bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-35: A Novel Immunomodulator in Hepatitis B Virus-Related Liver Diseases
Authors: Li Xuefen , Liu Xia , Wang Weilin
Published: March 2021

Chronic hepatitis B virus (HBV) infection is a risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC), however, little is known about the mechanisms involved in the progression of HBV-related diseases. It has been well acknowledged that host immune response was closely related to the clinical outcomes of patients with HBV infection. As the factors closely related to the immunomodulatory process, cytokines are crucial in the cell-cell communication and the host responses to HBV infection. Recently, a newly discovered cytokine, designated as interleukin-35 (IL-35), has been proved to be essential for the progression of chronic HBV infection, the development of cirrhosis, the transformation of cirrhosis to HCC, and the metastasis of HCC. Specifically, it showed various biological activities such as inhibiting the HBV-specific cytotoxic T lymphocyte (CTL) proliferation and cytotoxicity, deactivating the immature effector T-cells (Teffs), as well as delaying the proliferation of dendritic cells. It regulated the immune responses by acting as a “brake” on the activation of Teffs, which subsequently played important roles in the pathogenesis of various inflammatory diseases and malignancies. In this review, we focused on the most recent data on the relationship between IL-35 and chronic HBV infection, LC and HCC.
CaMKIIδ Splice Variants in the Healthy and Diseased Heart
Authors: Duran Javier , Nickel Lennart , Estrada Manuel , Backs Johannes , van den Hoogenhof Maarten M. G.
Published: March 2021

RNA splicing has been recognized in recent years as a pivotal player in heart development and disease. The Ca2+/calmodulin dependent protein kinase II delta (CaMKIIδ) is a multifunctional Ser/Thr kinase family and generates at least 11 different splice variants through alternative splicing. This enzyme, which belongs to the CaMKII family, is the predominant family member in the heart and functions as a messenger toward adaptive or detrimental signaling in cardiomyocytes. Classically, the nuclear CaMKIIδB and cytoplasmic CaMKIIδC splice variants are described as mediators of arrhythmias, contractile function, Ca2+ handling, and gene transcription. Recent findings also put CaMKIIδA and CaMKIIδ9 as cardinal players in the global CaMKII response in the heart. In this review, we discuss and summarize the new insights into CaMKIIδ splice variants and their (proposed) functions, as well as CaMKII-engineered mouse phenotypes and cardiac dysfunction related to CaMKIIδ missplicing. We also discuss RNA splicing factors affecting CaMKII splicing. Finally, we discuss the translational perspective derived from these insights and future directions on CaMKIIδ splicing research in the healthy and diseased heart.
CXCL11 Correlates With Antitumor Immunity and an Improved Prognosis in Colon Cancer
Authors: Cao Yingying , Jiao Nanlin , Sun Tiantian , Ma Yanru , Zhang Xinyu , Chen Haoyan , Hong Jie , Zhang Youwei
Published: March 2021

The chemokine ligand C-X-C motif chemokine ligand 11 (CXCL11) is involved in the progression of various cancers, but its biological roles in colorectal cancer (CRC) remain confused. Therefore, the prognostic value and underlying mechanism of CXCL11 in CRC were preliminarily evaluated. Three independent datasets were used for mRNA-related analysis: one dataset from the Cancer Genome Atlas (TCGA, n = 451) and two single-cell RNA sequencing (scRNA-seq) datasets from Gene Expression Omnibus (GEO): GSE146771 and GSE132465. In addition, a colon adenocarcinoma (COAD) patient cohort (the Yijishan Hospital cohort, YJSHC, n = 108) was utilized for analysis of cell infiltration by immunohistochemistry. We determined the distribution of CXCL11 in tumor tissue across all TCGA cancers and found that CXCL11 expression was significantly upregulated in both COAD and rectal adenocarcinoma (READ). However, the upregulation of CXCL11 mRNA was associated with a better prognosis in COAD, but not in READ. Within the YJSHC, the patients with a high abundance of intratumoral CXCL11+ cells had prolonged survival (p = 0.001). Furthermore, we found that the high CXCL11 expression group had a higher proportion of antitumor immune cells, and a lower proportion of protumor immune cells. Additionally, we discovered the changes of gene expression and enriched immune pathway network mediated by CXCL11. Interestingly, both cytotoxic genes (IFNG, GZMA, GZMB, GZMK, GZMM, and PRF1) and immunosuppressive molecules, including PD-L1, were positively correlated with CXCL11 expression. CXCL11, which promoted antitumor immunity to benefit survival, was identified as an independent prognostic biomarker in patients with COAD.
Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective
Authors: Chen Danze , Hao Shijia , Xu Jianzhen
Published: March 2021

Background

Increasing evidence indicates an association between the incidence of Alzheimer’s disease (AD) and cancer development. Despite advances being made by comparisons from epidemiological studies, common pathways and molecular mechanisms, little is known about the identities of the circular RNAs (circRNAs) involved in the development and progression of these two pathologies and their possible correlations. The aim of this study was to explore the circRNA relationship between AD and cancer.

Materials and Methods

In this investigation, circRNAs that were significantly dysregulated in AD or associated with AD diagnosis, clinical dementia severity, and neuropathological severity, were examined in a large panel of 28 cancer types. On the basis of shared abnormal circRNAs in AD and cancers, we constructed a circRNA-micro RNA (miRNA)-messenger RNA (mRNA) network by leveraging experimentally identified miRNA-circRNA and miRNA-mRNA interactions from crosslinking-immunoprecipitation sequencing data.

Results

An inverse correlation of expression pattern was found in acute myeloid leukemia, juvenile myelomonocytic leukemia, renal cell carcinoma, and myelofibrosis. CircRNAs associated with AD diagnosis and clinical severity demonstrated negative correlation in more cancer types. Notably, differentially expressed candidate circRNAs in temporal lobe epilepsy were not associated with any cancers. Gene Ontology and KEGG pathway analysis suggested the circRNA-regulated genes are significantly associated with interleukin-12-mediated signaling and viral response. CircPICALM, circRTN4 and circMAN2A1 are the hub nodes in the circRNA-miRNA-target network.

Conclusion

Our results indicated the relevance of inflammation signaling as a common pathogenesis shared by cancer and AD and provided novel insight for therapeutics targeting circRNAs.
Structural Proteomics Methods to Interrogate the Conformations and Dynamics of Intrinsically Disordered Proteins
Authors: Beveridge Rebecca , Calabrese Antonio N.
Published: March 2021

Intrinsically disordered proteins (IDPs) and regions of intrinsic disorder (IDRs) are abundant in proteomes and are essential for many biological processes. Thus, they are often implicated in disease mechanisms, including neurodegeneration and cancer. The flexible nature of IDPs and IDRs provides many advantages, including (but not limited to) overcoming steric restrictions in binding, facilitating posttranslational modifications, and achieving high binding specificity with low affinity. IDPs adopt a heterogeneous structural ensemble, in contrast to typical folded proteins, making it challenging to interrogate their structure using conventional tools. Structural mass spectrometry (MS) methods are playing an increasingly important role in characterizing the structure and function of IDPs and IDRs, enabled by advances in the design of instrumentation and the development of new workflows, including in native MS, ion mobility MS, top-down MS, hydrogen-deuterium exchange MS, crosslinking MS, and covalent labeling. Here, we describe the advantages of these methods that make them ideal to study IDPs and highlight recent applications where these tools have underpinned new insights into IDP structure and function that would be difficult to elucidate using other methods.
Photodynamic Antimicrobial Action of Asymmetrical Porphyrins Functionalized Silver-Detonation Nanodiamonds Nanoplatforms for the Suppression of Staphylococcus aureus Planktonic Cells and Biofilms
Authors: Openda Yolande I. , Ngoy Bokolombe P. , Nyokong Tebello
Published: March 2021

New asymmetrical porphyrin derivatives containing a p-hydroxyphenyl moiety and p-acetylphenyl moieties along with their functionalized silver-detonation nanodiamonds nanohybrids were characterized and their photophysicochemical properties were established. The study provides evidence that the metalated porphyrin derivatives were red-shifted in absorption wavelength and possessed high singlet oxygen quantum yield comparative to the unmetalated core, thus making them suitable agents for photodynamic antimicrobial chemotherapy. As a result of conjugation to detonation nanodiamonds and silver nanoparticles, these compounds proved to be more effective as they exhibited stronger antibacterial and anti-biofilm activities on the multi-drug resistant S. aureus strain due to synergetic effect, compared to Ps alone. This suggests that the newly prepared nanohybrids could be used as a potential antimicrobial agent in the treatment of biofilms caused by S. aureus strain.
Application of Metagenomic Next-Generation Sequencing in the Diagnosis of Pulmonary Infectious Pathogens From Bronchoalveolar Lavage Samples
Authors: Chen Yuqian , Feng Wei , Ye Kai , Guo Li , Xia Han , Guan Yuanlin , Chai Limin , Shi Wenhua , Zhai Cui , Wang Jian , Yan Xin , Wang Qingting , Zhang Qianqian , Li Cong , Liu Pengtao , Li Manxiang
Published: March 2021

Background

Metagenomic next-generation sequencing (mNGS) is a powerful method for pathogen detection. In this study, we assessed the value of mNGS for bronchoalveolar lavage (BAL) samples in the diagnosis of pulmonary infections.

Methods

From February 2018 to April 2019, BAL samples were collected from 235 patients with suspected pulmonary infections. mNGS and microbial culture were performed to evaluate the effectiveness of mNGS in pulmonary infection diagnosis.

Results

We employed mNGS to evaluate the alpha diversity, results suggesting that patients with confirmed pathogens had a lower microbial diversity index compared to that of patients with uncertain pathogens. For the patients admitted to the respiratory intensive care unit (RICU) or on a ventilator, they experienced a lower diversity index than that of the patients in the general ward or not on a ventilator. In addition, mNGS of BAL had a diagnostic sensitivity of 88.89% and a specificity of 14.86% in pulmonary infection, with 21.16% positive predictive value (PPV) and 83.87% negative predictive value (NPV). When rare pathogens were excluded, the sensitivity of mNGS decreased to 73.33%, and the specificity increased to 41.71%. For patients in the simple pulmonary infection group and the immunocompromised group, the main infection types were bacterial infection (58.33%) and mixed-infection (43.18%). Furthermore, mNGS had an advantage over culture in describing polymicrobial ecosystem, demonstrating the microbial distribution and the dominant strains of the respiratory tract in patients with different underlying diseases.

Conclusions

The study indicated that mNGS of BAL samples could provide more accurate diagnostic information in pulmonary infections and demonstrate the changes of respiratory microbiome in different underlying diseases. This method might play an important role in the clinical use of antimicrobial agents in the future.
SARS-CoV-2-Indigenous Microbiota Nexus: Does Gut Microbiota Contribute to Inflammation and Disease Severity in COVID-19?
Authors: Chattopadhyay Indranil , Shankar Esaki M.
Published: March 2021

Gut microbiome alterations may play a paramount role in determining the clinical outcome of clinical COVID-19 with underlying comorbid conditions like T2D, cardiovascular disorders, obesity, etc. Research is warranted to manipulate the profile of gut microbiota in COVID-19 by employing combinatorial approaches such as the use of prebiotics, probiotics and symbiotics. Prediction of gut microbiome alterations in SARS-CoV-2 infection may likely permit the development of effective therapeutic strategies. Novel and targeted interventions by manipulating gut microbiota indeed represent a promising therapeutic approach against COVID-19 immunopathogenesis and associated co-morbidities. The impact of SARS-CoV-2 on host innate immune responses associated with gut microbiome profiling is likely to contribute to the development of key strategies for application and has seldom been attempted, especially in the context of symptomatic as well as asymptomatic COVID-19 disease.
Drug Repurposing of the Alcohol Abuse Medication Disulfiram as an Anti-Parasitic Agent
Authors: Shirley Debbie-Ann , Sharma Ishrya , Warren Cirle A. , Moonah Shannon
Published: March 2021

Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic treatment is essential for managing patients infected with these parasites since control is otherwise challenging and there are no vaccines available for prevention. However, new antimicrobial therapies are urgently needed as significant problems exist with current treatments such as drug resistance, limited options, poor efficacy, as well as toxicity. This situation is made worse by the challenges of drug discovery and development which is costly especially for non-profitable infectious diseases, time-consuming, and risky with a high failure rate. Drug repurposing which involves finding new use for existing drugs may help to more rapidly identify therapeutic candidates while drastically cutting costs of drug research and development. In this perspective article, we discuss the importance of drug repurposing, review disulfiram pharmacology, and highlight emerging data that supports repurposing disulfiram as an anti-parasitic, exemplified by the major diarrhea-causing parasiteEntamoeba histolytica.
Whipworm-Associated Intestinal Microbiome Members Consistent Across Both Human and Mouse Hosts
Authors: Rosa Bruce A. , Snowden Caroline , Martin John , Fischer Kerstin , Kupritz Jonah , Beshah Ethiopia , Supali Taniawati , Gankpala Lincoln , Fischer Peter U. , Urban Joseph F. , Mitreva Makedonka
Published: March 2021

The human whipworm Trichuris trichiura infects 289 million people worldwide, resulting in substantial morbidity. Whipworm infections are difficult to treat due to low cure rates and high reinfection rates. Interactions between whipworm and its host’s intestinal microbiome present a potential novel target for infection control or prevention but are very complicated and are identified using inconsistent methodology and sample types across the literature, limiting their potential usefulness. Here, we used a combined 16S rRNA gene OTU analysis approach (QIIME2) for samples from humans and mice infected with whipworm (T. trichiura and T. muris, respectively) to identify for the first time, bacterial taxa that were consistently associated with whipworm infection spanning host species and infection status using four independent comparisons (baseline infected vs uninfected and before vs after deworming for both humans and mice). Using these four comparisons, we identified significant positive associations for seven taxa including Escherichia, which has been identified to induce whipworm egg hatching, and Bacteroides, which has previously been identified as a major component of the whipworm internal microbiome. We additionally identified significant negative associations for five taxa including four members of the order Clostridiales, two from the family Lachnospiraceae, including Blautia which was previously identified as positively associated with whipworm in independent human and mouse studies. Using this approach, bacterial taxa of interest for future association and mechanistic studies were identified, and several were validated by RT-qPCR. We demonstrate the applicability of a mouse animal model for comparison to human whipworm infections with respect to whipworm-induced intestinal microbiome disruption and subsequent restoration following deworming. Overall, the novel cross-species analysis approach utilized here provides a valuable research tool for studies of the interaction between whipworm infection and the host intestinal microbiome.
BECCS and DACCS as Negative Emission Providers in an Intermittent Electricity System: Why Levelized Cost of Carbon May Be a Misleading Measure for Policy Decisions
Authors: Lehtveer Mariliis , Emanuelsson Anna
Published: March 2021

Carbon dioxide removal (CDR) from the atmosphere is likely to be needed to limit global warming to 1.5 or 2°C and thereby for meeting the Paris Agreement. There is a debate which methods are most suitable and cost-effective for this goal and thus deeper understanding of system effects related to CDR are needed for effective governance of these technologies. Bio-Energy with Carbon Capture and Storage (BECCS) and Direct Air Carbon Capture and Storage (DACCS) are two CDR methods, that have a direct relation to the electricity system—BECCS via producing it and DACCS via consuming. In this work, we investigate how BECCS and DACCS interact with an intermittent electricity system to achieve net negative emissions in the sector using an energy system model and two regions with different wind and solar resource conditions. The analysis shows that DACCS has a higher levelized cost of carbon (LCOC) than BECCS, implying that it is less costly to capture CO2 using BECCS under the assumptions made in this study. However, due to a high levelized cost of electricity (LCOE) produced by BECCS, the total system cost is lower using DACCS as negative emission provider as it is more flexible and enables cheaper electricity production from wind and solar PV. We also find that the replacement effect outweighs the flexibility effect. Since variations in solar-based systems are more regular and shorter (daily cycles), one could assume that DACCS is better suited for such systems, whereas our results point in the opposite direction showing that DACCS is more competitive in the wind-based systems. The result is sensitive to the price of biomass and to the amount of negative emissions required from the electricity sector. Our results show that the use of the LCOC as often presented in the literature as a main indicator for choosing between different CDR options might be misleading and that broader system effects need to be considered for well-grounded decisions.
Case Report: Pheochromocytoma in a 59-Year-Old Woman Presenting With Hypotension
Authors: Wu Hao-Yu , Gao Tian-Jiao , Cao Yi-Wei , Liang Lei
Published: March 2021

Background: Pheochromocytoma patients who present with shock are extremely rare. Here, we report a patient who presented with shock and was diagnosed with pheochromocytoma.

Case Summary: A 59-year-old woman with a history of hypertension without any treatment for 5 years presented with chest tightness. Vital signs on arrival indicated blood pressure of 78/50 mmHg. Twelve-lead electrocardiogram indicated ST-segment depression in leads II, III, aVF, and V3–V6 and QT prolongation. Coronary angiogram revealed no evidence of coronary artery disease. Contrast-enhanced computed tomography demonstrated an inhomogeneous right adrenal mass (2.5 × 3.0 cm). Her 24-h urinary norepinephrine and catecholamine levels were elevated. The patient underwent laparoscopic right adrenalectomy. Histopathology confirmed adrenal pheochromocytoma with residual necrosis. The patient was diagnosed with pheochromocytoma. During the 2-year follow-up, the patient was asymptomatic, and her blood pressure remained normal without medication. ECG showed that the ST-segment depression in leads II, III, aVF, and V3–V6 and the QT prolongation had disappeared. The patient showed no signs of recurrence, with normal urine norepinephrine and catecholamine levels.

Conclusion: Patients with pheochromocytoma can present with hypotension or even shock. Clinicians should suspect pheochromocytoma when a patient with a history of hypertension has sudden hypotension or even shock.
On the Source Parameters and Genesis of the 2017, Mw 4 Montesano Earthquake in the Outer Border of the Val d’Agri Oilfield (Italy)
Authors: López-Comino José Ángel , Braun Thomas , Dahm Torsten , Cesca Simone , Danesi Stefania
Published: March 2021

On October 27, 2017, an Mw4 earthquake occurred close to the municipality of Montesano sulla Marcellana, less than 10 km external to the concession of the largest European onshore hydrocarbon reservoir—the Val d’Agri oilfield (Southern Italy). Being a weak event located outside the extended monitoring domain of the industrial concession, the relevance of this earthquake and the possible links with the hydrocarbon exploitation were not extensively discussed. Actually, the analysis of shallow seismic events close to subsurface exploitation domains plays a significant role in the definition of key parameters in order to discriminate between natural, triggered, and induced seismicity, especially in tectonically active regions. The study of weak-to-moderate earthquakes can improve the characterization of the potentially destructive seismic hazard of this particular area, already struck by M > 6.5 episodes in the past. In this work, we analyze the source parameters of this Mw4 earthquake by applying advanced seismological techniques to estimate the uncertainties derived from the moment tensor inversion and identify plausible directivity effects. The moment tensor is dominated by a NW–SE oriented normal faulting with a centroid depth of 14 km. A single ML2.1 aftershock was recorded and used as the empirical Green’s function to calculate the apparent source time function for the mainshock. Apparent durations (in the range 0.11–0.21 s, obtained from S-waves) define an azimuthal pattern, which reveals an asymmetric bilateral rupture with 70% of the rupture propagation in the N310°W direction, suggesting a rupture plane dipping to the SW. Our results tally with the activation of a deeper fault segment associated with the Eastern Agri Fault System close to the basement as the origin of the Montesano earthquake. Finally, the Coulomb stress rate induced by depletion of the oilfield is calculated to quantify the trigger potential estimated for the Montesano earthquake yielding relatively low probabilities below 10%. Our analyses point toward the conclusion that the Mw4 event was more likely due to the local natural tectonic stress, rather than induced or triggered by the long-term hydrocarbon extraction in the Val d’Agri oilfield.
Alpine Newts (Ichthyosaura alpestris) Avoid Habitats Previously Used by Parasite-Exposed Conspecifics
Authors: Daversa David R. , Manica Andrea , Bintanel Cenis Héctor , Lopez Pilar , Garner Trenton W. J. , Bosch Jaime
Published: March 2021

Many organisms avoid habitats posing risks of parasitism. Parasites are not generally conspicuous, however, which raises the question of what cues individuals use to detect parasitism risk. Here, we provide evidence in alpine newts (Ichthyosaura alpestris) that non-visual cues from parasite-exposed conspecifics inform habitat avoidance. Alpine newts breed in aquatic habitats and occasionally move among adjacent terrestrial habitat during breeding seasons. We completed experiments with newts whereby individuals had access to both habitats, and the aquatic habitats varied in prior occupancy by conspecifics with different histories of exposure to the parasitic skin fungus,Batrachochytrium dendrobatidis(Bd). Continuous filming of newt activity for 2 days provided little evidence that prior use of aquatic habitats by conspecifics, regardless of theirBdexposure history, immediately influenced newt habitat use. However, newts that encountered aquatic habitats used specifically byBd-exposed conspecifics on day 1 spent less time aquatic on day 2, whereas other newts did not alter habitat use. Responses could have been elicited by cues generated byBdstages on the conspecifics or, perhaps more likely, cues emitted by the conspecifics themselves. In either case, these observations suggest that newts use non-visual cues sourced from exposed conspecifics to detectBdrisk and that those cues cause newts to avoid aquatic habitats.Bdmay therefore influence host behavior in early phases of interactions, and possibly before any contact with infectious stages is made, creating potential for non-consumptive effects.
Soluble Sema4D in Plasma of Head and Neck Squamous Cell Carcinoma Patients Is Associated With Underlying Non-Inflamed Tumor Profile
Authors: Younis Rania H. , Ghita Ioana , Elnaggar Manar , Chaisuparat Risa , Theofilou Vasileios Ionas , Dyalram Donita , Ord Robert A. , Davila Eduardo , Tallon Luke J. , Papadimitriou John C. , Webb Tonya J. , Bentzen Søren M. , Lubek Joshua E.
Published: March 2021

Semaphorin 4D (Sema4D) is a glycoprotein that is expressed by several tumors and immune cells. It can function as a membrane bound protein or as a cleaved soluble protein (sSema4D). We sought to investigate the translational potential of plasma sSema4D as an immune marker in plasma of patients with head and neck squamous cell carcinoma (HNSCC). Paired peripheral blood and tumor tissue samples of 104 patients with HNSCC were collected at the same time point to allow for real time analysis. Scoring of the histological inflammatory subtype (HIS) was carried out using Sema4D immunohistochemistry on the tumor tissue. sSema4D was detected in plasma using direct ELISA assay. Defining elevated sSema4D as values above the 95thpercentile in healthy controls, our data showed that sSema4D levels in plasma were elevated in 25.0% (95% CI, 16.7–34.9%) of the patients with HNSCC and showed significant association with HIS immune excluded (HIS-IE) (p = 0.007), Sema4D+vetumor cells (TCs) (p = 0.018) and PD-L1+veimmune cells (ICs) (p = 0.038). A multi-variable logistic regression analysis showed that HIS was significantly (P = 0.004) associated with elevated sSema4D, an association not explained by available patient-level factors. Using the IO-360 nanoString platform, differential gene expression (DGE) analysis of 10 HNSCC tumor tissues showed that patients with high sSema4D in plasma (HsS4D) clustered as IFN-γnegative tumor immune signature and were mostly HIS-IE. The IC type in the HsS4D paired tumor tissue was predominantly myeloid, while the lymphoid compartment was higher in the low sSema4D (LsS4D). The Wnt signaling pathway was upregulated in the HsS4D group. Further analysis using the IO-360, 770 gene set, showed significant non-inflamed profile of the HsS4D tumors compared to the LsS4D. In conclusion, our data reveals an association between sSema4D and the histological inflammatory subtype.
Imiquimod Targets Toxoplasmosis Through Modulating Host Toll-Like Receptor-MyD88 Signaling
Authors: Hamie Maguy , Najm Rania , Deleuze-Masquefa Carine , Bonnet Pierre Antoine , Dubremetz Jean-François , El Sabban Marwan , El Hajj Hiba
Published: March 2021

Toxoplasma gondii is a prevalent parasite of medical and veterinary importance. Tachyzoïtes and bradyzoïtes are responsible for acute and chronic toxoplasmosis (AT and CT), respectively. In immunocompetent hosts, AT evolves into a persistent CT, which can reactivate in immunocompromised patients with dire consequences. Imiquimod is an efficient immunomodulatory drug against certain viral and parasitic infections. In vivo, treatment with Imiquimod, throughout AT, reduces the number of brain cysts while rendering the remaining cysts un-infectious. Post-establishment of CT, Imiquimod significantly reduces the number of brain cysts, leading to a delay or abortion of reactivation. At the molecular level, Imiquimod upregulates the expression of Toll-like receptors 7, 11, and 12, following interconversion from bradyzoïtes to tachyzoïtes. Consequently, MyD88 pathway is activated, resulting in the induction of the immune response to control reactivated Toxoplasma foci. This study positions Imiquimod as a potent drug against toxoplasmosis and elucidates its mechanism of action particularly against chronic toxoplasmosis, which is the most prevalent form of the disease.
Flipside of the Coin: Iron Deficiency and Colorectal Cancer
Authors: Aksan Aysegül , Farrag Karima , Aksan Sami , Schroeder Oliver , Stein Jürgen
Published: March 2021

Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.
Risk of Clinically Relevant Venous Thromboembolism in Critically Ill Patients With COVID-19: A Systematic Review and Meta-Analysis
Authors: Gratz Johannes , Wiegele Marion , Maleczek Mathias , Herkner Harald , Schöchl Herbert , Chwala Eva , Knöbl Paul , Schaden Eva
Published: March 2021

Background: Early during the course of the ongoing COVID-19 pandemic, reports suggested alarmingly high incidences for thromboembolic events in critically ill patients with COVID-19. However, the clinical relevance of these events was not reported in several studies. Additionally, more recent research showed contradictory results and suggested substantially lower rates of venous thromboembolism. Thus, the aim of the present study was to summarize evidence on the incidence of clinically relevant venous thromboembolism (VTE)—defined as VTE excluding isolated subsegmental pulmonary embolism (PE) and distal deep vein thrombosis (DVT)—in adult critically ill patients with COVID-19.

Methods: We performed a systematic review of studies reporting the incidence of clinically relevant PE and/or DVT in critically ill patients with COVID-19. Scientific reports published in the English language between January and October 2020 were included. We conducted a random-effects model meta-analysis to calculate incidence estimates of clinically relevant VTE and bleeding events. We also performed exploratory meta-regression and subgroup analyses of different diagnostic approaches and additional factors that possibly influenced the incidence of these outcomes.

Results: Fifty-four articles (5,400 patients) fulfilled the predefined inclusion criteria, of which 41 had a high risk of bias. The majority of included patients were male, > 60 years, and overweight. Twenty-one studies reported the use of prophylactic doses of heparin. Pooled incidences for clinically relevant PE were estimated at 8% (95% CI, 4–11%), for proximal DVT at 14% (95% CI, 9–20%), and—after exclusion of studies with a high risk of bias—for the composite outcome of VTE at 18% (95% CI, 13–24%). Clinically relevant bleeding occurred at a rate of 6% (95% CI, 2–9%).

Conclusions: We summarized currently available data on the rate of clinically relevant VTE in critically ill patients with COVID-19. Pooled incidence estimates were lower than those reported by previous review articles. In the absence of evidence-based anticoagulation guidelines for critically ill patients with COVID-19, the results of our study provide clinically important information for an individual risk-benefit assessment in this context.

Registration: The study protocol was prospectively registered in PROSPERO on June 22, 2020 (CRD42020193353; https://www.crd.york.ac.uk/prospero).
Taxonomic and Enzymatic Characterization of Flocculibacter collagenilyticus gen. nov., sp. nov., a Novel Gammaproteobacterium With High Collagenase Production
Authors: Li Jian , Cheng Jun-Hui , Teng Zhao-Jie , Sun Zhong-Zhi , He Xiao-Yan , Wang Peng , Shi Mei , Song Xiao-Yan , Chen Xiu-Lan , Zhang Yu-Zhong , Tian Xinmin , Zhang Xi-Ying
Published: March 2021

Collagens from marine animals are an important component of marine organic nitrogen. Collagenase-producing bacteria and their collagenases play important roles in collagen degradation and organic nitrogen recycling in the ocean. However, only a few collagenase-producing marine bacteria have been so far discovered. Here, we reported the isolation and characterization of a collagenase-secreting bacterium, designated strain SM1988T, isolated from a green algaCodium fragilesample. Strain SM1988Tis a Gram-negative, aerobic, oxidase-, and catalase-positive, unipolar flagellated, and rod-shaped bacterium capable of hydrolyzing casein, gelatin and collagens. Phylogenetic analysis revealed that strain SM1988Tformed a distinct phylogenetic lineage along with known genera within the familyPseudoalteromonadaceae, with 16S rRNA gene sequence similarity being less than 93.3% to all known species in the family. Based on the phylogenetic, genomic, chemotaxonomic and phenotypic data, strain SM1988Twas considered to represent a novel species in a novel genus in the familyPseudoalteromonadaceae, for which the nameFlocculibacter collagenilyticusgen. nov., sp. nov. is proposed, with the type strain being SM1988T(= MCCC 1K04279T= KCTC 72761T). Strain SM1988Tshowed a high production of extracellular collagenases, which had high activity against both bovine collagen and codfish collagen. Biochemical tests combined with genome and secretome analyses indicated that the collagenases secreted by strain SM1988Tare serine proteases from the MEROPS S8 family. These data suggest that strain SM1988Tacts as an important player in marine collagen degradation and recycling and may have a promising potential in collagen resource utilization.
Deep Brain Stimulation for Alzheimer's Disease: Stimulation Parameters and Potential Mechanisms of Action
Authors: Luo Yinpei , Sun Yuwei , Tian Xuelong , Zheng Xiaolin , Wang Xing , Li Weina , Wu Xiaoying , Shu Bin , Hou Wensheng
Published: March 2021

Deep brain stimulation (DBS) is a neurosurgical technique that regulates neuron activity by using internal pulse generators to electrodes in specific target areas of the brain. As a blind treatment, DBS is widely used in the field of mental and neurological diseases, although its mechanism of action is still unclear. In the past 10 years, DBS has shown a certain positive effect in animal models and patients with Alzheimer's disease (AD), but there are also different results that may be related to the stimulation parameters of DBS. Based on this, determining the optimal stimulation parameters for DBS in AD and understanding its mechanism of action are essential to promote the clinical application of DBS in AD. This review aims to explore the therapeutic effect of DBS in AD, and to analyze its stimulation parameters and potential mechanism of action. The keywords “Deep brain stimulation” and “Alzheimer's Disease” were used for systematic searches in the literature databases of Web of Science and PubMed (from 1900 to September 29, 2020). All human clinical studies and animal studies were reported in English, including individual case studies and long-term follow-up studies, were included. These studies described the therapeutic effects of DBS in AD. The results included 16 human clinical studies and 14 animal studies, of which 28 studies clearly demonstrated the positive effect of DBS in AD. We analyzed the current stimulation parameters of DBS in AD from stimulation target, stimulation frequency, stimulation start time, stimulation duration, unilateral/bilateral treatment and current intensity, etc., and we also discussed its potential mechanism of action from multiple aspects, including regulating related neural networks, promoting nerve oscillation, reducing β-amyloid and tau levels, reducing neuroinflammation, regulating the cholinergic system, inducing the synthesis of nerve growth factor.
Mosquito Host Seeking in 3D Using a Versatile Climate-Controlled Wind Tunnel System
Authors: Hinze Annika , Lantz Jörgen , Hill Sharon R. , Ignell Rickard
Published: March 2021

Future anthropogenic climate change is predicted to impact sensory-driven behaviors. Building on recent improvements in computational power and tracking technology, we have developed a versatile climate-controlled wind tunnel system, in which to study the effect of climate parameters, including temperature, precipitation, and elevated greenhouse gas levels, on odor-mediated behaviors in insects. To establish a baseline for future studies, we here analyzed the host-seeking behavior of the major malaria vector mosquito, Anopheles gambiae sensu strico, to human odor and carbon dioxide (CO2), under tightly controlled climatic conditions, and isolated from potential background contamination by the presence of an experimenter. When presented with a combination of human foot odor and CO2 (case study I), mosquitoes engaged in faster crosswind flight, spent more time in the filamentous odor plume and targeted the odor source more successfully. In contrast, female An. gambiae s. s. presented with different concentrations of CO2 alone, did not display host-seeking behavior (case study II). These observations support previous findings on the role of human host-associated cues in host seeking and confirm the role of CO2 as a synergist, but not a host-seeking cue on its own. Future studies are aimed at investigating the effect of climate change on odor-mediated behavior in mosquitoes and other insects. Moreover, the system will be used to investigate detection and processing of olfactory information in various behavioral contexts, by providing a fine-scale analysis of flight behavior.
Dissociable Cortical and Subcortical Mechanisms for Mediating the Influences of Visual Cues on Microsaccadic Eye Movements
Authors: Hafed Ziad M. , Yoshida Masatoshi , Tian Xiaoguang , Buonocore Antimo , Malevich Tatiana
Published: March 2021

Visual selection in primates is intricately linked to eye movements, which are generated by a network of cortical and subcortical neural circuits. When visual selection is performed covertly, without foveating eye movements toward the selected targets, a class of fixational eye movements, called microsaccades, is still involved. Microsaccades are small saccades that occur when maintaining precise gaze fixation on a stationary point, and they exhibit robust modulations in peripheral cueing paradigms used to investigate covert visual selection mechanisms. These modulations consist of changes in both microsaccade directions and frequencies after cue onsets. Over the past two decades, the properties and functional implications of these modulations have been heavily studied, revealing a potentially important role for microsaccades in mediating covert visual selection effects. However, the neural mechanisms underlying cueing effects on microsaccades are only beginning to be investigated. Here we review the available causal manipulation evidence for these effects’ cortical and subcortical substrates. In the superior colliculus (SC), activity representing peripheral visual cues strongly influences microsaccade direction, but not frequency, modulations. In the cortical frontal eye fields (FEF), activity only compensates for early reflexive effects of cues on microsaccades. Using evidence from behavior, theoretical modeling, and preliminary lesion data from the primary visual cortex and microstimulation data from the lower brainstem, we argue that the early reflexive microsaccade effects arise subcortically, downstream of the SC. Overall, studying cueing effects on microsaccades in primates represents an important opportunity to link perception, cognition, and action through unaddressed cortical-subcortical neural interactions. These interactions are also likely relevant in other sensory and motor modalities during other active behaviors.
Detection of Wandering Behaviors Using a Body-Worn Inertial Sensor in Patients With Cognitive Impairment: A Feasibility Study
Authors: Kamil Rebecca J. , Bakar Dara , Ehrenburg Matthew , Wei Eric X. , Pletnikova Alexandra , Xiao Grace , Oh Esther S. , Mancini Martina , Agrawal Yuri
Published: March 2021

Patients with Alzheimer's disease (AD) and AD related dementias (ADRD) often experience spatial disorientation that can lead to wandering behavior, characterized by aimless or purposeless movement. Wandering behavior has been associated with falls, caregiver burden, and nursing home placement. Despite the substantial clinical consequences of wandering, there is currently no standardized approach to objectively quantify wandering behavior. In this pilot feasibility study, we used a lightweight inertial sensor to examine mobility characteristics of a small group of 12 older adults with ADRD and mild cognitive impairment in their homes. Specifically, we evaluated their compliance with wearing a sensor for a minimum of 4 days. We also examined the ability of the sensor to measure turning frequency and direction changes, given that frequent turns and direction changes during walking have been observed in patients who wander. We found that all patients were able to wear the sensor yielding quantitative turn data including number of turns over time, mean turn duration, mean peak turn speed, and mean turn angle. We found that wanderers make more frequent, quicker turns compared to non-wanderers, which is consistent with pacing or lapping behavior. This study provides preliminary evidence that continuous monitoring in patients with dementia is feasible using a wearable sensor. More studies are needed to explore if objective measures of turning behaviors collected using inertial sensors can be used to identify wandering behavior.
Intraoperative Characterization of Subthalamic Nucleus-to-Cortex Evoked Potentials in Parkinson’s Disease Deep Brain Stimulation
Authors: Levinson Lila H. , Caldwell David J. , Cronin Jeneva A. , Houston Brady , Perlmutter Steve I. , Weaver Kurt E. , Herron Jeffrey A. , Ojemann Jeffrey G. , Ko Andrew L.
Published: March 2021

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective tool for treating medically refractory Parkinson’s disease (PD), but its neural mechanisms remain debated. Previous work has demonstrated that STN DBS results in evoked potentials (EPs) in the primary motor cortex (M1), suggesting that modulation of cortical physiology may be involved in its therapeutic effects. Due to technical challenges presented by high-amplitude DBS artifacts, these EPs are often measured in response to low-frequency stimulation, which is generally ineffective at PD symptom management. This study aims to characterize STN-to-cortex EPs seen during clinically relevant high-frequency STN DBS for PD. Intraoperatively, we applied STN DBS to 6 PD patients while recording electrocorticography (ECoG) from an electrode strip over the ipsilateral central sulcus. Using recently published techniques, we removed large stimulation artifacts to enable quantification of STN-to-cortex EPs. Two cortical EPs were observed – one synchronized with DBS onset and persisting during ongoing stimulation, and one immediately following DBS offset, here termed the “start” and the “end” EPs respectively. The start EP is, to our knowledge, the first long-latency cortical EP reported during ongoing high-frequency DBS. The start and end EPs differ in magnitude (p < 0.05) and latency (p < 0.001), and the end, but not the start, EP magnitude has a significant relationship (p < 0.001, adjusted for random effects of subject) to ongoing high gamma (80–150 Hz) power during the EP. These contrasts may suggest mechanistic or circuit differences in EP production during the two time periods. This represents a potential framework for relating DBS clinical efficacy to the effects of a variety of stimulation parameters on EPs.
Data Augmentation: Using Channel-Level Recombination to Improve Classification Performance for Motor Imagery EEG
Authors: Pei Yu , Luo Zhiguo , Yan Ye , Yan Huijiong , Jiang Jing , Li Weiguo , Xie Liang , Yin Erwei
Published: March 2021

The quality and quantity of training data are crucial to the performance of a deep-learning-based brain-computer interface (BCI) system. However, it is not practical to record EEG data over several long calibration sessions. A promising time- and cost-efficient solution is artificial data generation or data augmentation (DA). Here, we proposed a DA method for the motor imagery (MI) EEG signal called brain-area-recombination (BAR). For the BAR, each sample was first separated into two ones (named half-sample) by left/right brain channels, and the artificial samples were generated by recombining the half-samples. We then designed two schemas (intra- and adaptive-subject schema) corresponding to the single- and multi-subject scenarios. Extensive experiments using the classifier of EEGnet were conducted on two public datasets under various training set sizes. In both schemas, the BAR method can make the EEGnet have a better performance of classification (p < 0.01). To make a comparative investigation, we selected two common DA methods (noise-added and flipping), and the BAR method beat them (p < 0.05). Further, using the proposed BAR for augmentation, EEGnet achieved up to 8.3% improvement than a typical decoding algorithm CSP-SVM (p < 0.01), note that both the models were trained on the augmented dataset. This study shows that BAR usage can significantly improve the classification ability of deep learning to MI-EEG signals. To a certain extent, it may promote the development of deep learning technology in the field of BCI.