bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Autoantigen Atlas From Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19
Authors: Wang Julia Y. , Zhang Wei , Roehrl Victor B. , Roehrl Michael W. , Roehrl Michael H. 
Published: March 2022

COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. We used DS-affinity proteomics to define the autoantigen-ome of lung fibroblasts and bioinformatics analyses to study the relationship between autoantigenic proteins and COVID-induced alterations. Using DS-affinity, we identified an autoantigen-ome of 408 proteins from human HFL1 cells, at least 231 of which are known autoAgs. Comparing with available COVID data, 352 proteins of the autoantigen-ome have thus far been found to be altered at protein or RNA levels in SARS-CoV-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a connection between COVID infection and autoimmunity. The vast number of COVID-altered proteins with high intrinsic propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients. The variety of autoAgs related to mRNA metabolism, translation, and vesicles suggests a need for long-term monitoring of autoimmunity in COVID. The COVID autoantigen atlas we are establishing provides a detailed molecular map for further investigation of autoimmune sequelae of the pandemic, such as “long COVID” syndrome.Summary SentenceAn autoantigen-ome by dermatan sulfate affinity from human lung HFL1 cells may explain neurological and autoimmune manifestations of COVID-19.
Improving Access to HLA-Matched Kidney Transplants for African American Patients
Authors: Bekbolsynov Dulat , Mierzejewska Beata , Khuder Sadik , Ekwenna Obinna , Rees Michael , Green Robert C. , Stepkowski Stanislaw M. 
Published: March 2022

IntroductionKidney transplants fail more often in Black than in non-Black (White, non-Black Hispanic, and Asian) recipients. We used the estimated physicochemical immunogenicity for polymorphic amino acids of donor/recipient HLAs to select weakly immunogenic kidney transplants for Black vs. White or non-Black patients.MethodsOPTN data for 65,040 donor/recipient pairs over a 20-year period were used to calculate the individual physicochemical immunogenicity by hydrophobic, electrostatic and amino acid mismatch scores (HMS, EMS, AMS) and graft-survival outcomes for Black vs. White or vs. non-Black recipients, using Kaplan-Meier survival and Cox regression analyses. Simulations for re-matching recipients with donors were based on race-adjusted HMS thresholds with clinically achievable allocations.ResultsThe retrospective median kidney graft survival was 12.0 years in Black vs. 18.6 years in White (6.6-year difference; p&gt;0.001) and 18.4 years in non-Black (6.4-year difference; p&gt;0.01) recipients. Only 0.7% of Blacks received transplants matched at HLA-A/B/DR/DQ (HMS=0) vs. 8.1% in Whites (p&lt;0.001). Among fully matched Blacks (HMS=0), graft survival was 16.1-years and in well-matched Blacks (HMS ≤ 3.0) it was 14.0-years. Whites had 21.6-years survival at HMS ≤ 3.0 and 18.7-years at HMS ≤ 7.0 whereas non-Blacks had 22.0-year at HMS ≤ 3.0 and 18.7-year at HMS ≤ 7.0, confirming that higher HMS thresholds produced excellent survival. Simulation of ABO-compatible donor-recipient pairs using race-adjusted HMS thresholds identified weakly immunogenic matches at HMS=0 for 6.1% Blacks and 18.0% at HMS ≤ 3.0. Despite prioritizing Black patients, non-Black patients could be matched at the same level as in current allocation (47.0% vs 56.5%, at HMS ≤ 7.0).ConclusionsRace-adjusted HMS (EMS, AMS)-based allocation increased the number of weakly immunogenic donors for Black patients, while still providing excellent options for non-Black recipients.
Evaluation of Humoral and Cellular Responses in SARS-CoV-2 mRNA Vaccinated Immunocompromised Patients
Authors: Oyaert Matthijs , De Scheerder Marie-Angélique , Van Herrewege Sophie , Laureys Guy , Van Assche Sofie , Cambron Melissa , Naesens Leslie , Hoste Levi , Claes Karlien , Haerynck Filomeen , Kerre Tessa , Van Laecke Steven , Van Biesen Wim , Jacques Peggy , Verhasselt Bruno , Padalko Elizaveta 
Published: March 2022

BackgroundImmunocompromised patients are at increased risk of severe COVID-19 and impaired vaccine response. In this observational prospective study, we evaluated immunogenicity of the BNT162b2 mRNA vaccine in cohorts of primary or secondary immunocompromised patients.MethodsFive clinical groups of immunocompromised patients [primary immunodeficiency (PID) (n=57), people living with HIV (PLWH) (n=27), secondary immunocompromised patients with a broad variety of underlying rheumatologic (n=23) and homogeneous (multiple sclerosis) neurologic (n=53) conditions and chronic kidney disease (CKD) (n=39)] as well as a healthy control group (n=54) were included. Systemic humoral and cellular immune responses were evaluated by determination of anti-SARS-CoV-2 Spike antibodies using a TrimericS IgG assay (Diasorin) and through quantification of interferon gamma release in response to SARS-CoV-2 antigen with QuantiFERON SARS-CoV-2 assay (Qiagen), respectively. Responses were measured at pre-defined time-points after complete vaccination.ResultsAll healthy controls, PLWH and CKD-patients had detectable antibodies 10 to 14 days (T2) and 3 months (T3) after administration of the second vaccination. In contrast, only 94.5% of the PID, 50.0% of the rheumatologic and 48.0% of neurologic patients developed antibodies at T2 and only 89.1% of the PID, 52.4% of the rheumatologic and 50.0% of neurologic patients developed antibodies at T3. At T3 no significant differences in cellular response between the healthy control group and the PLWH and CKD groups were found, while proportions of reactive subjects were lower in PID and rheumatologic patients and higher in neurologic patients. Humoral and cellular immune responses significantly correlated in the healthy control, PID, PLWH groups for all 3 antigens.ConclusionPatients with acquired or inherited immune disorders may show variable immune responses to vaccination with the BNT162b2 mRNA vaccine against SARS-CoV-2. Whether humoral, cellular or both immune responses are delayed depends on the patient group, therapy and individual risk factors. These data may guide the counselling of patients with immune disorders regarding vaccination of SARS-CoV-2.
Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction
Authors: Hu Yunwei , Li Zuoyi , Chen Guanyu , Li Zhuang , Huang Jun , Huang Haixiang , Xie Yanyan , Chen Qian , Zhu Wenjie , Wang Minzhen , Chen Jianping , Su Wenru , Chen Xiaoqing , Liang Dan 
Published: March 2022

PurposeInflammation triggers the activation of CD4+T cells and the breakdown of blood–retinal barrier, thus contributing to the pathology of experimental autoimmune uveitis (EAU). We explored the anti-inflammatory effect of hydroxychloroquine (HCQ) on EAU and the potential mechanisms active in T cells and retinal vascular endothelial cells (RVECs).MethodsC57BL/6J mice were immunized with interphotoreceptor retinoid binding protein 1-20 (IRBP1–20) to induce EAU and then treated with the vehicle or HCQ (100 mg/kg/day). On day 7, 14, 21, 30 and 60 after immunization, clinical scores were evaluated. On day 14, histopathological scores were assessed, and retinas, spleens, and lymph nodes were collected for quantitative polymerase chain reaction or flow cytometry analysis. RVEC dysfunction was induced by tumor necrosis factor α (TNF-α) stimulation. The expression of cytokines, chemokines, adhesion molecules, and lectin-like oxidized LDL receptor-1 (LOX-1)/nuclear factor κB (NF-κB) was measured in RVECs with or without HCQ.ResultsHCQ treatment protected mice from uveitis, evidenced by reduced expression of inflammatory factors, chemokines, and adhesion molecules in the retina. In systemic immune response, HCQ inhibited the activation of naïve CD4+T cells and frequencies of T effector cells, and promoted T regulatory cells. HCQ decreased IRBP1-20–specific T cell responses and proliferation of CD4+T cells in vitro. Further studies established that TNF-α induced RVECs to express inflammatory cytokines, chemokines, and adhesion molecules, whereas HCQ alleviated the alterations via the LOX-1/NF-κB pathways.ConclusionsHCQ alleviates EAU by regulating the Teff/Treg balance and ameliorating RVECs dysfunction via the LOX-1/NF-κB axis. HCQ may be a promising therapeutic candidate for uveitis.
Effect of Grain Structure on the Failure Mechanism of Cu/Cu3Sn Investigated Via Molecular Dynamic Simulations
Authors: Zhang Jicheng , Jiang Zhitao , Zhang Yuanxiang 
Published: March 2022

The grain structure has a great influence on the mechanical reliability of miniaturized interconnect circuits. Under the working conditions, Cu3Sn will be the main intermetallic compound that forms during electromigration and the thermal ageing process, which can easily induce cracks between Cu3Sn and the copper pad. This paper investigated the effect of the Cu grain structure on the Cu3Sn/Cu interface reliability via molecular dynamic simulations. Single-crystal Cu, twin-crystal Cu, and polycrystalline Cu models were implemented to form the interface structure, and uniaxial tension simulations were performed at strain rates of 0.01, 0.1, and 0.5% ps−1 to evaluate the interfacial strength and interface failure mechanism. Results show that the polycrystalline Cu models always exhibits a lower degree of stress and shows a great ductile character. The existence of twin grain boundaries makes Cu layer more stable, and their failure processes are dominated by stair-rod type dislocations with a Burgers vector of 1/6 [110] instead of Shockley dislocations with a Burgers vector of 1/6 [112], which induce their interface models fail in Cu3Sn layer near the interface. The strain rate dependence mechanical character of both interface and grains would be the main reason of phenomenon for the difference failure character affected by grain structure and strain rate.
Impact of Isolation Time of COVID-19 Patients in Intensive Care Unit on Healthcare Workers Contamination and Nursing Care Intensity
Authors: Doyen Denis , Morand Lucas , Jozwiak Mathieu , Aurenche Mateu Didac , Saccheri Clément , Hyvernat Hervé , Cremoni Marion , Brglez Vesna , Bèle Nicolas , Bernardin Gilles , Seitz-Polski Barbara , Dellamonica Jean 
Published: March 2022

BackgroundThe optimal isolation time of COVID-19 patients in intensive care unit (ICU) is debated. We investigated the impact of two different COVID-19 patient isolation time strategies on healthcare workers (HCW) contamination, intensity of nursing care and potential associated adverse events.MethodsWe prospectively included all consecutive COVID-19 patients and HCW in our ICU in the first two pandemic waves (March to May 2020 and August to November 2020). Specific isolation measures for COVID-19 patients were released after two negative RT-PCR assays in the first wave and 14 days after the onset of symptoms in the second wave. Contamination of HCW was assessed at the end of each pandemic wave by combining both a RT-PCR assay and a serological test.ResultsOverall, 117 COVID-19 patients and 73 HCW were included. Despite an earlier release from isolation after ICU admission in the second than in the first wave [6 (4–8) vs. 15 (11–19) days, p &lt; 0.01], the proportion of HCW with a positive serological test (16 vs. 17%, p = 0.94) or with a positive RT-PCR assay (3 vs. 5%, p = 0.58) was not different between the two waves. Although a lower nurse-to-bed ratio, the intensity of nursing care was higher in the second than in the first wave. A longer isolation time was associated with accidental extubation (OR = 1.18, 95%CI:1.07–1.35, p = 0.005) but neither with ventilator-associated pneumonia nor with dysglycemia.ConclusionA shorter isolation time of COVID-19 patients in ICU was not associated with higher HCW contamination, while a longer isolation time seemed to be associated with higher accidental extubation.
Human Amnion Epithelial Cells and Their Derived Exosomes Alleviate Sepsis-Associated Acute Kidney Injury via Mitigating Endothelial Dysfunction
Authors: Chi Dongxuan , Chen Ying , Xiang Chengang , Yao Weijian , Wang Hui , Zheng Xizi , Xu Damin , Li Nan , Xie Min , Wang Suxia , Liu Gang , Li Shuangling , Yang Li 
Published: March 2022

BackgroundSepsis is characterized by organ dysfunction resulting from a patient’s dysregulated response to infection. Sepsis-associated acute kidney injury (S-AKI) is the most frequent complication contributing to the morbidity and mortality of sepsis. The prevention and treatment of S-AKI remains a significant challenge worldwide. In the recent years, human amnion epithelial cells (hAECs) have drawn much attention in regenerative medicine, yet the therapeutic efficiency of hAECs in S-AKI has not been evaluated.MethodsSeptic mice were induced by cecal ligation and puncture (CLP) operation. hAECs and their derived exosomes (EXOs) were injected into the mice via tail vein right after CLP surgery. The 7-day survival rate was observed. Serum creatinine level was measured and H&amp;E staining of tissue sections were performed 16 h after CLP. Transmission electron microscopy was used to examine the renal endothelial integrity in CLP mice. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) and EXOs. Zonula occludens-1 (ZO-1) localization was observed by immunofluorescence staining. Expression of phosphor-p65 (p-p65), p65, vascular cell adhesion molecule-1 (VCAM-1), and ZO-1 in the kidney were determined by Western blot.ResultshAECs decreased the mortality of CLP mice, ameliorated septic injury in the kidney, and improved kidney function. More precisely, hAECs suppressed systemic inflammation and maintained the renal endothelial integrity in septic animals. EXOs from hAECs exhibited similar renal protective effects as their parental cells. EXOs maintained endothelial cell adhesion junction in vitro and inhibited endothelial cell hyperactivation in vivo. Mechanistically, EXOs suppressed proinflammatory nuclear factor kappa B (NF-κB) pathway activation in LPS-treated HUVECs and in CLP mice kidneys.ConclusionOur results indicate that hAECs and their derived EXOs may ameliorate S-AKI via the prevention of endothelial dysfunction in the early stage of sepsis in mice. Stem cell or exosome-based therapy targeting endothelial disorders may be a promising alternative for treatment of S-AKI.
First Principles Calculation of Protein–Protein Dimer Affinities of ALS-Associated SOD1 Mutants
Authors: Hsueh Shawn C. C. , Nijland Mark , Peng Xubiao , Hilton Benjamin , Plotkin Steven S. 
Published: March 2022

Cu,Zn superoxide dismutase (SOD1) is a 32 kDa homodimer that converts toxic oxygen radicals in neurons to less harmful species. The dimerization of SOD1 is essential to the stability of the protein. Monomerization increases the likelihood of SOD1 misfolding into conformations associated with aggregation, cellular toxicity, and neuronal death in familial amyotrophic lateral sclerosis (fALS). The ubiquity of disease-associated mutations throughout the primary sequence of SOD1 suggests an important role of physicochemical processes, including monomerization of SOD1, in the pathology of the disease. Herein, we use a first-principles statistical mechanics method to systematically calculate the free energy of dimer binding for SOD1 using molecular dynamics, which involves sequentially computing conformational, orientational, and separation distance contributions to the binding free energy. We consider the effects of two ALS-associated mutations in SOD1 protein on dimer stability, A4V and D101N, as well as the role of metal binding and disulfide bond formation. We find that the penalty for dimer formation arising from the conformational entropy of disordered loops in SOD1 is significantly larger than that for other protein–protein interactions previously considered. In the case of the disulfide-reduced protein, this leads to a bound complex whose formation is energetically disfavored. Somewhat surprisingly, the loop free energy penalty upon dimerization is still significant for the holoprotein, despite the increased structural order induced by the bound metal cations. This resulted in a surprisingly modest increase in dimer binding free energy of only about 1.5 kcal/mol upon metalation of the protein, suggesting that the most significant stabilizing effects of metalation are on folding stability rather than dimer binding stability. The mutant A4V has an unstable dimer due to weakened monomer-monomer interactions, which are manifested in the calculation by a separation free energy surface with a lower barrier. The mutant D101N has a stable dimer partially due to an unusually rigid β-barrel in the free monomer. D101N also exhibits anticooperativity in loop folding upon dimerization. These computational calculations are, to our knowledge, the most quantitatively accurate calculations of dimer binding stability in SOD1 to date.
Body Complexion and Circulating Lipids in the Risk of TDP-43 Related Disorders
Authors: Esteban-García Noelia , Fernández-Beltrán Luis C. , Godoy-Corchuelo Juan Miguel , Ayala Jose L. , Matias-Guiu Jordi A. , Corrochano Silvia 
Published: March 2022

ObjectiveFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two distinct degenerative disorders with overlapping genetics, clinical manifestations, and pathology, including the presence of TDP-43 aggregates in nearly 50% of patients with FTD and 98% of all patients with ALS. Here, we evaluate whether different genetically predicted body lipid metabolic traits are causally associated with the risk of FTD with TDP-43 aggregates, compare it to their causal role in the risk of ALS, and identify genetic variants shared between these two TDP43 related disorders in relation to lipid metabolic traits.MethodsWe conducted two-sample Mendelian randomization analyses (2SMR) to evaluate the causal association of 9 body complexion and 9 circulating lipids traits with the risk of FTD with TDP-43 aggregates and the risk of ALS. The inverse-variance weighted method was the primary analysis, followed by secondary sensitive analyses. We then looked for common genetic variants between FTD and ALS in relation to lipid metabolic traits.ResultsGenetically increased trunk-predicted mass, fat-free mass, and higher circulating triglycerides levels were suggestively associated with a higher risk of FTD with TDP-43 aggregates. Circulating lipids, mainly LDL cholesterol, were causally associated with a higher risk of ALS. We identified two genetic variants, EIF4ENIF1 and HNRNPK, in relation to body complexion and circulating lipids shared between FTD with TDP-43 aggregates and ALS.ConclusionThis work provides evidence that body complexion and circulating lipids traits impact differentially on the risk of FTD and ALS, suggesting new and specific interventional approaches in the control of body lipid metabolism for FTD and ALS, and identified HNRNPK as a potential link between circulating lipids levels and these disorders.
Transcutaneous Auricular Vagus Nerve Stimulation Modulates the Prefrontal Cortex in Chronic Insomnia Patients: fMRI Study in the First Session
Authors: He Jia-Kai , Jia Bao-Hui , Wang Yu , Li Shao-Yuan , Zhao Bin , Zhou Zeng-Guang , Bi Yan-Zhi , Wu Mo-Zheng , Li Liang , Zhang Jin-Ling , Fang Ji-Liang , Rong Pei-Jing 
Published: March 2022

ObjectivesTranscutaneous auricular vagus nerve stimulation (taVNS) has been reported to be effective for chronic insomnia (CI). However, the appropriate population for taVNS to treat insomnia is unclear.MethodsTotal twenty-four patients with CI and eighteen health controls (HC) were recruited. Rest-state functional magnetic resonance imaging (Rs-fMRI) was performed before and after 30 min' taVNS at baseline. The activated and deactivated brain regions were revealed by different voxel-based analyses, then the seed-voxel functional connectivity analysis was calculated. In the CI group, 30 min of taVNS were applied twice daily for 4 weeks. Pittsburgh Sleep Quality Index (PSQI) and Flinders Fatigue Scale (FFS) were also assessed before and after 4 weeks of treatment in the CI group. The HC group did not receive any treatment. The correlations were estimated between the clinical scales' score and the brain changes.ResultsThe scores of PSQI (p &lt; 0.01) and FFS (p &lt; 0.05) decreased after 4 weeks in the CI group. Compared to the HC group, the first taVNS session up-regulated left dorsolateral prefrontal cortex (dlPFC) and decreased the functional connectivity (FCs) between dlPFC and bilateral medial prefrontal cortex in the CI group. The CI groups' baseline voxel wised fMRI value in the dlPFC were negatively correlated to the PSQI and the FFS score after 4 weeks treatment.ConclusionsIt manifests that taVNS has a modulatory effect on the prefrontal cortex in patients with CI. The initial state of dlPFC may predict the efficacy for taVNS on CI.
The Smoking Paradox in Stroke Patients Under Reperfusion Treatment Is Associated With Endothelial Dysfunction
Authors: Iglesias-Rey Ramón , Custodia Antía , Alonso-Alonso Maria Luz , López-Dequidt Iria , Rodríguez-Yáñez Manuel , Pumar José M. , Castillo José , Sobrino Tomás , Campos Francisco , Silva-Candal Andres da , Hervella Pablo 
Published: March 2022

ObjectiveThis study aimed to explore the association between smoking habit and the serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), in relation with the functional outcome of patients with acute ischemic stroke undergoing reperfusion treatment.MethodsObservational and retrospective study of a series of patients with acute ischemic stroke subjected to reperfusion treatments. Clinical, analytical, and neuroimaging parameters were analyzed. The main endpoint was the functional outcome at 3 months, measured by the modified Ranking Scale (mRS). Logistic regression models were used to analyze the association between smoking and sTWEAK levels with functional outcome and leukoaraiosis.ResultsThe results showed that smoking habit was associated with a good functional outcome at 3 months in patients with stroke (OR: 3.52; 95% CI: 1.03–11.9; p = 0.044). However, this independent association was lost after adjusting by sTWEAK levels (OR 1.73; 95% CI: 0.86–13.28; p = 0.116). sTWEAK levels were significantly lower in smoker patients [4015.5 (973.66–7921.83) pg/ml vs. 5,628 (2,848–10,202) pg/ml, p &lt; 0.0001], while sTWEAK levels were significantly higher in patients with poor functional outcomes at 3 months [10,284 (7,388–13.247) pg/ml vs. 3,405 (2,329–6,629) pg/ml, p &lt; 0.0001].ConclusionThe decrease in sTWEAK levels was associated with a good functional outcome in smoker patients with stroke undergoing reperfusion therapy.