bluuebunny/crossref_metadata_2025 huggingface dataset:
Dauricine Attenuates Spatial Memory Impairment and Alzheimer-Like Pathologies by Enhancing Mitochondrial Function in a Mouse Model of Alzheimer's Disease
Authors: Chen Chongyang , Liu Pan , Wang Jing , Yu Haitao , Zhang Zaijun , Liu Jianjun , Chen Xiao , Zhu Feiqi , Yang Xifei
Published: February 2021

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. No effective therapy is available for this disease. In this study, we investigated the potential therapeutic effects of dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid, on AD, and found that DAU administration significantly improved cognitive impairments in 3xTg-AD mice by decreasing Aβ plaques and hyperphosphorylated tau and increasing the hippocampal ATP level. Proteomic and western blot analyses revealed that DAU treatment mainly modified the expression of proteins involved in mitochondrial energy metabolism, such as Aco2, Ndufs1, Cox5a, and SDHB, and that of synapse-related proteins such as Syn1 and Syn2. Pathway analysis revealed that DAU modulated the tricarboxylic acid cycle, synaptic vesicle cycle, glycolysis, and gluconeogenesis in 3xTg-AD mice. Our study suggests that DAU may be a potential drug for the treatment of AD.
Dietary Vitamin A Impacts Refractory Telogen
Authors: Suo Liye , VanBuren Christine , Hovland Eylul Damla , Kedishvili Natalia Y. , Sundberg John P. , Everts Helen B.
Published: February 2021

Hair follicles cycle through periods of growth (anagen), regression (catagen), rest (telogen), and release (exogen). Telogen is further divided into refractory and competent telogen based on expression of bone morphogenetic protein 4 (BMP4) and wingless-related MMTV integration site 7A (WNT7A). During refractory telogen hair follicle stem cells (HFSC) are inhibited. Retinoic acid synthesis proteins localized to the hair follicle and this localization pattern changed throughout the hair cycle. In addition, excess retinyl esters arrested hair follicles in telogen. The purpose of this study was to further define these hair cycle changes. BMP4 and WNT7A expression was also used to distinguish refractory from competent telogen in C57BL/6J mice fed different levels of retinyl esters from two previous studies. These two studies produced opposite results; and differed in the amount of retinyl esters the dams consumed and the age of the mice when the different diet began. There were a greater percentage of hair follicles in refractory telogen both when mice were bred on an unpurified diet containing copious levels of retinyl esters (study 1) and consumed excess levels of retinyl esters starting at 12 weeks of age, as well as when mice were bred on a purified diet containing adequate levels of retinyl esters (study 2) and remained on this diet at 6 weeks of age. WNT7A expression was consistent with these results. Next, the localization of vitamin A metabolism proteins in the two stages of telogen was examined. Keratin 6 (KRT6) and cellular retinoic acid binding protein 2 (CRABP2) localized almost exclusively to refractory telogen hair follicles in study 1. However, KRT6 and CRABP2 localized to both competent and refractory telogen hair follicles in mice fed adequate and high levels of retinyl esters in study 2. In mice bred and fed an unpurified diet retinol dehydrogenase SDR16C5, retinal dehydrogenase 2 (ALDH1A2), and cytochrome p450 26B1 (CYP26B1), enzymes and proteins involved in RA metabolism, localized to BMP4 positive refractory telogen hair follicles. This suggests that vitamin A may contribute to the inhibition of HFSC during refractory telogen in a dose dependent manner.
Profiling of RNA N6-Methyladenosine Methylation Reveals the Critical Role of m6A in Chicken Adipose Deposition
Authors: Cheng Bohan , Leng Li , Li Ziwei , Wang Weijia , Jing Yang , Li Yudong , Wang Ning , Li Hui , Wang Shouzhi
Published: February 2021

One of the main objectives of broiler breeding is to prevent excessive abdominal adipose deposition. The role of RNA modification in adipose deposition is not clear. This study was aimed to map m6A modification landscape in chicken adipose tissue. MeRIP-seq was performed to compare the differences in m6A methylation pattern between fat and lean broilers. We found that start codons, stop codons, coding regions, and 3′-untranslated regions were generally enriched for m6A peaks. The high m6A methylated genes (fat birds vs. lean birds) were primarily associated with fatty acid biosynthesis and fatty acid metabolism, while the low m6A methylated genes were mainly involved in processes associated with development. Furthermore, we found that the mRNA levels of many genes may be regulated by m6A modification. This is the first comprehensive characterization of m6A patterns in the chicken adipose transcriptome, and provides a basis for studying the role of m6A modification in fat deposition.
Molecular and Clinicopathological Characterization of a Prognostic Immune Gene Signature Associated With MGMT Methylation in Glioblastoma
Authors: Zhao Liang , Zhang Jiayue , Xuan Shurui , Liu Zhiyuan , Wang Yu , Zhao Peng
Published: February 2021

Background: O6-methylguanine-DNA methyltransferase (MGMT) methylation status affects tumor chemo-resistance and the prognosis of glioblastoma (GBM) patients. We aimed to investigate the role of MGMT methylation in the regulation of GBM immunophenotype and discover an effective biomarker to improve prognosis prediction of GBM patients.

Methods: A total of 769 GBM patients with clinical information from five independent cohorts were enrolled in the present study. Samples from the Cancer Genome Atlas (TCGA) dataset were used as the training set, whereas transcriptome data from the Chinese Glioma Genome Atlas (CGGA) RNA-seq, CGGA microarray, GSE16011, and the Repository for Molecular Brain Neoplasia (REMBRANDT) cohort were used for validation. A series of bioinformatics approaches were carried out to construct a prognostic signature based on immune-related genes, which were tightly related to the MGMT methylation status. In silico analyses were performed to investigate the influence of the signature on immunosuppression and remodeling of the tumor microenvironment. Then, the utility of this immune gene signature was analyzed by the development and evaluation of a nomogram. In vitro experiments were further used to verify the immunologic function of the genes in the signature.

Results: We found that MGMT unmethylation was closely associated with immune-related biological processes in GBM. Sixty-five immune genes were more highly expressed in the MGMT unmethylated than the MGMT-methylated group. An immune gene-based risk model was further established to divide patients into high and low-risk groups, and the prognostic value of this signature was validated in several GBM cohorts. Functional analyses manifested a universal up-regulation of immune-related pathways in the high-risk group. Furthermore, the risk score was highly correlated to the immune cell infiltration, immunosuppression, inflammatory activities, as well as the expression levels of immune checkpoints. A nomogram was developed for clinical application. Knockdown of the five genes in the signature remodeled the immunosuppressive microenvironment by restraining M2 macrophage polarization and suppressing immunosuppressive cytokines production.

Conclusions:MGMT methylation is strongly related to the immune responses in GBM. The immune gene-based signature we identified may have potential implications in predicting the prognosis of GBM patients and mechanisms underlying the role of MGMT methylation.
Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer
Authors: Rodriguez-Casanova Aitor , Costa-Fraga Nicolás , Bao-Caamano Aida , López-López Rafael , Muinelo-Romay Laura , Diaz-Lagares Angel
Published: February 2021

Colorectal cancer (CRC) is one of the most common malignancies and is a major cause of cancer-related deaths worldwide. Thus, there is a clinical need to improve early detection of CRC and personalize therapy for patients with this disease. In the era of precision oncology, liquid biopsy has emerged as a major approach to characterize the circulating tumor elements present in body fluids, including cell-free DNA and RNA, circulating tumor cells, and extracellular vesicles. This non-invasive tool has allowed the identification of relevant molecular alterations in CRC patients, including some indicating the disruption of epigenetic mechanisms. Epigenetic alterations found in solid and liquid biopsies have shown great utility as biomarkers for early detection, prognosis, monitoring, and evaluation of therapeutic response in CRC patients. Here, we summarize current knowledge of the most relevant epigenetic mechanisms associated with cancer development and progression, and the implications of their deregulation in cancer cells and liquid biopsy of CRC patients. In particular, we describe the methodologies used to analyze these epigenetic alterations in circulating tumor material, and we focus on the clinical utility of epigenetic marks in liquid biopsy as tumor biomarkers for CRC patients. We also discuss the great challenges and emerging opportunities of this field for the diagnosis and personalized management of CRC patients.
Different Phenotypes in Pseudodominant Inherited Retinal Dystrophies
Authors: Habibi Imen , Falfoul Yosra , Tran Hoai Viet , El Matri Khaled , Chebil Ahmed , El Matri Leila , Schorderet Daniel F.
Published: February 2021

Retinal dystrophies (RD) are a group of Mendelian disorders caused by rare genetic variations leading to blindness. A pathogenic variant may manifest in both dominant or recessive mode and clinical and genetic heterogeneity makes it difficult to establish a precise diagnosis. In this study, families with autosomal dominant RD in successive generations were identified, and we aimed to determine the disease's molecular origin in these consanguineous families. Whole exome sequencing was performed in the index patient of each family. The aim was to determine whether these cases truly represented examples of dominantly inherited RD, or whether another mode of inheritance might be applicable. Six potentially pathogenic variants in four genes were identified in four families. In index patient with enhanced S-cone syndrome in F1, we identified a new digenetic combination: a heterozygous variant p.[G51A];[=] in RHO and a homozygous pathogenic variant p.[R311Q];[R311Q] in NR2E3. Helicoid subretinal fibrosis associated with recessive NR2E3 variant p.[R311Q];[R311Q] was identified in F2. A new frameshift variant c.[105delG];[105delG] in RDH12 was found in F3 with cone-rod dystrophy. In F4, the compound heterozygous variants p.[R964*];[W758*] were observed in IMPG2 with a retinitis pigmentosa (RP) phenotype. We showed that both affected parents and the offspring, were homozygous for the same variants in all four families. Our results provide evidence that in consanguineous families, autosomal recessive can be transmitted as pseudodominant inheritance in RD patients, and further extend our knowledge of pathogenic variants in RD genes.
FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity
Authors: Kapetanou Marianna , Nespital Tobias , Tain Luke S. , Pahl Andre , Partridge Linda , Gonos Efstathios S.
Published: February 2021

Proteostasis collapses during aging resulting, among other things, in the accumulation of damaged and aggregated proteins. The proteasome is the main cellular proteolytic system and plays a fundamental role in the maintenance of protein homeostasis. Our previous work has demonstrated that senescence and aging are related to a decline in proteasome content and activities, while its activation extends lifespan in vitro and in vivo in various species. However, the mechanisms underlying this age-related decline of proteasome function and the down-regulation in expression of its subunits remain largely unclear. Here, we demonstrate that the Forkhead box-O1 (FoxO1) transcription factor directly regulates the expression of a 20S proteasome catalytic subunit and, hence, proteasome activity. Specifically, we demonstrate that knockout of FoxO1, but not of FoxO3, in mice severely impairs proteasome activity in several tissues, while depletion of IRS1 enhances proteasome function. Importantly, we show that FoxO1 directly binds on the promoter region of the rate-limiting catalytic β5 proteasome subunit to regulate its expression. In summary, this study reveals the direct role of FoxO factors in the regulation of proteasome function and provides new insight into how FoxOs affect proteostasis and, in turn, longevity.
Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin
Authors: Darkwah Samuel , Park Eun Jeong , Myint Phyoe Kyawe , Ito Atsushi , Appiah Michael G. , Obeng Gideon , Kawamoto Eiji , Shimaoka Motomu
Published: February 2021

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.
Regulation of the Switchable Luminescence of Tridentate Platinum(II) Complexes by Photoisomerization
Authors: Li Yongguang , Fei Yuexuan , Sun Hongcheng , Yu Shuangjiang , Liu Junqiu
Published: February 2021

Organoplatinum (II) complexes are promising candidates for the construction of smart supramolecular materials due to their unique flat structures. This accompanied by intriguing luminescent properties, prompts the molecules to aggregate after external stimuli. Nevertheless, the utilization of photo-responsive subunits to modulate their assemble behaviors and functions are still rarely explored. In this work, azobenzene (azo)-appended tridentate platinum (II) complexes with different linkers have been designed and synthesized. The intermolecular hydrogen bonding, π-π stacking, and metal-metal interactions were finely controlled through the tiny alteration of the linkers, which was found to play a vital role in self-assembly, and photophysical and photoisomerization properties. Some of them exhibited dual emission bands originating from metal-perturbed triplet intraligand (3IL) and metal-metal to ligand charge transfer (3MMLCT) excited states due to the different intermolecular interactions. Based on this, the manipulation of switchable luminescence as well as the controllable morphologies have been realized by photoisomerization.
Nanostructure Determines the Wettability of Gold Surfaces by Ionic Liquid Ultrathin Films
Authors: Borghi Francesca , Mirigliano Matteo , Lenardi Cristina , Milani Paolo , Podestà Alessandro
Published: February 2021

Ionic liquids are employed in energy storage/harvesting devices, in catalysis and biomedical technologies, due to their tunable bulk and interfacial properties. In particular, the wettability and the structuring of the ionic liquids at the interface are of paramount importance for all those applications exploiting ionic liquids tribological properties, their double layer organization at electrified interfaces, and interfacial chemical reactions. Here we report an experimental investigation of the wettability and organization at the interface of an imidazolium-based ionic liquid ([Bmim][NTf2]) and gold surfaces, that are widely used as electrodes in energy devices, electronics, fluidics. In particular, we investigated the role of the nanostructure on the resulting interfacial interactions between [Bmim][NTf2] and atom-assembled or cluster-assembled gold thin films. Our results highlight the presence of the solid-like structured ionic liquid domains extending several tens of nanometres far from the gold interfaces, and characterized by different lateral extension, according to the wettability of the gold nanostructures by the IL liquid-phase.
Antimicrobial Peptides and Cell-Penetrating Peptides for Treating Intracellular Bacterial Infections
Authors: Buccini Danieli F. , Cardoso Marlon H. , Franco Octavio L.
Published: February 2021

Bacterial infections caused by intracellular pathogens are difficult to control. Conventional antibiotic therapies are often ineffective, as high doses are needed to increase the number of antibiotics that will cross the host cell membrane to act on the intracellular bacterium. Moreover, higher doses of antibiotics may lead to elevated severe toxic effects against host cells. In this context, antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) have shown great potential to treat such infections by acting directly on the intracellular pathogenic bacterium or performing the delivery of cargos with antibacterial activities. Therefore, in this mini-review, we cover the main AMPs and CPPs described to date, aiming at intracellular bacterial infection treatment. Moreover, we discuss some of the proposed mechanisms of action for these peptide classes and their conjugation with other antimicrobials.
Rock Physics Based Interpretation of Seismically Derived Elastic Volumes
Authors: Alabbad Abrar , Dvorkin Jack , Altowairqi Yazeed , Duan Zhou F.
Published: February 2021

A rock physics based seismic interpretation workflow has been developed to extract volumetric rock properties from seismically derived P- and S-wave impedances, Ip and Is. This workflow was first tested on a classic rock physics velocity-porosity model. Next, it was applied to two case studies: a carbonate and a clastic oil field. In each case study, we established rock physics models that accurately relate elastic properties to the rock’s volumetric properties, mainly the total porosity, clay content, and pore fluid. To resolve all three volumetric properties from only two inputs, Ip and Is, a site-specific geology driven relation between the pore fluid and porosity was derived as a hydrocarbon identifier. In order to apply this method at the seismic spatial scale, we created a coarse-scale elastic and volumetric variables by using mathematical upscaling at the wells. By using Ip and Is thus upscaled, we arrived at the accurate interpretation of the upscaled porosity, mineralogy, and water saturation both at the wells and in a simulated vertical impedance section generated by interpolation between the wells.
Mapping Complex Systems: Responses to Intimate Partner Violence Against Women in Three Refugee Camps
Authors: Horn Rebecca , Wachter Karin , Friis-Healy Elsa A. , Ngugi Sophia Wanjku , Creighton Joanne , Puffer Eve S.
Published: February 2021

Armed conflict and forced migration are associated with an increase in intimate partner violence (IPV) against women. Yet as risks of IPV intensify, familiar options for seeking help dissipate as families and communities disperse and seek refuge in a foreign country. The reconfiguration of family and community systems, coupled with the presence of local and international humanitarian actors, introduces significant changes to IPV response pathways. Drawing from intensive fieldwork, this article examines response options available to women seeking help for IPV in refugee camps against the backdrop of efforts to localize humanitarian assistance. This study employed a qualitative approach to study responses to IPV in three refugee camps: Ajuong Thok (South Sudan), Dadaab (Kenya), and Domiz (Iraqi Kurdistan). In each location, data collection activities were conducted with women survivors of IPV, members of the general refugee community, refugee leaders, and service providers. The sample included 284 individuals. Employing visual mapping techniques, analysis of data from these varied sources described help seeking and response pathways in the three camps, and the ways in which women engaged with various systems. The analysis revealed distinct pathways for seeking help in the camps, with several similarities across contexts. Women in all three locations often “persevered” in an abusive partnership for extended periods before seeking help. When women did seek help, it was predominantly with family members initially, and then community-based mechanisms. Across camps, participants typically viewed engaging formal IPV responses as a last resort. Differences between camp settings highlighted the importance of understanding complex informal systems, and the availability of organizational responses, which influenced the sequence and speed with which formal systems were engaged. The findings indicate that key factors in bridging formal and community-based systems in responding to IPV in refugee camps include listening to women and understanding their priorities, recognizing the importance of women in camps maintaining life-sustaining connections with their families and communities, engaging communities in transformative change, and shifting power and resources to local women-led organizations.
Neutrophil Extracellular Traps Promote Aberrant Macrophages Activation in Behçet’s Disease
Authors: Li Lu , Yu Xin , Liu Jinjing , Wang Zhimian , Li Chaoran , Shi Jing , Sun Luxi , Liu Yi , Zhang Fengchun , Chen Hua , Zheng Wenjie
Published: February 2021

Neutrophil extracellular traps (NETs) are upregulated and promote thrombosis in Behçet’s disease (BD). However, whether NETs promote autoinflammation in BD remains unclear. This study aimed to investigate the potential role of NETs in promoting macrophage activation in BD. Firstly, we quantified NETs by measuring double-stranded DNA (dsDNA) using PicoGreen and calculating the proportion of NETosis. Then macrophages were stimulated with BD- or healthy controls (HC)-derived NETs, and IL-8 and TNF-α production and IFN-γ+ CD4+ T cells differentiation were measured using ELISA and flow cytometry, respectively. The protein components in NETs were analyzed by western blot. Macrophages were stimulated with Histone H4 neutralized NETs, and IL-8 and TNF-α production were measured using ELISA. The level of 8-hydroxydeoxyguanosine (8-OHdG) DNA in NETs was measured using ELISA. The levels of reactive oxygen species (ROS) in serum and neutrophils were measured using ROS probes by a microplate reader and flow cytometry. We found that circulating NETs and neutrophil-derived NETs were significantly higher in BD than HC. BD NETs stimulated macrophages produced higher levels of IL-8 and TNF-α, and promoted IFN-γ+ CD4+ T cells differentiation. BD NETs were enriched in Histone H4, and neutralizing Histone H4 abrogated the BD NETs-mediated IL-8 production by macrophages, but not TNF-α. Also, BD neutrophils produced more 8-OHdG DNA than HC neutrophils, and the percentage of 8-OHdG DNA in dsDNA from BD neutrophils was also higher than that of HC neutrophils. The ROS levels in serum and neutrophils were both higher in BD than HC. Our findings suggested that excessive BD NETs promoted macrophages activation and facilitated IFN-γ+ CD4+ T cells differentiation. Higher levels of Histone H4 and oxidized DNA in BD NETs might mediate macrophages hyperactivation.
JNK1 Signaling Downstream of the EGFR Pathway Contributes to Aldara®-Induced Skin Inflammation
Authors: Le Aurore , Azouz Abdulkader , Thomas Séverine , Istaces Nicolas , Nguyen Muriel , Goriely Stanislas
Published: February 2021

c-Jun N-terminal protein kinase 1 (JNK1) is involved in multiple biological processes but its implication in inflammatory skin diseases is still poorly defined. Herein, we studied the role of JNK1 in the context of Aldara®-induced skin inflammation. We observed that constitutive ablation of JNK1 reduced Aldara®-induced acanthosis and expression of inflammatory markers. Conditional deletion of JNK1 in myeloid cells led to reduced skin inflammation, a finding that was associated with impaired Aldara®-induced inflammasome activation in vitro. Next, we evaluated the specific role of JNK1 in epidermal cells. We observed reduced Aldara®-induced acanthosis despite similar levels of inflammatory markers. Transcriptomic and epigenomic analysis of keratinocytes revealed the potential involvement of JNK1 in the EGFR signaling pathway. Finally, we show that inhibition of the EGFR pathway reduced Aldara®-induced acanthosis. Taken together, these data indicate that JNK1 plays a dual role in the context of psoriasis by regulating the production of inflammatory cytokines by myeloid cells and the sensitivity of keratinocytes to EGFR ligands. These results suggest that JNK1 could represent a valuable therapeutic target in the context of psoriasis.
Update on Antiviral Strategies Against COVID-19: Unmet Needs and Prospects
Authors: Liu Ching-Hsuan , Lu Cheng-Hua , Wong Shu Hui , Lin Liang-Tzung
Published: February 2021

By December 2020, the COVID-19 pandemic had caused more than 74 million confirmed cases and 1.6 million related deaths around the world. However, only a few drugs have been approved in certain areas and for use in conditional patients, and the vaccine candidates were only recently approved or authorized for emergency use without being fully implemented worldwide, suggesting that we are yet to reach effective control of the current outbreak as its uninhibited transmission continues precariously. Over the past few months, several therapeutic candidates have been proven ineffective in large clinical trials, while some other agents exhibited promising preliminary results. Meanwhile, the investigation of SARS-CoV-2-specific antivirals is underway. Despite still being preclinical, these agents could be beneficial for the long-term control of COVID-19 and deserve more research focus. In this article, we update the current status of therapeutic candidates that have been examined for COVID-19 management, including the virus-targeting inhibitors and host-targeting agents, with their antiviral efficacy in vitro, in vivo, and in clinical studies. Finally, we highlight the current challenges and future prospect of developing potent therapeutic agents against COVID-19.
Bronchoalveolar Lavage Fluid Reflects a TH1-CD21low B-Cell Interaction in CVID-Related Interstitial Lung Disease
Authors: Friedmann David , Unger Susanne , Keller Baerbel , Rakhmanov Mirzokhid , Goldacker Sigune , Zissel Gernot , Frye Björn C. , Schupp Jonas C. , Prasse Antje , Warnatz Klaus
Published: February 2021

Background

About 20% of patients with common variable immunodeficiency (CVID) suffer from interstitial lung disease (ILD) as part of a systemic immune dysregulation. Current understanding suggests a role of B cells in the pathogenesis based on histology and increased levels of BAFF and IgM associated with active disease corroborated by several reports which demonstrate the successful use of rituximab in CVID-ILD. It is debated whether histological confirmation by biopsy or even video-assisted thoracoscopy is required and currently not investigated whether less invasive methods like a bronchoalveolar lavage (BAL) might provide an informative diagnostic tool.

Objective

To gain insight into potential immune mechanisms underlying granulomatous and lymphocytic interstitial lung disease (GLILD) and to define biomarkers for progressive ILD by characterizing the phenotype of B- and T-cell populations and cytokine profiles in BAL fluid (BALF) of CVID-ILD compared to sarcoidosis patients and healthy donors (HD).

Methods

Sixty-four CVID, six sarcoidosis, and 25 HD BALF samples were analyzed by flow cytometric profiling of B- and T-cells and for cytokines by ELISA and Multiplexing LASER Bead technology.

Results

Both sarcoidosis and CVID-ILD are characterized by a predominantly T-cell mediated lymphocytosis in the BALF. There is an increase in T follicular helper (TFH)-like memory and decrease of regulatory T cells in CVID-ILD BALF. This TFH-like cell subset is clearly skewed toward TH1 cells in CVID-ILD. In contrast to sarcoidosis, CVID-ILD BALF contains a higher percentage of B cells comprising mostly CD21low B cells, but less class-switched memory B cells. BALF analysis showed increased levels of APRIL, CXCL10, and IL-17.

Conclusion

Unlike in sarcoidosis, B cells are expanded in BALF of CVID-ILD patients. This is associated with an expansion of TFH- and TPH-like cells and an increase in APRIL potentially supporting B-cell survival and differentiation and proinflammatory cytokines reflecting not only the previously described TH1 profile seen in CVID patients with secondary immune dysregulation. Thus, the analysis of BALF might be of diagnostic value not only in the diagnosis of CVID-ILD, but also in the evaluation of the activity of the disease and in determining potential treatment targets confirming the prominent role of B-cell targeted strategies.
Omega 3 Fatty Acid and Skin Diseases
Authors: Sawada Yu , Saito-Sasaki Natsuko , Nakamura Motonobu
Published: February 2021

Humans are exposed to various external environmental factors. Food intake is one of the most influential factors impacting daily lifestyle. Among nutrients obtained from foods, omega-3 polyunsaturated fatty acids (PUFAs) have various beneficial effects on inflammatory diseases. Furthermore, omega-3 PUFA metabolites, including resolvins, are known to demonstrate strong anti-inflammatory effects during allergic and inflammatory diseases; however, little is known regarding the actual impact of these metabolites on skin diseases. In this review, we focused on metabolites that have strong anti-inflammatory actions in various inflammatory diseases, as well as those that present antitumor actions in malignancies, in addition to the actual effect of omega-3 PUFA metabolites on various cells.
Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease
Authors: Roca Suarez Armando Andres , Testoni Barbara , Baumert Thomas F. , Lupberger Joachim
Published: February 2021

A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.
The Relevance of a Physical Active Lifestyle and Physical Fitness on Immune Defense: Mitigating Disease Burden, With Focus on COVID-19 Consequences
Authors: Filgueira Tayrine Ordonio , Castoldi Angela , Santos Lucas Eduardo R. , de Amorim Geraldo José , de Sousa Fernandes Matheus Santos , Anastácio Weydyson de Lima do Nascimento , Campos Eduardo Zapaterra , Santos Tony Meireles , Souto Fabrício Oliveira
Published: February 2021

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast spreading virus leading to the development of Coronavirus Disease-2019 (COVID-19). Severe and critical cases are characterized by damage to the respiratory system, endothelial inflammation, and multiple organ failure triggered by an excessive production of proinflammatory cytokines, culminating in the high number of deaths all over the world. Sedentarism induces worse, continuous, and progressive consequences to health. On the other hand, physical activity provides benefits to health and improves low-grade systemic inflammation. The aim of this review is to elucidate the effects of physical activity in physical fitness, immune defense, and its contribution to mitigate the severe inflammatory response mediated by SARS-CoV-2. Physical exercise is an effective therapeutic strategy to mitigate the consequences of SARS-CoV-2 infection. In this sense, studies have shown that acute physical exercise induces the production of myokines that are secreted in tissues and into the bloodstream, supporting its systemic modulatory effect. Therefore, maintaining physical activity influence balance the immune system and increases immune vigilance, and also might promote potent effects against the consequences of infectious diseases and chronic diseases associated with the development of severe forms of COVID-19. Protocols to maintain exercise practice are suggested and have been strongly established, such as home-based exercise (HBE) and outdoor-based exercise (OBE). In this regard, HBE might help to reduce levels of physical inactivity, bed rest, and sitting time, impacting on adherence to physical activity, promoting all the benefits related to exercise, and attracting patients in different stages of treatment for COVID-19. In parallel, OBE must improve health, but also prevent and mitigate COVID-19 severe outcomes in all populations. In conclusion, HBE or OBE models can be a potent strategy to mitigate the progress of infection, and a coadjutant therapy for COVID-19 at all ages and different chronic conditions.
Seasonality of the Microbial Community Composition in the North Atlantic
Authors: Bolaños Luis M. , Choi Chang Jae , Worden Alexandra Z. , Baetge Nicholas , Carlson Craig A. , Giovannoni Stephen
Published: February 2021

Planktonic communities constitute the basis of life in marine environments and have profound impacts in geochemical cycles. In the North Atlantic, seasonality drives annual transitions in the ecology of the water column. Phytoplankton bloom annually in spring as a result of these transitions, creating one of the major biological pulses in productivity on earth. The timing and geographical distribution of the spring bloom as well as the resulting biomass accumulation have largely been studied using the global capacity of satellite imaging. However, fine-scale variability in the taxonomic composition, spatial distribution, seasonal shifts, and ecological interactions with heterotrophic bacterioplankton has remained largely uncharacterized. The North Atlantic Aerosols and Marine Ecosystems Study (NAAMES) conducted four meridional transects to characterize plankton ecosystems in the context of the annual bloom cycle. Using 16S rRNA gene-based community profiles we analyzed the temporal and spatial variation in plankton communities. Seasonality in phytoplankton and bacterioplankton composition was apparent throughout the water column, with changes dependent on the hydrographic origin. From winter to spring in the subtropic and subpolar subregions, phytoplankton shifted from the predominance of cyanobacteria and picoeukaryotic green algae to diverse photosynthetic eukaryotes. By autumn, the subtropics were dominated by cyanobacteria, while a diverse array of eukaryotes dominated the subpolar subregions. Bacterioplankton were also strongly influenced by geographical subregions. SAR11, the most abundant bacteria in the surface ocean, displayed higher richness in the subtropics than the subpolar subregions. SAR11 subclades were differentially distributed between the two subregions. Subclades Ia.1 and Ia.3 co-occurred in the subpolar subregion, while Ia.1 dominated the subtropics. In the subtropical subregion during the winter, the relative abundance of SAR11 subclades “II” and 1c.1 were elevated in the upper mesopelagic. In the winter, SAR202 subclades generally prevalent in the bathypelagic were also dominant members in the upper mesopelagic zones. Co-varying network analysis confirmed the large-scale geographical organization of the plankton communities and provided insights into the vertical distribution of bacterioplankton. This study represents the most comprehensive survey of microbial profiles in the western North Atlantic to date, revealing stark seasonal differences in composition and richness delimited by the biogeographical distribution of the planktonic communities.
Face Mask Wearing Behaviors, Depressive Symptoms, and Health Beliefs Among Older People During the COVID-19 Pandemic
Authors: Kwan Rick Yiu Cho , Lee Paul Hong , Cheung Daphne Sze Ki , Lam Simon Ching
Published: February 2021

The COVID-19 pandemic has affected more than 100 countries. Despite the global shortage of face masks, the public has adopted universal mask wearing as a preventive measure in many Asian countries. The COVID-19 mortality rate is higher among older people, who may find that wearing a face mask protects their physical health but jeopardizes their mental health. This study aimed to explore the associations between depressive symptoms, health beliefs, and face mask wearing behaviors among older people. By means of an online survey conducted between March and April 2020, we assessed depressive symptoms, health beliefs regarding COVID-19, and face mask use and reuse among community-dwelling older people. General linear models were employed to explore the associations among these variables. Of the 355 valid participants, 25.6% experienced depressive symptoms. Health beliefs regarding the perceived severity of disease (p= 0.001) and perceived efficacy of practicing preventive measures (p= 0.005) were positively associated with face mask use. Those who reused face masks (p= 0.008) had a stronger belief in disease severity (p< 0.001), had poorer cues to preventive measures (p= 0.002), and were more likely to experience depressive symptoms. Mask reuse was significantly associated with depression only among those who perceived the disease as serious (p= 0.025) and those who had poorer cues to preventive measures (p= 0.004). In conclusion, health beliefs regarding perceived severity and efficacy contributed to more frequent face mask use, which was unrelated to depressive symptoms. Older people who had a stronger belief in disease severity had less adequate cues to preventive measures and reused face masks experienced greater depressive symptoms. A moderation effect of health beliefs (i.e., disease severity and cues to preventive measures) on face mask reuse and depression was observed.
Co-Occurrence of Listeria spp. and Spoilage Associated Microbiota During Meat Processing Due to Cross-Contamination Events
Authors: Zwirzitz Benjamin , Wetzels Stefanie U. , Dixon Emmanuel D. , Fleischmann Svenja , Selberherr Evelyne , Thalguter Sarah , Quijada Narciso M. , Dzieciol Monika , Wagner Martin , Stessl Beatrix
Published: February 2021

A large part of foodborne outbreaks related to Listeria monocytogenes are linked to meat and meat products. Especially, recontamination of meat products and deli-meat during slicing, packaging, and repackaging is in the focus of food authorities. In that regard, L. monocytogenes persistence in multi-species biofilms is one major issue, since they survive elaborate cleaning and disinfection measures. Here, we analyzed the microbial community structure throughout a meat processing facility using a combination of high-throughput full-length 16S ribosomal RNA (rRNA) gene sequencing and traditional microbiological methods. Samples were taken at different stages during meat cutting as well as from multiple sites throughout the facility environment to capture the product and the environmental associated microbiota co-occurring with Listeria spp. and L. monocytogenes. The listeria testing revealed a widely disseminated contamination (50%; 88 of 176 samples were positive for Listeria spp. and 13.6%; 24 of 176 samples were positive for L. monocytogenes). The pulsed-field gel electrophoresis (PFGE) typing evidenced 14 heterogeneous L. monocytogenes profiles with PCR-serogroup 1/2a, 3a as most dominant. PFGE type MA3-17 contributed to the resilient microbiota of the facility environment and was related to environmental persistence. The core in-house microbiota consisted mainly of the genera Acinetobacter, Pseudomonas, Psychrobacter (Proteobacteria), Anaerobacillus, Bacillus (Firmicutes), and Chryseobacterium (Bacteroidota). While the overall microbial community structure clearly differed between product and environmental samples, we were able to discern correlation patterns regarding the presence/absence of Listeria spp. in both sample groups. Specifically, our longitudinal analysis revealed association of Listeria spp. with known biofilm-producing Pseudomonas, Acinetobacter, and Janthinobacterium species on the meat samples. Similar patterns were also observed on the surface, indicating dispersal of microorganisms from this multispecies biofilm. Our data provided a better understanding of the built environment microbiome in the meat processing context and promoted more effective options for targeted disinfection in the analyzed facility.
Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
Authors: Ranieri Federico , Mariotto Sara , Dubbioso Raffaele , Di Lazzaro Vincenzo
Published: February 2021

In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited “dosage” of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.
APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease
Authors: Tunold Jon-Anders , Geut Hanneke , Rozemuller J. M. Annemieke , Henriksen Sandra Pilar , Toft Mathias , van de Berg Wilma D. J. , Pihlstrøm Lasse
Published: February 2021

Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia.

Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia.

Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease.

Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.