatment. There was no statistical significance in the comparison of the items between the two groups before treatment (all P > 0.05), and the difference in the bone scab quality score was not statistically significant after 4 weeks of treatment (P > 0.05), and after 8 weeks of treatment, the bone scab quality score, bone mineral density and AOFAS scores, pain, ankle mobility, and evaluations were higher than those of the control group (all P < 0.05), and there was no significant difference in the degree of swelling (P > 0.05). Standing bed combined with early anti-gravity running table training applied to postoperative patients with PER III or IV degree ankle fracture can reduce the degree of pain and improve the ankle joint function.
Amphetamine increases vascular permeability by modulating endothelial actin cytoskeleton and NO synthase via PAR-1 and VEGF-R
Authors: Böttner Julia , Fischer-Schaepmann Tina , Werner Sarah , Knauth Sarah , Jahnke Heinz-Georg , Thiele Holger , Büttner Petra 
Published: February 2024

AbstractAbuse of amphetamine-type stimulants is linked to cardiovascular adverse effects like arrhythmias, accelerated atherosclerosis, acute coronary syndromes and sudden cardiac death. Excessive catecholamine release following amphetamine use causes vasoconstriction and vasospasms, over time leading to hypertension, endothelial dysfunction or even cardiotoxicity. However, immediate vascular pathomechanisms related to amphetamine exposure, especially endothelial function, remain incompletely understood and were analyzed in this study. Pharmaco-pathological effects of acute d-amphetamine-sulfate (DAM) were investigated ex vivo using contraction–force measurements of rat carotid artery rings and in vitro using label-free, real-time electrochemical impedance spectroscopy (EIS) on endothelial and smooth muscle cells. Specific receptor and target blocking was used to identify molecular targets and to characterize intracellular signaling. DAM induced vasodilation represented by 29.3±2.5% decrease in vascular tone (p<0.001) involving vascular endothelial growth factor receptor (VEGF-R) and protease activated receptor 1 (PAR-1). EIS revealed that DAM induces endothelial barrier disruption (−75.9±1.1% of initial cellular impedance, p<0.001) also involving VEGF-R and PAR-1. Further, in response to DAM, Rho-associated protein kinase (ROCK) mediated reversible contraction of actin cytoskeleton resulting in endothelial barrier disruption. Dephosphorylation of Serine1177 (−50.8±3.7%, p<0.001) and Threonine495 (−44.8±6.5%, p=0.0103) of the endothelial NO synthase (eNOS) were also observed. Blocking of VEGF-R and PAR-1 restored baseline eNOS Threonine495 phosphorylation. DAM induced vasodilation, enhanced vascular permeability and actin cytoskeleton contraction and induced eNOS hypophosphorylation involving VEGF-R, PAR-1 and ROCK. These results may contribute to a better understanding of severe adverse cardiovascular effects in amphetamine abuse.