bluuebunny/crossref_metadata_2025 huggingface dataset:
Colorectal Cancer-Associated Immune Exhaustion Involves T and B Lymphocytes and Conventional NK Cells and Correlates With a Shorter Overall Survival
Authors: Sorrentino Carlo , D’Antonio Luigi , Fieni Cristiano , Ciummo Stefania Livia , Di Carlo Emma
Published: December 2021

Colorectal cancer (CRC) is one of the most common cancer worldwide, with a growing impact on public health and clinical management. Immunotherapy has shown promise in the treatment of advanced cancers, but needs to be improved for CRC, since only a limited fraction of patients is eligible for treatment, and most of them develop resistance due to progressive immune exhaustion. Here, we identify the transcriptional, molecular, and cellular traits of the immune exhaustion associated with CRC and determine their relationships with the patient’s clinic-pathological profile. Bioinformatic analyses of RNA-sequencing data of 594 CRCs from TCGA PanCancer collection, revealed that, in the wide range of immune exhaustion genes, those coding for PD-L1, LAG3 and T-bet were associated (Cramér’s V=0.3) with MSI/dMMR tumors and with a shorter overall survival (log-rank test: p=0.0004, p=0.0014 and p=0.0043, respectively), whereas high levels of expression of EOMES, TRAF1, PD-L1, FCRL4, BTLA and SIGLEC6 were associated with a shorter overall survival (log-rank test: p=0.0003, p=0.0188, p=0.0004, p=0.0303, p=0.0052 and p=0.0033, respectively), independently from the molecular subtype of CRC. Expression levels of PD-L1, PD-1, LAG3, EOMES, T-bet, and TIGIT were significantly correlated with each other and associated with genes coding for CD4+ and CD8+CD3+ T cell markers and NKp46+CD94+EOMES+T-bet+ cell markers, (OR >1.5, p<0.05), which identify a subset of group 1 innate lymphoid cells, namely conventional (c)NK cells. Expression of TRAF1 and BTLA co-occurred with both T cell markers, CD3γ, CD3δ, CD3ε, CD4, and B cell markers, CD19, CD20 and CD79a (OR >2, p<0.05). Expression of TGFβ1 was associated only with CD4+ and CD8+CD3ε+ T cell markers (odds ratio >2, p<0.05). Expression of PD-L2 and IDO1 was associated (OR >1.5, p<0.05) only with cNK cell markers, whereas expression of FCRL4, SIGLEC2 and SIGLEC6 was associated (OR >2.5; p<0.05) with CD19+CD20+CD79a+ B cell markers. Morphometric examination of immunostained CRC tissue sections, obtained from a validation cohort of 53 CRC patients, substantiated the biostatistical findings, showing that the highest percentage of immune exhaustion gene expressing cells were found in tumors from short-term survivors and that functional exhaustion is not confined to T lymphocytes, but also involves B cells, and cNK cells. This concept was strengthened by CYBERSORTx analysis, which revealed the expression of additional immune exhaustion genes, in particular FOXP1, SIRT1, BATF, NR4A1 and TOX, by subpopulations of T, B and NK cells. This study provides novel insight into the immune exhaustion landscape of CRC and emphasizes the need for a customized multi-targeted therapeutic approach to overcome resistance to current immunotherapy.
Systems Immunology Analyses Following Porcine Respiratory and Reproductive Syndrome Virus Infection and Vaccination
Authors: Bocard Loïc Vivien , Kick Andrew Robert , Hug Corinne , Lischer Heidi Erika Lisa , Käser Tobias , Summerfield Artur
Published: December 2021

This study was initiated to better understand the nature of innate immune responses and the relatively weak and delayed immune response against porcine reproductive and respiratory syndrome virus (PRRSV). Following modified live virus (MLV) vaccination or infection with two PRRSV-2 strains, we analyzed the transcriptome of peripheral blood mononuclear cells collected before and at three and seven days after vaccination or infection. We used blood transcriptional modules (BTMs)-based gene set enrichment analyses. BTMs related to innate immune processes were upregulated by PRRSV-2 strains but downregulated by MLV. In contrast, BTMs related to adaptive immune responses, in particular T cells and cell cycle, were downregulated by PRRSV-2 but upregulated by MLV. In addition, we found differences between the PRRSV strains. Only the more virulent strain induced a strong platelet activation, dendritic cell activation, interferon type I and plasma cell responses. We also calculated the correlations of BTM with the neutralizing antibody and the T-cell responses. Early downregulation (day 0–3) of dendritic cell and B-cell BTM correlated to both CD4 and CD8 T-cell responses. Furthermore, a late (day 3–7) upregulation of interferon type I modules strongly correlated to helper and regulatory T-cell responses, while inflammatory BTM upregulation correlated more to CD8 T-cell responses. BTM related to T cells had positive correlations at three days but negative associations at seven days post-infection. Taken together, this work contributes to resolve the complexity of the innate and adaptive immune responses against PRRSV and indicates a fundamentally different immune response to the less immunogenic MLV compared to field strains which induced robust adaptive immune responses. The identified correlates of T-cell responses will facilitate a rational approach to improve the immunogenicity of MLV.
The Immuno-Modulation Effect of Macrophage-Derived Extracellular Vesicles in Chronic Inflammatory Diseases
Authors: Xing Yi , Sun Xun , Dou Yiming , Wang Min , Zhao Yanmei , Yang Qiang , Zhao Yanhong
Published: December 2021

As natural nanocarriers and intercellular messengers, extracellular vesicles (EVs) control communication among cells. Under physiological and pathological conditions, EVs deliver generic information including proteins and nucleic acids to recipient cells and exert regulatory effects. Macrophages help mediate immune responses, and macrophage-derived EVs may play immunomodulatory roles in the progression of chronic inflammatory diseases. Furthermore, EVs derived from various macrophage phenotypes have different biological functions. In this review, we describe the pathophysiological significance of macrophage-derived extracellular vesicles in the development of chronic inflammatory diseases, including diabetes, cancer, cardiovascular disease, pulmonary disease, and gastrointestinal disease, and the potential applications of these EVs.
The “Dialogue” Between Central and Peripheral Immunity After Ischemic Stroke: Focus on Spleen
Authors: Yu Hongchen , Cai Yichen , Zhong Aiqin , Zhang Yunsha , Zhang Junping , Xu Shixin
Published: December 2021

The immune response generated by the body after the incidence of ischemic stroke, runs through the comprehensive process of aftermath. During this process of ischemic stroke, the central neuroinflammation and peripheral immune response seriously affect the prognosis of patients, which has been the focus of research in recent years. As this research scenario progressed, the “dialogue” between central nervous inflammation and peripheral immune response after ischemic stroke has become more closely related. It’s worth noting that the spleen, as an important peripheral immune organ, plays a pivotal role in this dialogue. Multiple mechanisms have previously been reported for brain-spleen crosstalk after ischemic stroke. Further, neuroinflammation in the brain can affect the peripheral immune state by activating/inhibiting spleen function. However, the activation of the peripheral immune inflammatory response can work reversibly in the spleen. It further affects intracerebral neuroinflammation through the injured blood-brain barrier. Therefore, paying close attention to the role of spleen as the pivot between central and peripheral immunity in ischemic stroke may help to provide a new target for immune intervention in the treatment of ischemic stroke. In the present review, we reviewed the important role of spleen in central neuroinflammation and peripheral immune response after ischemic stroke. We summarized the relevant studies and reports on spleen as the target of immune intervention which can provide new ideas for the clinical treatment of ischemic stroke.
NK Cells and Innate-Like T Cells After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis
Authors: Ruder Josefine , Rex Jordan , Obahor Simon , Docampo María José , Müller Antonia M. S. , Schanz Urs , Jelcic Ilijas , Martin Roland
Published: December 2021

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which autoreactive T and B cells play important roles. Other lymphocytes such as NK cells and innate-like T cells appear to be involved as well. To name a few examples, CD56brightNK cells were described as an immunoregulatory NK cell subset in MS while innate-like T cells in MS were described in brain lesions and with proinflammatory signatures. Autologous hematopoietic stem cell transplantation (aHSCT) is a procedure used to treat MS. This procedure includes hematopoietic stem/progenitor cell (HSPC) mobilization, then high-dose chemotherapy combined with anti-thymocyte globulin (ATG) and subsequent infusion of the patients own HSPCs to reconstitute a functional immune system. aHSCT inhibits MS disease activity very effectively and for long time, presumably due to elimination of autoreactive T cells. Here, we performed multidimensional flow cytometry experiments in peripheral blood lymphocytes of 27 MS patients before and after aHSCT to address its potential influence on NK and innate-like T cells. After aHSCT, the relative frequency and absolute numbers of CD56brightNK cells rise above pre-aHSCT levels while all studied innate-like T cell populations decrease. Hence, our data support an enhanced immune regulation by CD56brightNK cells and the efficient reduction of proinflammatory innate-like T cells by aHSCT in MS. These observations contribute to our current understanding of the immunological effects of aHSCT in MS.
Immunoinformatic Analysis Reveals Antigenic Heterogeneity of Epstein-Barr Virus Is Immune-Driven
Authors: Cirac Ana , Poirey Remy , Dieckmeyer Michael , Witter Klaus , Delecluse Henri-Jacques , Behrends Uta , Mautner Josef
Published: December 2021

Whole genome sequencing of Epstein-Barr virus (EBV) isolates from around the world has uncovered pervasive strain heterogeneity, but the forces driving strain diversification and the impact on immune recognition remained largely unknown. Using a data mining approach, we analyzed more than 300 T-cell epitopes in 168 published EBV strains. Polymorphisms were detected in approximately 65% of all CD8+ and 80% of all CD4+ T-cell epitopes and these numbers further increased when epitope flanking regions were included. Polymorphisms in CD8+ T-cell epitopes often involved MHC anchor residues and resulted in changes of the amino acid subgroup, suggesting that only a limited number of conserved T-cell epitopes may represent generic target antigens against different viral strains. Although considered the prototypic EBV strain, the rather low degree of overlap with most other viral strains implied that B95.8 may not represent the ideal reference strain for T-cell epitopes. Instead, a combinatorial library of consensus epitopes may provide better targets for diagnostic and therapeutic purposes when the infecting strain is unknown. Polymorphisms were significantly enriched in epitope versus non-epitope protein sequences, implicating immune selection in driving strain diversification. Remarkably, CD4+ T-cell epitopes in EBNA2, EBNA-LP, and the EBNA3 family appeared to be under negative selection pressure, hinting towards a beneficial role of immune responses against these latency type III antigens in virus biology. These findings validate this immunoinformatics approach for providing novel insight into immune targets and the intricate relationship of host defense and virus evolution that may also pertain to other pathogens.
Spatial Variation in Primary Production in the Eastern Indian Ocean
Authors: Liu Haijiao , Song Yuyao , Zhang Xiaodong , Zhang Guicheng , Wu Chao , Wang Xingzhou , Thangaraj Satheeswaran , Wang Dongxiao , Chen Ju , Sun Jun
Published: December 2021

To examine the spatial pattern and controlling factors of the primary productivity (PP) of phytoplankton in the eastern Indian Ocean (EIO), deck-incubation carbon fixation (a 14C tracer technique) and the related hydrographic properties were measured at 15 locations during the pre-summer monsoon season (February–April 2017). There are knowledge gaps in the field observations of PP in the EIO. The estimated daily carbon production rates integrated over the photic zone ranged from 113 to 817 mgC m–2 d–1, with a mean of 522 mgC m–2 d–1. The mixed-layer integrated primary production (MLD-PP) ranged from 29.0 to 303.7 mgC m–2 d–1 (mean: 177.2 mgC m–2 d–1). The contribution of MLD-PP to the photic zone-integrated PP (PZI-PP) varied between 19 and 51% (mean: 36%). Strong spatial variability in the carbon fixation rates was found in the study region. Specifically, the surface primary production rates were relatively higher in the Bay of Bengal domain affected by riverine flux and lower in the equatorial domain owing to the presence of intermonsoonal Wyrtki jets, which were characterized by a depression of thermocline and nitracline. The PZI-PP exhibited a linear (positive) relationship with nutrient values, but with no significance, indicating a partial control of macronutrients and a light limitation of carbon fixation. As evident from the vertical profiles, the primary production process mainly occurred above the nitracline depth and at high photosynthetic efficiency. Phytoplankton (>5 μm), including dinoflagellates, Trichodesmium, coccolithophores, and dissolved nutrients, are thought to have been correlated with primary production during the study period. The measured on-deck biological data of our study allow for a general understanding of the trends in PP in the survey area of the EIO and can be incorporated into global primary production models.
Spring Ichthyoplankton Assemblage Structure in the Yangtze Estuary Under Environmental Factors
Authors: Wang Yibang , Liang Cui , Chen Zhaomin , Liu Shude , Zhang Hui , Xian Weiwei
Published: December 2021

Estuaries, where fresh and salty water converge, provide abundant nutrients for ichthyoplankton. Ichthyoplankton, including fish eggs, larvae, and juveniles, are important fishery recruitment resources. The Yangtze Estuary and its adjacent waters comprise a typical large-scale estuary and supply many important fish spawning, feeding, and breeding areas. In this study, 1,291 ichthyoplankton individuals were collected in the Yangtze Estuary in spring, from 2013 to 2020. The aims of the study were to provide detailed information on characteristics of the ichthyoplankton assemblage, explore interannual variation, and evaluate the effects of environmental variables on the temporal variation in assemblage structure. Twenty-six species in seventeen families were identified. The dominant species were Coilia mystus, Chelidonichthys spinosus, Engraulis japonicus, Hypoatherina valenciennei, Larimichthys polyactis, Salanx ariakensis, Stolephorus commersonnii, and Trachidermus fasciatus. The ichthyoplankton assemblage changed significantly over time, and Chelidonichthys spinosus became one of the dominant species. Canonical correspondence analysis showed that temperature and chlorophyll a were the key factors affecting the assemblage structure in the Yangtze Estuary in spring.
Surface Metrology Principles for Snow and Ice Friction Studies
Authors: Brown Christopher A.
Published: December 2021

Recent advances in surface metrology science are applied to understanding friction with snow and ice. Conventional surface metrology’s measurement, analyses, and characterizations, have inherent limitations for elucidating tribological interactions. Strong functional correlations and confident discriminations with slider surface topographies, textures, or “roughness”, have largely eluded researchers using conventional methods. Building on 4 decades of research using multiscale geometric methods, two surface metrology axioms and corollaries are proposed with good potential to provide new technological insights.
MRI-Based Radiomics for Differentiating Orbital Cavernous Hemangioma and Orbital Schwannoma
Authors: Chen Liang , Shen Ya , Huang Xiao , Li Hua , Li Jian , Wei Ruili , Yang Weihua
Published: December 2021

Aim: The purpose of this work was to develop and evaluate magnetic resonance imaging (MRI)-based radiomics for differentiation of orbital cavernous hemangioma (OCH) and orbital schwannoma (OSC).

Methods: Fifty-eight patients (40 OCH and 18 OSC, confirmed pathohistologically) screened out from 216 consecutive patients who presented between 2015 and 2020 were divided into a training group (28 OCH and 12 OSC) and a validation group (12 OCH and 6 OSC). Radiomics features were extracted from T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI). T-tests, the least absolute shrinkage and selection operator (LASSO), and principal components analysis (PCA) were used to select features for use in the classification models. A logistic regression (LR) model, support vector machine (SVM) model, decision tree (DT) model, and random forest (RF) model were constructed to differentiate OCH from OSC. The models were evaluated according to their accuracy and the area under the receiver operator characteristic (ROC) curve (AUC).

Results: Six features from T1WI, five features from T2WI, and eight features from combined T1WI and T2WI were finally selected for building the classification models. The models using T2WI features showed superior performance on the validation data than those using T1WI features, especially the LR model and SVM model, which showed accuracy of 93% (85–100%) and 92%, respectively, The SVM model showed high accuracy of 93% (91–96%) on the combined feature group with an AUC of 98% (97–99%). The DT and RF models did not perform as well as the SVM model.

Conclusion: Radiomics analysis using an SVM model achieved an accuracy of 93% for distinguishing OCH and OSC, which may be helpful for clinical diagnosis.
Effects of Phenyllactic Acid, Lactic Acid Bacteria, and Their Mixture on Fermentation Characteristics and Microbial Community Composition of Timothy Silage
Authors: Li Ping , Lu Yongxiang , Zhao Man , Chen Liangyin , Zhang Changbin , Cheng Qiming , Chen Chao
Published: December 2021

This study investigated the effects of phenyllactic acid (PL), lactic acid bacteria (LAB), and their mixture on fermentation characteristics and microbial community composition of timothy silage. Timothy silages were treated without (CK) or with PL [10 mg/kg fresh matter (FM) basis], LAB inoculant (IN; a mixture of Lactobacillus plantarum and L.buchneri, 105 cfu/g FM), and their mixture (PI) and stored at ambient temperature (5°C∼15°C) in a dark room for 60 days. Compared with CK, all treated silages showed lower (P < 0.05) levels of butyric acid and ammonia-N. Treatment with PL enhanced (P < 0.05) the crude protein preservation of silage by favoring the growth of L. curvatus and Saccharomyces cerevisiae and inhibition of lactic acid–assimilating yeast belonging to Issatchenkia during ensiling. In particular, treatment with PL advanced (P < 0.05) the productions of lactic acid and volatile fatty acid in IN-treated silage. Therefore, PL used as a new additive exhibited potential for improving silage fermentation when it is combined with LAB IN during ensiling.
Pediococcus pentosaceus: Screening and Application as Probiotics in Food Processing
Authors: Qi Yining , Huang Le , Zeng Yan , Li Wen , Zhou Diao , Xie Jianhua , Xie Junyan , Tu Qiang , Deng Dun , Yin Jia
Published: December 2021

Lactic acid bacteria (LAB) are vital probiotics in the food processing industry, which are widely spread in food additives and products, such as meat, milk, and vegetables. Pediococcus pentosaceus (P. pentosaceus), as a kind of LAB, has numerous probiotic effects, mainly including antioxidant, cholesterol-lowering, and immune effects. Recently, the applications in the probiotic- fermentation products have attracted progressively more attentions. However, it is necessary to screen P. pentosaceus with abundant functions from diverse sources due to the limitation about the source and species of P. pentosaceus. This review summarized the screening methods of P. pentosaceus and the exploration methods of probiotic functions in combination with the case study. The screening methods included primary screening and rescreening including gastric acidity resistance, bile resistance, adhesion, antibacterial effects, etc. The application and development prospects of P. pentosaceus were described in detail, and the shortcomings in the practical application of P. pentosaceus were evaluated to make better application of P. pentosaceus in the future.
Dimethyl Sulfoxide Enhances Kaposi’s Sarcoma-Associated Herpesvirus Production During Lytic Replication
Authors: Kang Su-Kyung , Lee Myung-Ju , Ryu Ho-Hyun , Lee Jisu , Lee Myung-Shin
Published: December 2021

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an etiologic agent of Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman disease. In studies of KSHV, efficient virus production and isolation are essential. Reactivation of KSHV can be initiated by treating latently infected cells with chemicals, such as 12-O-tetradecanoyl-phorbol-13-acetate and sodium butyrate. These chemicals have been used as tools to induce lytic replication and viral production in KSHV-producing cell lines. Dimethyl sulfoxide (DMSO) is an organosulfur compound that is frequently used as an aprotic solvent similar to water. In experiments exploring signaling pathways in KSHV-infected cells, DMSO treatment alone as a vehicle affected the lytic gene expression of KSHV. However, to the best of our knowledge, the effects of DMSO on KSHV-producing cells have not yet been reported. Therefore, in this study, we investigated whether DMSO could be used as a reagent to enhance viral production during lytic replication in KSHV-producing cells and assessed the underlying mechanisms. The effects of DMSO on KSHV production were analyzed in iSLK BAC16 cells, which have been widely used for recombinant KSHV production. We found that the production of KSHV virions was significantly increased by treatment with DMSO during the induction of lytic replication. Mechanistically, lytic genes of KSHV were enhanced by DMSO treatment, which was correlated with virion production. Additionally, DMSO induced the phosphorylation of JNK during lytic replication, and inhibition of JNK abolished the effects of DMSO on lytic replication and virion production. Our findings showed that additional treatment with DMSO during the induction of lytic replication significantly improved the yield of KSHV production.
Expression, Localization, and Protein Interactions of the Partitioning Proteins in the Gonococcal Type IV Secretion System
Authors: Callaghan Melanie M. , Koch Birgit , Hackett Kathleen T. , Klimowicz Amy K. , Schaub Ryan E. , Krasnogor Natalio , Dillard Joseph P.
Published: December 2021

Partitioning proteins are well studied as molecular organizers of chromosome and plasmid segregation during division, however little is known about the roles partitioning proteins can play within type IV secretion systems. The single-stranded DNA (ssDNA)-secreting gonococcal T4SS has two partitioning proteins, ParA and ParB. These proteins work in collaboration with the relaxase TraI as essential facilitators of type IV secretion. Bacterial two-hybrid experiments identified interactions between each partitioning protein and the relaxase. Subcellular fractionation demonstrated that ParA is found in the cellular membrane, whereas ParB is primarily in the membrane, but some of the protein is in the soluble fraction. Since TraI is known to be membrane-associated, these data suggest that the gonococcal relaxosome is a membrane-associated complex. In addition, we found that translation of ParA and ParB is controlled by an RNA switch. Different mutations within the stem-loop sequence predicted to alter folding of this RNA structure greatly increased or decreased levels of the partitioning proteins.
Circadian Clock Genes Modulate Immune, Cell Cycle and Apoptosis in the Diagnosis and Prognosis of Pan-Renal Cell Carcinoma
Authors: Liu Shuwen , Cheng Yongxian , Wang Shaoxiang , Liu Huiyu
Published: December 2021

Background: Pan-renal cell carcinoma (pan-RCC) is mainly divided into renal clear cell carcinoma (KIRC), renal papillary cell carcinoma (KIRP), and chromophobe cell carcinoma (KICH). Pan-RCC is a common malignant neoplasm with a high incidence and poor prognosis. Several studies have demonstrated a close association between cancer development and circadian rhythms; however, the clinical significance and molecular mechanism of the clock gene remain unclear in pan-RCC.

Methods: In this study, we systematically characterized the alterations of 15 well-known clock genes of three types of kidney cancer. Bioinformatics methods, including differential expression analysis, survival analysis, signing pathway analysis, co-expression network analysis, and drug sensitivity analysis were used to study the diagnosis, prognostic role, and mechanism of clock genes.

Results: Thirteen rhythmic genes fluctuated in circadian rhythm in the kidney tissue of mice, and the opposite trend of these rhythm phases was also found in baboons. There are twelve clock genes that were differentially expressed in at least two types of RCC, of which NR1D1, DBP, BHLHE40, CRY1, and CLOCK had the same trend in RCC. Changes in clock control genes may be regulated through methylation, copy number, and mutations. Five rhythmic genes, including PER2, DBP, PER3, CRY2, and RORA, have significant prognostic role in patient survival in at least two types of kidney cancer. Immune infiltration analysis showed that the expression of these rhythmic genes related to prognosis was positively correlated with the infiltration levels of CD4 and CD8 T cells. Pathway analysis suggests that the clock genes is widely related to cancer-related signaling pathways, such as apoptosis, cell cycle, and other pathways. The PPI network showed that circadian genes are closely linked to cancer-related genes such as HIF-1A, TP53, and ERBB2. Moreover, clock gene expression is correlated with the sensitivity of anticancer drugs such as bleomycin and methotrexate in pan-RCC.

Conclusion: Taken together, the abnormal expression of biological clock genes plays an important role in the clinical prognosis of RCC through immunity, cell cycle, and apoptosis. These findings provide a reliable basis for the diagnosis, prognosis, and drug guidance for RCC.
Lesion Distribution and Early Changes of Right Hemisphere in Chinese Patients With Post-stroke Aphasia
Authors: Fan Ruiwen , Gao Ying , Zhang Hua , Xin Xiyan , Sang Feng , Tan Zhongjian , Zhang Binlong , Li Xiaolin , Huang Xing , Li Shuren , Chang Jingling
Published: December 2021

The role of the right hemisphere (RH) in post-stroke aphasia (PSA) has not been completely understood. In general, the language alterations in PSA are normally evaluated from the perspective of the language processing models developed from Western languages such as English. However, the successful application of the models for assessing Chinese-language functions in patients with PSA has not been reported. In this study, the features of specific language-related lesion distribution and early variations of structure in RH in Chinese patients with PSA were investigated. Forty-two aphasic patients (female: 13, male: 29, mean age: 58 ± 12 years) with left hemisphere (LH) injury between 1 and 6 months after stroke were included. The morphological characteristics, both at the levels of gray matter (GM) and white matter (WM), were quantified by 3T multiparametric brain MRI. The Fridriksson et al.’s dual-stream model was used to compare language-related lesion regions. Voxel-based lesion-symptom mapping (VLSM) analysis has been performed. Our results showed that lesions in the precentral, superior frontal, middle frontal, and postcentral gyri were responsible for both the production and comprehension dysfunction of Chinese patients with PSA and were quite different from the lesions described by using the dual-stream model of Fridriksson et al. Furthermore, gray matter volume (GMV) was found significantly decreased in RH, and WM integrity was disturbed in RH after LH injury in Chinese patients with PSA. The different lesion patterns between Chinese patients with PSA and English-speaking patients with PSA may indicate that the dual-stream model of Fridriksson et al. is not suitable for the assessment of Chinese-language functions in Chinese patients with PSA in subacute phase of recovery. Moreover, decreased structural integrity in RH was found in Chinese patients with PSA.
Design and Development of a Mobile Health (mHealth) Platform for Dementia Prevention in the Prevention of Dementia by Mobile Phone Applications (PRODEMOS) Project
Authors: Hafdi Melanie , Eggink Esmé , Hoevenaar-Blom Marieke P. , Witvliet M. Patrick , Andrieu Sandrine , Barnes Linda , Brayne Carol , Brooks Rachael , Coley Nicola , Georges Jean , van der Groep Abraham , van Marwijk Harm , van der Meijden Mark , Song Libin , Song Manshu , Wang Youxin , Wang Wenzhi , Wang Wei , Wimo Anders , Ye Xiaoyan , Moll van Charante Eric P. , Richard Edo
Published: December 2021

Background: Mobile health (mHealth) has the potential to bring preventive healthcare within reach of populations with limited access to preventive services, by delivering personalized support at low cost. Although numerous mHealth interventions are available, very few have been developed following an evidence-based rationale or have been tested for efficacy. This article describes the systematic development of a coach-supported mHealth application to improve healthy lifestyles for the prevention of dementia and cardiovascular disease in the United Kingdom (UK) and China.

Methods: Development of the Prevention of Dementia by Mobile Phone applications (PRODEMOS) platform built upon the experiences with the Healthy Aging Through Internet Counseling in the Elderly (HATICE) eHealth platform. In the conceptualization phase, experiences from the HATICE trial and needs and wishes of the PRODEMOS target population were assessed through semi-structured interviews and focus group sessions. Initial technical development of the platform was based on these findings and took place in consecutive sprint sessions. Finally, during the evaluation and adaptation phase, functionality and usability of the platform were evaluated during pilot studies in UK and China.

Results: The PRODEMOS mHealth platform facilitates self-management of a healthy lifestyle by goal setting, progress monitoring, and educational materials on healthy lifestyles. Participants receive remote coaching through a chat functionality. Based on lessons learned from the HATICE study and end-users, we made the intervention easy-to-use and included features to personalize the intervention. Following the pilot studies, in which in total 77 people used the mobile application for 6 weeks, the application was made more intuitive, and we improved its functionalities.

Conclusion: Early involvement of end-users in the development process and during evaluation phases improved acceptability of the mHealth intervention. The actual use and usability of the PRODEMOS intervention will be assessed during the ongoing PRODEMOS randomized controlled trial, taking a dual focus on effectiveness and implementation outcomes.
Sustained Loss of Bdnf Affects Peripheral but Not Central Vestibular Targets
Authors: Elliott Karen L. , Kersigo Jennifer , Lee Jeong Han , Yamoah Ebenezer N. , Fritzsch Bernd
Published: December 2021

The vestibular system is vital for proper balance perception, and its dysfunction contributes significantly to fall-related injuries, especially in the elderly. Vestibular ganglion neurons innervate vestibular hair cells at the periphery and vestibular nuclei and the uvula and nodule of the cerebellum centrally. During aging, these vestibular ganglion neurons degenerate, impairing vestibular function. A complete understanding of the molecular mechanisms involved in neurosensory cell survival in the vestibular system is unknown. Brain-derived neurotrophic factor (BDNF) is specifically required for the survival of vestibular ganglion neurons, as its loss leads to early neuronal death. Bdnf null mice die within 3 weeks of birth, preventing the study of the long-term effects on target cells. We use Pax2-cre to conditionally knock out Bdnf, allowing mice survival to approximately 6 months of age. We show that a long-term loss of Bdnf leads to a significant reduction in the number of vestibular ganglion neurons and a reduction in the number of vestibular hair cells. There was no significant decrease in the central targets lateral vestibular nucleus (LVN) or the cerebellum at 6 months. This suggests that the connectivity between central target cells and other neurons suffices to prevent their loss despite vestibular hair cell and ganglion neuron loss. Whether the central neurons would undergo eventual degeneration in the absence of Bdnf remains to be determined.
Stroke Epidemiology, Care, and Outcomes in Kenya: A Scoping Review
Authors: Waweru Peter , Gatimu Samwel Maina
Published: December 2021

Background: Stroke is a leading cause of death and disability in sub-Saharan Africa with increasing incidence. In Kenya, it is a neglected condition with a paucity of evidence despite its need for urgent care and hefty economic burden. Therefore, we reviewed studies on stroke epidemiology, care, and outcomes in Kenya to highlight existing evidence and gaps on stroke in Kenya.

Methods: We reviewed all published studies on epidemiology, care, and outcomes of stroke in Kenya between 1 January 1990 to 31 December 2020 from PubMed, Web of Science, EBSCOhost, Scopus, and African journal online. We excluded case reports, reviews, and commentaries. We used the Newcastle-Ottawa scale adapted for cross-sectional studies to assess the quality of included studies.

Results: Twelve articles were reviewed after excluding 111 duplicates and 94 articles that did not meet the inclusion criteria. Five studies were of low quality, two of medium quality, and five of high quality. All studies were hospital-based and conducted between 2003 and 2017. Of the included studies, six were prospective and five were single-center. Stroke patients in the studies were predominantly female, in their seventh decade with systemic hypertension. The mortality rate ranged from 5 to 27% in-hospital and 23.4 to 26.7% in 1 month.

Conclusions: Our study highlights that stroke is a significant problem in Kenya, but current evidence is of low quality and limited in guiding policy development and improving stroke care. There is thus a need for increased investment in hospital- and community-based stroke care and research.
3D U-Net Improves Automatic Brain Extraction for Isotropic Rat Brain Magnetic Resonance Imaging Data
Authors: Hsu Li-Ming , Wang Shuai , Walton Lindsay , Wang Tzu-Wen Winnie , Lee Sung-Ho , Shih Yen-Yu Ian
Published: December 2021

Brain extraction is a critical pre-processing step in brain magnetic resonance imaging (MRI) analytical pipelines. In rodents, this is often achieved by manually editing brain masks slice-by-slice, a time-consuming task where workloads increase with higher spatial resolution datasets. We recently demonstrated successful automatic brain extraction via a deep-learning-based framework, U-Net, using 2D convolutions. However, such an approach cannot make use of the rich 3D spatial-context information from volumetric MRI data. In this study, we advanced our previously proposed U-Net architecture by replacing all 2D operations with their 3D counterparts and created a 3D U-Net framework. We trained and validated our model using a recently released CAMRI rat brain database acquired at isotropic spatial resolution, including T2-weighted turbo-spin-echo structural MRI and T2*-weighted echo-planar-imaging functional MRI. The performance of our 3D U-Net model was compared with existing rodent brain extraction tools, including Rapid Automatic Tissue Segmentation, Pulse-Coupled Neural Network, SHape descriptor selected External Regions after Morphologically filtering, and our previously proposed 2D U-Net model. 3D U-Net demonstrated superior performance in Dice, Jaccard, center-of-mass distance, Hausdorff distance, and sensitivity. Additionally, we demonstrated the reliability of 3D U-Net under various noise levels, evaluated the optimal training sample sizes, and disseminated all source codes publicly, with a hope that this approach will benefit rodent MRI research community.

Significant Methodological Contribution: We proposed a deep-learning-based framework to automatically identify the rodent brain boundaries in MRI. With a fully 3D convolutional network model, 3D U-Net, our proposed method demonstrated improved performance compared to current automatic brain extraction methods, as shown in several qualitative metrics (Dice, Jaccard, PPV, SEN, and Hausdorff). We trust that this tool will avoid human bias and streamline pre-processing steps during 3D high resolution rodent brain MRI data analysis. The software developed herein has been disseminated freely to the community.
Capping Protein Regulator and Myosin 1 Linker 3 (CARMIL3) as a Molecular Signature of Ischemic Neurons in the DWI-T2 Mismatch Areas After Stroke
Authors: Yeh Shin-Joe , Hsu Pang-Hung , Yeh Ti-Yen , Yang Wei-Kang , Chang Ko-Ping , Chiang Chien-Sung , Tang Sung-Chun , Tsai Li-Kai , Jeng Jiann-Shing , Hsieh Sung-Tsang
Published: December 2021

Ischemic stroke with a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) or T2-weighted images indicates onset within 4.5 h, but the pathological substrates in the DWI-T2 mismatch and T2(+) areas remain elusive. In this study, proteomics was used to explore (1) the protein expression profiles in the T2(+), mismatch, and contralateral areas, and (2) the protein with the highest expression in the T2(+) area in the brains of male Sprague-Dawley rats within 4.5 h after middle cerebral artery occlusion (MCAO). The expression of the candidate protein was further validated in (1) rat brain subjected to MCAO, (2) rat primary cortical neuronal culture with oxygen-glucose deprivation (OGD), and (3) infarcted human brain tissues. This study showed that apoptosis was observed in the T2(+) and mismatch regions and necroptosis in the T2(+) region of rat brains after MCAO. We identified capping protein regulator and myosin 1 linker 3 (CARMIL3) as the candidate molecule in the T2(+) and mismatch areas, exclusively in neurons, predominantly in the cytoplasm, and most abundant in the mismatch area. The CARMIL3(+) neurons and neurites in the mismatch and T2(+) areas were larger than those in the control area, and associated with (1) increased expression of sulfonylurea receptor 1 (SUR1), indicating edema, (2) accumulation of p62, indicating impaired autophagy, and (3) increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG), indicating oxidative stress. The increased expression of CARMIL3 was validated in a cell model of cortical neurons after OGD and in infarcted human brain tissues. In conclusion, this study shows that the mismatch and T2(+) areas within 4.5 h after ischemia are characterized by upregulated expression of CARMIL3 in neurons, particularly the mismatch area, which is associated with neuronal edema, impaired autophagy, and oxidative stress, indicating that CARMIL3 serves as a molecular signature of brain ischemia.
Antimicrobial Effect of a Proteolytic Enzyme From the Fruits of Solanum granuloso-leprosum (Dunal) Against Helicobacter pylori
Authors: Salinas Ibáñez Ángel Gabriel , Vallés Diego , Adaro Mauricio , Barberis Sonia , Vega Alba E.
Published: December 2021

Helicobacter pylori is a gram-negative, helix-shaped, and microaerophilic bacteria that colonizes the human gastric mucosa, causing chronic infections, gastritis, peptic ulcer, lymphomas associated with lymphoid mucosa tissue, and gastric cancer. H. pylori is considered a Type 1 human carcinogen by WHO. The prevalence of the infection is estimated in more than half of the world population. Treatment of H. pylori infection includes antibiotics and proton pump inhibitors, but the increasing antibiotic resistance promotes the research of novel, more effective, and natural antibacterial compounds. The aim of this work was to study the effect of the partially purified proteolytic extract (RAP) of the fruits from Solanum granuloso-leprosum (Dunal), a South American native plant, and a purified fraction named granulosain I, against H. pylori, to obtain natural food additives for the production of anti-H. pylori functional foods. Furthermore, granulosain I and RAP could be used as natural adjuncts to conventional therapies. Granulosain I and RAP antibacterial activity was evaluated as minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against H. pylori NCTC 11638 (reference strain) and twelve H. pylori wild strains, using a microdilution plating technique (Clinical and Laboratory Standards Institute). All the strains tested were susceptible to granulosain I with MIC from 156.25 to 312.5 μg/mL and MBC from 312.5 to 625 μg/mL, respectively. Besides, all the strains tested were susceptible to the RAP with MIC from 312.5 to 625 μg/mL and MBC from 625 to 1,250 μg/mL, respectively. The effect of granulosain I and RAP on the transcription of H. pylori genes encoding pathogenic factors, omp18, ureA, and flaA, with respect to a housekeeping gene (16S rRNA), was evaluated by RT-PCR technique. The band intensity between pathogenic factors and control gene was correlated under treated or untreated conditions, using the ImageJ program. Granulosain I and RAP significantly decreased the expression of pathogenic factors: omp18, ureA, and flaA. The combined inhibitory effect of granulosain I or RAP and an antibiotic such as, amoxicillin (AML, 10 μg), clarithromycin (CLA, 15 μg), levofloxacin (LEV, 5 μg), and metronidazole (MTZ, 5 μg) was evaluated, using the agar diffusion technique. Granulosain I and RAP showed significant synergistic effect on AML, CLA, and LEV, but no significant effect on MTZ was observed. Besides, granulosain I and RAP did not show toxicological effects at the concentrations studied. Finally, granulosain I and RAP could be used as safe natural food additives and as adjuvants for conventional therapies against H. pylori.
Organic Food Consumption During the Complementary Feeding Period and Respiratory or Allergic Diseases Up to Age 5.5 Years in the ELFE Cohort
Authors: Payet David , Adjibade Moufidath , Baudry Julia , Ghozal Manel , Camier Aurore , Nicklaus Sophie , Adel-Patient Karine , Divaret-Chauveau Amandine , Gauvreau-Béziat Julie , Vin Karine , Lioret Sandrine , Charles Marie Aline , Kesse-Guyot Emmanuelle , de Lauzon-Guillain Blandine
Published: December 2021

Objectives: To assess (1) whether a history of allergy is associated with feeding with organic foods (OFs) during the complementary feeding period and (2) whether OF consumption in infancy is related to the incidence of respiratory and allergic diseases up to age 5.5 years.

Study Design: Analyses involved more than 8,000 children from the nationwide Étude Longitudinale Française depuis l'Enfance (ELFE) birth cohort. Associations between family or infant history of allergy and frequency of OF consumption during the complementary feeding period were assessed with multinomial logistic regression. Associations between OF consumption in infancy and respiratory or allergic diseases between age 1 and 5.5 years were assessed with logistic regression.

Results: A family history of allergy or cow's milk protein allergy at age 2 months was strongly and positively related to feeding with OF during the complementary feeding period. Feeding with OF during the complementary feeding period was not related to respiratory diseases or eczema up to age 5.5 years. Compared to infrequent consumption of both organic and commercial complementary foods, frequent OF consumption without commercial complementary foods was associated with a higher risk of food allergy, whereas frequent commercial complementary food consumption without OF use was associated with a lower risk of food allergy.

Conclusions: This study suggests that a history of allergy strongly affects feeding with OF during the complementary feeding period. However, OF consumption was not associated with reduced odds of food allergy later in childhood but could be associated with increased odds, which should be examined more deeply.
Evolution of Nutritional Habits Behaviour of Spanish Population Confined Through Social Media
Authors: Mariscal-Arcas Miguel , Delgado-Mingorance Sonia , Saenz de Buruaga Borja , Blas-Diaz Alba , Latorre Jose Antonio , Martinez-Bebia Manuel , Gimenez-Blasi Nuria , Conde-Pipo Javier , Cantero Leticia , Lopez-Moro Alejandro , Jimenez-Casquet Maria Jose
Published: December 2021

Introduction: In Spain, on 14 March 2020, a state of alarm is declared to face the health emergency situation caused by the COVID-19 coronavirus, limiting the freedom of movement of people. The Spanish population is confined.

Objective: With this situation, “NUTRITIONAL HEALTH IS NOT CONFINED” arises a research project that seeks to promote nutritional education based on the pattern of the Mediterranean diet (MD) using new computer technologies. It is about providing the population with the information of general interest about the promotion of a healthy diet through social networks and analysing the impact of its dissemination, in the form of a longitudinal intervention study of the Spanish nutritional evolution during confinement, with a daily survey format, and it is intended to assess food consumption during the period of confinement. Materials and methods: In total, 936 participants were asked every day. Short publications were published every day based on the scientific evidence (FAO, WHO, AECOSAN) through social media such as Instagram, accompanied by a questionnaire of 11 questions (yes/no) where it was intended to assess the evolution of daily consumption.

Results and Discussion: The diffusion through social media has allowed to have a greater reach of the population. We observed that mood throughout confinement generally improves. There are certain eating habits from the MD that are well established in the daily diet of our population, such as the consumption of fruits, vegetables, legumes, dairy products, and eggs. It seems that enjoying good health is a growing concern in pandemic situations, which is why inappropriate behaviours such as “snacking” between meals or the consumption of processed foods such as snacks, industrial pastries, soft drinks, and sweets are avoided, increasing the amount of healthy food such as meat and fish. This study opens up future avenues of research promoting MD and implements new cohort nutritional databases, especially about young adult people, who are adept at navigating digital spaces and therefore using social media.