bluuebunny/crossref_metadata_2025 huggingface dataset:
Biased Random Walk With Restart on Multilayer Heterogeneous Networks for MiRNA–Disease Association Prediction
Authors: Qu Jia , Wang Chun-Chun , Cai Shu-Bin , Zhao Wen-Di , Cheng Xiao-Long , Ming Zhong
Published: August 2021

Numerous experiments have proved that microRNAs (miRNAs) could be used as diagnostic biomarkers for many complex diseases. Thus, it is conceivable that predicting the unobserved associations between miRNAs and diseases is extremely significant for the medical field. Here, based on heterogeneous networks built on the information of known miRNA–disease associations, miRNA function similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases, we developed a computing model of biased random walk with restart on multilayer heterogeneous networks for miRNA–disease association prediction (BRWRMHMDA) through enforcing degree-based biased random walk with restart (BRWR). Assessment results reflected that an AUC of 0.8310 was gained in local leave-one-out cross-validation (LOOCV), which proved the calculation algorithm’s good performance. Besides, we carried out BRWRMHMDA to prioritize candidate miRNAs for esophageal neoplasms based on HMDD v2.0. We further prioritize candidate miRNAs for breast neoplasms based on HMDD v1.0. The local LOOCV results and performance analysis of the case study all showed that the proposed model has good and stable performance.
Retinoic Acid Induces Functionally Suppressive Foxp3+RORγt+ T Cells In Vitro
Authors: Martínez-Blanco Mónica , Lozano-Ojalvo Daniel , Pérez-Rodríguez Leticia , Benedé Sara , Molina Elena , López-Fandiño Rosina
Published: August 2021

Introduction

CD4+ T cells with regulatory function co-expressing Foxp3 and RORγt are linked to the development of oral tolerance towards innocuous food antigens in mice. This study aimed to discern the role played by IL-6 and retinoic acid (RA) in the in vitro generation of Foxp3+RORγt+ T cells and to investigate whether such cells have suppressive properties.

Methods

CD4+CD25- T cells isolated from the spleen of BALB/c mice, were stimulated in the presence of IL-2 alone or together with TFG-β and different concentrations of IL-6 and/or RA. Percentage of Foxp3+, RORγt+, IL-17+, Foxp3+RORγt-, Foxp3+RORγt+, and Foxp3-RORγt+ T cells within the total CD4+ T cell population, production of cytokines (IL-10 and IL-17A) and gene expression (Foxp3, Rorc, Tgfb1, Il6, Il10, and Il17) were assessed at different time points. The phenotype and ability of cells generated from CD4+CD44-CD62L+ cells in the presence of RA to suppress effector T cell proliferation was assessed.

Results

TGF-β plus IL-6 induced the generation of Foxp3+ and double positive Foxp3+RORγt+ T cells to a higher extent than TGF-β alone at the beginning of the incubation period, although expression of Foxp3 subsequently declined. RA, added to TGF-β, increased Foxp3 and Rorc expression and Foxp3 and RORγt transcription and promoted the differentiation of Foxp3+RORγt- and Foxp3+RORγt+ cells that expressed and secreted IL-17. Foxp3+ T cells generated in vitro in presence of RA were functionally suppressive.

Conclusions

Under the influence of IL-2 and TGF-β, suppressive Foxp3+RORγt+ T cells that express and secrete IL-17 can be produced in vitro and RA further contributes to stabilize this phenotype.
Safety Assessment of Microbicide 2P23 on the Rectal and Vaginal Microbiota and Its Antiviral Activity on HIV Infection
Authors: Gao Zhengqin , Fu Rui , Li Xiaobo , Wang Ji , He Yuxian
Published: August 2021

Containment of the AIDS pandemic requires reducing HIV transmission. HIV infection is initiated by the fusion of the membrane between the virus and the cell membrane of the host. 2P23 is an effective HIV membrane fusion inhibitor that may be a good entry inhibitor microbicide candidate. This study evaluated the potential of using gel-formulated 2P23 as a topical microbicide to prevent sexual transmission of HIV in the rectum and vagina. Our data revealed that 2P23 formulated in gel is effective against HIV. There was no change in antiviral activity at 25°C for 4 months or 60°C for 1 week. In addition, we demonstrated that the 2P23 gel was stable and fully functional at pH 4.0–8.0 and under different concentrations of H2O2. Finally, the 2P23 gel exhibited no cytotoxicity or antimicrobial activity and did not induce inflammatory changes in the rectal or vaginal mucosal epithelium in New Zealand rabbits after 20 mg/day daily rectovaginal application for 14 consecutive days. Despite repeated tissue sampling and 2P23 gel treatment, the inflammatory cytokines and microbiota of the rectum and vagina remained stable. These results add to general knowledge on the in vivo evaluation of anti-HIV microbicide application concerning inflammatory cytokines and microbiota changes in the rectum and vagina. These findings suggest that the 2P23 gel is an excellent candidate for further development as a safe and effective pre-exposure prophylactic microbicide for the prevention of HIV transmission.
COVID-19 Vaccination in Fragile Patients: Current Evidence and an Harmonized Transdisease Trial
Authors: Agrati Chiara , Di Cosimo Serena , Fenoglio Daniela , Apolone Giovanni , Ciceri Fabio , Ciliberto Gennaro , Baldanti Fausto , Costantini Massimo , Giannarelli Diana , Ippolito Giuseppe , Locatelli Franco , Mantovani Alberto , Morrone Aldo , Tagliavini Fabrizio , Uccelli Antonio , Zinzani Pier Luigi , Silvestris Nicola , Rescigno Maria
Published: August 2021

Patients diagnosed with malignancy, neurological and immunological disorders, i.e., fragile patients, have been excluded from COVID-19 vaccine trials. However, this population may present immune response abnormalities, and relative reduced vaccine responsiveness. Here we review the limited current evidence on the immune responses to vaccination of patients with different underlying diseases. To address open questions we present the VAX4FRAIL study aimed at assessing immune responses to vaccination in a large transdisease cohort of patients with cancer, neurological and rheumatological diseases.
SARS-CoV-2 Proteome Harbors Peptides Which Are Able to Trigger Autoimmunity Responses: Implications for Infection, Vaccination, and Population Coverage
Authors: Karami Fath Mohsen , Jahangiri Abolfazl , Ganji Mahmoud , Sefid Fatemeh , Payandeh Zahra , Hashemi Zahra Sadat , Pourzardosht Navid , Hessami Anahita , Mard-Soltani Maysam , Zakeri Alireza , Rahbar Mohammad Reza , Khalili Saeed
Published: August 2021

Autoimmune diseases (ADs) could occur due to infectious diseases and vaccination programs. Since millions of people are expected to be infected with SARS-CoV-2 and vaccinated against it, autoimmune consequences seem inevitable. Therefore, we have investigated the whole proteome of the SARS-CoV-2 for its ability to trigger ADs. In this regard, the entire proteome of the SARS-CoV-2 was chopped into more than 48000 peptides. The produced peptides were searched against the entire human proteome to find shared peptides with similar experimentally confirmed T-cell and B-cell epitopes. The obtained peptides were checked for their ability to bind to HLA molecules. The possible population coverage was calculated for the most potent peptides. The obtained results indicated that the SARS-CoV-2 and human proteomes share 23 peptides originated from ORF1ab polyprotein, nonstructural protein NS7a, Surface glycoprotein, and Envelope protein of SARS-CoV-2. Among these peptides, 21 peptides had experimentally confirmed equivalent epitopes. Amongst, only nine peptides were predicted to bind to HLAs with known global allele frequency data, and three peptides were able to bind to experimentally confirmed HLAs of equivalent epitopes. Given the HLAs which have already been reported to be associated with ADs, the ESGLKTIL, RYPANSIV, NVAITRAK, and RRARSVAS were determined to be the most harmful peptides of the SARS-CoV-2 proteome. It would be expected that the COVID-19 pandemic and the vaccination against this pathogen could significantly increase the ADs incidences, especially in populations harboring HLA-B*08:01, HLA-A*024:02, HLA-A*11:01 and HLA-B*27:05. The Southeast Asia, East Asia, and Oceania are at higher risk of AD development.
The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation In Vitro
Authors: Gaunt Christopher M. , Rainbow Daniel B. , Mackenzie Ruairi J. , Jarvis Lorna B. , Mousa Hani S. , Cunniffe Nicholas , Georgieva Zoya , Brown J. William , Coles Alasdair J. , Jones Joanne L.
Published: August 2021

The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (atRA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of atRA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.
Proteomics Mapping of the ISGylation Landscape in Innate Immunity
Authors: Thery Fabien , Eggermont Denzel , Impens Francis
Published: August 2021

During infection, pathogen sensing and cytokine signaling by the host induce expression of antimicrobial proteins and specialized post-translational modifications. One such protein is ISG15, a ubiquitin-like protein (UBL) conserved among vertebrates. Similar to ubiquitin, ISG15 covalently conjugates to lysine residues in substrate proteins in a process called ISGylation. Mice deficient for ISGylation or lacking ISG15 are strongly susceptible to many viral pathogens and several intracellular bacterial pathogens. Although ISG15 was the first UBL discovered after ubiquitin, the mechanisms behind its protective activity are poorly understood. Largely, this stems from a lack of knowledge on the ISG15 substrate repertoire. To unravel the antiviral activity of ISG15, early studies used mass spectrometry-based proteomics in combination with ISG15 pulldown. Despite reporting hundreds of ISG15 substrates, these studies were unable to identify the exact sites of modification, impeding a clear understanding of the molecular consequences of protein ISGylation. More recently, a peptide-based enrichment approach revolutionized the study of ubiquitin allowing untargeted discovery of ubiquitin substrates, including knowledge of their exact modification sites. Shared molecular determinants between ISG15 and ubiquitin allowed to take advantage of this technology for proteome-wide mapping of ISG15 substrates and modification sites. In this review, we provide a comprehensive overview of mass spectrometry-based proteomics studies on protein ISGylation. We critically discuss the relevant literature, compare reported substrates and sites and make suggestions for future research.
Aerosol Induced Changes in Sea Surface Temperature Over the Bay of Bengal Due to COVID-19 Lockdown
Authors: Sarin T. S. , Vinoj V. , Swain D. , Landu K. , Suhas E.
Published: August 2021

The role of COVID-19 pandemic lockdown in improving air quality was reported extensively for land regions globally. However, limited studies have explored these over oceanic areas close to high anthropogenic activities and emissions. The Bay of Bengal (BoB) basin is one such region adjacent to the highly populated South Asian region. We find that Aerosol Optical Depth (AOD) over the BoB declined by as much as 0.1 or 30% during the peak lockdown of April 2020 compared to long-term climatology during 2003–2019. Simultaneously, the sea surface temperature (SST) rose by 0.5–1.5°C over the central and north-western parts of the BoB with an average increase of 0.83°C. We show that up to 30% of this observed warming is attributable to reduced atmospheric aerosols. The study highlights the importance of anthropogenic emissions reduction due to COVID lockdown on short-term changes to SST over ocean basins with implications to regional weather.
Bacterial and Fungal Diversity in Sediment and Water Column From the Abyssal Regions of the Indian Ocean
Authors: Barnes Natasha Maria , Damare Samir R. , Shenoy Belle Damodara
Published: August 2021

The deep sea is the largest environment on Earth, comprising important resources of commercial interest. It is composed of a wide variety of ecosystems, which is home to often unique organisms that are yet to be described. The deep-sea is one of the least studied environments, where research is strongly linked to technological access and advances. With the recent advances in the next-generation sequencing and bioinformatics tools, there is an enhanced understanding of microbial diversity and ecological functions in deep sea. Multidisciplinary programs are being undertaken to investigate into microbial communities in diverse marine environments. As compared to other Oceans, the deeper parts of Indian Ocean are still poorly sampled and studied for bacterial, and more so fungal diversity. The studies reporting usage of modern sequencing tools to describe uncultured microbial diversity have seen a rise in numbers in the last decade. In this review, we summarize the important findings of research works carried on bacterial and fungal diversity from the abyssal regions of the Indian Ocean and provide our views on possible future paths.
Surface and Size Effects on the Behaviors of Point Defects in Irradiated Crystalline Solids
Authors: Ozturk Abdurrahman , Gencturk Merve , Ahmed Karim
Published: August 2021

We present an elaborate study of the surface and size effects on the transient and steady-state behaviors of point defects in irradiated solids. In this investigation, both pure Ni and binary Ni-Cr were utilized as model systems. We utilize the spatially-resolved rate-theory (SRRT) modeling approach, and directly account for the effects of dose rate, production bias, and defects recombination, reactions with volumetric sinks, and diffusion to surface sinks. Several simulations were conducted to investigate the effects of these parameters in both coupled and decoupled manners. In the presence of production bias, the effects of surface and size persist even as the surface to volume ratio decreases. This was associated with a surface-induced and size-regulated instability. This instability is only triggered above a critical size between 100 and 500 nm. The critical size decreases with increasing dose rate, increasing production bias, or lowering the temperature. Moreover, this instability results in a pattern that favors the separation of vacancies and interstitials. Once this pattern develops, anomalies in the dependence on size for the transient and steady-state concentrations of point defects and the surface/boundary sink strength are observed. These anomalies tend to render irradiation damage more severe. For pure Ni, it was shown that vacancy supersaturation increases with size, and the rate of increase also rises with size. For the binary Ni-Cr system, it was shown that the magnitude of enrichment/depletion of Ni/Cr at the boundary increases with size, and the width of the enrichment/depletion layer also increases with size. The results obtained here agree well with experimental observations in irradiated materials such as the formation of void denuded zones adjacent to grain boundaries and the size and temperature dependence of the radiation resistance of nanomaterials. The size-dependent behaviors reported here also shed new light on the radiation tolerance of nanomaterials, i.e., the irradiation-induced instabilities are suppressed in such materials. Lastly, the implications of the results obtained here on the development of efficient reduced order models or the utilization of ion irradiation as a surrogate to neutron irradiation are discussed.
Computational Geometry-Based 3D Yarn Path Modeling of Wound SiCf/SiC-Cladding Tubes and Its Application to Meso-Scale Finite Element Model
Authors: Tang Jianbo , Zhao Gang , Wang Jun , Ding Yue , Feng Yajie , Chen Yunsheng , Zhang Chao , Huang Qing , Xin Shiqing , Xu Jian
Published: August 2021

The filament winding process is a competitive performing technology for nuclear fuel cladding tubes due to its high automation. The study of the yarn path on the mandrel surface is vital to design and produce the cladding tube with the desired mechanical properties, reducing manufacturing time and costs. The geodesic and semi-geodesic trajectories are used to create a 3D yarn path in this paper. A 3D yarn path optimization method based on the principle of minimum potential energy is proposed to simulate the overlap effect in accord with the real winding process. The finite element (FE) mesh based on the 3D yarn path has been used for the mechanical analysis of the cladding tube. The embedded region constraint is applied to define the interaction between the matrix mesh and the yarn mesh to model the meso-structure of the cladding tube. Based on the meso-scale FE model, the mechanical behavior of the wound SiCf/SiC nuclear fuel cladding tube is studied in detail. The results show that due to the neglect of the overlap effect, the conventional laminate model overestimates the cladding tube strength. The proposed meso-scale FE model can accurately predict the failure of the cladding tube. The results also confirm that the creation of a 3D yarn path and the derived meso-scale FE model, representing an accurate wound structure, are of importance to the prediction of the performance of the cladding tube.
Bruton Tyrosine Kinase Inhibition and Its Role as an Emerging Treatment in Pemphigus
Authors: Patsatsi Aikaterini , Murrell Dedee F.
Published: August 2021

Bruton Tyrosine Kinase (BTK) has a key role in multiple pathways involved in inflammation and autoimmunity. Therefore, BTK has become a new therapeutic target for a group of hematologic and autoimmune disorders. The pharmaceutical industry has invested in the clinical development of BTK inhibitors during the last decade. Ibrutinib, for example, which was the first BTK inhibitor to be used in clinical trials, has two approved indications, mantle cell lymphoma and chronic lymphocytic leukemia, and remains under evaluation for additional indications. Rillzabrutinib (PRN1008) is a new, highly potent and selective inhibitor of BTK. Early studies performed in canine pemphigus demonstrated effectiveness. A proof-of-concept, multicenter, phase 2 trial has recently showed the efficacy and safety of oral rilzabrutinib in pemphigus vulgaris. In this mini review, we present evidence regarding the mechanisms affected by BTK inhibition and the concept of BTK inhibition as an emerging new treatment in pemphigus.
Wildlife Is a Potential Source of Human Infections of Enterocytozoon bieneusi and Giardia duodenalis in Southeastern China
Authors: Zhang Yan , Mi Rongsheng , Yang Lijuan , Gong Haiyan , Xu Chunzhong , Feng Yongqi , Chen Xinsheng , Huang Yan , Han Xiangan , Chen Zhaoguo
Published: August 2021

Wildlife is known to be a source of high-impact pathogens affecting people. However, the distribution, genetic diversity, and zoonotic potential of Cryptosporidium, Enterocytozoon bieneusi, and Giardia duodenalis in wildlife are poorly understood. Here, we conducted the first molecular epidemiological investigation of these three pathogens in wildlife in Zhejiang and Shanghai, China. Genomic DNAs were derived from 182 individual fecal samples from wildlife and then subjected to a nested polymerase chain reaction–based sequencing approach for detection and characterization. Altogether, 3 (1.6%), 21 (11.5%), and 48 (26.4%) specimens tested positive for Cryptosporidium species, E. bieneusi, and G. duodenalis, respectively. Sequence analyses revealed five known (BEB6, D, MJ13, SC02, and type IV) and two novel (designated SH_ch1 and SH_deer1) genotypes of E. bieneusi. Phylogenetically, novel E. bieneusi genotype SH_deer1 fell into group 6, and the other genotypes were assigned to group 1 with zoonotic potential. Three novel Cryptosporidium genotypes (Cryptosporidium avian genotype V-like and C. galli-like 1 and 2) were identified, C. galli-like 1 and 2 formed a clade that was distinct from Cryptosporidium species. The genetic distinctiveness of these two novel genotypes suggests that they represent a new species of Cryptosporidium. Zoonotic assemblage A (n = 36) and host-adapted assemblages C (n = 1) and E (n = 7) of G. duodenalis were characterized. The overall results suggest that wildlife act as host reservoirs carrying zoonotic E. bieneusi and G. duodenalis, potentially enabling transmission from wildlife to humans and other animals.
In vitro Antifungal Susceptibility Profiles of Cryptococcus neoformans var. grubii and Cryptococcus gattii Clinical Isolates in Guangxi, Southern China
Authors: Al-Odaini Najwa , Li Xiu-ying , Li Bing-kun , Chen Xing-chun , Huang Chun-yang , Lv Chun-ying , Pan Kai-su , Zheng Dong-yan , Zheng Yan-qing , Liao Wan-qing , Cao Cun-wei
Published: August 2021

This study analyzed thein vitrodrug sensitivity ofCryptococcusspp. from Guangxi, Southern China. One hundred three strains ofCryptococcuswere recovered from 86 patients; 14 were HIV positive and 72 were HIV negative. Ninety-two strains were identified asCryptococcus neoformansvar.grubii, while 11 strains were identified asCryptococcus gattii(5C. gattii sensu strictoand 6Cryptococcus deuterogattii). The recovered strains were tested against commonly used antifungal drugs (fluconazole, amphotericin B, 5-fluorocytosine, itraconazole, and voriconazole) and to novel antifungal drugs (posaconazole and isavuconazole) using CLSI M27-A4 method. The results showed that all isolates were susceptible to most antifungal drugs, of which the minimum inhibitory concentration (MIC) ranges were as follows: 0.05–4 μg/ml for fluconazole, 0.25–1 μg/ml for amphotericin B; 0.0625–2 μg/ml for 5-fluorocytosine, 0.0625–0.25 μg/ml for itraconazole, 0.0078–0.25 μg/ml for voriconazole, 0.0313–0.5 μg/ml for posaconazole, 0.0020–0.125 μg/ml for isavuconazole forC. neoformansvar.grubiiisolates, and 1–16 μg/ml for fluconazole, 0.125–1 μg/ml for 5-fluorocytosine, 0.25–1 μg/ml for amphotericin B, 0.0625–0.25 μg/ml for itraconazole, 0.0156–0.125 μg/ml for voriconazole, 0.0156–0.25 μg/ml for posaconazole, and 0.0078–0.125 μg/ml for isavuconazole forC. gattiiisolates. Furthermore, someC. neoformansvar.grubiiisolates were found to be susceptible-dose dependent to 5-fluorocytosine and itraconazole. In addition, a reduction in the potency of fluconazole againstC. gattiiis possible. We observed no statistical differences in susceptibility ofC. neoformansvar.grubiiandC. gattiiin the tested strains. Continuous observation of antifungal susceptibility ofCryptococcusisolates is recommended to monitor the emergence of resistant strains.
Non-enzymatic Transformation of Aflatoxin B1 by Pseudomonas geniculata m29
Authors: Yao Yuanyuan , Shu Xian , Wang Dongdong , Kan Wenjie , Su Pengfei , Hu Hao , Chen Xu , Wang Dacheng , Huang Shengwei , Wu Lifang
Published: August 2021

Aflatoxin B1 (AFB1) is the most harmful mycotoxin produced by filamentous fungi and presents a serious threat to human and animal health. Therefore, it is essential to protect humans and animals from AFB1-induced acute and chronic toxicity. In this study, Pseudomonas strain m29 having a high efficiency of AFB1 transformation was isolated from soil. The transformation ratio by m29 was more than 97% within 24 h, and the optimum temperature for transformation was 37°C. Moreover, the AFB1 transforming activity was mainly attributed to the cell-free supernatant of strain m29. The metabolite that plays a crucial role in AFB1 transformation is likely 1,2-dimethylhydrazine or 1,1-dimethylhydrazine, as identified by GC-MS and LC-MS analysis. AFB1 was transformed into a product with molecular formula C17H14O7. To the best of our knowledge, this is the first study of non-enzymatic AFB1 transformation by bacteria. Importantly, this AFB1 transformation mechanism could be universal to various microorganisms.
Urinary Proteomics Identifying Novel Biomarkers for the Diagnosis and Phenotyping of Carotid Artery Stenosis
Authors: Wang Wei , Wu Jianqiang , Liu Peng , Tang Xiaoyue , Pang Haiyu , Xie Ting , Xu Fang , Shao Jiang , Chen Yuexin , Liu Bao , Zheng Yuehong
Published: August 2021

Background: Carotid artery stenosis (CAS) is caused by the formation of atherosclerotic plaques inside the arterial wall and accounts for 20–30% of all strokes. The development of an early, noninvasive diagnostic method and the identification of high-risk patients for ischemic stroke is essential to the management of CAS in clinical practice.

Methods: We used the data-independent acquisition (DIA) technique to conduct a urinary proteomic study in patients with CAS and healthy controls. We identified the potential diagnosis and risk stratification biomarkers of CAS. And Ingenuity pathway analysis was used for functional annotation of differentially expressed proteins (DEPs). Furthermore, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic values of DEPs.

Results: A total of 194 DEPs were identified between CAS patients and healthy controls by DIA quantification. The bioinformatics analysis showed that these DEPs were correlated with the pathogenesis of CAS. We further identified 32 DEPs in symptomatic CAS compared to asymptomatic CAS, and biological function analysis revealed that these proteins are mainly related to immune/inflammatory pathways. Finally, a biomarker panel of six proteins (ACP2, PLD3, HLA-C, GGH, CALML3, and IL2RB) exhibited potential diagnostic value in CAS and good discriminative power for differentiating symptomatic and asymptomatic CAS with high sensitivity and specificity.

Conclusions: Our study identified novel potential urinary biomarkers for noninvasive early screening and risk stratification of CAS.
Language in Behavioral Variant Frontotemporal Dementia: Another Stone to Be Turned in Latin America
Authors: Geraudie Amandine , Díaz Rivera Mariano , Montembeault Maxime , García Adolfo M.
Published: August 2021

Beyond canonical deficits in social cognition and interpersonal conduct, behavioral variant frontotemporal dementia (bvFTD) involves language difficulties in a substantial proportion of cases. However, since most evidence comes from high-income countries, the scope and relevance of language deficits in Latin American bvFTD samples remain poorly understood. As a first step toward reversing this scenario, we review studies reporting language measures in Latin American bvFTD cohorts relative to other groups. We identified 24 papers meeting systematic criteria, mainly targeting phonemic and semantic fluency, naming, semantic processing, and comprehension skills. The evidence shows widespread impairments in these domains, often related to overall cognitive disturbances. Some of these deficits may be as severe as in other diseases where they are more widely acknowledged, such as Alzheimer's disease. Considering the prevalence and informativeness of language deficits in bvFTD patients from other world regions, the need arises for more systematic research in Latin America, ideally spanning multiple domains, in diverse languages and dialects, with validated batteries. We outline key challenges and pathways of progress in this direction, laying the ground for a new regional research agenda on the disorder.
Visual Field Reconstruction in Hemianopia Using fMRI Based Mapping Techniques
Authors: Halbertsma Hinke N. , Bridge Holly , Carvalho Joana , Cornelissen Frans W. , Ajina Sara
Published: August 2021

Purpose

A stroke that includes the primary visual cortex unilaterally leads to a loss of visual field (VF) representation in the hemifield contralateral to the damage. While behavioral procedures for measuring the VF, such as perimetry, may indicate that a patient cannot see in a particular area, detailed psychophysical testing often detects the ability to perform detection or discrimination of visual stimuli (“blindsight”). The aim of this study was to determine whether functional magnetic resonance imaging (fMRI) could be used to determine whether perimetrically blind regions of the VF were still represented in VF maps reconstructed on the basis of visually evoked neural activity.

Methods

Thirteen patients with hemianopia and nine control participants were scanned using 3T MRI while presented with visual stimulation. Two runs of a dynamic “wedge and ring” mapping stimulus, totaling approximately 10 min, were performed while participants fixated centrally. Two different analysis approaches were taken: the conventional population receptive field (pRF) analysis and micro-probing (MP). The latter is a variant of the former that makes fewer assumptions when modeling the visually evoked neural activity. Both methods were used to reconstruct the VF by projecting modeled activity back onto the VF. Following a normalization step, these “coverage maps” can be compared to the VF sensitivity plots obtained using perimetry.

Results

While both fMRI-based approaches revealed regions of neural activity within the perimetrically “blind” sections of the VF, the MP approach uncovered more voxels in the lesioned hemisphere in which a modest degree of visual sensitivity was retained. Furthermore, MP-based analysis indicated that both early (V1/V2) and extrastriate visual areas contributed equally to the retained sensitivity in both patients and controls.

Conclusion

In hemianopic patients, fMRI-based approaches for reconstructing the VF can pick up activity in perimetrically blind regions of the VF. Such regions of the VF may be particularly amenable for rehabilitation to regain visual function. Compared to conventional pRF modeling, MP reveals more voxels with retained visual sensitivity, suggesting it is a more sensitive approach for VF reconstruction.
Modern Technology in Multi-Shell Diffusion MRI Reveals Diffuse White Matter Changes in Young Adults With Relapsing-Remitting Multiple Sclerosis
Authors: Beaudoin Ann-Marie , Rheault François , Theaud Guillaume , Laberge Frédéric , Whittingstall Kevin , Lamontagne Albert , Descoteaux Maxime
Published: August 2021

Objective

To characterize microstructural white matter changes related to relapsing-remitting multiple sclerosis using advanced diffusion MRI modeling and tractography. The association between imaging data and patient’s cognitive performance, fatigue severity and depressive symptoms is also explored.

Methods

In this cross-sectional study, 24 relapsing-remitting multiple sclerosis patients and 11 healthy controls were compared using high angular resolution diffusion imaging (HARDI). The imaging method includes a multi-shell scheme, free water correction to obtain tissue-specific measurements, probabilistic tracking algorithm robust to crossing fibers and white matter lesions, automatic streamlines and bundle dissection and tract-profiling with tractometry. The neuropsychological evaluation included the Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, Modified Fatigue Impact Scale and Beck Depression Inventory-II.

Results

Bundle-wise analysis by tractometry revealed a difference between patients and controls for 11 of the 14 preselected white matter bundles. In patients, free water corrected fractional anisotropy was significantly reduced while radial and mean diffusivities were increased, consistent with diffuse demyelination. The fornix and left inferior fronto-occipital fasciculus exhibited a higher free water fraction. Eight bundles showed an increase in total apparent fiber density and four bundles had a higher number of fiber orientations, suggesting axonal swelling and increased organization complexity, respectively. In the association study, depressive symptoms were associated with diffusion abnormalities in the right superior longitudinal fasciculus.

Conclusion

Tissue-specific diffusion measures showed abnormalities along multiple cerebral white matter bundles in patients with relapsing-remitting multiple sclerosis. The proposed methodology combines free-water imaging, advanced bundle dissection and tractometry, which is a novel approach to investigate cerebral pathology in multiple sclerosis. It opens a new window of use for HARDI-derived measures and free water corrected diffusion measures. Advanced diffusion MRI provides a better insight into cerebral white matter changes in relapsing-remitting multiple sclerosis, namely diffuse demyelination, edema and increased fiber density and complexity.
Adult Neurogenesis and Stroke: A Tale of Two Neurogenic Niches
Authors: Ceanga Mihai , Dahab Mahmoud , Witte Otto W. , Keiner Silke
Published: August 2021

In the aftermath of an acute stroke, numerous signaling cascades that reshape the brain both in the perilesional zone as well as in more distal regions are activated. Despite continuous improvement in the acute treatment of stroke and the sustained research efforts into the pathophysiology of stroke, we critically lag in our integrated understanding of the delayed and chronic responses to ischemic injury. As such, the beneficial or maladaptive effect of some stroke-induced cellular responses is unclear, restricting the advancement of therapeutic strategies to target long-term complications. A prominent delayed effect of stroke is the robust increase in adult neurogenesis, which raises hopes for a regenerative strategy to counter neurological deficits in stroke survivors. In the adult brain, two regions are known to generate new neurons from endogenous stem cells: the subventricular zone (SVZ) and the dentate subgranular zone (SGZ) of the hippocampus. While both niches respond with an increase in neurogenesis post-stroke, there are significant regional differences in the ensuing stages of survival, migration, and maturation, which may differently influence functional outcome. External interventions such as rehabilitative training add a further layer of complexity by independently modulating the process of adult neurogenesis. In this review we summarize the current knowledge regarding the effects of ischemic stroke on neurogenesis in the SVZ and in the SGZ, and the influence of exogenous stimuli such as motor activity or enriched environment (EE). In addition, we discuss the contribution of SVZ or SGZ post-stroke neurogenesis to sensory, motor and cognitive recovery.
Chronic Sensing of Subthalamic Local Field Potentials: Comparison of First and Second Generation Implantable Bidirectional Systems Within a Single Subject
Authors: Cummins Daniel D. , Kochanski Ryan B. , Gilron Roee , Swann Nicole C. , Little Simon , Hammer Lauren H. , Starr Philip A.
Published: August 2021

Background

Many adaptative deep brain stimulation (DBS) paradigms rely upon the ability to sense neural signatures of specific clinical signs or symptoms in order to modulate therapeutic stimulation. In first-generation bidirectional neurostimulators, the ability to sense neural signals during active stimulation was often limited by artifact. Newer devices, with improved design specifications for sensing, have recently been developed and are now clinically available.

Objective

To compare the sensing capabilities of the first-generation Medtronic PC + S and second-generation Percept PC neurostimulators within a single patient.

Methods

A 42-year-old man with Parkinson’s disease was initially implanted with left STN DBS leads connected to a PC + S implantable pulse generator. Four years later, the PC + S was replaced with the Percept PC. Local field potential (LFP) signals were recorded, both with stimulation OFF and ON, at multiple timepoints with each device and compared. Offline processing of time series data included artifact removal using digital filtering and template subtraction, before subsequent spectral analysis. With Percept PC, embedded processing of spectral power within a narrow frequency band was also utilized.

Results

In the absence of stimulation, both devices demonstrated a peak in the beta range (approximately 20 Hz), which was stable throughout the 4-year period. Similar to previous reports, recordings with the PC + S during active stimulation demonstrated significant stimulation artifact, limiting the ability to recover meaningful LFP signal. In contrast, the Percept PC, using the same electrodes and stimulation settings, produced time series data during stimulation with spectral analysis revealing a peak in the beta-band. Online analysis by the Percept demonstrated a reduction in beta-band activity with increasing stimulation amplitude.

Conclusion

This report highlights recent advances in implantable neurostimulator technology for DBS, demonstrating improvements in sensing capabilities during active stimulation between first- and second-generation devices. The ability to reliably sense during stimulation is an important step toward both the clinical implementation of adaptive algorithms and the further investigation into the neurophysiology underlying movement disorders.
Transcriptomic Effects of Healthspan-Promoting Dietary Interventions: Current Evidence and Future Directions
Authors: Wahl Devin , LaRocca Thomas J.
Published: August 2021

Aging is the greatest risk factor most diseases, including cardiovascular disorders, cancers, diabetes, and neurodegeneration, but select nutritional interventions may profoundly reduce the risk for these conditions. These interventions include calorie restriction, intermittent fasting, protein restriction, and reducing intake of certain amino acids. Certain ad libitum diets, including the Mediterranean, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, and Okinawan diets also promote healthy aging. Evidence indicates that these dietary strategies influence aging and healthspan by acting on the biological “hallmarks of aging” and especially upstream nutrient sensing pathways. Recent advances in “omics” technologies, including RNA-sequencing (transcriptomics), have increased our understanding of how such nutritional interventions may influence gene expression related to these biological mediators of aging, primarily in pre-clinical studies. However, whether these effects are also reflected in the human transcriptome, which may provide insight on other downstream/related cellular processes with aging, is an emerging topic. Broadly, the investigation of how these nutritional interventions influence the transcriptome may provide novel insight into pathways associated with aging, and potential targets to treat age-associated disease and increase healthspan. Therefore, the purpose of this mini review is to summarize what is known about the transcriptomic effects of key dietary/nutritional interventions in both pre-clinical models and humans, address gaps in the literature, and provide insight into future research directions.
Chronic Cadmium Exposure Alters Cardiac Matrix Metalloproteinases in the Heart of Sprague-Dawley Rat
Authors: Das Sandra Concepcion , Varadharajan Kavitha , Shanmugakonar Muralitharan , Al-Naemi Hamda A.
Published: August 2021

The aim of this study was to evaluate the role of chronic cadmium exposure in modulating cardiac matrix metalloproteinases (MMPs) in the heart of rats. Adult male Sprague-Dawley rats were exposed to 15 ppm CdCl2 in drinking water for 10 weeks followed by withdrawal of cadmium treatment for 4 weeks. Following the completion of the treatment, gene expression of inflammatory mediators (IL-1β, IL-6, IL-10, TNF-α and NF-κB), protein expression of MMP-2, MMP-9 and their respective inhibitors- TIMP-1 and TIMP-2, and gelatinolytic activity of MMP-2 and MMP-9 were determined. At the protein level, cadmium incites a differential effect on the expression and activity of gelatinases and their endogenous inhibitors in an exposure-dependent manner. Results also show that the administered cadmium dose elicits an inflammatory response until week 10 that slightly diminishes after 4 weeks. This study provides evidence of cadmium-induced imbalance in the MMP-TIMP system in the cardiac tissue. This imbalance may be mediated by cadmium-induced inflammation that could contribute to various cardiovascular pathologies.
Preclinical Pharmacokinetics, Tissue Distribution, and Primary Safety Evaluation of Indo5, a Novel Selective Inhibitor of c-Met and Trks
Authors: Luo Teng , Zhang Fei-Xiang , Zhao Ke , Gao Hui-Ying , Zhang Shou-Guo , Wang Lin , Dou Gui-Fang , Liu Ting , Yu Miao , Zhan Yi-Qun , Chen Hui , Yang Xiao-Ming , Li Chang-Yan
Published: August 2021

The compound [3-(1H-benzimidazol-2-methylene)-5-(2-methylphenylaminosulfo)-2-indolone], known as Indo5, is a novel selective inhibitor of c-Met and Trks, and it is a promising anticancer candidate against hepatocellular carcinoma (HCC). Assessing the pharmacokinetic properties, tissue distribution, and toxicity of Indo5 is critical for its medicinal evaluation. A series of sensitive and specific liquid chromatography-tandem mass spectrometry methods were developed and validated to determine the concentration of Indo5 in rat plasma and tissue homogenates. These methods were then applied to investigate the pharmacokinetics and tissue distribution of Indo5 in rats. After intravenous injection of Indo5, the maximum concentration (Cmax) and the time at which Cmax was reached (Tmax) were 1,565.3 ± 286.2 ng/ml and 1 min, respectively. After oral administration, Cmax and Tmax were 54.7 ± 10.4 ng/ml and 2.0 ± 0.48 h, respectively. We calculated the absolute oral bioavailability of Indo5 in rats to be 1.59%. Following intravenous injection, the concentrations of Indo5 in various tissues showed the following order: liver > kidney ≈ heart > lung ≈ large intestine ≈ small intestine ≈ stomach > spleen > brain ≈ testes; hence, Indo5 distributed highest in the liver and could not cross the blood–brain or blood–testes barriers. Continuous injection of Indo5 for 21 days did not lead to liver injury, considering unchanged ALT and AST levels, normal histological architecture of the liver, and normal number and frequencies of immune cells in the liver, indicating a very low toxicity of Indo5 in vivo. Collectively, our findings provide a comprehensive understanding of the biological actions of Indo5 in vivo and further support its development as an antitumor treatment for HCC patients.
Congenital Anomalies Programmed by Maternal Diabetes and Obesity on Offspring of Rats
Authors: Araujo-Silva Vanessa Caruline , Santos-Silva Alice , Lourenço Andressa Silva , Barros-Barbosa Cristielly Maria , Moraes-Souza Rafaianne Queiroz , Soares Thaigra Sousa , Karki Barshana , Paula Verônyca Gonçalves , Sinzato Yuri Karen , Damasceno Débora Cristina , Volpato Gustavo Tadeu
Published: August 2021

Embryo-fetal exposure to maternal disorders during intrauterine life programs long-term consequences for the health and illness of offspring. In this study, we evaluated whether mild diabetic rats that were given high-fat/high-sugar (HF/HS) diet presented maternal and fetal changes at term pregnancy. Female rats received citrate buffer (non-diabetic-ND) or streptozotocin (diabetic-D) after birth. According to the oral glucose tolerance test (OGTT), the experimental groups (n = 11 animals/group) were composed of non-diabetic and diabetic receiving standard diet (S) or HF/HS diet. High-fat/high-sugar diet (30% kcal of lard) in chow and water containing 5% sucrose and given 1 month before mating and during pregnancy. During and at the end of pregnancy, obesity and diabetes features were determined. After laparotomy, blood samples, periovarian fat, and uterine content were collected. The diabetic rats presented a higher glycemia and percentage of embryonic losses when compared with the NDS group. Rats DHF/HS presented increased obesogenic index, caloric intake, and periovarian fat weight and reduced gravid uterus weight in relation to the other groups. Besides, this association might lead to the inflammatory process, confirmed by leukocytosis. Obese rats (NDHF/HS and DHF/HS) showed higher triglyceride levels and their offspring with lower fetal weight and ossification sites, indicating intrauterine growth restriction. This finding may contribute to vascular alterations related to long-term hypertensive disorders in adult offspring. The fetuses from diabetic dams showed higher percentages of skeletal abnormalities, and DHF/HS dams still had a higher rate of anomalous fetuses. Thus, maternal diabetes and/or obesity induces maternal metabolic disorders that contribute to affect fetal development and growth.
Analysis of the Segregation Distortion of FcRAN1 Genotypes Based on Whole-Genome Resequencing of Fig (Ficus carica L.) Breeding Parents
Authors: Ikegami Hidetoshi , Shirasawa Kenta , Yakushiji Hiroshi , Yabe Shiori , Sato Masaru , Hayashi Takeshi , Tashiro Kosuke , Nogata Hitoshi
Published: August 2021

The common fig (Ficus carica L.) has a gynodioecious breeding system, and its sex phenotype is an important trait for breeding because only female plant fruits are edible. During breeding to select for female plants, we analyzed the FcRAN1 genotype, which is strongly associated with the sex phenotype. In 12 F1 populations derived from 13 cross combinations, the FcRAN1 genotype segregation ratio was 1:1, whereas the M119-226 × H238-107 hybridization resulted in an extremely male-biased segregation ratio (178:7 = male:female). This finding suggests that the segregation distortion was caused by some genetic factor(s). A whole-genome resequencing of breeding parents (paternal and maternal lines) identified 9,061 high-impact SNPs in the parents. A genome-wide linkage analysis exploring the gene(s) responsible for the distortion revealed 194 high-impact SNPs specific to Caprifig6085 (i.e., seed parent ancestor) and 215 high-impact SNPs specific to H238-107 (i.e., pollen parent) in 201 annotated genes. A comparison between the annotated genes and the genes required for normal embryo or gametophyte development and function identified several candidate genes possibly responsible for the segregation distortion. This is the first report describing segregation distortion in F. carica.