bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification
Authors: Wu Dan , Shi Yuxin , Zhang Hao , Miao Changhong
Published: February 2023

Sepsis 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

Palmitoylation 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

Lipopolysaccharide (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

Giant 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

Tailoring 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

Understanding 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

Prolonged 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

EDA 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

During 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

Recent 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

Paracrystalline 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

Dynamics 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

Structural 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

Dimension 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

The 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.
Ischemic wound revascularization by the stromal vascular fraction relies on host-donor hybrid vessels
Authors: Vuerich Roman , Groppa Elena , Vodret Simone , Ring Nadja Annelies Ruth , Stocco Chiara , Bossi Fleur , Agostinis Chiara , Cauteruccio Matteo , Colliva Andrea , Ramadan Mohammad , Simoncello Francesca , Benvenuti Federica , Agnelli Anna , Dore Franca , Mazzarol Flavia , Moretti Massimo , Paulitti Alice , Palmisano Silvia , De Manzini Nicolò , Chiesa Mattia , Casaburo Manuel , Raucci Angela , Lorizio Daniela , Pompilio Giulio , Bulla Roberta , Papa Giovanni , Zacchigna Serena
Published: February 2023

Nonhealing wounds place a significant burden on both quality of life of affected patients and health systems. Skin substitutes are applied to promote the closure of nonhealing wounds, although their efficacy is limited by inadequate vascularization. The stromal vascular fraction (SVF) from the adipose tissue is a promising therapy to overcome this limitation. Despite a few successful clinical trials, its incorporation in the clinical routine has been hampered by their inconsistent results. All these studies concluded by warranting pre-clinical work aimed at both characterizing the cell types composing the SVF and shedding light on their mechanism of action. Here, we established a model of nonhealing wound, in which we applied the SVF in combination with a clinical-grade skin substitute. We purified the SVF cells from transgenic animals to trace their fate after transplantation and observed that it gave rise to a mature vascular network composed of arteries, capillaries, veins, as well as lymphatics, structurally and functionally connected with the host circulation. Then we moved to a human-in-mouse model and confirmed that SVF-derived endothelial cells formed hybrid human-mouse vessels, that were stabilized by perivascular cells. Mechanistically, SVF-derived endothelial cells engrafted and expanded, directly contributing to the formation of new vessels, while a population of fibro-adipogenic progenitors stimulated the expansion of the host vasculature in a paracrine manner. These data have important clinical implications, as they provide a steppingstone toward the reproducible and effective adoption of the SVF as a standard care for nonhealing wounds.
Development of softening and ballasted flocculation as a pretreatment process for seawater desalination through a reverse osmosis membrane
Authors: Yadai Tomohiro , Suzuki Yoshihiro
Published: February 2023

Efficient desalination through a reverse osmosis (RO) membrane requires the prior removal of blockade-causing substances from raw seawater. To achieve ultrahigh-speed processing of a pretreatment process for seawater RO desalination, we combine traditional softening with ballasted flocculation (SBF) for Ca2+ and Mg2+ removal. An alkaline mixture of Ca(OH)2 and Na2CO3 was the most suitable softening agent for Ca2+ and Mg2+ removal with a reduced amount of generated sludge. This softening treatment simultaneously removed the suspended solids and bacteria from actual seawater. The settling velocity of the suspended solids generated via seawater softening was extremely low. Under the optimum conditions for desalinating actual seawater using an anionic polymer flocculant and microsand, the settling velocity exceeded 3.5 cm/s, 833 times higher than that of softening without ballasted flocculation. The amount of sludge after standing for 3 min was 76.5% lower in SBF than in conventional softening. The silt density index of the treated seawater met the water-supply standard of RO membranes (i.e., <3.0). Furthermore, the SBF-generated sludge exhibited considerably improved dewatering property than the sludge obtained via conventional softening. SBF can efficiently and quickly remove the causative substances of RO membrane fouling from seawater, thereby improving the treatability of generated sludge. SBF provides a new pretreatment process for seawater desalination using RO membranes.
User-focused evaluation of National Ecological Observatory Network streamflow estimates
Authors: Rhea Spencer , Gubbins Nicholas , DelVecchia Amanda G. , Ross Matthew R. V. , Bernhardt Emily S.
Published: February 2023

Accurately estimating stream discharge is crucial for many ecological, biogeochemical, and hydrologic analyses. As of September 2022, The National Ecological Observatory Network (NEON) provided up to 5 years of continuous discharge estimates at 28 streams across the United States. NEON created rating curves at each site in a Bayesian framework, parameterized using hydraulic controls and manual measurements of discharge. Here we evaluate the reliability of these discharge estimates with three approaches. We (1) compared predicted to observed discharge, (2) compared predicted to observed stage, and (3) calculated the proportion of discharge estimates extrapolated beyond field measurements. We considered 1,523 site-months of continuous streamflow predictions published by NEON. Of these, 39% met our highest quality criteria, 11% fell into an intermediate classification, and 50% of site-months were classified as unreliable. We provided diagnostic metrics and categorical evaluations of continuous discharge and stage estimates by month for each site, enabling users to rapidly query for suitable NEON data.
Exposure to infection when accessing groceries reveals racial and socioeconomic inequities in navigating the pandemic
Authors: O’Brien Daniel T. , Ristea Alina , Dass Sarina
Published: February 2023

Disasters often create inequitable consequences along racial and socioeconomic lines, but a pandemic is distinctive in that communities must navigate the ongoing hazards of infection exposure. We examine this for accessing essential needs, specifically groceries. We propose three strategies for mitigating risk when accessing groceries: visit grocery stores less often; prioritize generalist grocery stores; seek out stores whose clientele have lower infection rates. The study uses a unique combination of data to examine racial and socioeconomic inequities in the ability to employ these strategies in the census block groups of greater Boston, MA in April 2020, including cellphone-generated GPS records to observe store visits, a resident survey, localized infection rates, and demographic and infrastructural characteristics. We also present an original quantification of the amount of infection risk exposure when visiting grocery stores using visits, volume of visitors at each store, and infection rates of those visitors’ communities. Each of the three strategies for mitigating exposure were employed in Boston, though differentially by community. Communities with more Black and Latinx residents and lower income made relatively more grocery store visits. This was best explained by differential use of grocery delivery services. Exposure and exposure per visit were higher in communities with more Black and Latinx residents and higher infection rates even when accounting for strategies that diminish exposure. The findings highlight two forms of inequities: using wealth to transfer risk to others through grocery deliveries; and behavioral segregation by race that makes it difficult for marginalized communities to avoid hazards.
Logistic regression technique is comparable to complex machine learning algorithms in predicting cognitive impairment related to post intensive care syndrome
Authors: Wu TingTing , Wei YueQing , Wu JingBing , Yi BiLan , Li Hong
Published: February 2023

To evaluate the performance of machine learning (ML) models and to compare it with logistic regression (LR) technique in predicting cognitive impairment related to post intensive care syndrome (PICS-CI). We conducted a prospective observational study of ICU patients at two tertiary hospitals. A cohort of 2079 patients was screened, and finally 481 patients were included. Seven different ML models were considered, decision tree (DT), random forest (RF), XGBoost, neural network (NN), naïve bayes (NB), and support vector machine (SVM), and compared with logistic regression (LR). Discriminative ability was evaluated by area under the receiver operating characteristic curve (AUC), calibration belt plots, and Hosmer–Lemeshow test was used to assess calibration. Decision curve analysis was performed to quantify clinical utility. Duration of delirium, poor Richards–Campbell sleep questionnaire (RCSQ) score, advanced age, and sepsis were the most frequent and important candidates risk factors for PICS-CI. All ML models showed good performance (AUC range: 0.822–0.906). NN model had the highest AUC (0.906 [95% CI 0.857–0.955]), which was slightly higher than, but not significantly different from that of LR (0.898 [95% CI 0.847–0.949]) (P > 0.05, Delong test). Given the overfitting and complexity of some ML models, the LR model was then used to develop a web-based risk calculator to aid decision-making (https://model871010.shinyapps.io/dynnomapp/). In a low dimensional data, LR may yield as good performance as other complex ML models to predict cognitive impairment after ICU hospitalization.
Correlation analysis between immune-related genes and cell infiltration revealed prostate cancer immunotherapy biomarkers linked to T cells gamma delta
Authors: Niu Wenkang , Zhang Tingting , Ma Lei
Published: February 2023

Prostate cancer (PCa) is a urological malignancy with poor prognosis. Immune-related genes are associated with immune infiltration in prostate cancer, but their role in immunogenic PCa is less well understood. We assessed the infiltration patterns of 22 immune cells in PCa and the relationship of immune-related differentially expressed genes (IDEGs) with them. The 87 IDEGs are involved in the interaction between the extracellular matrix and the tumor microenvironment. The model, including seven IDEGs (SLPI, DES, IAPP, NPY, ISG15, PLA2G2A, and HLA-DMB), showed a good predictive power. The SLPI expression is positively correlated with the infiltration level of T cells gamma delta. In addition, PCa has high infiltration levels in Macrophages M1 (18.07%) and Dendritic cells activated (17.64%). The correlation analysis between IDEGs and immune cell infiltration suggested that PCa immunotherapy biomarkers may be closely related to T cells gamma delta.
Vaccination status and long COVID symptoms in patients discharged from hospital
Authors: Nascimento Teresa Cristina D. C. , do Valle Costa Livia , Ruiz Amanda Danieletto , Ledo Carla B. , Fernandes Valeria Paes Lima , Cardoso Luiz Francisco , Junior José Mauro Vieira , Saretta Roberta , Kalil-Filho Roberto , Drager Luciano F.
Published: February 2023

Effective vaccination against coronavirus mitigates the risk of hospitalisation and mortality; however, it is unclear whether vaccination status influences long COVID symptoms in patients who require hospitalisation. The available evidence is limited to outpatients with mild disease. Here, we evaluated 412 patients (age: 60 ± 16 years, 65% males) consecutively admitted to two Hospitals in Brazil due to confirmed coronavirus disease 2019 (COVID-19). Compared with patients with complete vaccination (n = 185) before infection or hospitalisation, those with no or incomplete vaccination (n = 227) were younger and had a lower frequency of several comorbidities. Data during hospitalisation revealed that the no or incomplete vaccination group required more admissions to the intensive care unit (ICU), used more corticosteroids, and had higher rates of pulmonary embolism or deep venous thrombosis than the complete vaccination group. Ninety days after hospital discharge, patients with no or incomplete vaccination presented a higher frequency of symptoms (≥ 1) than patients with complete vaccination (40 vs. 27%; p = 0.013). After adjusting for confounders, no or incomplete vaccination (odds ratio [OR] 1.819; 95% confidence interval [CI] 1.175–2.815), female sex (OR 2.435; 95% CI 1.575–3.764) and ICU admission during hospitalisation (OR 1.697; 95% CI 1.062–2.712) were independently associated with ≥ 1 symptom 90 days after hospital discharge. In conclusion, even in patients with severe COVID-19, vaccination mitigates the probability of long COVID symptoms.
Mechanochemical effects underlying the mechanically activated catalytic hydrogenation of carbon monoxide
Authors: Carta Maria , Sanna Anna Laura , Porcheddu Andrea , Garroni Sebastiano , Delogu Francesco
Published: February 2023

In this work, we highlight and measure the intensity of mechanochemical effects at work in the hydrogenation of carbon monoxide by comparing the activity of a supported Co–Fe catalyst subjected, respectively, to ball milling and simple powder agitation. Paying due regard to the discontinuous nature of ball milling, we show that mechanochemical hydrogenation proceeds at significantly higher rate and disclose its connection with individual impacts. Experimental evidence suggests that the enhanced catalytic activity we observe can be ascribed to local processes affecting the amount of powder that gets involved in individual impacts.
Efficacy evaluation of some fumigants against Fusarium oxysporum and enhancement of tomato growth as elicitor-induced defense responses
Authors: El-Aswad Ahmed F. , Aly Maher I. , Alsahaty Sameh A. , Basyony Ayman B. A.
Published: February 2023

Fusarium wilt, the most serious soil-borne pathogen, is a serious problem for tomato production worldwide. The presented study evaluated the antifungal activity against Fusarium oxysporum f. sp. lycopersici in vitro and in vivo for nine fumigants. In addition, the research examined the possibility of enhancing the growth of tomato plants in order to increase resistance against this disease by using four chemical inducers. The results indicated that at 20 mg/L, the radial growth of the pathogen was inhibited 100% by formaldehyde and > 80% by phosphine. Among the essential oils investigated, neem oil was the most effective, however, it only achieved 40.54% at 500 mg/L. The values of EC50 for all fumigants, except dimethyl disulfide (DMDS) and carbon disulfide (CS2), were lower than those for thiophanate-methyl. Phosphine was the highest efficient. The elicitors can be arranged based on their effectiveness, gibberellic acid (GA3) > sorbic acid > cytokinin (6-benzylaminopurine) > indole-3-butyric acid. The change in root length, fresh weight, and dry weight was greater with soil drench than with foliar application. The fumigant generators formaldehyde, phosphine and 1,4-dichlorobenzene and bio-fumigants citrus and neem oils as well as elicitors gibberellic and sorbic acid could be one of the promising alternatives to methyl bromide against Fusarium oxysporum as an important component of integrated management of Fusarium wilt.
Metagenome reveals caprine abomasal microbiota diversity at early and late stages of Haemonchus contortus infection
Authors: Aboshady Hadeer M. , Choury Alice , Montout Laura , Félicité Yoann , Godard Xavier , Bambou Jean-Christophe
Published: February 2023

Haemonchus contortus is one of the most detrimental gastrointestinal nematode parasites for small ruminants, especially in tropics and subtropics. Gastrointestinal nematode and microbiota share the same microhabitat; thus they interact with each other and their host. Metagenomics tools provide a promising way to examine the alterations in the gastric microbial composition induces by gastrointestinal parasites. In this study, we used metagenomics tools to characterize the impact of H. contortus infection on the caprine abomasal microbiota at early and late stage of infection and compared it with non-infected control. Our results showed that H. contortus infection caused a significant increase in abomasal pH at early (7 days post-infection) and late stage of infection (56 days post-infection). The analysis of alpha and beta diversity showed that the microbiota diversity both in number and in proportion was significantly affected at early and late stage of infection. All microbiota classes are impacted by H. contortus infection but Clostridia and Bacteroidia are more concerned. In infected animals, the genera Prevotella decreased at 7 and 56 days post-infection. Here we showed that the abomasal microbiota was significantly affected early after H. contortus infection, and these changes persist at late stage of the infection.
Quantifying the retention of emotions across story retellings
Authors: He Tianyou , Breithaupt Fritz , Kübler Sandra , Hills Thomas T.
Published: February 2023

Story retelling is a fundamental medium for the transmission of information between individuals and among social groups. Besides conveying factual information, stories also contain affective information. Though natural language processing techniques have advanced considerably in recent years, the extent to which machines can be trained to identify and track emotions across retellings is unknown. This study leverages the powerful RoBERTa model, based on a transformer architecture, to derive emotion-rich story embeddings from a unique dataset of 25,728 story retellings. The initial stories were centered around five emotional events (joy, sadness, embarrassment, risk, and disgust—though the stories did not contain these emotion words) and three intensities (high, medium, and low). Our results indicate (1) that RoBERTa can identify emotions in stories it was not trained on, (2) that the five emotions and their intensities are preserved when they are transmitted in the form of retellings, (3) that the emotions in stories are increasingly well-preserved as they experience additional retellings, and (4) that among the five emotions, risk and disgust are least well-preserved, compared with joy, sadness, and embarrassment. This work is a first step toward quantifying situation-driven emotions with machines.
Oleuropein confers neuroprotection against rotenone-induced model of Parkinson’s disease via BDNF/CREB/Akt pathway
Authors: Singh Richa , Zahra Walia , Singh Saumitra Sen , Birla Hareram , Rathore Aaina Singh , Keshri Priyanka Kumari , Dilnashin Hagera , Singh Shekhar , Singh Surya Pratap
Published: February 2023

Major pathological features of Parkinson’s disease (PD) include increase in oxidative stress leading to the aggregation of α-synuclein, mitochondrial dysfunction and apoptosis of dopaminergic neurons. In addition, downregulation of the expression of neurotrophic factors like-Brain Derived Neurotrophic Factor (BDNF) is also involved in PD progression. There has been a lot of interest in trophic factor-based neuroprotective medicines over the past few decades to treat PD symptoms. Rotenone, an insecticide, inhibits the mitochondrial complex I causing overproduction of ROS, oxidative stress, and aggregation of α-synuclein. It has been shown that BDNF and Tropomyosin receptor kinase B (TrkB) interaction initiates the regulation of neuronal cell development and differentiation by the serine/threonine protein kinases like Akt and GSK-3β. Additionally, Transcription factor CREB (cAMP Response Element-binding protein) also determines the gene expression of BDNF. The homeostasis of these signalling cascades is compromised with the progression of PD. Therefore, maintaining the equilibrium of these signalling cascades will delay the onset of PD. Oleuropein (OLE), a polyphenolic compound present in olive leaves has been documented to cross blood brain barrier and shows potent antioxidative property. In the present study, the dose of 8, 16 and 32 mg/kg body weight (bwt) OLE was taken for dose standardisation. The optimised doses of 16 and 32 mg/kg bwt was found to be neuroprotective in Rotenone induced PD mouse model. OLE improves motor impairment and upregulate CREB regulation along with phosphorylation of Akt and GSK-3β in PD mouse. In addition, OLE also reduces the mitochondrial dysfunction by activation of enzyme complexes and downregulates the proapoptotic markers in Rotenone intoxicated mouse model. Overall, our study suggests that OLE may be used as a therapeutic agent for treatment of PD by regulating BDNF/CREB/Akt signalling pathway.
Effects of grain size and small-scale bedform architecture on CO2 saturation from buoyancy-driven flow
Authors: Ni Hailun , Bakhshian Sahar , Meckel T. A.
Published: February 2023

Small-scale (mm-dm scale) heterogeneity has been shown to significantly impact CO2 migration and trapping. To investigate how and why different aspects of small-scale heterogeneity affect the amount of capillary trapping during buoyancy-driven upward migration of CO2, we conducted modified invasion percolation simulations on heterogeneous domains. Realistic simulation domains are constructed by varying two important aspects of small-scale geologic heterogeneity: sedimentary bedform architecture and grain size contrast between the matrix and the laminae facies. Buoyancy-driven flow simulation runs cover 59 bedform architecture and 40 grain size contrast cases. Simulation results show that the domain effective CO2 saturation is strongly affected by both grain size and bedform architecture. At high grain size contrasts, bedforms with continuous ripple lamination at the cm scale tend to retain higher CO2 saturation than bedforms with discontinuous or cross lamination. In addition, the “extremely well sorted” grain sorting cases tend to have lower CO2 saturation than expected for cross-laminated domains. Finally, both a denser CO2 phase and greater interfacial tension increase CO2 saturation. Again, variation in fluid properties seems to have a greater effect on CO2 saturation for cross-laminated domains. This result suggests that differences in bedform architecture can impact how CO2 saturation values respond to other variables such as grain sorting and fluid properties.
Dual blockage of both PD-L1 and CD47 enhances the therapeutic effect of oxaliplatin and FOLFOX in CT-26 mice tumor model
Authors: Alimohammadi Reza , Mahmoodi Chalbatani Ghanbar , Alimohammadi Masoumeh , Ghaffari-Nazari Haniyeh , Rahimi Arezou , Mortaz Esmail , Mossafa Nariman , Boon Louis , Jalali Seyed Amir
Published: February 2023

Colorectal cancer is a poorly immunogenic. Such property can be reverted by using ICD. However, ICD inducers can also induce the expression of inhibitory checkpoint receptors CD47 and PD-L1 on tumor cells, making CRC tumors resistant to mainly CD8 T cell killing and macrophage-mediated phagocytosis. In this study, we examined the therapeutic effect of Oxaliplatin and FOLFOX regimen in combination with blocking antibodies against CD47 and PD-L1. FOLFOX and Oxaliplatin treatment lead to an increase in CD47 and PD-L1 expression on CT-26 cells invitro and invivo. Combining blocking antibodies against CD47 and PD-L1 with FOLFOX leads to a significant increase in survival and a decrease in tumor size. This triple combining regimen also leads to a significant decrease in Treg and MDSC and a significant increase in CD8 + INF-γ + lymphocytes and M1/M2 macrophage ratio in the tumor microenvironment. Our study showed triple combining therapy with FOLFOX, CD47 and PD-L1 is an effective treatment regimen in CT-26 mice tumor model and may consider as a potential to translate to the clinic.
A novel visceral adiposity index predicts bone loss in female early rheumatoid arthritis patients detected by HR-pQCT
Authors: Yue Jiang , Wong Priscilla C. H. , Zhang Ying , Peng Feng , Griffith James F. , Xu Jiankun , Xiao Fan , Li Tena K. , Hung Vivian , Qin Ling , Tam Lai-Shan
Published: February 2023

The purpose of this prospective study is to compare the Chinese visceral adiposity index (CVAI) between early rheumatoid arthritis (ERA) patients and healthy controls; and to assess the relationship between CVAI and the bone microstructure using high-resolution peripheral quantitative computed tomography (HR-pQCT) in ERA patients. 104 female ERA and 100 age-, gender- and BMI-matched healthy controls were recruited for the comparison of CVAI. All ERA patients were prospectively followed for 1 year. HR-pQCT scan of the distal radius, tibia and second metacarpal head were performed at baseline and after one-year. ERA patients were divided into two sub-groups according to the median CVAI value (65.73) (low CVAI and high CVAI groups). CVAI in the ERA group was significantly higher than the controls group (p = 0.01). At baseline, the high CVAI group had a higher ESR level (p = 0.004) while the cortical volumetric bone mineral density (vBMD) was lower (at both the distal radius and tibia, all p < 0.05) compared to the low CVAI group. Linear regression analysis revealed that a higher baseline CVAI was an independent predictor of a lower cortical vBMD at month 12 (distal radius: B = − 0.626, p = 0.022, 95%CI − 1.914  to  − 0.153; tibia: B = − 0.394, p = 0.003, 95%CI − 1.366 to − 0.290); and a greater reduction in trabecular vBMD (tibia: B = 0.444, p = 0.001, 95%CI 0.018–0.063; distal radius: B = 0.356, p = 0.008, 95%CI 0.403–0.063). In summary, CVAI is an independent predictor of trabecular bone loss in female patients with ERA, which may be augmented by a chronic inflammatory state in patients with visceral dysfunction of fat metabolism.

Trial registration:http://Clinicaltrial.gov no: NCT01768923, 16/01/2013.