bluuebunny/crossref_metadata_2025 huggingface dataset:
Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis
Authors: Bamra Tanvir , Shafi Taj , Das Sushmita , Kumar Manjay , Dikhit Manas Ranjan , Kumar Ajay , Kumar Ashish , Abhishek Kumar , Pandey Krishna , Sen Abhik , Das Pradeep
Published: April 2021

Summary Statement

Leishmaniasecretes over 151 proteins duringin vitrocultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance inLeishmaniainfection.

Visceral Leishmaniasis is a persistent infection, caused byLeishmania donovaniin Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins ofLeishmaniaparasite; however, related studies are meagre. We have identified a novel secretoryLeishmania donovaniglycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude thatLeishmania donovaniMevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement ofLeishmaniain the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.
What Do Weather Disasters Cost? An Analysis of Weather Impacts in Tanzania
Authors: Msemo Hellen E. , Taylor Andrea L. , Birch Cathryn E. , Dougill Andrew J. , Hartley Andrew , Woodhams Beth J.
Published: April 2021

Weather-related disasters negatively impact livelihoods and socioeconomic activities and often lead to the loss of lives and homes. This study uses disaster data from the Disaster Management Department (DMD) in Tanzania to describe the spatial distribution of weather-related disasters, their socioeconomic impacts and highlight opportunities to improve production and uptake of weather and climate information by climate sensitive sectors. Between 2000 and 2019, severe weather accounted for ~69% of disasters in Tanzania. The Government spent over 20.5 million USD in response to these disasters, which destroyed over 35,700 houses and 1,000 critical infrastructures (roads, bridges, schools, and hospitals), affected over 572,600 people, caused over 240 injuries and 450 deaths. To reduce these impacts, it is important to understand the decision-making process in terms of what and how national guidelines create and enabling environment for integration of weather and climate information into disaster risk reduction strategies. For example, the National Transport Policy which is supposed to provide cross-sectorial guidelines on the use of weather and climate information addresses the use to marine industry but remains silent to other climate sensitive sectors and the public. Whilst weather warnings are available Tanzania continues to suffer from the impacts of weather-related disasters. There is a clear need to better understand the value of weather warning information at short timescales (1–5 days) and how this information can be better used in the individual decision-making processes of those receiving advisories and warnings. The review of policies to guide on cross- sectoral actions to foster the uptake of weather and climate services, decisions across climate sensitive sectors, both nationally and sub-national level is recommended.
Associations Between the Use of Renin–Angiotensin System Inhibitors and the Risks of Severe COVID-19 and Mortality in COVID-19 Patients With Hypertension: A Meta-Analysis of Observational Studies
Authors: Dai Xiao-Ce , An Zhuo-Yu , Wang Zi-Yang , Wang Zi-Zhen , Wang Yi-Ren
Published: April 2021

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share a target receptor with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The use of ACEIs/ARBs may cause angiotensin-converting enzyme 2 receptor upregulation, facilitating the entry of SARS-CoV-2 into host cells. There is concern that the use of ACEIs/ARBs could increase the risks of severe COVID-19 and mortality. The impact of discontinuing these drugs in patients with COVID-19 remains uncertain. We aimed to assess the association between the use of ACEIs/ARBs and the risks of mortality and severe disease in patients with COVID-19. A systematic search was performed in PubMed, EMBASE, Cochrane Library, andMedRxiv.orgfrom December 1, 2019, to June 20, 2020. We also identified additional citations by manually searching the reference lists of eligible articles. Forty-two observational studies including 63,893 participants were included. We found that the use of ACEIs/ARBs was not significantly associated with a reduction in the relative risk of all-cause mortality [odds ratio (OR) = 0.87, 95% confidence interval (95% CI) = 0.75–1.00;I2= 57%,p= 0.05]. We found no significant reduction in the risk of severe disease in the ACEI subgroup (OR = 0.95, 95% CI = 0.88–1.02,I2= 50%,p= 0.18), the ARB subgroup (OR = 1.03, 95% CI = 0.94–1.13,I2= 62%,p= 0.48), or the ACEI/ARB subgroup (OR = 0.83, 95% CI = 0.65–1.08,I2= 67%,p= 0.16). Moreover, seven studies showed no significant difference in the duration of hospitalization between the two groups (mean difference = 0.33, 95% CI = −1.75 to 2.40,p= 0.76). In conclusion, the use of ACEIs/ARBs appears to not have a significant effect on mortality, disease severity, or duration of hospitalization in COVID-19 patients. On the basis of the findings of this meta-analysis, there is no support for the cessation of treatment with ACEIs or ARBs in patients with COVID-19.
Prediction of HF-Related Mortality Risk Using Genetic Risk Score Alone and in Combination With Traditional Risk Factors
Authors: Hu Dong , Xiao Lei , Li Shiyang , Hu Senlin , Sun Yang , Wang Yan , Wang Dao Wen
Published: April 2021

Background: Common variants may contribute to the variation of prognosis of heart failure (HF) among individual patients, but no systematical analysis was conducted using transcriptomic and whole exome sequencing (WES) data. We aimed to construct a genetic risk score (GRS) and estimate its potential as a predictive tool for HF-related mortality risk alone and in combination with traditional risk factors (TRFs).

Methods and Results: We reanalyzed the transcriptomic data of 177 failing hearts and 136 healthy donors. Differentially expressed genes (fold change >1.5 or <0.68 and adjusted P < 0.05) were selected for prognosis analysis using our whole exome sequencing and follow-up data with 998 HF patients. Statistically significant variants in these genes were prepared for GRS construction. Traditional risk variables were in combination with GRS for the construct of the composite risk score. Kaplan–Meier curves and receiver operating characteristic (ROC) analysis were used to assess the effect of GRS and the composite risk score on the prognosis of HF and discriminant power, respectively. We found 157 upregulated and 173 downregulated genes. In these genes, 31 variants that were associated with the prognosis of HF were finally identified to develop GRS. Compared with individuals with low risk score, patients with medium- and high-risk score showed 2.78 (95%CI = 1.82–4.24, P = 2 × 10−6) and 6.54 (95%CI = 4.42–9.71, P = 6 × 10−21) -fold mortality risk, respectively. The composite risk score combining GRS and TRF predicted mortality risk with an HR = 5.41 (95% CI = 2.72–10.64, P = 1 × 10−6) for medium vs. low risk and HR = 22.72 (95% CI = 11.9–43.48, P = 5 × 10−21) for high vs. low risk. The discriminant power of GRS is excellent with a C statistic of 0.739, which is comparable to that of TRF (C statistic = 0.791). The combination of GRS and TRF could significantly increase the predictive ability (C statistic = 0.853).

Conclusions: The 31-SNP GRS could well distinguish those HF patients with poor prognosis from those with better prognosis and provide clinician with reference for the intensive therapy, especially when combined with TRF.

Clinical Trial Registration:https://www.clinicaltrials.gov/, identifier: NCT03461107.
Vagus Nerve Stimulation in Early Stage of Acute Myocardial Infarction Prevent Ventricular Arrhythmias and Cardiac Remodeling
Authors: Zhao Shuang , Dai Yan , Ning Xiaohui , Tang Min , Zhao Yunzi , Li Zeyi , Zhang Shu
Published: April 2021

Aims: To evaluate whether low level left vagus nerve stimulation (LLVNS) in early stage of myocardial infarction (MI) could effectively prevent ventricular arrhythmias (VAs) and protect cardiac function, and explore the underlying mechanisms.

Methods and Results: After undergoing implantable cardioverter defibrillators (ICD) and left cervical vagal stimulators implantation and MI creation, 16 dogs were randomly divided into three groups: the MI (n = 6), MI+LLVNS (n = 5), and sham operation (n = 5) groups. LLVNS was performed for 3 weeks. VAs, the left ventricular function, the density of the nerve fibers in the infarction area and gene expression profiles were analyzed. Compared with the MI group, dogs in the MI+LLVNS group had a lower VAs incidence (p < 0.05) and better left ventricular function. LLVNS significantly inhibited excessive sympathetic nerve sprouting with the evidences of decreased density of TH, GAP43 and NF positive nerves (p < 0.05). The gene expression profiling found a total of 206 genes differentially expressed between MI+LLVNS and MI dogs, mainly involved in cardiac tissue remodeling, cardiac neural remodeling, immune response and apoptosis. These genes, including 55 up-regulated genes and 151 down-regulated genes, showed more protective expressions under LLVNS.

Conclusions: This study suggests that LLVNS was delivered without altering heart rate, contributing to reduced incidences of VAs and improved left ventricular function. The potential mechanisms included suppressing cardiac neuronal sprouting, inhibiting excessive sympathetic nerve sprouting and subduing pro-inflammatory responses by regulating gene expressions from a canine experimental study.
Modeling and Simulation of a Novel Sustainable Ammonia Production Process From Food Waste and Brown Water
Authors: Ghavam Seyedehhoma , Taylor Caroline M. , Styring Peter
Published: April 2021

Global demand for both clean energy carriers and agricultural nutrients continues to grow rapidly, alongside increasing quantities of waste globally, interlinked challenges that may be addressed with interlinked solutions. We report on the potential efficiency and Greenhouse Gas (GHG) intensity of several configurations of a new, sustainability-driven ammonia (NH3) production processes to determine whether a waste-based process designed first around carbon dioxide (CO2) capture can compete with other available NH3 technologies. This is assessed via different scenarios: Two hydrogen generating options are paired with four CO2 fates. For either an anaerobic digestion-centered process or a two-stage dark fermentation coupled with anaerobic digestion process, the resultant CO2 may be captured and injected, sold to the marketplace, released directly in the atmosphere, or converted to urea in order to produce a green substitute for synthetic NH3. Modeled yields range from 47 t NH3 when the resultant CO2 is released or captured, or 3.8 t NH3 and 76.5 t urea when the system is designed to produce no unutilized CO2. Among the technologies assessed, NH3 production where CO2 is captured for anaerobic digestion-only is the most efficient for GHG emissions and water consumption, while the two-stage requires less energy on a fertilizer-N basis. GHG emissions for anaerobic digestion-only are approximately 8% lower than the two-stage. The best of the proposed technology configurations consumes about 41% less energy than water electrolysis coupled with Haber-Bosch and approximately 27% lower energy than Steam Methane Reforming (SMR) coupled with Haber-Bosch per kg NH3.
Sulfur Poisoning and Performance Recovery of SOFC Air Electrodes
Authors: Hong Junsung , Anisur M. R. , Heo Su Jeong , Dubey Pawan Kumar , Singh Prabhakar
Published: April 2021

The sulfur poisoning and performance recovery of the state-of-the-art SOFC cathodes (La0.80Sr0.20)0.95MnO3±δ (LSM) and (La0.60Sr0.40)0.95Co0.20Fe0.80O3–δ (LSCF), have been studied. Electrochemical impedance spectroscopy measurements of LSCF|GDC and LSM|YSZ half-cells are carried out in alternating atmospheres of air and SO2–air at 700°C for hundreds of hours. In the presence of SO2, the electrochemical performance of both the cells decays with ohmic and non-ohmic losses, owing to the absorption and chemical interaction of SO2 with the electrodes. In LSCF, the SrO segregated on the surface tends to absorb and react with SO2, forming SrSO4 followed by the exsolution of Co-Fe. As for LSM, SO2 is absorbed onto the Sr-rich areas of LSM, including the active reaction sites near the TPBs, leading to Sr exsolution and SrSO4 formation, leaving a Sr-deficient LSM. During the subsequent exposure to air, the performance of the sulfur-contaminated LSM is almost restored. The LSM particles, exposed to alternating atmospheres of air and SO2-air during the electrochemical tests, show a relatively clean surface with sparsely distributed SrSO4 particles, indicating a high stability against sulfur poisoning. It is suggested that the loosely adsorbed SO2 at the TPBs is readily swept away by the SO2-free air flow, recovering its ORR activity, whereas the Sr-deficient LSM due to Sr-exsolution stays modified, contributing to the incomplete performance restoration. Unlike the case of LSM, the performance of the sulfur-poisoned LSCF partially recovers during the subsequent exposure to air. Correspondingly, the LSCF particles have a modified morphology covered with numerous nanoparticles, mostly SrSO4, showing the irreversible aspect of the sulfur poisoning. The morphology modification is not concentrated near the electrode/electrolyte interface but over the entire cathode, indicating that the degree of recovery from sulfur poisoning is closely related to the presence of SrO and chemical activity of Sr in the electrodes at the solid-gas interface. These results also show the potential application of LSM for a sulfur sensor available in high-temperature harsh conditions.
Complementary Contribution of Fungi and Bacteria to Lignocellulose Digestion in the Food Stored by a Neotropical Higher Termite
Authors: Moreira Edimar A. , Persinoti Gabriela F. , Menezes Letícia R. , Paixão Douglas A. A. , Alvarez Thabata M. , Cairo João P. L. Franco , Squina Fabio M. , Costa-Leonardo Ana Maria , Rodrigues Andre , Sillam-Dussès David , Arab Alberto
Published: April 2021

Lignocellulose digestion in termites is achieved through the functional synergy between gut symbionts and host enzymes. However, some species have evolved additional associations with nest microorganisms that collaborate in the decomposition of plant biomass. In a previous study, we determined that plant material packed with feces inside the nests of Cornitermes cumulans (Syntermitinae) harbors a distinct microbial assemblage. These food nodules also showed a high hemicellulolytic activity, possibly acting as an external place for complementary lignocellulose digestion. In this study, we used a combination of ITS sequence analysis, metagenomics, and metatranscriptomics to investigate the presence and differential expression of genes coding for carbohydrate-active enzymes (CAZy) in the food nodules and the gut of workers and soldiers. Our results confirm that food nodules express a distinct set of CAZy genes suggesting that stored plant material is initially decomposed by enzymes that target the lignin and complex polysaccharides from fungi and bacteria before the passage through the gut, where it is further targeted by a complementary set of cellulases, xylanases, and esterases produced by the gut microbiota and the termite host. We also showed that the expression of CAZy transcripts associated to endoglucanases and xylanases was higher in the gut of termites than in the food nodules. An additional finding in this study was the presence of fungi in the termite gut that expressed CAZy genes. This study highlights the importance of externalization of digestion by nest microbes and provides new evidence of complementary digestion in the context of higher termite evolution.
AGNEP: An Agglomerative Nesting Clustering Algorithm for Phenotypic Dimension Reduction in Joint Analysis of Multiple Phenotypes
Authors: Liu Fengrong , Zhou Ziyang , Cai Mingzhi , Wen Yangjun , Zhang Jin
Published: April 2021

Genome-wide association study (GWAS) has identified thousands of genetic variants associated with complex traits and diseases. Compared with analyzing a single phenotype at a time, the joint analysis of multiple phenotypes can improve statistical power by taking into account the information from phenotypes. However, most established joint algorithms ignore the different level of correlations between multiple phenotypes; instead of that, they simultaneously analyze all phenotypes in a genetic model. Thus, they may fail to capture the genetic structure of phenotypes and consequently reduce the statistical power. In this study, we develop a novel method agglomerative nesting clustering algorithm for phenotypic dimension reduction analysis (AGNEP) to jointly analyze multiple phenotypes for GWAS. First, AGNEP uses an agglomerative nesting clustering algorithm to group correlated phenotypes and then applies principal component analysis (PCA) to generate representative phenotypes for each group. Finally, multivariate analysis is employed to test associations between genetic variants and the representative phenotypes rather than all phenotypes. We perform three simulation experiments with various genetic structures and a real dataset analysis for 19 Arabidopsis phenotypes. Compared to established methods, AGNEP is more powerful in terms of statistical power, computing time, and the number of quantitative trait nucleotides (QTNs). The analysis of the Arabidopsis real dataset further illustrates the efficiency of AGNEP for detecting QTNs, which are confirmed by The Arabidopsis Information Resource gene bank.
Polyvalent Bacterial Lysate Protects Against Pneumonia Independently of Neutrophils, IL-17A or Caspase-1 Activation
Authors: Ferrara Florencia , Rial Analía , Suárez Norma , Chabalgoity José Alejandro
Published: April 2021

Polyvalent bacterial lysates have been in use for decades for prevention and treatment of respiratory infections with reported clinical benefits. However, besides claims of broad immune activation, the mode of action is still a matter of debate. The lysates, formulated with the main bacterial species involved in respiratory infections, are commonly prepared by chemical or mechanical disruption of bacterial cells, what is believed influences the biological activity of the product. Here, we prepared two polyvalent lysates with the same composition but different method of bacterial cell disruption and evaluated their biological activity in a comparative fashion. We found that both bacterial lysates induce NF-kB activation in a MyD88 dependent manner, suggesting they work as TLR agonists. Further, we found that a single intranasal dose of any of the two lysates, is sufficient to protect against pneumococcal pneumonia, suggesting that they exert similar biological activity. We have previously shown that protection against pneumococcal pneumonia can also be induced by prior S. pneumoniae sub lethal infection or therapeutic treatment with a TLR5 agonist. Protection in those cases depends on neutrophil recruitment to the lungs, and can be associated with increased local expression of IL-17A. Here, we show that bacterial lysates exert protection against pneumococcal pneumonia independently of neutrophils, IL-17A or Caspase-1/11 activation, suggesting the existence of redundant mechanisms of protection. Trypsin-treated lysates afford protection to the same extent, suggesting that just small peptides suffice to exert the protective effect or that the molecules responsible for the protective effect are not proteins. Understanding the mechanism of action of bacterial lysates and deciphering the active components shall allow redesigning them with more precisely defined formulations and expanding their range of action.
Case Report: Non-episodic Angioedema With Eosinophilia in a Young Lactating Woman
Authors: Hirmatsu-Ito Mizuho , Nakamura Nobuhisa , Miyabe Megumi , Matsubara Tatsuaki , Naruse Keiko
Published: April 2021

Angioedema with eosinophilia is classified into two types: episodic angioedema with eosinophilia (EAE), known as Gleich’s syndrome, and non-episodic angioedema with eosinophilia (NEAE). We present the case of a young lactating woman with non-episodic angioedema. She had no history of parasitic or nonparasitic infections. Physical examination showed striking, non-pitting edema in both lower extremities. Her weight had not changed significantly throughout the course of the illness. She exhibited no other symptoms, and her vital signs were normal. There was no evidence of anemia, hypoalbuminemia, thyroid dysfunction, heart failure, renal failure, or postpartum cardiomyopathy. Based on these findings, we diagnosed her with angioedema with eosinophilia. Given the scarcity of information about this condition, we explored the dynamics between cytokines/chemokines and edema in this patient. We successfully quantified the edema by bioimpedance analysis. In addition, we revealed the involvement of interleukin-5 (IL-5), thymus- and activation-regulated chemokine/C-C motif chemokine ligand-17 (TARC/CCL-17), eotaxin-3/CCL-26, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-4/CCL-13 (MCP-4/CCL-13), eotaxin-1/CCL-11, and regulated on activation, normal T expressed and secreted/CCL-5 (RANTES/CCL-5) in NEAE. Lastly, we elucidated the strong association between these parameters. To the best of our knowledge, this is the first such study of its kind.
An Unbiased Flow Cytometry-Based Approach to Assess Subset-Specific Circulating Monocyte Activation and Cytokine Profile in Whole Blood
Authors: Kiefer Jurij , Zeller Johannes , Bogner Balázs , Hörbrand Isabel A. , Lang Friederike , Deiss Emil , Winninger Oscar , Fricke Mark , Kreuzaler Sheena , Smudde Eva , Huber-Lang Markus , Peter Karlheinz , Woollard Kevin J. , Eisenhardt Steffen U.
Published: April 2021

Monocytes are the third most frequent type of leukocytes in humans, linking innate and adaptive immunity and are critical drivers in many inflammatory diseases. Based on the differential expression of surface antigens, three monocytic subpopulations have been suggested in humans and two in rats with varying inflammatory and phenotype characteristics. Potential intervention strategies that aim to manipulate these cells require an in-depth understanding of monocyte behavior under different conditions. However, monocytes are highly sensitive to their specific activation state and expression of surface markers, which can change during cell isolation and purification. Thus, there is an urgent need for an unbiased functional analysis of activation in monocyte subtypes, which is not affected by the isolation procedure. Here, we present a flow cytometry-based protocol for evaluating subset-specific activation and cytokine expression of circulating blood monocytes both in humans and rats using small whole blood samples (50 - 100 μL). In contrast to previously described monocyte isolation and flow cytometry visualization methods, the presented approach virtually leaves monocyte subsets in a resting state or fixes them in their current state and allows for an unbiased functional endpoint analysis without prior cell isolation. This protocol is a comprehensive tool for studying differential monocyte regulation in the inflammatory and allogeneic immune response in vitro and vivo.
Acute Transverse Myelitis (ATM):Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222)
Authors: Román Gustavo C. , Gracia Fernando , Torres Antonio , Palacios Alexis , Gracia Karla , Harris Diógenes
Published: April 2021

Introduction

Although acute transverse myelitis (ATM) is a rare neurological condition (1.34-4.6 cases per million/year) COVID-19-associated ATM cases have occurred during the pandemic.

Case-finding methods

We report a patient from Panama with SARS-CoV-2 infection complicated by ATM and present a comprehensive clinical review of 43 patients with COVID-19-associated ATM from 21 countries published from March 2020 to January 2021. In addition, 3 cases of ATM were reported as serious adverse events during the clinical trials of the COVID-19 vaccine ChAdOx1 nCoV-19 (AZD1222).

Results

All patients had typical features of ATM with acute onset of paralysis, sensory level and sphincter deficits due to spinal cord lesions demonstrated by imaging. There were 23 males (53%) and 20 females (47%) ranging from ages 21- to 73- years-old (mean age, 49 years), with two peaks at 29 and 58 years, excluding 3 pediatric cases. The main clinical manifestations were quadriplegia (58%) and paraplegia (42%). MRI reports were available in 40 patients; localized ATM lesions affected ≤3 cord segments (12 cases, 30%) at cervical (5 cases) and thoracic cord levels (7 cases); 28 cases (70%) had longitudinally-extensive ATM (LEATM) involving ≥4 spinal cord segments (cervicothoracic in 18 cases and thoracolumbar-sacral in 10 patients). Acute disseminated encephalomyelitis (ADEM) occurred in 8 patients, mainly women (67%) ranging from 27- to 64-years-old. Three ATM patients also had blindness from myeloneuritis optica (MNO) and two more also had acute motor axonal neuropathy (AMAN).

Conclusions

We found ATM to be an unexpectedly frequent neurological complication of COVID-19. Most cases (68%) had a latency of 10 days to 6 weeks that may indicate post-infectious neurological complications mediated by the host’s response to the virus. In 32% a brief latency (15 hours to 5 days) suggested a direct neurotropic effect of SARS-CoV-2. The occurrence of 3 reported ATM adverse effects among 11,636 participants in the AZD1222 vaccine trials is extremely high considering a worldwide incidence of 0.5/million COVID-19-associated ATM cases found in this report. The pathogenesis of ATM remains unknown, but it is conceivable that SARS-CoV-2 antigens –perhaps also present in the AZD1222 COVID-19 vaccine or its chimpanzee adenovirus adjuvant– may induce immune mechanisms leading to the myelitis.
Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation
Authors: Gao Yiyuan , Wang Yuedi , Luo Feifei , Chu Yiwei
Published: April 2021

Chimeric antigen receptors (CARs) or bispecific antibodies (bsAbs) redirected T cell against tumors is one of the most promising immunotherapy approaches. However, insufficient clinical outcomes are still observed in treatments of both solid and non-solid tumors. Limited efficacy and poor persistence are two major challenges in redirected T cell therapies. The immunological synapse (IS) is a vital component during the T cell response, which largely determines the clinical outcomes of T cell-based therapies. Here, we review the structural and signaling characteristics of IS formed by natural T cells and redirected T cells. Furthermore, inspired by the elaborate natural T cell receptor-mediated IS, we provide potential strategies for higher efficacy and longer persistence of redirected T cells.
Myeloid ATP Citrate Lyase Regulates Macrophage Inflammatory Responses In Vitro Without Altering Inflammatory Disease Outcomes
Authors: Verberk Sanne G. S. , van der Zande Hendrik J. P. , Baardman Jeroen , de Goede Kyra E. , Harber Karl J. , Keuning Eelco D. , Lambooij Joost M. , Otto Frank , Zawistowska-Deniziak Anna , de Vries Helga E. , de Winther Menno P. J. , Guigas Bruno , Van den Bossche Jan
Published: April 2021

Macrophages are highly plastic, key regulators of inflammation. Deregulation of macrophage activation can lead to excessive inflammation as seen in inflammatory disorders like atherosclerosis, obesity, multiple sclerosis and sepsis. Targeting intracellular metabolism is considered as an approach to reshape deranged macrophage activation and to dampen the progression of inflammatory disorders. ATP citrate lyase (Acly) is a key metabolic enzyme and an important regulator of macrophage activation. Using a macrophage-specific Acly-deficient mouse model, we investigated the role of Acly in macrophages during acute and chronic inflammatory disorders. First, we performed RNA sequencing to demonstrate that Acly-deficient macrophages showed hyperinflammatory gene signatures in response to acute LPS stimulation in vitro. Next, we assessed endotoxin-induced peritonitis in myeloid-specific Acly-deficient mice and show that, apart from increased splenic Il6 expression, systemic and local inflammation were not affected by Acly deficiency. Also during obesity, both chronic low-grade inflammation and whole-body metabolic homeostasis remained largely unaltered in mice with Acly-deficient myeloid cells. Lastly, we show that macrophage-specific Acly deletion did not affect the severity of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. These results indicate that, despite increasing inflammatory responses in vitro, macrophage Acly deficiency does not worsen acute and chronic inflammatory responses in vivo. Collectively, our results indicate that caution is warranted in prospective long-term treatments of inflammatory disorders with macrophage-specific Acly inhibitors. Together with our earlier observation that myeloid Acly deletion stabilizes atherosclerotic lesions, our findings highlight that therapeutic targeting of macrophage Acly can be beneficial in some, but not all, inflammatory disorders.
Toll-Like Receptors Gene Polymorphisms in Autoimmune Disease
Authors: Zhang Yingchi , Liu Jia , Wang Changlun , Liu Junxian , Lu Wei
Published: April 2021

Toll-like receptors (TLRs) are important initiators of the immune response, both innate and acquired. Evidence suggests that gene polymorphisms within TLRs cause malfunctions of certain key TLR-related signaling pathways, which subsequently increases the risk of autoimmune diseases. We illustrate and discuss the current findings on the role of Toll-like receptor gene polymorphisms in numerous autoimmune diseases in this review, such as type 1 diabetes mellitus, Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. The study of genetic variation in TLRs in different populations has shown a complex interaction between immunity and environmental factors. This interaction suggests that TLR polymorphisms affect the susceptibility to autoimmune diseases differently in various populations. The identification of Toll-like receptor gene polymorphisms can expand our understanding of the pathogenesis of autoimmune diseases, which will subsequently guide effective medical management and provide insight into prognosis and advanced treatments.
Automation Concepts for Industrial-Scale Production of Seaweed
Authors: Solvang Torfinn , Bale Emil Scott , Broch Ole Jacob , Handå Aleksander , Alver Morten Omholt
Published: April 2021

In order to industrialize macroalgal cultivation in Norway, new automated methods and solutions for seeding, deployment and harvesting need to be developed. Today's solutions are time and resource demanding, still yielding volumes nationally in the range of 100–200 tons per year in total (not including wild harvest), while the potential is in the megaton range. Standardization of equipment and automation can be one way to upscale production. Here we present results from a design study of a module-based solution for industrial cultivation, with specific solutions for spinning of thin seedling strings onto longlines, and a robotic module for interaction with the submerged farm at deployment and harvest. A reduced-scale physical prototype of the farm concept with the robot has been built for testing of deployment and harvesting techniques. The concept has been named SPOKe: Standardized Production of Kelp.
Molecular Epidemiology and Clinical Features of Enteroviruses-Associated Hand, Foot, and Mouth Disease and Herpangina Outbreak in Zunyi, China, 2019
Authors: Ai Yuanhang , Zhang Weiwei , Wu Jie , Zhang Jingzhi , Shen Meijing , Yao Shifei , Deng Chengmin , Li Xiaoqian , Wu Dejing , Tian Peng , Cheng Xiaoju , Zha He , Wu Kaifeng
Published: April 2021

Background: Hand, foot and mouth disease (HFMD) and herpangina (HA), two of the most common childhood infectious diseases, are associated with enteroviruses (EVs) infection. The aim of this study was to identify the molecular epidemiology of enterovirus causing HFMD/HA in Zunyi, China, during 2019, and to describe the clinical features of the cases.

Methods: We collected the information on demographic and clinical characteristics, laboratory data of laboratory-confirmed EVs associated HFMD/HA cases in Zunyi Medical University Third Affiliated Hospital between March 1 and July 31, 2019. EV types were determined by either one-step real time RT-PCR or partial VP1 gene sequencing and sequence alignment. Phylogenetic analysis of CVA6, CVA2, and CVA5 were established based on the partial VP1 gene sequences by neighbor-joining method. Differences in clinical characteristics and laboratory results of the cases were compared among patients infected with the most prevalent EV types.

Results: From 1 March to 31 July 2019, 1,377 EVs associated HFMD/HA inpatients were confirmed. Of them, 4 (0.3%, 4/1,377) were EV-A71-associated cases, 84 (6.1%, 84/1,377) were CVA16-associated cases, and 1,289 (93.6%, 1,289/1,377) were non-EV-A71/CVA16-associated cases. Of the randomly selected 372 non-EV-A71/CVA16 cases, EV types have been successfully determined in 273 cases including 166 HFMD and 107 HA cases. For HFMD cases, the three most common types were CVA6 (80.7%, 134/166), CVA2 (5.4%, 9/166) and CVA5 (3.0%, 5/166); similarly, for HA cases, the three most prevalent serotypes were CVA6 (36.5%, 39/107), CVA2 (21.5%, 23/107) and CVA5 (18.7%, 20/107). Phylogenetic analysis showed that subclade D of CVA5, and subclade E of CVA6 and CVA2 were predominant in Zunyi during the outbreak in 2019. Compared with the cases caused by CVA16, the incidence of high fever and severe infection associated with CVA2, CVA5, and CVA6 was higher.

Conclusions: The recent HFMD/HA outbreak in Zunyi is due to a larger incidence of CVA6, CVA2, and CVA5. Novel diagnostic reagents and vaccines against these types would be important to monitor and control EV infections.
Insights on the Evolutionary Genomics of the Blautia Genus: Potential New Species and Genetic Content Among Lineages
Authors: Maturana José Luis , Cárdenas Juan P.
Published: April 2021

Blautia, a genus established in 2008, is a relevantly abundant taxonomic group present in the microbiome of human and other mammalian gastrointestinal (GI) tracts. Several described (or proposed) Blautia species are available at this date. However, despite the increasing level of knowledge about Blautia, its diversity is still poorly understood. The increasing availability of Blautia genomic sequences in the public databases opens the possibility to study this genus from a genomic perspective. Here we report the pangenome analysis and the phylogenomic study of 225 Blautia genomes available in RefSeq. We found 33 different potential species at the genomic level, 17 of them previously undescribed; we also confirmed by genomic standards the status of 4 previously proposed new Blautia species. Comparative genomic analyses suggest that the Blautia pangenome is open, with a relatively small core genome (∼ 700–800 gene families). Utilizing a set of representative genomes, we performed a gene family gain/loss model for the genus, showing that despite terminal nodes suffered more massive gene gain events than internal nodes (i.e., predicted ancestors), some ancestors were predicted to have gained an important number of gene families, some of them associated with the possible acquisition of metabolic abilities. Gene loss events remained lower than gain events in most cases. General aspects regarding pangenome composition and gene gain/loss events are discussed, as well as the proposition of changes in the taxonomic assignment of B. coccoidesTY and the proposition of a new species, “B. pseudococcoides.”
Effects of Hydrogen Peroxide Stress on the Nucleolar Redox Environment and Pre-rRNA Maturation
Authors: Sapio Russell T. , Burns Chelsea J. , Pestov Dimitri G.
Published: April 2021

Identifying biologically relevant molecular targets of oxidative stress may provide new insights into disease mechanisms and accelerate development of novel biomarkers. Ribosome biogenesis is a fundamental prerequisite for cellular protein synthesis, but how oxidative stress affects ribosome biogenesis has not been clearly established. To monitor and control the redox environment of ribosome biogenesis, we targeted a redox-sensitive roGFP reporter and catalase, a highly efficient H2O2 scavenger, to the nucleolus, the primary site for transcription and processing of rRNA in eukaryotic cells. Imaging of mouse 3T3 cells exposed to non-cytotoxic H2O2 concentrations revealed increased oxidation of the nucleolar environment accompanied by a detectable increase in the oxidative damage marker 8-oxo-G in nucleolar RNA. Analysis of pre-rRNA processing showed a complex pattern of alterations in pre-rRNA maturation in the presence of H2O2, including inhibition of the transcription and processing of the primary 47S transcript, accumulation of 18S precursors, and inefficient 3′-end processing of 5.8S rRNA. This work introduces new tools for studies of the redox biology of the mammalian nucleolus and identifies pre-rRNA maturation steps sensitive to H2O2 stress.
Association Between sTREM2, an Immune Biomarker of Microglial Activation, and Aging-Related Brain Volume Changes in Community-Dwelling Older Adults: A 7-Year Follow-Up Study
Authors: Orihashi Ryuzo , Mizoguchi Yoshito , Imamura Yoshiomi , Yamada Shigeto , Monji Akira
Published: April 2021

Background

This study aimed to investigate the association between serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble form of an innate immune receptor expressed on the microglia, and brain volume in older adults.

Methods

The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum sTREM2 level measurements, brain MRI, Mini-Mental State Examination (MMSE), and clinical dementia rating (CDR) were performed at Time 1 (2009–2011). Follow-up brain MRI, MMSE, and CDR were performed at Time 2 (2016–2017). The interval between Time 1 and Time 2 was approximately 7 years. Sixty-nine participants (16 men, mean age 72.69 ± 3.18 years; 53 women, mean age 72.68 ± 4.64 years) completed this study. We analyzed the correlation between serum sTREM2 levels (Time 1) and brain volume (Time 1, Time 2, and Time 1–Time 2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping.

Results

Participants in this study had lower MMSE and higher CDR scores 7 years after the baseline evaluation. However, analyses at the cluster level by applying multiple comparison corrections (family wise error; P < 0.05) showed no correlation between serum sTREM2 levels and volume of different brain regions, either cross-sectional or longitudinal.

Conclusion

Serum sTREM2 level could not serve as an immune biomarker of aging-related volume changes in brain regions closely related to cognitive function in older adults aged 65 years and above.
Altered Inhibitory Mechanisms in Parkinson’s Disease: Evidence From Lexical Decision and Simple Reaction Time Tasks
Authors: Letanneux Alban , Velay Jean-Luc , Viallet François , Pinto Serge
Published: April 2021

Introduction

Although the motor signs of Parkinson’s disease (PD) are well defined, nonmotor symptoms, including higher-level language deficits, have also been shown to be frequent in patients with PD. In the present study, we used a lexical decision task (LDT) to find out whether access to the mental lexicon is impaired in patients with PD, and whether task performance is affected by bradykinesia.

Materials and Methods

Participants were 34 nondemented patients with PD, either without (off) medication (n = 16) or under optimum (on) medication (n = 18). A total of 19 age-matched control volunteers were also recruited. We recorded reaction times (RTs) to the LDT and a simple RT (control) task. In each task, stimuli were either visual or auditory. Statistical analyses consisted of repeated-measures analyses of variance and Tukey’s HSD post hoc tests.

Results

In the LDT, participants with PD both off and on medication exhibited intact access to the mental lexicon in both modalities. In the visual modality, patients off medication were just as fast as controls when identifying real words, but slower when identifying pseudowords. In the visual modality of the control task, RTs for pseudowords were significantly longer for PD patients off medication than for controls, revealing an unexpected but significant lexicality effect in patients that was not observed in the auditory modality. Performances of patients on medication did not differ from those of age-matched controls.

Discussion

Motor execution was not slowed in patients with PD either off or on medication, in comparison with controls. Regarding lexical access, patients off medication seemed to (1) have difficulty inhibiting a cognitive-linguistic process (i.e., reading) when it was not required (simple reaction time task), and (2) exhibit a specific pseudoword processing deficit in the LDT, which may have been related to impaired lateral word inhibition within the mental lexicon. These deficits seemed to be compensated by medication.
Gesture Recognition Using Surface Electromyography and Deep Learning for Prostheses Hand: State-of-the-Art, Challenges, and Future
Authors: Li Wei , Shi Ping , Yu Hongliu
Published: April 2021

Amputation of the upper limb brings heavy burden to amputees, reduces their quality of life, and limits their performance in activities of daily life. The realization of natural control for prosthetic hands is crucial to improving the quality of life of amputees. Surface electromyography (sEMG) signal is one of the most widely used biological signals for the prediction of upper limb motor intention, which is an essential element of the control systems of prosthetic hands. The conversion of sEMG signals into effective control signals often requires a lot of computational power and complex process. Existing commercial prosthetic hands can only provide natural control for very few active degrees of freedom. Deep learning (DL) has performed surprisingly well in the development of intelligent systems in recent years. The significant improvement of hardware equipment and the continuous emergence of large data sets of sEMG have also boosted the DL research in sEMG signal processing. DL can effectively improve the accuracy of sEMG pattern recognition and reduce the influence of interference factors. This paper analyzes the applicability and efficiency of DL in sEMG-based gesture recognition and reviews the key techniques of DL-based sEMG pattern recognition for the prosthetic hand, including signal acquisition, signal preprocessing, feature extraction, classification of patterns, post-processing, and performance evaluation. Finally, the current challenges and future prospects in clinical application of these techniques are outlined and discussed.
Immune Checkpoint Blockade Therapy May Be a Feasible Option for Primary Pulmonary Lymphoepithelioma-like Carcinoma
Authors: Wu Zuohong , Xian Xinghong , Wang Ke , Cheng Deyun , Li Weimin , Chen Bojiang
Published: April 2021

Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of non-small cell lung cancer (NSCLC) for which there is currently no recognized treatment. Recently, favorable immune checkpoint blockade responses have been observed in PPLELC. This study aimed to review the effects of this regimen in patients with advanced PPLELC. PPLELC patients treated with immune checkpoint inhibitors at West China Hospital between January 2008 and December 2019 were retrospectively identified. Demographic parameters and antitumor treatment details were retrieved and reviewed. Among 128 patients diagnosed with PPLELC, 5 who received immune checkpoint inhibitors at advanced stages were included in the analysis. All of these patients were female nonsmokers with a median age of 55.6 (range 53-58) years at diagnosis. Their median PD-L1 expression was 40% (range, 30-80%). Although the patients underwent surgeries, chemotherapy and radiotherapy, all the treatments failed. Immune checkpoint inhibitors were administered palliatively, and three patients responded favorably, with the best overall response being partial remission (PR). Thus, immune checkpoint inhibitors may be a promising treatment for advanced PPLELC, and large clinical trials are warranted to obtain more evidence regarding this regimen.