bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification
Authors: Wu Dan , Shi Yuxin , Zhang Hao , Miao Changhong 
Published: February 2023

AbstractSepsis is a life-threatening disorder disease defined as infection-induced dysregulated immune responses and multiple organ dysfunction. The imbalance between hyperinflammation and immunosuppression is a crucial feature of sepsis immunity. Epigenetic modifications, including histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA, play essential roles in regulating sepsis immunity through epi-information independent of the DNA sequence. In recent years, the mechanisms of histone modification in sepsis have received increasing attention, with ongoing discoveries of novel types of histone modifications. Due to the capacity for prolonged effects on immune cells, histone modifications can induce immune cell reprogramming and participate in the long-term immunosuppressed state of sepsis. Herein, we systematically review current mechanisms of histone modifications involved in the regulation of sepsis, summarize their role in sepsis from an immune perspective and provide potential therapeutic opportunities targeting histone modifications in sepsis treatment.
Repositioning Lomitapide to block ZDHHC5-dependant palmitoylation on SSTR5 leads to anti-proliferation effect in preclinical pancreatic cancer models
Authors: Wang Yumeng , Zhang Shujie , He Huiqin , Luo Hongyi , Xia Yannan , Jiang Yuanyuan , Jiang Jingwei , Sun Li 
Published: February 2023

AbstractPalmitoylation of proteins plays important roles in various physiological processes, such as cell proliferation, inflammation, cell differentiation etc. However, inhibition of protein palmitoylation has led to few new drugs to date. ZDHHC5 serves as a key enzyme to catalyze palmitoylation on SSTR5 (a proven anti-proliferation receptor in pancreatic cells). Herein, we compare single-cell transcriptome data between pancreatic cancer tissues and normal pancreas tissues and identify that ZDHHC5 is a potential target to inhibit proliferation of pancreatic cancer cells. In addition, we report the repositioning of an orphan drug (Lomitapide) as an inhibitor of ZDHHC5, and we speculate that this inhibitor may be able to block palmitylation on SSTR5. Pharmacological blockade of ZDHHC5 with Lomitapide results in attenuated cancer cell growth and proliferation which collectively contributes to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of ZDHHC5 in pancreatic cancer, representing a new class of palmitoylation targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell palmitoylation.
NMDARs antagonist MK801 suppresses LPS-induced apoptosis and mitochondrial dysfunction by regulating subunits of NMDARs via the CaM/CaMKII/ERK pathway
Authors: Han Wei-Min , Hao Xiao-Bin , Hong Yi-Xiang , Zhao Shan-Shan , Chen Xu-Chang , Wang Ruiying , Wang Yan , Li Gang 
Published: February 2023

AbstractLipopolysaccharide (LPS) displays a robust immunostimulatory ability upon Toll-like receptor 4 (TLR4) recognition. N-methyl-D-aspartate receptors (NMDARs) are highly compartmentalized in most cells and implicated in various inflammatory disorders. However, the relationship between TLR4 and NMDARs has not been explored deeply. This study aimed to examine the role of NMDARs and its specific inhibitor MK801 in LPS-treated endothelial cell dysfunction and the related mechanism in vivo and in vitro. The results showed that pre-treatment with MK801 significantly decreased LPS-induced cell death, cellular Ca2+, cellular reactive oxygen species, and glutamate efflux. Moreover, MK801 restrained LPS-induced mitochondrial dysfunction by regulating mitochondrial membrane potential and mitochondrial Ca2+ uptake. The oxygen consumption, basal and maximal respiration rate, and ATP production in LPS-treated HUVECs were reversed by MK801 via regulating ATP synthesis-related protein SDHB2, MTCO1, and ATP5A. The molecular pathway involved in MK801-regulated LPS injury was mediated by phosphorylation of CaMKII and ERK and the expression of MCU, MCUR1, and TLR4. LPS-decreased permeability in HUVECs was improved by MK801 via the Erk/ZO-1/occluding/Cx43 axis. Co-immunoprecipitation assay and western blotting showed three subtypes of NMDARs, NMDAζ1, NMDAε2, and NMDAε4 were bound explicitly to TLR4, suppressed by LPS, and promoted by MK801. Deficiency of NMDAζ1, NMDAε2, or NMDAε4 induced cell apoptosis, Ca2+ uptake, ROS production, and decreased basal and maximal respiration rate, and ATP production, suggesting that NMDARs integrity is vital for cell and mitochondrial function. In vivo investigation showed MK801 improved impairment of vascular permeability, especially in the lung and mesentery in LPS-injured mice. Our study displayed a novel mechanism and utilization of MK801 in LPS-induced ECs injury and permeability.
Giant cell arteritis: reviewing the advancing diagnostics and management
Authors: Bilton Edward J. , Mollan Susan P. 
Published: February 2023

AbstractGiant Cell Arteritis (GCA) is well known to be a critical ischaemic disease that requires immediate medical recognition to initiate treatment and where one in five people still suffer visual loss. The immunopathophysiology has continued to be characterised, and the influencing of ageing in the development of GCA is beginning to be understood. Recent national and international guidelines have supported the directed use of cranial ultrasound to reduce diagnostic delay and improve clinical outcomes. Immediate high dose glucocorticoids remain the standard emergency treatment for GCA, with a number of targeted agents that have been shown in clinical trials to have superior clinical efficacy and steroid sparing effects. The aim of this review was to present the latest advances in GCA that have the potential to influence routine clinical practice.
Evolution of protease activation and specificity via alpha-2-macroglobulin-mediated covalent capture
Authors: Knyphausen Philipp , Rangel Pereira Mariana , Brear Paul , Hyvönen Marko , Jermutus Lutz , Hollfelder Florian 
Published: February 2023

AbstractTailoring of the activity and specificity of proteases is critical for their utility across industrial, medical and research purposes. However, engineering or evolving protease catalysts is challenging and often labour intensive. Here, we describe a generic method to accelerate this process based on yeast display. We introduce the protease selection system A2Mcap that covalently captures protease catalysts by repurposed alpha-2-macroglobulin (A2Ms). To demonstrate the utility of A2Mcap for protease engineering we exemplify the directed activity and specificity evolution of six serine proteases. This resulted in a variant of Staphylococcus aureus serin-protease-like (Spl) protease SplB, an enzyme used for recombinant protein processing, that no longer requires activation by N-terminal signal peptide removal. SCHEMA-based domain shuffling was used to map the specificity determining regions of Spl proteases, leading to a chimeric scaffold that supports specificity switching via subdomain exchange. The ability of A2Mcap to overcome key challenges en route to tailor-made proteases suggests easier access to such reagents in the future.
Malodour classification with low-cost flexible electronics
Authors: Ozer Emre , Kufel Jedrzej , Biggs John , Rana Anjit , Rodriguez Francisco J. , Lee-Clark Thomas , Sou Antony , Ramsdale Catherine , White Scott , Garlapati Suresh Kumar , Valliappan Palaniappan , Rahmanudin Aiman , Komanduri Venuskrishnan , Saez Glenn Sunley , Gollu Sankara , Brown Gavin , Dudek Piotr , Persaud Krishna C. , Turner Michael L. , Murray Stephanie , Bates Susan , Treloar Robert , Newby Brian , Ford Jane 
Published: February 2023

AbstractUnderstanding body malodour in a measurable manner is essential for developing personal care products. Body malodour is the result of bodily secretion of a highly complex mixture of volatile organic compounds. Current body malodour measurement methods are manual, time consuming and costly, requiring an expert panel of assessors to assign a malodour score to each human test subject. This article proposes a technology-based solution to automate this task by developing a custom-designed malodour score classification system comprising an electronic nose sensor array, a sensor readout interface and a machine learning hardware fabricated on low-cost flexible substrates. The proposed flexible integrated smart system is to augment the expert panel by acting like a panel assessor but could ultimately replace the panel to reduce the test and measurement costs. We demonstrate that it can classify malodour scores as good as or even better than half of the assessors on the expert panel.
Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19
Authors: Mothes Ronja , Pascual-Reguant Anna , Koehler Ralf , Liebeskind Juliane , Liebheit Alina , Bauherr Sandy , Philipsen Lars , Dittmayer Carsten , Laue Michael , von Manitius Regina , Elezkurtaj Sefer , Durek Pawel , Heinrich Frederik , Heinz Gitta A. , Guerra Gabriela M. , Obermayer Benedikt , Meinhardt Jenny , Ihlow Jana , Radke Josefine , Heppner Frank L. , Enghard Philipp , Stockmann Helena , Aschman Tom , Schneider Julia , Corman Victor M. , Sander Leif E. , Mashreghi Mir-Farzin , Conrad Thomas , Hocke Andreas C. , Niesner Raluca A. , Radbruch Helena , Hauser Anja E. 
Published: February 2023

AbstractProlonged lung pathology has been associated with COVID-19, yet the cellular and molecular mechanisms behind this chronic inflammatory disease are poorly understood. In this study, we combine advanced imaging and spatial transcriptomics to shed light on the local immune response in severe COVID-19. We show that activated adventitial niches are crucial microenvironments contributing to the orchestration of prolonged lung immunopathology. Up-regulation of the chemokines CCL21 and CCL18 associates to endothelial-to-mesenchymal transition and tissue fibrosis within these niches. CCL21 over-expression additionally links to the local accumulation of T cells expressing the cognate receptor CCR7. These T cells are imprinted with an exhausted phenotype and form lymphoid aggregates that can organize in ectopic lymphoid structures. Our work proposes immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and perpetuates tissue remodeling.
Structural insights into pathogenic mechanism of hypohidrotic ectodermal dysplasia caused by ectodysplasin A variants
Authors: Yu Kang , Huang Chenhui , Wan Futang , Jiang Cailing , Chen Juan , Li Xiuping , Wang Feng , Wu Jian , Lei Ming , Wu Yiqun 
Published: February 2023

AbstractEDA is a tumor necrosis factor (TNF) family member, which functions together with its cognate receptor EDAR during ectodermal organ development. Mutations of EDA have long been known to cause X‐linked hypohidrotic dysplasia in humans characterized by primary defects in teeth, hair and sweat glands. However, the structural information of EDA interaction with EDAR is lacking and the pathogenic mechanism of EDA variants is poorly understood. Here, we report the crystal structure of EDA C-terminal TNF homology domain bound to the N-terminal cysteine-rich domains of EDAR. Together with biochemical, cellular and mouse genetic studies, we show that different EDA mutations lead to varying degrees of ectodermal developmental defects in mice, which is consistent with the clinical observations on human patients. Our work extends the understanding of the EDA signaling mechanism, and provides important insights into the molecular pathogenesis of disease-causing EDA variants.
The ubiquitination landscape of the influenza A virus polymerase
Authors: Günl Franziska , Krischuns Tim , Schreiber Julian A. , Henschel Lea , Wahrenburg Marius , Drexler Hannes C. A. , Leidel Sebastian A. , Cojocaru Vlad , Seebohm Guiscard , Mellmann Alexander , Schwemmle Martin , Ludwig Stephan , Brunotte Linda 
Published: February 2023

AbstractDuring influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication.
Transcription factor binding sites are frequently under accelerated evolution in primates
Authors: Zhang Xinru , Fang Bohao , Huang Yi-Fei 
Published: February 2023

AbstractRecent comparative genomic studies have identified many human accelerated elements (HARs) with elevated substitution rates in the human lineage. However, it remains unknown to what extent transcription factor binding sites (TFBSs) are under accelerated evolution in humans and other primates. Here, we introduce two pooling-based phylogenetic methods with dramatically enhanced sensitivity to examine accelerated evolution in TFBSs. Using these new methods, we show that more than 6000 TFBSs annotated in the human genome have experienced accelerated evolution in Hominini, apes, and Old World monkeys. Although these TFBSs individually show relatively weak signals of accelerated evolution, they collectively are more abundant than HARs. Also, we show that accelerated evolution in Pol III binding sites may be driven by lineage-specific positive selection, whereas accelerated evolution in other TFBSs might be driven by nonadaptive evolutionary forces. Finally, the accelerated TFBSs are enriched around developmental genes, suggesting that accelerated evolution in TFBSs may drive the divergence of developmental processes between primates.
Pt-induced atomic-level tailoring towards paracrystalline high-entropy alloy
Authors: He Xingjia , Zhang Yu , Gu Xinlei , Wang Jiangwei , Qi Jinlei , Hao Jun , Wang Longpeng , Huang Hao , Wen Mao , Zhang Kan , Zheng Weitao 
Published: February 2023

AbstractParacrystalline state achieved in the diamond system guides a direction to explore the missing link between amorphous and crystalline states. However, such a state is still challenging to reach in alloy systems in a controlled manner. Here, based on the vast composition space and the complex atomic interactions in the high-entropy alloys (HEAs), we present an “atomic-level tailoring” strategy to create the paracrystalline HEA. The addition of atomic-level Pt with the large and negative mixing enthalpy induces the local atomic reshuffling around Pt atoms for the well-targeted local amorphization, which separates severe-distorted crystalline Zr-Nb-Hf-Ta-Mo HEA into the high-density crystalline MRO motifs on atomic-level. The paracrystalline HEA exhibits high hardness (16.6 GPa) and high yield strength (8.37 GPa) and deforms by nanoscale shear-banding and nanocrystallization modes. Such an enthalpy-guided strategy in HEAs can provide the atomic-level tailoring ability to purposefully regulate structural characteristics and desirable properties.
Direct generation of protein conformational ensembles via machine learning
Authors: Janson Giacomo , Valdes-Garcia Gilberto , Heo Lim , Feig Michael 
Published: February 2023

AbstractDynamics and conformational sampling are essential for linking protein structure to biological function. While challenging to probe experimentally, computer simulations are widely used to describe protein dynamics, but at significant computational costs that continue to limit the systems that can be studied. Here, we demonstrate that machine learning can be trained with simulation data to directly generate physically realistic conformational ensembles of proteins without the need for any sampling and at negligible computational cost. As a proof-of-principle we train a generative adversarial network based on a transformer architecture with self-attention on coarse-grained simulations of intrinsically disordered peptides. The resulting model, idpGAN, can predict sequence-dependent coarse-grained ensembles for sequences that are not present in the training set demonstrating that transferability can be achieved beyond the limited training data. We also retrain idpGAN on atomistic simulation data to show that the approach can be extended in principle to higher-resolution conformational ensemble generation.
Nanostructure-free crescent-shaped microparticles as full-color reflective pigments
Authors: Yang Yi , Kim Jong Bin , Nam Seong Kyeong , Zhang Mengmeng , Xu Jiangping , Zhu Jintao , Kim Shin-Hyun 
Published: February 2023

AbstractStructural colors provide a promising visualization with high color saturation, iridescent characteristics, and fade resistance. However, pragmatic uses are frequently impeded by complex manufacturing processes for sophisticated nanostructures. Here, we report a facile emulsion-templating strategy to produce crescent-shaped microparticles as structural color pigments. The micro-crescents exhibit brilliant colors under directional light originating from total internal reflections and optical interferences in the absence of periodic nanostructures while being transparent under ambient light. The colors are finely tunable by adjusting the size of the micro-crescents, which can be further mixed to enrich the variety. Importantly, the pre-defined convex surface secures high stability of colors and enables structural coloration on target surfaces through direct deposition as inks. We anticipate this class of nanostructure-free structural colorants is pragmatic as invisible inks in particular for anti-counterfeiting patches and color cosmetics with distinctive impressions due to low-cost, scalable manufacturing, unique optical properties, and versatility.
A spectral method for assessing and combining multiple data visualizations
Authors: Ma Rong , Sun Eric D. , Zou James 
Published: February 2023

AbstractDimension reduction is an indispensable part of modern data science, and many algorithms have been developed. However, different algorithms have their own strengths and weaknesses, making it important to evaluate their relative performance, and to leverage and combine their individual strengths. This paper proposes a spectral method for assessing and combining multiple visualizations of a given dataset produced by diverse algorithms. The proposed method provides a quantitative measure – the visualization eigenscore – of the relative performance of the visualizations for preserving the structure around each data point. It also generates a consensus visualization, having improved quality over individual visualizations in capturing the underlying structure. Our approach is flexible and works as a wrapper around any visualizations. We analyze multiple real-world datasets to demonstrate the effectiveness of the method. We also provide theoretical justifications based on a general statistical framework, yielding several fundamental principles along with practical guidance.
A proteogenomic view of Parkinson’s disease causality and heterogeneity
Authors: Kaiser Sergio , Zhang Luqing , Mollenhauer Brit , Jacob Jaison , Longerich Simonne , Del-Aguila Jorge , Marcus Jacob , Raghavan Neha , Stone David , Fagboyegun Olumide , Galasko Douglas , Dakna Mohammed , Bilican Bilada , Dovlatyan Mary , Kostikova Anna , Li Jingyao , Peterson Brant , Rotte Michael , Sanz Vinicius , Foroud Tatiana , Hutten Samantha J. , Frasier Mark , Iwaki Hirotaka , Singleton Andrew , Marek Ken , Crawford Karen , Elwood Fiona , Messa Mirko , Serrano-Fernandez Pablo 
Published: February 2023

AbstractThe pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.