bluuebunny/crossref_metadata_2025 huggingface dataset:
Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study
Authors: Charfeddine Salma , Ibnhadjamor Hassen , Jdidi Jihen , Torjmen Slim , Kraiem Salma , Bahloul Amine , Makni Ahmed , Kallel Nesrine , Moussa Nedia , Boudaya Mariem , Touil Imen , Ghrab Aiman , Elghoul Jamel , Meddeb Zeineb , Thabet Yamina , Ben Salem Kais , Addad Faouzi , Bouslama Kamel , Milouchi Sami , Hammami Rania , Abdessalem Salem , Abid Leila
Published: May 2022

Objective

Non-respiratory long-coronavirus disease 2019 (COVID-19) symptoms are mainly related to a long-lasting endothelial dysfunction and microcirculation impairment. We hypothesized that Sulodexide, a purified glycosaminoglycan mixture with a beneficial endothelial effect in arterial and venous peripheral diseases, may be effective in a subset of patients with long COVID-19.

Approach and Results

We conducted a multicenter prospective quasi-experimental study. A total of 290 patients from the TUN-EndCOV study with long-COVID-19 symptoms and endothelial dysfunction were included. The endothelial function was clinically assessed using a post-occlusive reactive hyperemia protocol with finger thermal monitoring device. Endothelial quality index (EQI) was assessed at inclusion and at 21 days later. The study population was assigned to a sulodexide group (144 patients) or a no-medical treatment group (146 patients). Clinical characteristics were similar at inclusion in the two groups. Fatigue, shortness of breath, and chest pain were the most common symptoms, respectively, 54.5, 53.8, and 28.3%. At 21 days, the sulodexide group improved significantly better than the no-medical treatment group in chest pain (83.7 vs. 43.6%, p < 10−3), palpitations (85.2 vs. 52.9%, p = 0.009), and endothelial function [median delta-EQI 0.66 (0.6) vs. 0.18 (0.3); p < 10−3]. Endothelial function improvement was significantly correlated with chest pain and palpitations recovery (AUC, i.e., area under the curve = 0.66, CI [0.57– 0.75], p = 0.001 and AUC = 0.60, CI [0.51– 0.69], p = 0.03, respectively).

Conclusion

Sulodexide significantly improves long-lasting post-COVID-19 endothelial dysfunction and alleviates chest pain and palpitations.
Exploration for Byproduct Critical Element Resources: Proxy Development Using a LA–ICP–MS Database
Authors: McNulty Brian A. , Jowitt Simon M.
Published: May 2022

The transition towards zero-CO2 energy generation, storage and transport will require a range of metals that are often considered critical and are produced as byproducts of the production of other metals. This means that the reliance of some critical elements on the production of main metal commodities, such as Cu and Ni, is a significant source of supply risk. However, how can we evaluate resource scarcity and supply risks for elements that we do not routinely analyze for and characterize in present day mined ores? Here we demonstrate a method for exploring for and assessing the byproduct critical element potential of magmatic sulfide and volcanogenic massive sulfide deposits using a LA–ICP–MS database. Our results indicate there are significant enrichments of Sb, Bi, Cd, Co, Se and Te in pentlandite (Ni sulfide), chalcopyrite (Cu sulfide) and sphalerite (Zn sulfide) within these systems, demonstrating the need for a holistic approach to critical element research with unrecovered byproducts in existing mining supply chains having the potential to solve perceived resource scarcity challenges.
Holocene Temperature Variations in Semi-Arid Central Mongolia—A Chronological and Sedimentological Perspective From a 7400-year Lake Sediment Record From the Khangai Mountains
Authors: Bliedtner Marcel , Strobel Paul , Struck Julian , Salazar Gary , Szidat Sönke , Nowaczyk Norbert , Bazarradnaa Enkhtuya , Lloren Ronald , Dubois Nathalie , Haberzettl Torsten , Zech Roland
Published: May 2022

Semi-arid Mongolia is a highly sensitive region to climate changes, but the region’s Holocene paleoclimatic evolution and its underlying forcing mechanisms have been the subject of much recent debate. Here we present a continuous 7.4 ka sediment record from the high-altitude Shireet Naiman Nuur (Nuur = lake) in the central Mongolian Khangai Mountains. We extensively dated the sediments and analyzed elemental composition and bulk isotopes for lake sediment characterization. Our results show that 14C-dating of bulk organic carbon and terrestrial macrofossils provide a robust and precise chronology for the past 7.4 ± 0.3 cal ka BP at Shireet Naiman Nuur and 14C-ages are mostly in stratigraphic order. The 14C-based chronology is confirmed by paleomagnetic secular variations, which resemble the predictions of spherical harmonic geomagnetic field models. The very good chronological control makes paleomagnetic secular variation stratigraphy a powerful tool for evaluating and refining regional 14C-chronologies when compared to the record presented here. The lake sediment proxies TOC, N, log (Ca/Ti) and log (Si/Ti) reveal increased lake primary productivity and high growing season temperatures from 7.4 ± 0.3 to 4.3 ± 0.2 cal ka BP, which is likely the result of stronger summer insolation and pronounced warming. Reduced summer insolation thereafter results in decreased productivity and low growing season temperatures at Shireet Naiman Nuur from 4.3 ± 0.3 cal ka BP until present day. The globally acknowledged 4.2 ka event also appears as a pronounced cooling event at Shireet Naiman Nuur, and additional abrupt cooling events occurred during minima in total solar irradiance at ∼3.4, 2.8 and 2.4 ka BP. Low lake primary productivity and growing season temperatures are likely the result of longer ice cover periods at the high-altitude (2,429 m a.s.l.) Shireet Naiman Nuur. This leads to shorter mixing periods of the lake water which is supported by more positive δ13CTOC because of increased incorporation of dissolved HCO3− by aquatic producers during periods of longer ice cover.
Educational Reforms Amid COVID-19 in Thailand
Authors: Poungjinda Wachiraporn , Pathak Shubham
Published: May 2022

Education is essential for any country to secure its future, but COVID-19 has caused considerable difficulty in Thailand. The COVID-19 pandemic harms the education of the students. The online education system is adopted in almost all parts of the globe. However, the pandemic has been impacting the overall quality of the education system. This research explored the experiences of law students in Thailand by analyzing several factors which affect their intellect. The methodology adopted for this study was a multiple method study. The sample size of 330 law students selected from leading Thai universities was analyzed qualitatively through Strength, Weakness, Opportunity, and Threat (SWOT) analysis and regression model for the quantitative analysis. The findings revealed that factors including internet availability, accessibility to own gadgets, online resources, government, social media, and classrooms have a significant impact on the education system of Thai law students. The study paves way for further microanalysis of the educational system in Thailand with the perceptions and experiences of teachers and parents.
Effect of Hyperglycemia-Related Acute Metabolic Disturbance on Thyroid Function Parameters in Adults
Authors: Iwamoto Yuichiro , Kimura Tomohiko , Tatsumi Fuminori , Sugisaki Toshitomo , Kubo Masato , Nakao Erina , Dan Kazunori , Wamata Ryo , Iwamoto Hideyuki , Takahashi Kaio , Sanada Junpei , Fushimi Yoshiro , Katakura Yukino , Shimoda Masashi , Nakanishi Shuhei , Mune Tomoatsu , Kaku Kohei , Kaneto Hideaki
Published: May 2022

Non-thyroidal illness (NTI) is a condition in which the hypothalamic-pituitary-thyroid system and thyroid hormone metabolism are abnormal due to non-thyroidal diseases. Although NTI has been reported to occur in hyperglycemic emergencies in children, there have been few studies in adult cases. In this study, we examined adult patients with hyperglycemia regarding the frequency of NTI and its triggers. Adult diabetic patients who were hospitalized for diabetic ketosis (DK), diabetic ketoacidosis (DKA), or hyperglycemic hyperosmolarity syndrome (HHS) were included in the study. Compared with the DK group, the DKA and HHS groups had higher admission blood glucose, Anion Gap, serum osmolality, creatinine, and urea nitrogen, and lower pH and eGFR. The frequency of NTI in the DKA, HHS, and DK groups was 80%, 70%, and 50%, respectively, and thyroid stimulating hormone (TSH) and free thyroxine 3 (FT3) were significantly improved after treatment for hyperglycemia. Multiple regression analysis showed a significant correlation between the decrease in FT3 level and 3-hydroxybutyrate and albumin. Acute metabolic failure associated with hyperglycemia tends to be associated with a high rate of NTI and low FT3 levels at the start of treatment. The data in this study clearly shows that transient NTI is frequently observed in subjects with acute metabolic disorders such as DKA, HHS and DK. In addition, we should bear in mind that thyroid hormone replacement therapy is not necessary in subjects with NTI due to DKA, HHS and DK, especially when overt symptoms of hypothyroidism are not observed.
Cooperative Resilience of Cyber–Physical Power Systems Under Hybrid Attacks via Dynamic Topology
Authors: Jin Jiahui , Liu Yonghui , Li Peiyue , Chang Mengyan
Published: May 2022

In this study, the cooperative resilience of cyber–physical power systems under hybrid attacks is investigated. First, a detection model of physical attacks depending on the residual of the output impedance angle is established. Second, by analyzing the encrypted communication between physical and cyber systems, a detection algorithm for cyberattacks is proposed. Then, by using an enumeration method, islanded cyber–physical power systems are built with non-attacked and repaired parts. Moreover, to save resilient resources, cooperative optimization is established after the individual optimization of islanded cyber and physical systems. Since the building and optimization are executed alternately, the topology of the systems is dynamic. Finally, simulation results demonstrate the effectiveness of the proposed method.
Zinc Doping Enhances the Electrocatalytic Properties of Cobalt Borides for the Hydrogen Evolution Reaction
Authors: Quílez-Bermejo Javier , García-Dalí Sergio , Karthik Raj , Canevesi Rafael , Izquierdo María T. , Emo Mélanie , Celzard Alain , Fierro Vanessa
Published: May 2022

Electrochemical water splitting requires new, low-cost cathode electrodes for the hydrogen evolution reaction to enable the worldwide implementation of electrolyzers. Cobalt borides are proposed as one of the most promising materials to overcome the limitations of the commercial electrocatalysts, but the catalytic activity still needs to be improved to be competitive. Here, we report that the introduction of zinc into cobalt boride to produce a ternary cobalt boride is an efficient route to further improve the catalytic activity towards the hydrogen evolution reaction (HER) of cobalt boride. The ternary Co-Zn-B was prepared by an easy chemical reduction method to achieve superior HER electrocatalytic performance with a lower overpotential than the homologous Co-B. The larger surface area, structural order, crystallization degree and, in particular, the different surface chemistry seem to be key factors for this improvement.
Green Supply Chain Management and Corporate Performance Among Manufacturing Firms in Pakistan
Authors: Qalati Sikandar Ali , Kumari Sonia , Soomro Ishfaque Ahmed , Ali Rajib , Hong Yifan
Published: May 2022

A common perception is lowering the environmental consequences of firms’ supply chain activities is a costly idea that poses a challenge to the corporate world. This study aimed to examine the relationship between green supply chain management (GSCM) and corporate performance among listed firms in Pakistan, using the general panel method of moments (GMM) and ANOVA techniques. At the same time, the Granger causality technique provides robust results. The study focused on manufacturing firms, covering periods from 2009 to 2020. The study engaged a modified balanced scorecard framework to adopt five metrics of corporate performance, namely, gross profit ratio, net profit ratio, customer dimension, learning growth dimension, and efficiency dimension. The study incorporated the two measures of the GSCM initiative and two control variables. The findings from the panel GMM estimates reveal that GSCM positively and negatively impacted the five corporate performance metrics explored. ANOVA results indicate significant differences in customer satisfaction, profitability, and efficiency performance metrics among the top and low GSCM practicing corporations. On the other hand, Granger causality results specify a moderate causal association between GSCM implementation and firm performance in Pakistan. Implying that poor GSCM practice may not yield the expected benefits, instead, conscientious efforts should be put in place to ensure that practicing GSCM initiative should be effectively carried out.
Concentrations and Species of Mercury in Municipal Sludge of Selected Chinese Cities and Potential Mercury Emissions From Sludge Treatment and Disposal
Authors: Liu Jing , Lin Li , Wang Keyun , Ding Rui , Xie Zhouqing , Zhang Pengfei
Published: May 2022

Municipal sewage has been identified as an important source of mercury (Hg) to the environment, and sewage sludge is the major sink of sewage-borne Hg. Knowledge of Hg species in sludge and potential Hg emissions during sludge treatment/disposal is still limited. A survey on Hg concentrations and species in sewage sludge of 16 provinces and municipalities in China was conducted. Hg was detected in all sewage sludge samples, with total Hg (THg) concentrations ranging from 0.3 to 7.7 mg/kg. Results from sequential chemical extractions (SCE) indicated that sludge-borne Hg mainly occurred in the form of Hg sulfide, with a small amount of organo-chelated Hg (Hg-OM) and HgO, and a negligible amount of soluble Hg. Thermal decomposition results indicated that Hg is generally released from sludge at a temperature range of 200–400°C, with the highest release at 250–350°C (38%–86%), consistent with the thermal decomposition of HgS, Hg-OM, and HgO. THg in sewage samples under ventilation at room temperature remained constant over a month period, indicating negligible Hg emission under such conditions. The mass loading of sludge-borne THg in China for year 2019 was estimated to be 30 tons, about 3.6% of the total anthropogenic THg released (including direct and secondary anthropogenic releases) in China. At the temperature range for sludge incineration, sludge carbonization, and sludge/brick/cement production, most of the Hg in sludge will be released to air due to thermal decomposition of Hg compounds. As such, Hg-capture systems are essential in sludge treatment processes involving high temperatures.
Effects of Elevated Temperature on Resources Competition of Nutrient and Light Between Benthic and Planktonic Algae
Authors: Mei Xueying , Gao Shanshan , Liu Yang , Hu Jie , Razlustkij Vladimir , Rudstam Lars G. , Jeppesen Erik , Liu Zhengwen , Zhang Xiufeng
Published: May 2022

Climate warming, a serious environmental problem worldwide, is considered a major threat to aquatic ecosystems. A primary feature of climate warming is elevated temperatures which in shallow aquatic ecosystems might affect competition for light and nutrient between benthic algae on the sediment surface and planktonic algae in the water. The outcomes of such competition would not only affect the distribution of primary production, but also determine the fundamental character of shallow aquatic habitats as clear water or turbid water systems. We conducted a mesocosm study to evaluate the effects of elevated temperature on competition between planktonic algae and benthic algae for light and nutrients. We found that elevated temperature increased the concentrations of total nitrogen (TN), total phosphorus (TP), and total suspended solids (TSS) in overlying water and enhanced the growth of planktonic algae (measured as chlorophylla, Chla), but decreased light intensity and benthic algal biomass (Chla). Our results indicate that elevated temperature can increase the growth of planktonic algae and enhance their competitive advantage over the benthic algae in shallow lakes, thereby contributing to eutrophication and a decline in water quality. These findings shed further light on the effects of global warming on aquatic ecosystems.
Analysis of the Expression and Role of Keratin 17 in Human Tumors
Authors: Zhang Hanqun , Zhang Yun , Feng Zhiyu , Lu Liang , Li Yong , Liu Yuncong , Chen Yanping
Published: May 2022

Objective: We aimed to explore the expression and carcinogenic effect of KRT17 in human tumors and provide useful information for the study of KRT17.

Methods: We used databases including the Cancer Genome Atlas, Gene Expression Omnibus, GTEx, and GEPIA2 to analyze the expression, mutation, and prognosis of KRT17 in human tumors. Through webservers, including UALCAN, TIMER2.0, and STRING, we learned about the genetic variation, immune cell penetration, and enrichment analysis of KRT17-related genes.

Results: KRT17 was highly expressed in most tumors (such as esophageal cancer, lung cancer, cervical cancer, etc.), and the high expression level correlated with tumor stage and prognosis. In addition, amplification was the main type of KRT17 tumor variation, with an amplification rate of about 9%, followed by mutation, with a mutation rate of 4%. Moreover, KRT17 was strongly associated with tumor-infiltrating immune cells (such as macrophages, CD8+T, Tregs, and cancer-associated fibroblasts). KEGG analysis suggested that KRT17 may play a role in tumor pathogenesis following human papillomavirus infection, and the gene ontology enrichment analysis indicated that the carcinogenicity of KRT17 can be attributed to cadherin binding, intermediate fibrocytoskeleton and epidermal development.

Conclusion: KRT17 may play an important role in the occurrence, development, and prognosis of malignant tumors. We provided a relatively comprehensive description of the carcinogenic role of KRT17 in different tumors for the first time.
Case Report: Challenges of Non-Invasive Prenatal Testing (NIPT): A Case Report of Confined Placental Mosaicism and Clinical Considerations
Authors: Bonanni Giulia , Trevisan Valentina , Zollino Marcella , De Santis Marco , Romanzi Federica , Lanzone Antonio , Bevilacqua Elisa
Published: May 2022

Since the introduction of cell-free (cf) DNA analysis, Non-Invasive Prenatal Testing (NIPT) underwent a deep revolution. Pregnancies at high risk for common fetal aneuploidies can now be easily identified through the analysis of chromosome-derived components found in maternal circulation, with the highest sensitivity and specificity currently available. Consequently, the last decade has witnessed a widespread growth in cfDNA-based NIPT use, enough to be often considered an alternative method to other screening modalities. Nevertheless, the use of NIPT in clinical practice is still not devoid of discordant results. Hereby, we report a case of confined placental mosaicism (CPM) in which a NIPT false-positive result for trisomy 13 required not only amniocentesis but also cordocentesis, to rule out the fetal aneuploidy, with the additional support of molecular cytogenetics on placental DNA at delivery. Relevant aspects allowing for precision genetic diagnosis and counselling, including the number of analysed metaphases on the different fetal cells compartments and a repeated multidisciplinary evaluation, are discussed.
RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration
Authors: Castelli Lydia M. , Benson Bridget C. , Huang Wan-Ping , Lin Ya-Hui , Hautbergue Guillaume M.
Published: May 2022

Short repeated sequences of 3−6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches.
Education and Consent for Population-Based DNA Screening: A Mixed-Methods Evaluation of the Early Check Newborn Screening Pilot Study
Authors: Peay Holly L. , Gwaltney Angela You , Moultrie Rebecca , Cope Heidi , Boyea Beth Lincoln‐ , Porter Katherine Ackerman , Duparc Martin , Alexander Amir A. , Biesecker Barbara B. , Isiaq Aminah , Check Jennifer , Gehtland Lisa , Bailey Donald B. , King Nancy M. P.
Published: May 2022

A challenge in implementing population-based DNA screening is providing sufficient information, that is, understandable and acceptable, and that supports informed decision making. Early Check is an expanded newborn screening study offered to mothers/guardians whose infants have standard newborn screening in North Carolina. We developed electronic education and consent to meet the objectives of feasibility, acceptability, trustworthiness, and supporting informed decisions. We used two methods to evaluate Early Check among mothers of participating infants who received normal results: an online survey and interviews conducted via telephone. Survey and interview domains included motivations for enrollment, acceptability of materials and processes, attitudes toward screening, knowledge recall, and trust. Quantitative analyses included descriptive statistics and assessment of factors associated with knowledge recall and trust. Qualitative data were coded, and an inductive approach was used to identify themes across interviews. Survey respondents (n = 1,823) rated the following as the most important reasons for enrolling their infants: finding out if the baby has the conditions screened (43.0%), and that no additional blood samples were required (20.1%). Interview respondents (n = 24) reported the value of early knowledge, early intervention, and ease of participation as motivators. Survey respondents rated the study information as having high utility for decision making (mean 4.7 to 4.8 out of 5) and 98.2% agreed that they had sufficient information. Knowledge recall was relatively high (71.8–92.5% correct), as was trust in Early Check information (96.2% strongly agree/agree). Attitudes about Early Check screening were positive (mean 0.1 to 0.6 on a scale of 0–4, with lower scores indicating more positive attitudes) and participants did not regret participation (e.g., 98.6% strongly agreed/agreed Early Check was the right decision). Interview respondents further reported positive attitudes about Early Check materials and processes. Early Check provides a model for education and consent in large-scale DNA screening. We found evidence of high acceptability, trustworthiness and knowledge recall, and positive attitudes among respondents. Population-targeted programs need to uphold practices that result in accessible information for those from diverse backgrounds. Additional research on those who do not select screening, although ethically and practically challenging, is important to inform population-based DNA screening practices.
Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma
Authors: De Beck Lien , Awad Robin Maximilian , Basso Veronica , Casares Noelia , De Ridder Kirsten , De Vlaeminck Yannick , Gnata Alessandra , Goyvaerts Cleo , Lecocq Quentin , San José-Enériz Edurne , Verhulst Stefaan , Maes Ken , Vanderkerken Karin , Agirre Xabier , Prosper Felipe , Lasarte Juan José , Mondino Anna , Breckpot Karine
Published: May 2022

Immunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in the preclinical B16-OVA melanoma model. Making use of tumor transcriptomic and functional analyses, methylation-targeted epigenetic reprogramming was shown to induce tumor cell cycle arrest and apoptosis in vitro coinciding with transient tumor growth delay and an IFN-I response in immune-competent mice. In consideration of a potential impact on immune cells, the drug was shown not to interfere with dendritic cell maturation or T-cell activation in vitro. Notably, the drug promoted dendritic cell and, to a lesser extent, T-cell infiltration in vivo, yet failed to sensitize tumor cells to programmed cell death-1 inhibition. Instead, it increased therapeutic efficacy of TCR-redirected T cell and dendritic cell vaccination, jointly increasing overall survival of B16-OVA tumor-bearing mice. The reported data confirm the prospect of methylation-targeted epigenetic reprogramming in melanoma and sustain dual G9a and DNMT inhibition as a strategy to tip the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma.
Remdesivir and Its Combination With Repurposed Drugs as COVID-19 Therapeutics
Authors: Chatterjee Bhaswati , Thakur Suman S.
Published: May 2022

The SARS-CoV-2 virus needs multiple copies for its multiplication using an enzyme RNA-dependent RNA polymerase (RdRp). Remdesivir inhibits viral RdRp, controls the multiplication of the virus, and protects patients. However, treatment of COVID-19 with remdesivir involves adverse effects. Many ongoing clinical trials are exploring the potential of the combination of remdesivir with repurposed drugs by targeting multiple targets of virus and host human simultaneously. Better results were obtained with the remdesivir–baricitinib combination treatment for COVID-19 compared to the treatment with remdesivir alone. Notably, recovery from COVID-19 was found to be 8 days less via the remdesivir–baricitinib combination treatment as compared to remdesivir treatment alone. Furthermore, the mortality rate via the remdesivir–baricitinib combination treatment was lower compared to the remdesivir-only treatment. Remdesivir targets the SARS-CoV-2 enzyme while baricitinib targets the host human enzyme. Simultaneously, remdesivir and baricitinib as a combination inhibit their target viral RdRp and human Janus kinase, respectively. Ongoing trials for the combination of drugs will suggest in the future whether they may reduce the recovery time, reduce the mortality rate, and improve patient clinical status for noninvasive ventilation. In the future, simultaneously targeting virus replication enzymes and host human kinases may be the strategy for SARS-CoV-2 therapeutics.
Distinct Injury Responsive Regulatory T Cells Identified by Multi-Dimensional Phenotyping
Authors: Guo Fei , Hancock Brandon , Griffith Alec , Lin Hui , Howard Kaitlyn , Keegan Joshua , Zhang Fan , Chicoine Adam , Cahill Laura , Ng Julie , Lederer James
Published: May 2022

CD4+ regulatory T cells (Tregs) activate and expand in response to different types of injuries, suggesting that they play a critical role in controlling the immune response to tissue and cell damage. This project used multi-dimensional profiling techniques to comprehensively characterize injury responsive Tregs in mice. We show that CD44high Tregs expand in response to injury and were highly suppressive when compared to CD44low Tregs. T cell receptor (TCR) repertoire analysis revealed that the CD44high Treg population undergo TCRαβ clonal expansion as well as increased TCR CDR3 diversity. Bulk RNA sequencing and single-cell RNA sequencing with paired TCR clonotype analysis identified unique differences between CD44high and CD44low Tregs and specific upregulation of genes in Tregs with expanded TCR clonotypes. Gene ontology analysis for molecular function of RNA sequencing data identified chemokine receptors and cell division as the most enriched functional terms in CD44high Tregs versus CD44low Tregs. Mass cytometry (CyTOF) analysis of Tregs from injured and uninjured mice verified protein expression of these genes on CD44high Tregs, with injury-induced increases in Helios, Galectin-3 and PYCARD expression. Taken together, these data indicate that injury triggers the expansion of a highly suppressive CD44high Treg population that is transcriptionally and phenotypically distinct from CD44low Tregs suggesting that they actively participate in controlling immune responses to injury and tissue damage.
Seroconversion to mRNA SARS-CoV-2 Vaccines in Hematologic Patients
Authors: Fattizzo Bruno , Bortolotti Marta , Rampi Nicolò , Cavallaro Francesca , Giannotta Juri Alessandro , Bucelli Cristina , Cassin Ramona , Da Vià Matteo Claudio , Galassi Giulia , Noto Alessandro , Pettine Loredana , Rossi Francesca Gaia , Sciumè Mariarita , Ceriotti Ferruccio , Consonni Dario , Barcellini Wilma , Baldini Luca
Published: May 2022

Hematologic patients show lower responses to SARS-CoV-2 vaccines, but predictors of seroconversion are lacking. In this prospective cohort study, hematologic patients undergoing SARS-CoV-2 mRNA vaccination at a single center in Milan, Italy, were sampled for anti-Spike and anti-Nucleocapsid IgG titer at 5 ± 1 weeks and at 3 months from the second vaccine dose. Patients (N = 393) received either BNT162b2 (Pfizer-BioNTech, 48%) or MRNA-1273 (Moderna, 52%), and 284 (72%) seroconverted and 100% persisted at 3 months. Non-response was higher in chronic lymphocytic leukemia (CLL) and lymphoma patients, and in those treated with small molecules and monoclonal antibodies. In myeloid neoplasms, lower responses were detected in patients with acute myeloid leukemia treated with venetoclax plus hypomethylating agents and in patients with myelofibrosis receiving ruxolitinib. Multivariable analysis showed that seroconversion was favorably associated with a diagnosis other than indolent lymphoma/CLL [OR 8.5 (95% CI 4.1–17.6)], lack of B-cell-depleting therapy [OR 3.15 (1.7–5.9)], and IgG levels within the normal range [OR 2.2 (1.2–4.2)]. We developed a simple algorithm according to these 3 risk factors [(A) diagnosis of indolent lymphoma/CLL, (B) B-cell-depleting treatment, and (C) low IgG] to predict non-response. IgG levels and treatment may be modifiable risk factors and should be considered for timing of vaccine administration.
The Genetic Risk for COVID-19 Severity Is Associated With Defective Immune Responses
Authors: Kuijpers Yunus , Chu Xiaojing , Jaeger Martin , Moorlag Simone J. C. F. M. , Koeken Valerie A. C. M. , Zhang Bowen , Nooijer Aline de , Grondman Inge , Gupta Manoj Kumar , Janssen Nico , Mourits Vera P. , de Bree L. Charlotte J. , de Mast Quirijn , van de Veerdonk Frank L. , Joosten Leo A. B. , Li Yang , Netea Mihai G. , Xu Cheng-Jian
Published: May 2022

Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.
Hyaladherins May be Implicated in Alcohol-Induced Susceptibility to Bacterial Pneumonia
Authors: Crotty Kathryn M. , Yeligar Samantha M.
Published: May 2022

Although the epidemiology of bacterial pneumonia and excessive alcohol use is well established, the mechanisms by which alcohol induces risk of pneumonia are less clear. Patterns of alcohol misuse, termed alcohol use disorders (AUD), affect about 15 million people in the United States. Compared to otherwise healthy individuals, AUD increase the risk of respiratory infections and acute respiratory distress syndrome (ARDS) by 2-4-fold. Levels and fragmentation of hyaluronic acid (HA), an extracellular glycosaminoglycan of variable molecular weight, are increased in chronic respiratory diseases, including ARDS. HA is largely involved in immune-assisted wound repair and cell migration. Levels of fragmented, low molecular weight HA are increased during inflammation and decrease concomitant with leukocyte levels following injury. In chronic respiratory diseases, levels of fragmented HA and leukocytes remain elevated, inflammation persists, and respiratory infections are not cleared efficiently, suggesting a possible pathological mechanism for prolonged bacterial pneumonia. However, the role of HA in alcohol-induced immune dysfunction is largely unknown. This mini literature review provides insights into understanding the role of HA signaling in host immune defense following excessive alcohol use. Potential therapeutic strategies to mitigate alcohol-induced immune suppression in bacterial pneumonia and HA dysregulation are also discussed.
Burgeoning Exploration of the Role of Natural Killer Cells in Anti-PD-1/PD-L1 Therapy
Authors: Bai Rilan , Cui Jiuwei
Published: May 2022

Antibodies targeting programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) have been considered breakthrough therapies for a variety of solid and hematological malignancies. Although cytotoxic T cells play an important antitumor role during checkpoint blockade, they still show a potential killing effect on tumor types showing loss of/low major histocompatibility complex (MHC) expression and/or low neoantigen load; this knowledge has shifted the focus of researchers toward mechanisms of action other than T cell-driven immune responses. Evidence suggests that the blockade of the PD-1/PD-L1 axis may also improve natural killer (NK)-cell function and activity through direct or indirect mechanisms, which enhances antitumor cytotoxic effects; although important, this topic has been neglected in previous studies. Recently, some studies have reported evidence of PD-1 and PD-L1 expression in human NK cells, performed exploration of the intrinsic mechanism by which PD-1/PD-L1 blockade enhances NK-cell responses, and made some progress. This article summarizes the recent advances regarding the expression of PD-1 and PD-L1 molecules on the surface of NK cells as well as the interaction between anti-PD-1/PD-L1 drugs and NK cells and associated molecular mechanisms in the tumor microenvironment.
Tackling Drug Resistance and Other Causes of Treatment Failure in Leishmaniasis
Authors: Wijnant Gert-Jan , Dumetz Franck , Dirkx Laura , Bulté Dimitri , Cuypers Bart , Van Bocxlaer Katrien , Hendrickx Sarah
Published: May 2022

Leishmaniasis is a tropical infectious disease caused by the protozoan Leishmania parasite. The disease is transmitted by female sand flies and, depending on the infecting parasite species, causes either cutaneous (stigmatizing skin lesions), mucocutaneous (destruction of mucous membranes of nose, mouth and throat) or visceral disease (a potentially fatal infection of liver, spleen and bone marrow). Although more than 1 million new cases occur annually, chemotherapeutic options are limited and their efficacy is jeopardized by increasing treatment failure rates and growing drug resistance. To delay the emergence of resistance to existing and new drugs, elucidating the currently unknown causes of variable drug efficacy (related to parasite susceptibility, host immunity and drug pharmacokinetics) and improved use of genotypic and phenotypic tools to define, measure and monitor resistance in the field are critical. This review highlights recent progress in our understanding of drug action and resistance in Leishmania, ongoing challenges (including setbacks related to the COVID-19 pandemic) and provides an overview of possible strategies to tackle this public health challenge.
Novel Fish Predator Causes Sustained Changes in Its Prey Populations
Authors: Nõomaa Kristiina , Kotta Jonne , Szava-Kovats Robert , Herkül Kristjan , Eschbaum Redik , Vetemaa Markus
Published: May 2022

Ecosystems are simultaneously regulated by bottom-up (resources) and top-down forces (predators). However, because predator-prey interactions operate on spatial scales beyond the reach of manipulative experimentation, the actual roles of predators remain poorly understood. In ecosystems where predators are naturally absent, biological invasions provide a unique experiment to shed light on the large-scale and long-term effects of predators in the recipient ecosystem. We combined data from long-term benthic monitoring, environmental conditions, and a census of round goby population to identify changes in the dominant benthic bivalve population (Mytilus trossulus and Macoma balthica) following round goby (Neogobius melanostomus) invasion. This study demonstrates a substantial change in the food web, with earlier primarily bottom-up regulated communities facing strong top-down control effects. The introduction of a novel predator to a species-poor ecosystem substantially reduced dominant invertebrate populations in a large part of the study area, sometimes with a time lag of 1−3 years. In general, the effects were less in high productivity areas. In some cases, community recovery was observed but rarely to pre-invasion levels, raising the question of the ability of bivalve communities to act as a natural filter. This study demonstrates long-term trends in benthic communities and by excluding possible effects due to the changing environment provides more evidence that invasive species transform coastal ecosystems over time and space.
Protein Methylation in Diabetic Kidney Disease
Authors: Cheng Ye , Chen Yanna , Wang Guodong , Liu Pei , Xie Guiling , Jing Huan , Chen Hongtao , Fan Youlin , Wang Min , Zhou Jun
Published: May 2022

Chronic kidney disease (CKD) is defined by persistent urine aberrations, structural abnormalities, or impaired excretory renal function. Diabetes is the leading cause of CKD. Their common pathological manifestation is renal fibrosis. Approximately half of all patients with type 2 diabetes and one-third with type 1 diabetes will develop CKD. However, renal fibrosis mechanisms are still poorly understood, especially post-transcriptional and epigenetic regulation. And an unmet need remains for innovative treatment strategies for preventing, arresting, treating, and reversing diabetic kidney disease (DKD). People believe that protein methylation, including histone and non-histone, is an essential type of post-translational modification (PTM). However, prevalent reviews mainly focus on the causes such as DNA methylation. This review will take insights into the protein part. Furthermore, by emphasizing the close relationship between protein methylation and DKD, we will summarize the clinical research status and foresee the application prospect of protein methyltransferase (PMT) inhibitors in DKD treatment. In a nutshell, our review will contribute to a more profound understanding of DKD’s molecular mechanism and inspire people to dig into this field.
Protocol for a Sepsis Model Utilizing Fecal Suspension in Mice: Fecal Suspension Intraperitoneal Injection Model
Authors: Tsuchida Takumi , Wada Takeshi , Mizugaki Asumi , Oda Yoshitaka , Kayano Katsuhide , Yamakawa Kazuma , Tanaka Shinya
Published: May 2022

Background

Various animal models of sepsis have been developed to optimize sepsis treatment. However, therapeutic agents that were successful in animal models were rarely effective in human clinical trials. The cecal ligation and puncture (CLP) model is currently the gold standard for sepsis studies. However, its limitations include the high variability among researchers and the difficulty in comparing animals with different cecum shapes and sizes. In this study, we established a protocol for the creation of a simple and accessible sepsis rodent model using fecal suspensions that minimized differences in technical effects among researchers and individual differences in animals.

Methods

A mouse model of sepsis using fecal suspension intraperitoneal injection (FSI) was created using fresh stool excreted within 24 h. The collected fresh stool was dissolved in saline solution and filtered. The obtained fecal suspension was injected intraperitoneally into the mice. Moreover, fecal suspensions with different concentrations were prepared, and the survival rates were compared among the fecal suspensions for each concentration. To assess the validity of the FSI as a sepsis model, CLP and FSI with similar mortality rates were compared pathologically, physiologically, immunologically, and bacteriologically. Histopathological comparison was evaluated by hematoxylin-eosin and Gram staining of the parenchymal organs. Physiological evaluation was performed by comparing the respiratory rate, body temperature, and blood gas analysis results. Immunological assessment was performed using multiplex analysis. Bacteriological comparisons were performed by culturing ascites fluid.

Results

The FSI model increased mortality in proportion to the fecal suspension concentration. The mortality rate was reduced with antibiotic administration. In various comparative experiments conducted using the FSI and CLP models, both models showed findings consistent with sepsis. Furthermore, the FSI model showed less variability among the individuals in each test.

Conclusion

This is the first detailed and accurate report of a protocol for creating a sepsis model using fecal suspension. The FSI model is a minimally invasive and accessible sepsis rodent model. Its clinical validity as a sepsis model was proven via histological, physiological, microbiological, and immunological evaluation methods. The FSI model minimizes individual differences between mice and helps to conduct accurate studies after the onset of sepsis.
Spatial and Temporal Trends in HIV/AIDS Burden Among Worldwide Regions From 1990 to 2019: A Secondary Analysis of the Global Burden of Disease Study 2019
Authors: He Huan , Ou Zejin , Yu Danfeng , Li Yongzhi , Liang Yuanhao , He Wenqiao , Gao Yuhan , Wu Fei , Chen Qing
Published: May 2022

Purpose

HIV/AIDS is a critical public health concern worldwide. This article investigated the spatial and temporal trends in HIV/AIDS burden from 1990 to 2019.

Methods

Data were extracted from the Global Burden of Disease (GBD) Study 2019. The estimated annual percentage change (EAPC) and the age-standardized rate (ASR) were used to quantify the change in trends at the global, regional, and national levels.

Results

In terms of temporal trends, during the period 1990–2004, increasing trends in prevalence (EAPC = 7.47, 95% confidence interval [CI] 5.84, 9.12), death (EAPC = 10.85, 95% CI 8.90–12.84), and disability-adjusted life years (DALYs) (EAPC = 10.40, 95% CI 8.47–12.36) of HIV/AIDS were observed. During the period 2005–2019, the global trends in HIV/AIDS incidence, death, and DALYs of HIV/AIDS decreased, with the EAPCs of −2.68 (95% CI−2.82–−2.53), −6.73 (95% CI −6.98–−6.47), and −6.75 (95% CI −6.95–−6.54), respectively. However, the disease prevalence showed a slight increasing trend (EAPC = 0.71, 95% CI 0.54–0.87). In terms of spatial trends, over the past 15 years, trends in HIV/AIDS incidence of HIV/AIDS appeared upward in High-middle and High sociodemographic index (SDI) areas (EAPC = 6.51, 95% CI 5.50–7.53; EAPC = 2.31, 95% CI 2.02–2.60, respectively).

Conclusion

Decreasing trends in HIV/AIDS incidence, death, and DALYs have been observed worldwide over the past 15 years, especially in death and DALYs rates. However, the global population living with HIV/AIDS is still increasing. It is worth noting that an unfavorable trend emerged in High-middle and High SDI areas. Prevention and control of HIV/AIDS still need to be strengthened to counteract these concerning trends.