bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe COVID-19 associated hyperglycemia is caused by beta cell dysfunction: a prospective cohort study
Authors: Gojda Jan , Koudelková Kateřina , Ouřadová Anna , Lang Alexander , Krbcová Magdaléna , Gvozdeva Alexandra , Šebo Viktor , Slagmolen Lotte , Potočková Jana , Tůma Petr , Rossmeislová Lenka , Anděl Michal , Karpe Fredrik , Schlesinger Sabrina 
Published: July 2023

Abstract
Background
COVID-19, an infectious disease caused by SARS-CoV-2, was shown to be associated with an increased risk of new-onset diabetes. Mechanisms contributing to the development of hyperglycemia are still unclear. We aimed to study whether hyperglycemia is related to insulin resistance and/or beta cell dysfunction.

Materials and methods
Survivors of severe COVID-19 but without a known history of diabetes were examined at baseline (T0) and after 3 (T3) and 6 (T6) months: corticosteroids use, indirect calorimetry, and OGTT. Insulin response and sensitivity (IS) were expressed as insulinogenic (IGI), disposition (DI), and Matsuda insulin sensitivity index (ISI). Resting energy expenditure (REE) and respiratory quotient (RQ) was calculated from the gas exchange and nitrogen losses.

Results
26 patients (out of 37) with complete outcome data were included in the analysis (age ~59.0 years; BMI ~ 30.4, 35% women). Patients were hypermetabolic at T0 (30.3 ± 4.0 kcal/kg lean mass/day, ~120% predicted) but REE declined over 6 months (ΔT6-T0 mean dif. T6-T0 (95% CI): −5.4 (−6.8, −4.1) kcal/kg FFM/day, p < 0.0001). 17 patients at T0 and 13 patients at T6 had hyperglycemia. None of the patients had positive islet autoantibodies. Insulin sensitivity in T0 was similarly low in hyperglycemic (H) and normoglycemic patients (N) (T0 ISIH = 3.12 ± 1.23, ISIN = 3.47 ± 1.78, p = 0.44), whereas insulin response was lower in the H group (DIH = 3.05 ± 1.79 vs DIN = 8.40 ± 5.42, p = 0.003). Over 6 months ISI (ΔT6-T0 mean dif. T6-T0 for ISI (95% CI): 1.84 (0.45, 3.24), p = 0.01)) increased in the H group only.

Conclusions
Patients with severe COVID-19 had increased REE and insulin resistance during the acute phase due to the infection and corticosteroid use, but these effects do not persist during the follow-up period. Only patients with insufficient insulin response developed hyperglycemia, indicating that beta cell dysfunction, rather than insulin resistance, was responsible for its occurrence.
BCKDK regulates breast cancer cell adhesion and tumor metastasis by inhibiting TRIM21 ubiquitinate talin1
Authors: Xu Chunlan , Yang Kunao , Xuan Zuodong , Li Jinxin , Liu Yankuo , Zhao Yue , Zheng Zeyuan , Bai Yang , Shi Zhiyuan , Shao Chen , Zhang Lei , Sun Huimin 
Published: July 2023

AbstractBreast cancer is the most common malignant cancer in women worldwide. Cancer metastasis is the major cause of cancer-related deaths. BCKDK is associated with various diseases, including proliferation, migration, and invasion in multiple types of human cancers. However, the relevance of BCKDK to the development and progression of breast cancers and its function is unclear. This study found that BCKDK was overexpressed in breast cancer, associated with poor prognosis, and implicated in tumor metastasis. The downregulation of BCKDK expression inhibited the migration of human breast cancer cells in vitro and diminished lung metastasis in vivo. BCKDK perturbed the cadherin-catenin complex at the adherens junctions (AJs) and assembled focal adhesions (FAs) onto the extracellular matrix, thereby promoting the directed migration of breast cancer cells. We observed that BCKDK acted as a conserved regulator of the ubiquitination of cytoskeletal protein talin1 and the activation of the FAK/MAPK pathway. Further studies revealed that BCKDK inhibited the binding of talin1 to E3 ubiquitin ligase-TRIM21, leading to the decreased ubiquitination/degradation of talin1. In conclusion, identifying BCKDK as a biomarker for breast cancer metastasis facilitated further research on diagnostic biomarkers. Elucidating the mechanism by which BCKDK exerted its biological effect could provide a new theoretical basis for developing new markers for breast cancer metastasis and contribute to developing new therapies for the clinical treatment of breast cancer patients.
NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells
Authors: Petillo Sara , Sproviero Elena , Loconte Luisa , Cuollo Lorenzo , Zingoni Alessandra , Molfetta Rosa , Fionda Cinzia , Soriani Alessandra , Cerboni Cristina , Petrucci Maria Teresa , Fazio Francesca , Paolini Rossella , Santoni Angela , Cippitelli Marco 
Published: July 2023

AbstractNatural Killer (NK) cells act as important regulators in the development and progression of hematological malignancies and their suppressor activity against Multiple Myeloma (MM) cells has been confirmed in many studies. Significant changes in the distribution of NK cell subsets and dysfunctions of NK cell effector activities were described in MM patients and correlated with disease staging. Thus, restoring or enhancing the functionality of these effectors for the treatment of MM represents a critical need. Neddylation is a post-translational modification that adds a ubiquitin-like molecule, NEDD8, to the substrate protein. One of the outcomes is the activation of the Cullin Ring Ligases (CRLs), a class of ubiquitin-ligases that controls the degradation of about 20% of proteasome-regulated proteins. Overactivation of CRLs has been described in cancer and can lead to tumor growth and progression. Thus, targeting neddylation represents an attractive approach for cancer treatment. Our group has recently described how pharmacologic inhibition of neddylation increases the expression of the NKG2D activating receptor ligands, MICA and MICB, in MM cells, making these cells more susceptible to NK cell degranulation and killing. Here, we extended our investigation to the direct role of neddylation on NK cell effector functions exerted against MM. We observed that inhibition of neddylation enhanced NK cell-mediated degranulation and killing against MM cells and improved Daratumumab/Elotuzumab-mediated response. Mechanistically, inhibition of neddylation increased the expression of Rac1 and RhoA GTPases in NK cells, critical mediators for an efficient degranulation at the immunological synapse of cytotoxic lymphocytes, and augmented the levels of F-actin and perforin polarization in NK cells contacting target cells. Moreover, inhibition of neddylation partially abrogated TGFβ-mediated repression of NK cell effector activity. This study describes the role of neddylation on NK cell effector functions and highlights the positive immunomodulatory effects achieved by the inhibition of this pathway in MM.
Bcl-2 family inhibitors sensitize human cancer models to therapy
Authors: Valentini Elisabetta , Di Martile Marta , Brignone Matteo , Di Caprio Marica , Manni Isabella , Chiappa Michela , Sergio Ilaria , Chiacchiarini Martina , Bazzichetto Chiara , Conciatori Fabiana , D’Aguanno Simona , D’Angelo Carmen , Ragno Rino , Russillo Michelangelo , Colotti Gianni , Marchesi Francesco , Bellone Maria Laura , Dal Piaz Fabrizio , Felli Maria Pia , Damia Giovanna , Del Bufalo Donatella 
Published: July 2023

AbstractBH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT-199, the first specific Bcl-2 inhibitor, was approved by FDA for the treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a therapeutic strategy to enhance the efficacy of anticancer treatment.
ZHX2 deficiency enriches hybrid MET cells through regulating E-cadherin expression
Authors: He Yan , Zhang Qimin , Chen Yuanhong , Wu Yingjian , Quan Yuan , Chen Weihua , Yao Jing , Zhang Peijing 
Published: July 2023

AbstractGrowing evidence indicates that the epithelial to mesenchymal (E/M) hybrid state plays a key role in tumorigenesis. Importantly, a hybrid mesenchymal to epithelial transition (MET) state in which individual cells express both epithelial and mesenchymal markers was recently identified in vivo, further strengthening the bonds between the hybrid EMT state and cancer progression. However, the role and the molecular mechanisms by which the hybrid MET state is maintained in triple-negative breast cancer cells (TNBC) remain elusive. Here, we find that loss of ZHX2 expression results in the hybrid MET phenotype in mesenchymal TNBC cells. Mechanistically, through directly binding to the CDH1 promoter, depletion of ZHX2 specifically reactivates expression of CDH1 encoding E-cadherin, an epithelial marker that is crucial for maintaining epithelial phenotype. Functionally, loss of ZHX2 expression enriches the hybrid MET cells and inhibits the migration and dissemination of TNBC cells or organoids, which could be reversed by restoration of E-cadherin. Moreover, depletion of ZHX2 suppresses lung metastasis in preclinical models of TNBC. In patients with TNBC, ZHX2 expression was amplified and negatively correlated with the expression of E-cadherin. These findings suggest that loss of ZHX2 promotes the hybrid MET state to impair TNBC progression.
AraC interacts with p75NTR transmembrane domain to induce cell death of mature neurons
Authors: Lopes-Rodrigues Vanessa , Boxy Pia , Sim Eunice , Park Dong Ik , Habeck Michael , Carbonell Josep , Andersson Annika , Fernández-Suárez Diana , Nissen Poul , Nykjær Anders , Kisiswa Lilian 
Published: July 2023

AbstractCytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75NTRis responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75NTRsignalling in the cell death of mature neurons, we used mature cerebellar granule neurons’ primary cultures from p75NTRknockout andp75NTRCys259mice. Evaluation of neurite degeneration, cell death and p75NTRsignalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75NTRresulting in uncoupling of p75NTRfrom the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. Our findings identify p75NTRas a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.
The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease
Authors: Fu Jing , Li Shirong , Ma Huihui , Yang Jun , Pagnotti Gabriel M. , Brown Lewis M. , Weiss Stephen J. , Mapara Markus Y. , Lentzsch Suzanne 
Published: July 2023

AbstractMultiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or usingPd-1h-/-bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using aPd-1h-/-myeloma bone disease mouse model wherein myeloma cells injected intoPd-1h-/-Rag2-/-results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.
Optimal reactive nitrogen control pathways identified for cost-effective PM2.5 mitigation in Europe
Authors: Liu Zehui , Rieder Harald E. , Schmidt Christian , Mayer Monika , Guo Yixin , Winiwarter Wilfried , Zhang Lin 
Published: July 2023

AbstractExcess reactive nitrogen (Nr), including nitrogen oxides (NOx) and ammonia (NH3), contributes strongly to fine particulate matter (PM2.5) air pollution in Europe, posing challenges to public health. Designing cost-effective Nr control roadmaps for PM2.5 mitigation requires considering both mitigation efficiencies and implementation costs. Here we identify optimal Nr control pathways for Europe by integrating emission estimations, air quality modeling, exposure-mortality modeling, Nr control experiments and cost data. We find that phasing out Nr emissions would reduce PM2.5 by 2.3 ± 1.2 μg·m−3 in Europe, helping many locations achieve the World Health Organization (WHO) guidelines and reducing PM2.5-related premature deaths by almost 100 thousand in 2015. Low-ambition NH3 controls have similar PM2.5 mitigation efficiencies as NOx in Eastern Europe, but are less effective in Western Europe until reductions exceed 40%. The efficiency for NH3 controls increases at high-ambition reductions while NOx slightly decreases. When costs are considered, strategies for both regions uniformly shift in favor of NH3 controls, as NH3 controls up to 50% remain 5-11 times more cost-effective than NOx per unit PM2.5 reduction, emphasizing the priority of NH3 control policies for Europe.
Atlas-scale single-cell multi-sample multi-condition data integration using scMerge2
Authors: Lin Yingxin , Cao Yue , Willie Elijah , Patrick Ellis , Yang Jean Y. H. 
Published: July 2023

AbstractThe recent emergence of multi-sample multi-condition single-cell multi-cohort studies allows researchers to investigate different cell states. The effective integration of multiple large-cohort studies promises biological insights into cells under different conditions that individual studies cannot provide. Here, we present scMerge2, a scalable algorithm that allows data integration of atlas-scale multi-sample multi-condition single-cell studies. We have generalized scMerge2 to enable the merging of millions of cells from single-cell studies generated by various single-cell technologies. Using a large COVID-19 data collection with over five million cells from 1000+ individuals, we demonstrate that scMerge2 enables multi-sample multi-condition scRNA-seq data integration from multiple cohorts and reveals signatures derived from cell-type expression that are more accurate in discriminating disease progression. Further, we demonstrate that scMerge2 can remove dataset variability in CyTOF, imaging mass cytometry and CITE-seq experiments, demonstrating its applicability to a broad spectrum of single-cell profiling technologies.
Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5
Authors: Hunashal Yamanappa , Kumar Ganesan Senthil , Choy Meng S. , D’Andréa Éverton D. , Da Silva Santiago Andre , Schoenle Marta V. , Desbonnet Charlene , Arthur Michel , Rice Louis B. , Page Rebecca , Peti Wolfgang 
Published: July 2023

AbstractPenicillin-binding proteins (PBPs) are essential for the formation of the bacterial cell wall. They are also the targets of β-lactam antibiotics. In Enterococcus faecium, high levels of resistance to β-lactams are associated with the expression of PBP5, with higher levels of resistance associated with distinct PBP5 variants. To define the molecular mechanism of PBP5-mediated resistance we leveraged biomolecular NMR spectroscopy of PBP5 – due to its size (>70 kDa) a challenging NMR target. Our data show that resistant PBP5 variants show significantly increased dynamics either alone or upon formation of the acyl-enzyme inhibitor complex. Furthermore, these variants also exhibit increased acyl-enzyme hydrolysis. Thus, reducing sidechain bulkiness and expanding surface loops results in increased dynamics that facilitates acyl-enzyme hydrolysis and, via increased β-lactam antibiotic turnover, facilitates β-lactam resistance. Together, these data provide the molecular basis of resistance of clinical E. faecium PBP5 variants, results that are likely applicable to the PBP family.
Two-dimensional Kβ-Kα fluorescence spectrum by nonlinear resonant inelastic X-ray scattering
Authors: Tamasaku Kenji , Taguchi Munetaka , Inoue Ichiro , Osaka Taito , Inubushi Yuichi , Yabashi Makina , Ishikawa Tetsuya 
Published: July 2023

AbstractHigh sensitivity of the Kβ fluorescence spectrum to electronic state is widely used to investigate spin and oxidation state of first-row transition-metal compounds. However, the complex electronic structure results in overlapping spectral features, and the interpretation may be hampered by ambiguity in resolving the spectrum into components representing different electronic states. Here, we tackle this difficulty with a nonlinear resonant inelastic X-ray scattering (RIXS) scheme, where we leverage sequential two-photon absorption to realize an inverse process of the Kβ emission, and measure the successive Kα emission. The nonlinear RIXS reveals two-dimensional (2D) Kβ-Kα fluorescence spectrum of copper metal, leading to better understanding of the spectral feature. We isolate 3d-related satellite peaks in the 2D spectrum, and find good agreement with our multiplet ligand field calculation. Our work not only advances the fluorescence spectroscopy, but opens the door to extend RIXS into the nonlinear regime.
Revealing broken valley symmetry of quantum emitters in WSe2 with chiral nanocavities
Authors: Yang Longlong , Yuan Yu , Fu Bowen , Yang Jingnan , Dai Danjie , Shi Shushu , Yan Sai , Zhu Rui , Han Xu , Li Hancong , Zuo Zhanchun , Wang Can , Huang Yuan , Jin Kuijuan , Gong Qihuang , Xu Xiulai 
Published: July 2023

AbstractSingle photon emission of quantum emitters (QEs) carrying internal degrees of freedom such as spin and angular momentum plays an important role in quantum optics. Recently, QEs in two-dimensional semiconductors have attracted great interest as promising quantum light sources. However, whether those QEs are characterized by the same valley physics as delocalized valley excitons is still under debate. Moreover, the potential applications of such QEs still need to be explored. Here we show experimental evidence of valley symmetry breaking for neutral QEs in WSe2 monolayer by interacting with chiral plasmonic nanocavities. The anomalous magneto-optical behaviour of the coupled QEs suggests that the polarization state of emitted photon is modulated by the chiral nanocavity instead of the valley-dependent optical selection rules. Calculations of cavity quantum electrodynamics further show the absence of intrinsic valley polarization. The cavity-dependent circularly polarized single-photon output also offers a strategy for future applications in chiral quantum optics.
Topological nodal line in superfluid 3He and the Anderson theorem
Authors: Kamppinen T. , Rysti J. , Volard M.-M. , Volovik G. E. , Eltsov V. B. 
Published: July 2023

AbstractSuperconductivity and superfluidity with anisotropic pairing—such as d-wave in cuprates and p-wave in superfluid 3He—are strongly suppressed by impurities. Meanwhile, for applications, the robustness of Cooper pairs to disorder is highly desired. Recently, it has been suggested that unconventional systems become robust if the impurity scattering mixes quasiparticle states only within individual subsystems obeying the Anderson theorem that protects conventional superconductivity. Here, we experimentally verify this conjecture by measuring the temperature dependence of the energy gap in the polar phase of superfluid 3He. We show that oriented columnar non-magnetic defects do not essentially modify the energy spectrum, which has a Dirac nodal line. Although the scattering is strong, it preserves the momentum along the length of the columns and forms robust subsystems according to the conjecture. This finding may stimulate future experiments on the protection of topological superconductivity against disorder and on the nature of topological fermionic flat bands.
Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor
Authors: Zhang Hailiang , Bai Lin , Wu Xin-Qiang , Tian Xi , Feng Jinwen , Wu Xiaohui , Shi Guo-Hai , Pei Xiaoru , Lyu Jiacheng , Yang Guojian , Liu Yang , Xu Wenhao , Anwaier Aihetaimujiang , Zhu Yu , Cao Da-Long , Xu Fujiang , Wang Yue , Gan Hua-Lei , Sun Meng-Hong , Zhao Jian-Yuan , Qu Yuanyuan , Ye Dingwei , Ding Chen 
Published: July 2023

AbstractThe tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic–area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.