bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution and Expression of the Immune System of a Facultatively Anadromous Salmonid
Authors: Colgan Thomas J. , Moran Peter A. , Archer Louise C. , Wynne Robert , Hutton Stephen A. , McGinnity Philip , Reed Thomas E.
Published: February 2021

Vertebrates have evolved a complex immune system required for the identification of and coordinated response to harmful pathogens. Migratory species spend periods of their life-cycle in more than one environment, and their immune system consequently faces a greater diversity of pathogens residing in different environments. In facultatively anadromous salmonids, individuals may spend parts of their life-cycle in freshwater and marine environments. For species such as the brown trout Salmo trutta, sexes differ in their life-histories with females more likely to migrate to sea while males are more likely to stay and complete their life-cycle in their natal river. Salmonids have also undergone a lineage-specific whole genome duplication event, which may provide novel immune innovations but our current understanding of the differences in salmonid immune expression between the sexes is limited. We characterized the brown trout immune gene repertoire, identifying a number of canonical immune genes in non-salmonid teleosts to be duplicated in S. trutta, with genes involved in innate and adaptive immunity. Through genome-wide transcriptional profiling (“RNA-seq”) of male and female livers to investigate sex differences in gene expression amplitude and alternative splicing, we identified immune genes as being generally male-biased in expression. Our study provides important insights into the evolutionary consequences of whole genome duplication events on the salmonid immune gene repertoire and how the sexes differ in constitutive immune expression.
Interleukin-22 From Type 3 Innate Lymphoid Cells Aggravates Lupus Nephritis by Promoting Macrophage Infiltration in Lupus-Prone Mice
Authors: Hu Lingzhen , Hu Jingyi , Chen Liheng , Zhang Yi , Wang Qingqing , Yang Xuyan
Published: February 2021

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Our previous studies demonstrated increased serum and renal Interleukin (IL)-22 in LN patients and MRL/lpr mice. This study investigated the role of IL-22 and its mechanism in LN. Here, we found that IL-22 was mainly produced by type 3 innate lymphoid cells (ILC3) in kidney of MRL/lpr mice. The systemic illness and local renal lesion were significantly alleviated in IL-22 or IL-22R gene knockout (KO) mice (IL-22 KO or IL-22R KO MRL/lpr mice) than control mice (MRL/lpr mice). IL-22 KO or IL-22R KO MRL/lpr mice had significantly slighter infiltration of macrophage in kidney than MRL/lpr mice. Consistently, by RNA-Seq, the expression of (CC motif) ligand 2 (CCL2) and (CXC motif) ligand 10 (CXCL10) was decreased in kidney of KO mice compared with control mice. By immunoblotting, significantly increased levels of STAT3 phosphorylation were found in the kidney of control mice compared to KO mice. In vitro, primary kidney epithelial cells from control mouse stimulated with recombinant IL-22 (rIL-22) expressed higher levels of CCL2, CXCL10, and phosphorylated STAT3. At the same time, when primary kidney epithelial cells were treated with rIL-22, transwell assay demonstrated their supernatant recruited more macrophages. In human kidney epithelial cell line (HK2) cells, when treated with rIL-22, we observed similar results with primary mouse kidney epithelial cells. Moreover, when cells were stimulated with rIL-22 following pre-treatment with STAT3 pathway inhibitor, the expression of CCL2 and CXCL10 were significantly reversed. Our findings demonstrate that IL-22 binding to IL-22R in kidney epithelial cells activated the STAT3 signaling pathway, enhanced the chemokine secretion and then promoted macrophage infiltration to the kidney of MRL/lpr mice, thus aggravated LN in lupus-prone mice. These findings indicate that IL-22 may play a pathogenic role in LN and may provide a promising novel therapeutic target for LN.
Lymphoma Heterogeneity Unraveled by Single-Cell Transcriptomics
Authors: Ysebaert Loic , Quillet-Mary Anne , Tosolini Marie , Pont Frederic , Laurent Camille , Fournié Jean-Jacques
Published: February 2021

High-definition transcriptomic studies through single-cell RNA sequencing (scRNA-Seq) have revealed the heterogeneity and functionality of the various microenvironments across numerous solid tumors. Those pioneer studies have highlighted different cellular signatures correlated with clinical response to immune checkpoint inhibitors. scRNA-Seq offers also a unique opportunity to unravel the intimate heterogeneity of the ecosystems across different lymphoma entities. In this review, we will first cover the basics and future developments of the technology, and we will discuss its input in the field of translational lymphoma research, from determination of cell-of-origin and functional diversity, to monitoring of anti-cancer targeted drugs response and toxicities, and how new improvements in both data collection and interpretation will further foster precision medicine in the upcoming years.
A Proteome-Wide Immunoinformatics Tool to Accelerate T-Cell Epitope Discovery and Vaccine Design in the Context of Emerging Infectious Diseases: An Ethnicity-Oriented Approach
Authors: Oyarzun Patricio , Kashyap Manju , Fica Victor , Salas-Burgos Alexis , Gonzalez-Galarza Faviel F. , McCabe Antony , Jones Andrew R. , Middleton Derek , Kobe Bostjan
Published: February 2021

Emerging infectious diseases (EIDs) caused by viruses are increasing in frequency, causing a high disease burden and mortality world-wide. The COVID-19 pandemic caused by the novel SARS-like coronavirus (SARS-CoV-2) underscores the need to innovate and accelerate the development of effective vaccination strategies against EIDs. Human leukocyte antigen (HLA) molecules play a central role in the immune system by determining the peptide repertoire displayed to the T-cell compartment. Genetic polymorphisms of the HLA system thus confer a strong variability in vaccine-induced immune responses and may complicate the selection of vaccine candidates, because the distribution and frequencies of HLA alleles are highly variable among different ethnic groups. Herein, we build on the emerging paradigm of rational epitope-based vaccine design, by describing an immunoinformatics tool (Predivac-3.0) for proteome-wide T-cell epitope discovery that accounts for ethnic-level variations in immune responsiveness. Predivac-3.0 implements both CD8+ and CD4+ T-cell epitope predictions based on HLA allele frequencies retrieved from the Allele Frequency Net Database. The tool was thoroughly assessed, proving comparable performances (AUC ~0.9) against four state-of-the-art pan-specific immunoinformatics methods capable of population-level analysis (NetMHCPan-4.0, Pickpocket, PSSMHCPan and SMM), as well as a strong accuracy on proteome-wide T-cell epitope predictions for HIV-specific immune responses in the Japanese population. The utility of the method was investigated for the COVID-19 pandemic, by performing in silico T-cell epitope mapping of the SARS-CoV-2 spike glycoprotein according to the ethnic context of the countries where the ChAdOx1 vaccine is currently initiating phase III clinical trials. Potentially immunodominant CD8+ and CD4+ T-cell epitopes and population coverages were predicted for each population (the Epitope Discovery mode), along with optimized sets of broadly recognized (promiscuous) T-cell epitopes maximizing coverage in the target populations (the Epitope Optimization mode). Population-specific epitope-rich regions (T-cell epitope clusters) were further predicted in protein antigens based on combined criteria of epitope density and population coverage. Overall, we conclude that Predivac-3.0 holds potential to contribute in the understanding of ethnic-level variations of vaccine-induced immune responsiveness and to guide the development of epitope-based next-generation vaccines against emerging pathogens, whose geographic distributions and populations in need of vaccinations are often well-defined for regional epidemics.
Neutrophils Encompass a Regulatory Subset Suppressing T Cells in Apparently Healthy Cattle and Mice
Authors: Rambault Marion , Doz-Deblauwe Émilie , Le Vern Yves , Carreras Florence , Cunha Patricia , Germon Pierre , Rainard Pascal , Winter Nathalie , Remot Aude
Published: February 2021

Neutrophils that reside in the bone marrow are swiftly recruited from circulating blood to fight infections. For a long time, these first line defenders were considered as microbe killers. However their role is far more complex as cross talk with T cells or dendritic cells have been described for human or mouse neutrophils. In cattle, these new roles are not documented yet. We identified a new subset of regulatory neutrophils that is present in the mouse bone marrow or circulate in cattle blood under steady state conditions. These regulatory neutrophils that display MHC-II on the surface are morphologically indistinguishable from classical MHC-IIneg neutrophils. However MHC-IIpos and MHC-IIneg neutrophils display distinct transcriptomic profiles. While MHC-IIneg and MHC-IIpos neutrophils display similar bacterial phagocytosis or killing activity, MHC-IIpos only are able to suppress T cell proliferation under contact-dependent mechanisms. Regulatory neutrophils are highly enriched in lymphoid organs as compared to their MHC-IIneg counterparts and in the mouse they express PDL-1, an immune checkpoint involved in T-cell blockade. Our results emphasize neutrophils as true partners of the adaptive immune response, including in domestic species. They open the way for discovery of new biomarkers and therapeutic interventions to better control cattle diseases.
Ozone-Induced Oxidative Stress, Neutrophilic Airway Inflammation, and Glucocorticoid Resistance in Asthma
Authors: Enweasor Chioma , Flayer Cameron H. , Haczku Angela
Published: February 2021

Despite recent advances in using biologicals that target Th2 pathways, glucocorticoids form the mainstay of asthma treatment. Asthma morbidity and mortality remain high due to the wide variability of treatment responsiveness and complex clinical phenotypes driven by distinct underlying mechanisms. Emerging evidence suggests that inhalation of the toxic air pollutant, ozone, worsens asthma by impairing glucocorticoid responsiveness. This review discusses the role of oxidative stress in glucocorticoid resistance in asthma. The underlying mechanisms point to a central role of oxidative stress pathways. The primary data source for this review consisted of peer-reviewed publications on the impact of ozone on airway inflammation and glucocorticoid responsiveness indexed in PubMed. Our main search strategy focused on cross-referencing “asthma and glucocorticoid resistance” against “ozone, oxidative stress, alarmins, innate lymphoid, NK and γδ T cells, dendritic cells and alveolar type II epithelial cells, glucocorticoid receptor and transcription factors”. Recent work was placed in the context from articles in the last 10 years and older seminal research papers and comprehensive reviews. We excluded papers that did not focus on respiratory injury in the setting of oxidative stress. The pathways discussed here have however wide clinical implications to pathologies associated with inflammation and oxidative stress and in which glucocorticoid treatment is essential.
Phenotype, Susceptibility, Autoimmunity, and Immunotherapy Between Kawasaki Disease and Coronavirus Disease-19 Associated Multisystem Inflammatory Syndrome in Children
Authors: Chen Ming-Ren , Kuo Ho-Chang , Lee Yann-Jinn , Chi Hsin , Li Sung Chou , Lee Hung-Chang , Yang Kuender D.
Published: February 2021

Coronavirus disease-19 (COVID-19) in children is usually mild but some are susceptible to a Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C) in the convalescent stage, posing a need to differentiate the phenotype, susceptibility, autoimmunity, and immunotherapy between KD and MIS-C, particularly in the upcoming mass vaccination of COVID-19. Patients with MIS-C are prone to gastrointestinal symptoms, coagulopathy, and shock in addition to atypical KD syndrome with fever, mucocutaneous lesions, lymphadenopathy, and/or cardiovascular events. MIS-C manifests KD-like symptoms that alert physicians to early recognize and adopt the KD treatment regimen for patients with MIS-C. MIS-C linked to COVID-19 teaches us infection-associated autoimmune vasculitis and vice versa. Studies on genetic susceptibility have identified certain human leukocyte antigen (HLA) locus and toll-like receptor (TLR) associated with KD and/or COVID-19. Certain HLA subtypes, such as HLA-DRB1 and HLA-MICA A4 are associated with KD. HLA-B*46:01 is proposed to be the risk allele of severe COVID-19 infection, and blood group O type is a protective factor of COVID-19. The autoimmune vasculitis of KD, KD shock syndrome (KDSS), or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE) resulting in hyperinflammation with T helper 17 (Th17)/Treg imbalance with augmented Th17/Th1 mediators: interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), Interferon (IFNγ), and IL-17A, and lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-β). There are certain similarities and differences in phenotypes, susceptibility, and pathogenesis of KD, KDSS, and MIS-C, by which a physician can make early protection, prevention, and precision treatment of the diseases. The evolution of immunotherapies for the diseases has shown that intravenous immunoglobulin (IVIG) alone or combined with corticosteroids is the standard treatment for KD, KDSS, and MIS-C. However, a certain portion of patients who revealed a treatment resistance to IVIG or IVIG plus corticosteroids, posing a need to early identify the immunopathogenesis, to protect hosts with genetic susceptibility, and to combat Th17/Treg imbalance by anti-cytokine or pro-Treg for reversal of the hyperinflammation and IVIG resistance. Based on physiological and pathological immunity of the diseases under genetic susceptibility and host milieu conditions, a series of sequential regimens are provided to develop a so-called “Know thyself, enemy (pathogen), and ever-victorious” strategy for the prevention and immunotherapy of KD and/or MIS-C.
COVID-19 Impairs Immune Response to Candida albicans
Authors: Moser Dominique , Biere Katharina , Han Bing , Hoerl Marion , Schelling Gustav , Choukér Alexander , Woehrle Tobias
Published: February 2021

Infection with SARS-CoV-2 can lead to Coronavirus disease-2019 (COVID-19) and result in severe acute respiratory distress syndrome (ARDS). Recent reports indicate an increased rate of fungal coinfections during COVID-19. With incomplete understanding of the pathogenesis and without any causative therapy available, secondary infections may be detrimental to the prognosis. We monitored 11 COVID-19 patients with ARDS for their immune phenotype, plasma cytokines, and clinical parameters on the day of ICU admission and on day 4 and day 7 of their ICU stay. Whole blood stimulation assays with lipopolysaccharide (LPS), heat-killed Listeria monocytogenes (HKLM), Aspergillus fumigatus, and Candida albicans were used to mimic secondary infections, and changes in immune phenotype and cytokine release were assessed. COVID-19 patients displayed an immune phenotype characterized by increased HLA-DR+CD38+ and PD-1+ CD4+ and CD8+ T cells, and elevated CD8+CD244+ lymphocytes, compared to healthy controls. Monocyte activation markers and cytokines IL-6, IL-8, TNF, IL-10, and sIL2Rα were elevated, corresponding to monocyte activation syndrome, while IL-1β levels were low. LPS, HKLM and Aspergillus fumigatus antigen stimulation provoked an immune response that did not differ between COVID-19 patients and healthy controls, while COVID-19 patients showed an attenuated monocyte CD80 upregulation and abrogated release of IL-6, TNF, IL-1α, and IL-1β toward Candida albicans. This study adds further detail to the characterization of the immune response in critically ill COVID-19 patients and hints at an increased susceptibility for Candida albicans infection.
Comparison of the Humphrey Field Analyzer and Photopic Negative Response of Focal Macular Electroretinograms in the Evaluation of the Relationship Between Macula Structure and Function
Authors: Hirooka Kazuyuki , Yokoyama Kenji , Tokumo Kana , Kiuchi Yoshiaki
Published: February 2021

Purpose: To investigate the association between macular inner retinal layer thickness and macula visual field (VF) mean deviation as measured by the Humphrey Field Analyzer (HFA) or macular function as measured by focal macular electroretinograms (ERGs) in patients with glaucoma.

Methods: The participants in this cross-sectional study were 71 patients with glaucoma and 10 healthy controls. Macular inner retinal layer thickness and function were measured in all participants using optical coherence tomography (OCT) and HFA or focal macular ERGs, respectively. Macular OCT images were segmented into the macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer/inner plexiform layer (GCL/IPL), and ganglion cell complex (GCC). Spearman correlation analysis was used to assess the relationship between macular inner retinal layer thickness and function.

Results: Focal macular ERGs were composed of a negative wave (N1), a positive wave (P1), and a slow negative wave (N2). The N2 response density was significantly reduced in eyes with glaucoma, and was significantly associated with the thickness of the mRNFL (R = 0.317), GCL/IPL (R = 0.372), or GCC (R = 0.367). The observed structure–function relationship was also significantly correlated with the HFA VF mean deviation for each thickness [mRNFL (R = 0.728), GCL/IPL (R = 0.603), or GCC (R = 0.754)].

Conclusions: Although a significant correlation was found between the N2 response density and the thickness of the macular inner layer, the observed structure–function relationship with the mean deviation of the HFA VF was higher than that of the N2 response density.
Evaluation of the Inflammatory Cytokines and IL-10 Network in Individuals Co-infected With Human T-Cell Lymphotropic Virus and Hepatitis C Virus (HTLV/HCV)
Authors: Pereira Felicidade Mota , Ramos Pablo Ivan Pereira , Lirio Monique , Mercês Atta Ajax , Silva de Oliveira Isabela , Nascimento Fabio Carneiro Vosqui , Silva Marcelo Costa , Galvão-Castro Bernardo , Rios Grassi Maria Fernanda
Published: February 2021

Background

Co-infection between the human T-cell lymphotropic virus (HTLV) and the hepatitis C virus (HCV) can modify the natural history of HCV infection. The aim of this study was to describe the inflammatory cytokines and IL-10 network in patients co-infected with HTLV and HCV viruses in Bahia, Brazil.

Methods

Samples from 31 HTLV/HCV co-infected individuals and 27 HCV monoinfected individuals were evaluated. IFN-γ, TNF-α, IL-10, IL-8, and IL-1 cytokines were quantified by ELISA. Clinical, laboratory data were obtained from patient records. Serum levels of the cytokines were log10-transformed and data mining was performed using Z-score statistics and correlation analysis.

Results

Co-infected individuals presented a tendency toward higher production of INF-γ compared to the HCV monoinfected group. Regarding cytokine pairs, there was a positive correlation (P-value < 0.05) between IL-1 and IL-8 in the HTLV/HCV co-infected group and uninfected controls, and two correlations in the HCV mono-infected group IL-8 – IL10 and IL- INF-γ – IL-10 pairs. There was no significant difference between the groups for the other parameters analyzed.

Conclusion

The results presented herein indicated that HTLV/HCV co-infection was associated with a trend in IFN-γ production while HCV-infected individuals presented a positive correlation with both inflammatory cytokines (IL-8 and IFN-γ) and the regulatory cytokine IL-10.
Equivolumetric Protocol Generates Library Sizes Proportional to Total Microbial Load in 16S Amplicon Sequencing
Authors: Cruz Giuliano Netto Flores , Christoff Ana Paula , de Oliveira Luiz Felipe Valter
Published: February 2021

High-throughput sequencing of 16S rRNA amplicon has been extensively employed to perform microbiome characterization worldwide. As a culture-independent methodology, it has allowed high-level profiling of sample bacterial composition directly from samples. However, most studies are limited to information regarding relative bacterial abundances (sample proportions), ignoring scenarios in which sample microbe biomass can vary widely. Here, we use an equivolumetric protocol for 16S rRNA amplicon library preparation capable of generating Illumina sequencing data responsive to input DNA, recovering proportionality between observed read counts and absolute bacterial abundances within each sample. Under specified conditions, we show that the estimation of colony-forming units (CFU), the most common unit of bacterial abundance in classical microbiology, is challenged mostly by resolution and taxon-to-taxon variation. We propose Bayesian cumulative probability models to address such issues. Our results indicate that predictive errors vary consistently below one order of magnitude for total microbial load and abundance of observed bacteria. We also demonstrate our approach has the potential to generalize to previously unseen bacteria, but predictive performance is hampered by specific taxa of uncommon profile. Finally, it remains clear that high-throughput sequencing data are not inherently restricted to sample proportions only, and such technologies bear the potential to meet the working scales of traditional microbiology.
Biocide-Induced Emergence of Antibiotic Resistance in Escherichia coli
Authors: Merchel Piovesan Pereira Beatriz , Wang Xiaokang , Tagkopoulos Ilias
Published: February 2021

Biocide use is essential and ubiquitous, exposing microbes to sub-inhibitory concentrations of antiseptics, disinfectants, and preservatives. This can lead to the emergence of biocide resistance, and more importantly, potential cross-resistance to antibiotics, although the degree, frequency, and mechanisms that give rise to this phenomenon are still unclear. Here, we systematically performed adaptive laboratory evolution of the gut bacteria Escherichia coli in the presence of sub-inhibitory, constant concentrations of ten widespread biocides. Our results show that 17 out of 40 evolved strains (43%) also decreased the susceptibility to medically relevant antibiotics. Through whole-genome sequencing, we identified mutations related to multidrug efflux proteins (mdfA and acrR), porins (envZ and ompR), and RNA polymerase (rpoA and rpoBC), as mechanisms behind the resulting (cross)resistance. We also report an association of several genes (yeaW, pyrE, yqhC, aes, pgpA, and yeeP-isrC) and specific mutations that induce cross-resistance, verified through mutation repairs. A greater capacity for biofilm formation with respect to the parent strain was also a common feature in 11 out of 17 (65%) cross-resistant strains. Evolution in the biocides chlorophene, benzalkonium chloride, glutaraldehyde, and chlorhexidine had the most impact in antibiotic susceptibility, while hydrogen peroxide and povidone-iodine the least. No cross-resistance to antibiotics was observed for isopropanol, ethanol, sodium hypochlorite, and peracetic acid. This work reinforces the link between exposure to biocides and the potential for cross-resistance to antibiotics, presents evidence on the underlying mechanisms of action, and provides a prioritized list of biocides that are of greater concern for public safety from the perspective of antibiotic resistance.

Significance Statement

Bacterial resistance and decreased susceptibility to antimicrobials is of utmost concern. There is evidence that improper biocide (antiseptic and disinfectant) use and discard may select for bacteria cross-resistant to antibiotics. Understanding the cross-resistance emergence and the risks associated with each of those chemicals is relevant for proper applications and recommendations. Our work establishes that not all biocides are equal when it comes to their risk of inducing antibiotic resistance; it provides evidence on the mechanisms of cross-resistance and a risk assessment of the biocides concerning antibiotic resistance under residual sub-inhibitory concentrations.
Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?
Authors: Pasternak Alexander O. , Psomas Christina K. , Berkhout Ben
Published: February 2021

Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function. However, due to the persistence of long-lived HIV reservoirs, therapy interruption almost inevitably leads to a fast viral rebound. A small percentage of individuals who are able to control HIV replication for extended periods after therapy interruption are of particular interest because they may represent a model of long-term HIV remission without ART. These individuals are characterized by a limited viral reservoir and low reservoir measures can predict post-treatment HIV remission. However, most individuals with a low reservoir still experience fast viral rebound. In this Perspective, we discuss the possible reasons behind this and propose to develop an integral profile, composed of viral and host biomarkers, that could allow the accurate prediction of post-treatment HIV remission. We also propose to incorporate information on the chromatin context of the proviral integration sites into the characterization of the HIV reservoir, as this likely influences the reactivation capacity of latent proviruses and, together with the actual number of intact proviruses, contributes to the replication competence of the reservoir.
Influences of Stress and Sex on the Paraventricular Thalamus: Implications for Motivated Behavior
Authors: Rowson Sydney A. , Pleil Kristen E.
Published: February 2021

The paraventricular nucleus of the thalamus (PVT) is a critical neural hub for the regulation of a variety of motivated behaviors, integrating stress and reward information from environmental stimuli to guide discrete behaviors via several limbic projections. Neurons in the PVT are activated by acute and chronic stressors, however several roles of the PVT in behavior modulation emerge only following repeated stress exposure, pointing to a role for hypothalamic pituitary adrenal (HPA) axis modulation of PVT function. Further, there may be a reciprocal relationship between the PVT and HPA axis in which chronic stress-induced recruitment of the PVT elicits an additional role for the PVT to regulate motivated behavior by modulating HPA physiology and thus the neuroendocrine response to stress itself. This complex interaction may make the PVT and its role in influencing motivated behavior particularly susceptible to chronic stress-induced plasticity in the PVT, especially in females who display increased susceptibility to stress-induced maladaptive behaviors associated with neuropsychiatric diseases. Though literature is describing the sex-specific effects of acute and chronic stress exposure on HPA axis activation and motivated behaviors, the impact of sex on the role of the PVT in modulating the behavioral and neuroendocrine response to stress is less well established. Here, we review what is currently known regarding the acute and chronic stress-induced activation and behavioral role of the PVT in male and female rodents. We further explore stress hormone and neuropeptide signaling mechanisms by which the HPA axis and PVT interact and discuss the implications for sex-dependent effects of chronic stress on the PVT’s role in motivated behaviors.
Key Role of Microglial Matrix Metalloproteinases in Choroidal Neovascularization
Authors: Kim Juhee , Kim Jong-Heon , Do Ji Yeon , Lee Jung Yi , Yanai Ryoji , Lee In-kyu , Suk Kyoungho , Park Dong Ho
Published: February 2021

Age-related macular degeneration (AMD), especially neovascular AMD with choroidal neovascularization (CNV), is the leading cause of blindness in the elderly. Although matrix metalloproteinases (MMPs) are involved in pathological ocular angiogenesis, including CNV, the cellular origin of MMPs in AMD remains unknown. The present study investigated the role of microglial MMPs in CNV. MMP activities were analyzed by gelatin zymography in aqueous humor samples from patients with CNV and laser-induced CNV mice. Active MMP-9 was increased in the aqueous humor samples from neovascular AMD patients compared with control subjects. In the retinal pigment epithelium (RPE)/choroid from CNV mice, active MMP-9 increased, beginning 1 h post-CNV induction, and remained upregulated until Day 7. In RPE/choroid from CNV mice, active MMP-9 was suppressed by minocycline, a known microglial inhibitor, at 6 h and 1-day post-CNV induction. Flow cytometry revealed that the proportion of activated microglia increased very early, beginning at 1 h post-CNV induction, and was maintained until Day 7. Similarly, immunohistochemistry revealed increased microglial activation and MMP-9 expression on CNV lesions at 6 h and 1-day post-CNV induction. SB-3CT, an MMP inhibitor, decreased vascular leakage and lesion size in laser-induced CNV mice. These findings indicated nearly immediate recruitment of activated microglia and very early MMP-9 activation in the RPE/choroid. The present study newly identified a potential role for early microglial MMP-9 expression in CNV, and furthermore that modulating microglial MMP expression is a novel putative therapeutic for CNV.
Arm-Hand Boost Therapy During Inpatient Stroke Rehabilitation: A Pilot Randomized Controlled Trial
Authors: Meyer Sarah , Verheyden Geert , Kempeneers Kristof , Michielsen Marc
Published: February 2021

Objective: It was the aim to assess feasibility, safety, and potential efficacy of a new intensive, focused arm-hand BOOST program and to investigate whether there is a difference between early vs. late delivery of the program in the sub-acute phase post stroke.

Methods: In this pilot RCT, patients with stroke were randomized to the immediate group (IG): 4 weeks (4 w) BOOST +4 w CONTROL or the delayed group (DG): 4 w CONTROL +4 w BOOST, on top of their usual inpatient care program. The focused arm-hand BOOST program (1 h/day, 5x/week, 4 weeks) consisted of group exercises with focus on scapula-setting, core-stability, manipulation and complex ADL tasks. Additionally, 1 h per week the Armeo®Power (Hocoma AG, Switzerland) was used. The CONTROL intervention comprised a dose-matched program (24 one-hour sessions in 4 w) of lower limb strengthening exercises and general reconditioning. At baseline, after 4 and 8 weeks of training, the Fugl-Meyer assessment upper extremity (FMA-UE), action research arm test (ARAT), and stroke upper limb capacity scale (SULCS) were administered.

Results: Eighteen participants (IG: n = 10, DG: n = 8) were included, with a median (IQR) time post stroke of 8.6 weeks (5–12). No adverse events were experienced. After 4 weeks of training, significant between-group differences were found for FMA-UE (p = 0.003) and SULCS (p = 0.033) and a trend for ARAT (p = 0.075) with median (IQR) change scores for the IG of 9 (7–16), 2 (1–3), and 12.5 (1–18), respectively, and for the DG of 0.5 (−3 to 3), 1 (0–1), and 1.5 (−1 to 9), respectively. In the IG, 80% of patients improved beyond the minimal clinical important difference of FMA-UE after 4 weeks, compared to none of the DG patients. Between 4 and 8 weeks of training, patients in the DG tend to show larger improvements when compared to the IG, however, between-group comparisons did not reach significance.

Conclusions: Results of this pilot RCT showed that an intensive, specific arm-hand BOOST program, on top of usual care, is feasible and safe in the sub-acute phase post stroke and suggests positive, clinical meaningful effects on upper limb function, especially when delivered in the early sub-acute phase post stroke.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT04584177
Object-Location Memory Training in Older Adults Leads to Greater Deactivation of the Dorsal Default Mode Network
Authors: Mikos Ania , Malagurski Brigitta , Liem Franziskus , Mérillat Susan , Jäncke Lutz
Published: February 2021

Substantial evidence indicates that cognitive training can be efficacious for older adults, but findings regarding training-related brain plasticity have been mixed and vary depending on the imaging modality. Recent years have seen a growth in recognition of the importance of large-scale brain networks on cognition. In particular, task-induced deactivation within the default mode network (DMN) is thought to facilitate externally directed cognition, while aging-related decrements in this neural process are related to reduced cognitive performance. It is not yet clear whether task-induced deactivation within the DMN can be enhanced by cognitive training in the elderly. We previously reported durable cognitive improvements in a sample of healthy older adults (age range = 60–75) who completed 6 weeks of process-based object-location memory training (N = 36) compared to an active control training group (N = 31). The primary aim of the current study is to evaluate whether these cognitive gains are accompanied by training-related changes in task-related DMN deactivation. Given the evidence for heterogeneity of the DMN, we examine task-related activation/deactivation within two separate DMN branches, a ventral branch related to episodic memory and a dorsal branch more closely resembling the canonical DMN. Participants underwent functional magnetic resonance imaging (fMRI) while performing an untrained object-location memory task at four time points before, during, and after the training period. Task-induced (de)activation values were extracted for the ventral and dorsal DMN branches at each time point. Relative to visual fixation baseline: (i) the dorsal DMN was deactivated during the scanner task, while the ventral DMN was activated; (ii) the object-location memory training group exhibited an increase in dorsal DMN deactivation relative to the active control group over the course of training and follow-up; (iii) changes in dorsal DMN deactivation did not correlate with task improvement. These results indicate a training-related enhancement of task-induced deactivation of the dorsal DMN, although the specificity of this improvement to the cognitive task performed in the scanner is not clear.
Neurobehavioral Effects of LSVT® LOUD on Auditory-Vocal Integration in Parkinson’s Disease: A Preliminary Study
Authors: Li Yongxue , Tan Mingdan , Fan Hao , Wang Emily Q. , Chen Ling , Li Jingting , Chen Xi , Liu Hanjun
Published: February 2021

Individuals with Parkinson’s disease (PD) are impaired in auditory-vocal integration, characterized by abnormal compensatory responses to auditory feedback errors during self-monitoring of vocal production. The present study examined whether auditory feedback control of vocal pitch production in PD can benefit from Lee Silverman voice treatment (LSVT®LOUD), a high effort, intensive speech treatment for hypokinetic dysarthria in PD. Before and immediately after LSVT LOUD, 12 individuals with PD were instructed to produce sustained vowel sounds while hearing their voice unexpectedly pitch-shifted by −200 cents. Their vocal responses and event-related potentials (ERPs) to pitch perturbations were measured to assess the treatment outcomes. A group of 12 healthy controls were one-to-one pair matched by age, sex, and language. Individuals with PD exhibited abnormally enhanced vocal and ERP P2 responses to pitch perturbations relative to healthy controls. Successful treatment with LSVT LOUD, however, led to significantly smaller and faster vocal compensations that were accompanied by significantly larger P2 responses. Moreover, improved vocal loudness during passage reading was significantly correlated with reduced vocal compensations for pitch perturbations. These preliminary findings provide the first neurobehavioral evidence for beneficial effects of LSVT LOUD on impaired auditory-vocal integration associated with PD, which may be related to improved laryngeal motor functions and a top-down modulation of the speech motor network by LSVT LOUD.
Understanding the Link Between Maternal Overnutrition, Cardio-Metabolic Dysfunction and Cognitive Aging
Authors: Peleg-Raibstein Daria
Published: February 2021

Obesity has long been identified as a global epidemic with major health implications such as diabetes and cardiovascular disease. Maternal overnutrition leads to significant health issues in industrial countries and is one of the risk factors for the development of obesity and related disorders in the progeny. The wide accessibility of junk food in recent years is one of the major causes of obesity, as it is low in nutrient content and usually high in salt, sugar, fat, and calories. An excess of nutrients during fetal life not only has immediate effects on the fetus, including increased growth and fat deposition in utero, but also has long-term health consequences. Based on human studies, it is difficult to discern between genetic and environmental contributions to the risk of disease in future generations. Consequently, animal models are essential for studying the impact of maternal overnutrition on the developing offspring. Recently, animal models provided some insight into the physiological mechanisms that underlie developmental programming. Most of the studies employed thus far have focused only on obesity and metabolic dysfunctions in the offspring. These studies have advanced our understanding of how maternal overnutrition in the form of high-fat diet exposure can lead to an increased risk of obesity in the offspring, but many questions remain open. How maternal overnutrition may increase the risk of developing brain pathology such as cognitive disabilities in the offspring and increase the risk to develop metabolic disorders later in life? Further, does maternal overnutrition exacerbate cognitive- and cardio-metabolic aging in the offspring?
Vitamin C Acutely Affects Brain Perfusion and Mastication-Induced Perfusion Asymmetry in the Principal Trigeminal Nucleus
Authors: Viggiano Andrea , Ponticorvo Sara , Canna Antonietta , Secondulfo Carmine , Sbordone Ludovico , Russo Antonio , Monda Marcellino , Di Salle Francesco , Esposito Fabrizio
Published: February 2021

Prolonged mastication may induce an asymmetric modification of the local perfusion of the trigeminal principal nucleus. The aim of the present study was to evaluate the possible influence of vitamin C (vit. C) on such effect. Four groups of healthy volunteers underwent arterial spin labeling magnetic resonance imaging (ASL-MRI) to evaluate the local perfusion of the trigeminal nuclei after a vit. C-enriched lunch or a control lunch. Two ASL-MRI scans were acquired, respectively, before and after a 1 h-long masticating exercise or a 1 h long resting period. The results showed (i) an increased global perfusion of the brain in the vit. C-enriched lunch groups, (ii) an increased local perfusion of the right principal trigeminal nucleus (Vp) due to mastication, and (iii) a reduction of the rightward asymmetry of the Vp perfusion, due to mastication, after the vit C-enriched meal compared to the control meal. These results confirmed a long-lasting effect of prolonged mastication on Vp perfusion and also suggest a possible effect of vit. C on cerebral vascular tone regulation. Moreover, the data strongly draw attention on the side-to-side relation in Vp perfusion as a possible physiological parameter to be considered to understand the origin of pathological conditions like migraine.
Case Report: Energy- and Nutrient-Dense Formula for Growth Faltering: A Report of Two Cases From India
Authors: Kareem Zahid Ul , Panuganti Suresh Kumar , Bhatia Shikha
Published: February 2021

Infants hospitalized for critical illnesses are at a high risk of undernutrition because of increased nutrient requirements (due to increased metabolism) and decreased nutrient intake (due to disease-related problems such as anorexia or feeding difficulties). This can result in a slowing down of their normal growth, referred to as “growth faltering.” Appropriate nutritional management of these infants is extremely important to avoid long-term adverse outcomes. Administration of energy- and nutrient-dense formula (ENDF; 100 kcal energy and 2.6 g protein per 100 mL, with added micronutrients) can be an effective means of increasing the nutrient and energy intake of these children. Despite the high prevalence of undernutrition and growth faltering among pediatric patients in India, there is a paucity of literature on the use of ENDF in Indian infants. Herein, we report the successful use of ENDF for the nutritional management of two infants hospitalized for growth faltering because of severe upper airway obstruction. The aim of nutritional management was to achieve satisfactory weight gain, which can lead to spontaneous resolution of upper airway obstruction. ENDF was initially administered to provide 50–100 kcal/kg/day, and the dose was gradually increased to 160–185 kcal/kg/day. Both infants tolerated the formula well and showed satisfactory weight gain. These cases clearly demonstrate that early administration of ENDF is an effective means of increasing nutrient and energy intake of critically ill infants, thereby facilitating catchup growth, without any notable adverse effects.
Alterations in Gut Microbial Communities Across Anatomical Locations in Inflammatory Bowel Diseases
Authors: Zhou Youlian , He Yan , Liu Le , Zhou Wanyan , Wang Pu , Hu Han , Nie Yuqiang , Chen Ye
Published: February 2021

We previously discovered that gut microbiota can serve as universal microbial biomarkers for diagnosis, disease activity assessment, and predicting the response to infliximab treatment for inflammatory bowel diseases (IBD). Much still remains unknown about the relationship between alterations in gut microbiota and IBD affected bowel region, in particular in the case of ulcerative colitis (UC) and colonic Crohn's disease (cCD) without endoscopic and biopsy data. In the current study gut microbiota from a population in China was found to be distinct from that of the Western world [Human Microbiome Project (HMP) data]. Furthermore, both gut microbiota greatly differed from microbiota of other anatomical locations (oral, skin, airway, and vagina), with higher alpha-diversity (Chinese gut > HMP gut > oral microbiome > airway microbiome > skin microbiome > vaginal microbiome), and marked differences in microbiome composition. In patients with IBD in China, UC was characterized by the presence of Gardnerella, while cCD was characterized by the presence of Fusobacterium. Moreover, gut microbiota, such as Gardnerella and Fusobacterium, may be potential biomarkers for identifying UC from cCD. Together, this study revealed crucial differences in microbial communities across anatomical locations, and demonstrated that there was an important association between IBD affected bowel region and gut microbiota.
Dietary Modulation of Oxidative Stress From Edible Insects: A Mini-Review
Authors: D'Antonio Veronica , Serafini Mauro , Battista Natalia
Published: February 2021

Edible insects are proposed as a nutritious and environmentally sustainable alternative source to animal proteins, due to their numerous advantages in terms of reduced ecological impact and high nutritional value. However, the novelty for edible insects relies on the content of bioactive ingredients potentially able to induce a functional effect in the body. The present review summarizes the main findings on the antioxidant properties of edible insects available in the literature. A total of 30 studies involving animals, cell cultures, or in vitro experimental studies evaluating the antioxidant effect of edible insects are presented in this work. When the antioxidant activity was investigated, using a wide variety of in vitro tests and in cellular models, positive results were shown. Dietary supplementation with edible insects was also able to counteract dietary oxidative stress in animal models, restoring the balance of antioxidant enzymes and reducing the formation of oxidation damage markers. On the basis of the reviewed evidences, edible insects might represent a source of novel redox ingredients at low ecological impact able to modulate oxidative stress. However, due to the fact that majority of these evidences have been obtained in vitro and in cellular and animal models, dietary intervention trials are needed to assess the efficacy of edible insect consumption to modulate redox status in humans.
The Clinical Outcomes and Toxicities of Induction Chemotherapy Followed by Concurrent Chemoradiotherapy Plus Adjuvant Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma
Authors: Zou Rui , Yuan Jing-Jing , Li Qiang , Ding Jian-Wu , Liao Bing , Tu Zi-Wei , Hu Rong-Huan , Gong Dan , Hu Jia-Li , Zeng Lei
Published: February 2021

Purpose

To analyze the outcomes and toxicities of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy (ACT) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).

Methods

Retrospective analysis of 163 patients with LA-NPC referred from August 2015 to December 2018 was carried out. All patients underwent platinum-based ICT followed by CCRT plus ACT.

Results

The median follow-up time was 40 months, ranging from 5 to 69 months. The 3-year disease-free survival (DFS), overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates were 80.8, 90.0, 91.6, and 87.4%, respectively. The most frequent acute grade 3/4 adverse events were leukopenia (66.8%), neutropenia (55.8%), mucositis (41.1%), thrombocytopenia (27.0%), and anemia (14.7%).

Conclusion

ICT followed by CCRT plus ACT did not seemingly enhance DFS and OS in LA-NPC patients compared to the addition of ICT to CCRT (historical controls). In contrast, ICT followed by CCRT plus ACT had more acute adverse events than ICT followed by CCRT. Longer-term clinical studies are required to examine the treatment outcomes and late toxicities.
Machine Learning Based on Multi-Parametric MRI to Predict Risk of Breast Cancer
Authors: Tao Weijing , Lu Mengjie , Zhou Xiaoyu , Montemezzi Stefania , Bai Genji , Yue Yangming , Li Xiuli , Zhao Lun , Zhou Changsheng , Lu Guangming
Published: February 2021

Purpose

Machine learning (ML) can extract high-throughput features of images to predict disease. This study aimed to develop nomogram of multi-parametric MRI (mpMRI) ML model to predict the risk of breast cancer.

Methods

The mpMRI included non-enhanced and enhanced T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC), Ktrans, Kep, Ve, and Vp. Regions of interest were annotated in an enhanced T1WI map and mapped to other maps in every slice. 1,132 features and top-10 principal components were extracted from every parameter map. Single-parametric and multi-parametric ML models were constructed via 10 rounds of five-fold cross-validation. The model with the highest area under the curve (AUC) was considered as the optimal model and validated by calibration curve and decision curve. Nomogram was built with the optimal ML model and patients’ characteristics.

Results

This study involved 144 malignant lesions and 66 benign lesions. The average age of patients with benign and malignant lesions was 42.5 years old and 50.8 years old, respectively, which were statistically different. The sixth and fourth principal components of Ktrans had more importance than others. The AUCs of Ktrans, Kep, Ve and Vp, non-enhanced T1WI, enhanced T1WI, T2WI, and ADC models were 0.86, 0.81, 0.81, 0.83, 0.79, 0.81, 0.84, and 0.83 respectively. The model with an AUC of 0.90 was considered as the optimal model which was validated by calibration curve and decision curve. Nomogram for the prediction of breast cancer was built with the optimal ML models and patient age.

Conclusion

Nomogram could improve the ability of breast cancer prediction preoperatively.