bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Diversity and Signatures of Selection for Thermal Stress in Cattle and Other Two Bos Species Adapted to Divergent Climatic Conditions
Authors: Freitas Pedro H. F. , Wang Yachun , Yan Ping , Oliveira Hinayah R. , Schenkel Flavio S. , Zhang Yi , Xu Qing , Brito Luiz F.
Published: February 2021

Understanding the biological mechanisms of climatic adaptation is of paramount importance for the optimization of breeding programs and conservation of genetic resources. The aim of this study was to investigate genetic diversity and unravel genomic regions potentially under selection for heat and/or cold tolerance in thirty-two worldwide cattle breeds, with a focus on Chinese local cattle breeds adapted to divergent climatic conditions, Datong yak (Bos grunniens; YAK), and Bali (Bos javanicus) based on dense SNP data. In general, moderate genetic diversity levels were observed in most cattle populations. The proportion of polymorphic SNP ranged from 0.197 (YAK) to 0.992 (Mongolian cattle). Observed and expected heterozygosity ranged from 0.023 (YAK) to 0.366 (Sanhe cattle; SH), and from 0.021 (YAK) to 0.358 (SH), respectively. The overall average inbreeding (±SD) was: 0.118 ± 0.028, 0.228 ± 0.059, 0.194 ± 0.041, and 0.021 ± 0.004 based on the observed versus expected number of homozygous genotypes, excess of homozygosity, correlation between uniting gametes, and runs of homozygosity (ROH), respectively. Signatures of selection based on multiple scenarios and methods (FST, HapFLK, and ROH) revealed important genomic regions and candidate genes. The candidate genes identified are related to various biological processes and pathways such as heat-shock proteins, oxygen transport, anatomical traits, mitochondrial DNA maintenance, metabolic activity, feed intake, carcass conformation, fertility, and reproduction. This highlights the large number of biological processes involved in thermal tolerance and thus, the polygenic nature of climatic resilience. A comprehensive description of genetic diversity measures in Chinese cattle and YAK was carried out and compared to 24 worldwide cattle breeds to avoid potential biases. Numerous genomic regions under positive selection were detected using three signature of selection methods and candidate genes potentially under positive selection were identified. Enriched function analyses pinpointed important biological pathways, molecular function and cellular components, which contribute to a better understanding of the biological mechanisms underlying thermal tolerance in cattle. Based on the large number of genomic regions identified, thermal tolerance has a complex polygenic inheritance nature, which was expected considering the various mechanisms involved in thermal stress response.
Bovine Pre-adipocyte Adipogenesis Is Regulated by bta-miR-150 Through mTOR Signaling
Authors: Chen Xingyi , Raza Sayed Haidar Abbas , Ma Xinhao , Wang Jiangfang , Wang Xiaohui , Liang Chengcheng , Yang Xinran , Mei Chugang , Suhail Syed Muhammad , Zan Linsen
Published: February 2021

Micro RNA (miR) are recognized for their important roles in biological processes, particularly in regulatory componentization. Among the miR, miR-150 has been the focus of intense scrutiny, mostly due to its role in malignant tumors. A comparison between steer and bull adipose tissues identified bta-miR-150 as one of the nine downregulated miRNAs, although its function remains unknown (GEO:GSE75063). The present study aimed to further characterize the role of bta-miR-150 in cattle. bta-miR-150 has a negative regulatory effect on the differentiation of bovine adipocytes and promotes proliferation. Overexpression of bta-miR-150 can promote mRNA and protein expression of the marker genes CDK1, CDK2, and PCNA, increase the number of EdU-stained cells, promote adipocyte proliferation, inhibit adipocyte differentiation, and reduce lipid droplet formation. Results of RNA-seq and WGCNA analyses showed that the mammalian target of the rapamycin signaling pathway, which plays a major regulatory role, is dysregulated by the overexpression and inhibition of miR-150. We found that the target gene of bta-miR-150 is AKT1 and that bta-miR-150 affects AKT1 phosphorylation levels. These results showed that bta-miR-150 plays a role in adipogenic differentiation and might therefore have applications in the beef industry.
Interferon α Enhances B Cell Activation Associated With FOXM1 Induction: Potential Novel Therapeutic Strategy for Targeting the Plasmablasts of Systemic Lupus Erythematosus
Authors: Akita Kanae , Yasaka Ken , Shirai Tsuyoshi , Ishii Tomonori , Harigae Hideo , Fujii Hiroshi
Published: February 2021

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38+CD43+B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFNαon B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFNαpromoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFNαpreferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferonα. This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.
Improved Functionality of Exhausted Intrahepatic CXCR5+ CD8+ T Cells Contributes to Chronic Antigen Clearance Upon Immunomodulation
Authors: Kumashie Kingsley Gideon , Cebula Marcin , Hagedorn Claudia , Kreppel Florian , Pils Marina C. , Koch-Nolte Friedrich , Rissiek Björn , Wirth Dagmar
Published: February 2021

Chronic hepatotropic viral infections are characterized by exhausted CD8+ T cells in the presence of cognate antigen in the liver. The impairment of T cell response limits the control of chronic hepatotropic viruses. Immune-modulatory strategies are attractive options to re-invigorate exhausted T cells. However, in hepatotropic viral infections, the knowledge about immune-modulatory effects on the in-situ regulation of exhausted intrahepatic CD8+ T cells is limited. In this study, we elucidated the functional heterogeneity in the pool of exhausted CD8+ T cells in the liver of mice expressing the model antigen Ova in a fraction of hepatocytes. We found a subpopulation of intrahepatic CXCR5+ Ova-specific CD8+ T cells, which are profoundly cytotoxic, exhibiting efficient metabolic functions as well as improved memory recall and self-maintenance. The intrahepatic Ova-specific CXCR5+ CD8+ T cells are possibly tissue resident cells, which may rely largely on OXPHOS and glycolysis to fuel their cellular processes. Importantly, host conditioning with CpG oligonucleotide reinvigorates and promotes exhausted T cell expansion, facilitating complete antigen eradication. The CpG oligonucleotide-mediated reinvigoration may support resident memory T cell formation and the maintenance of CXCR5+ Ova-specific CD8+ T cells in the liver. These findings suggest that CpG oligodinucleotide may preferentially target CXCR5+ CD8+ T cells for expansion to facilitate the revival of exhausted T cells. Thus, therapeutic strategies aiming to expand CXCR5+ CD8+ T cells might provide a novel approach against chronic liver infection.
Therapeutic Potential of Pharmacological Targeting NLRP3 Inflammasome Complex in Cancer
Authors: Tezcan Gulcin , Garanina Ekaterina E. , Alsaadi Mohammad , Gilazieva Zarema E. , Martinova Ekaterina V. , Markelova Maria I. , Arkhipova Svetlana S. , Hamza Shaimaa , McIntyre Alan , Rizvanov Albert A. , Khaiboullina Svetlana F.
Published: February 2021

Introduction

Dysregulation of NLRP3 inflammasome complex formation can promote chronic inflammation by increased release of IL-1β. However, the effect of NLRP3 complex formation on tumor progression remains controversial. Therefore, we sought to determine the effect of NLRP3 modulation on the growth of the different types of cancer cells, derived from lung, breast, and prostate cancers as well as neuroblastoma and glioblastoma in-vitro.

Method

The effect of Caspase 1 inhibitor (VX765) and combination of LPS/Nigericin on NLRP3 inflammasome activity was analyzed in A549 (lung cancer), MCF-7 (breast cancer), PC3 (prostate cancer), SH-SY5Y (neuroblastoma), and U138MG (glioblastoma) cells. Human fibroblasts were used as control cells. The effect of VX765 and LPS/Nigericin on NLRP3 expression was analyzed using western blot, while IL-1β and IL-18 secretion was detected by ELISA. Tumor cell viability and progression were determined using Annexin V, cell proliferation assay, LDH assay, sphere formation assay, transmission electron microscopy, and a multiplex cytokine assay. Also, angiogenesis was investigated by a tube formation assay. VEGF and MMPs secretion were detected by ELISA and a multiplex assay, respectively. Statistical analysis was done using one-way ANOVA with Tukey’s analyses and Kruskal–Wallis one-way analysis of variance.

Results

LPS/Nigericin increased NRLP3 protein expression as well as IL-1β and IL-18 secretion in PC3 and U138MG cells compared to A549, MCF7, SH-SY5Y cells, and fibroblasts. In contrast, MIF expression was commonly found upregulated in A549, PC3, SH-SY5Y, and U138MG cells and fibroblasts after Nigericin treatment. Nigericin and a combination of LPS/Nigericin decreased the cell viability and proliferation. Also, LPS/Nigericin significantly increased tumorsphere size in PC3 and U138MG cells. In contrast, the sphere size was reduced in MCF7 and SH-SY5Y cells treated with LPS/Nigericin, while no effect was detected in A549 cells. VX765 increased secretion of CCL24 in A549, MCF7, PC3, and fibroblasts as well as CCL11 and CCL26 in SH-SY5Y cells. Also, VX765 significantly increased the production of VEGF and MMPs and stimulated angiogenesis in all tumor cell lines.

Discussion

Our data suggest that NLRP3 activation using Nigericin could be a novel therapeutic approach to control the growth of tumors producing a low level of IL-1β and IL-18.
Use of the Tissue Common Rejection Module Score in Kidney Transplant as an Objective Measure of Allograft Inflammation
Authors: Zarinsefat Arya , Guerra Jose M. Arreola , Sigdel Tara , Damm Izabella , Sarwal Reuben , Chan-on Chitranon , Szabo Gyula , Aguilar-Frasco Jorge L. , Ixtlapale-Carmona Xicohtencatl , Salinas-Ramos Carlos , Ramirez-Martinez Leonardo , Ramirez Claudio , Vilatoba Mario , Morales Buenrostro Luis E. , Alberu Josefina M. , Sarwal Minnie M.
Published: February 2021

Long-term kidney transplant (KT) allograft outcomes have not improved as expected despite a better understanding of rejection and improved immunosuppression. Previous work had validated a computed rejection score, the tissue common rejection module (tCRM), measured by amplification-based assessment of 11 genes from formalin-fixed paraffin-embedded (FFPE) biopsy specimens, which allows for quantitative, unbiased assessment of immune injury. We applied tCRM in a prospective trial of 124 KT recipients, and contrasted assessment by tCRM and histology reads from 2 independent pathologists on protocol and cause biopsies post-transplant. Four 10-μm shaves from FFPE biopsy specimens were used for RNA extraction and amplification by qPCR of the 11 tCRM genes, from which the tCRM score was calculated. Biopsy diagnoses of either acute rejection (AR) or borderline rejection (BL) were considered to have inflammation present, while stable biopsies had no inflammation. Of the 77 biopsies that were read by both pathologists, a total of 40 mismatches in the diagnosis were present. The median tCRM scores for AR, BL, and stable diagnoses were 4.87, 1.85, and 1.27, respectively, with an overall significant difference among all histologic groups (Kruskal-Wallis, p < 0.0001). There were significant differences in tCRM scores between pathologists both finding inflammation vs. disagreement (p = 0.003), and both finding inflammation vs. both finding no inflammation (p < 0.001), along with overall significance between all scores (Kruskal-Wallis, p < 0.001). A logistic regression model predicting graft inflammation using various clinical predictor variables and tCRM revealed the tCRM score as the only significant predictor of graft inflammation (OR: 1.90, 95% CI: 1.40–2.68, p < 0.0001). Accurate, quantitative, and unbiased assessment of rejection of the clinical sample is critical. Given the discrepant diagnoses between pathologists on the same samples, individuals could utilize the tCRM score as a tiebreaker in unclear situations. We propose that the tCRM quantitative score can provide unbiased quantification of graft inflammation, and its rapid evaluation by PCR on the FFPE shave can become a critical adjunct to help drive clinical decision making and immunosuppression delivery.
The Potential Regulatory Roles of Circular RNAs in Tumor Immunology and Immunotherapy
Authors: Fang Zhixiao , Jiang Chunjie , Li Shengli
Published: February 2021

Circular RNAs (circRNAs) are covalently closed RNA molecules in eukaryotes with features of high stability, tissue-specific and cell-specific expression. According to their biogenesis, circRNAs are mainly classified into five types, i.e. exonic circRNAs (EciRNAs), exon-intron circRNAs (EIciRNAs), intronic RNAs (CiRNAs), fusion circRNAs (f-circRNAs), and read-through circRNAs (rt-circRNAs). CircRNAs have been emerging as important non-coding regulatory RNAs in a variety of human cancers. CircRNA4s were revealed to exert regulatory function through multiple mechanisms, such as sponges/decoys of miRNAs and proteins, enhancers of protein functions, protein scaffolds, protein recruitment, or protein translation templates. Furthermore, some circRNAs are intensively associated with immune cells in tumor immune microenvironment (TIME), e.g. circARSP91 and natural killer cells. Through regulating immune checkpoint genes, circRNAs are demonstrated to modulate the immune checkpoint blockade immunotherapy, e.g. circCPA4 could up-regulate PD-L1 expression. In summary, we reviewed the molecular features of circRNAs and mechanisms how they exert functions. We further summarized functional implications of circRNA regulations in tumor immunology and immunotherapy. Further understanding of the regulatory roles of circRNAs in tumor immunology and immunotherapy will benefit tumor treatment.
Environmental Drivers of Mesophotic Echinoderm Assemblages of the Southeastern Pacific Ocean
Authors: Mecho Ariadna , Dewitte Boris , Sellanes Javier , van Gennip Simon , Easton Erin E. , Gusmao Joao B.
Published: February 2021

Mesophotic ecosystems (50–400 m depth) of the southeastern Pacific have rarely been studied because of the logistical challenges in sampling across this remote zone. This study assessed how oxygen concentrations and other environmental predictors explain variation in echinoderm assemblages at these mesophotic systems, where this group is among the predominant fauna. We compiled data on echinoderm taxa at 91 sampling stations, from historical and recent surveys (between 1950 and 2019), covering a longitudinal gradient of approximately 3,700 km along with the Nazca, Salas y Gómez, and Juan Fernández ridges. Uni- and multivariate model-based tools were applied to analyze the patterns of benthic fauna in relation to environmental factors. Our results indicate a significant positive relationship between echinoderm species richness and depth, oxygen, and salinity. Changes in echinoderm community composition were significantly explained by oxygen, longitude, and chlorophyll-a. We observed notable species turnovers at ∼101 and ∼86°W, where assemblages tend to be more variable across stations. This turnover possibly reflects the effects of physical barriers to dispersion (e.g., currents) and habitat changes. Echinoderm assemblages observed around Easter and Desventuradas Islands presented a high occurrence of potentially endemic taxa and distinct species assemblages. This study is the first to assess the structure of mesophotic echinoderm assemblages of the southeastern Pacific Ocean along a large spatial scale. The information reported here could help design appropriate management tools for the vast, recently created, marine protected areas in the southeastern Pacific.
Light-Dependent Phenomena and Related Molecular Mechanisms in Giant Clam-Dinoflagellate Associations: A Review
Authors: Ip Yuen K. , Chew Shit F.
Published: February 2021

Giant clams can grow to large sizes despite living in oligotrophic waters of the tropical Indo-Pacific as they maintain a mutualistic relationship with symbiotic dinoflagellates (zooxanthellae) and receive photosynthate from them. The phototrophic dinoflagellates live extracellularly inside a tubular system located mainly in the colorful outer mantle and have no access to the ambient seawater. Hence, the clam host needs to absorb exogenous inorganic carbon (Ci), nitrogen (N) and phosphorus (P), and supply them to the symbionts. As photosynthesizing symbionts need more nutrients in light than in the dark, the uptake rates of these exogenous nutrients by the host must increase during illumination, implying that the host’s transporters involved need to be regulated by some kind of light-responsive mechanisms. Furthermore, the growth and development of the host can also be augmented by light, because of the photosynthate donated by the photosynthesizing symbionts. Consequently, giant clams display many light-dependent phenomena related to phototrophy, antioxidative defense, biomineralization, as well as absorption of exogenous Ci, N, and P. These phenomena may involve collaborations among enzymes and transporters in several organs of the host, whereby the gene and protein expression levels of these biocatalysts are up- or down-regulated during illumination. This review aims to examine the molecular mechanisms of light-dependent physiological phenomena that occur in intact giant clam-dinoflagellate associations, and to highlight the differences between giant clams and scleractinian corals in those regards. As the population of giant clams in nature are dwindling due to climate change and anthropogenic activities, a good understanding of their light-dependent processes may generate new ideas to improve their growth and survival under rapidly changing environmental conditions.
Radiation-Induced Optical Coherence Tomography Angiography Retinal Alterations in Patients With Nasopharyngeal Carcinoma
Authors: Li Zijing , Zhan Zongyi , Xiao Jianhui , Lan Yuqing
Published: February 2021

Aim: The aim of the study was to investigate the early neurovascular alterations of the retina in radiation encephalopathy (RE) patients with normal-ranged visual acuity after radiotherapy for nasopharyngeal carcinoma.

Methods: Fifty-five RE patients and 54 healthy age-matched subjects were enrolled in this retrospective cross-sectional case–control study. The best corrected visual acuity (LogMAR) of the included eye should not be more than 0. The vessel density and thickness of different locations in the retina were acquired automatically using optical coherence tomography angiography (OCTA). The data were then compared between the RE patients and the controls. The location included the whole retina, the superficial vascular plexus (SVP)/the ganglion cell complex (GCC), the deep vascular plexus (DVP), and the choroid in the macular area, as well as the inside disc and peripapillary area in the optic nerve head (ONH). The risk factors in OCTA retinal impairments were analyzed using a backward multiple linear regression. The relationships between mean deviation (MD) and pattern standard deviation (PSD) in the visual field (VF) and the OCTA parameters were also analyzed in RE patients.

Results: The vessel density of the GCC was significantly reduced in RE patients compared with controls (p = 0.018), and the reductions were mainly shown in the parafoveal (p = 0.049) and perifoveal fields (p = 0.006). The thickness of the GCC was correspondingly reduced (whole image GCC mean thickness: p = 0.044; parafoveal thickness: p = 0.038; perifoveal thickness: p = 0.038). In addition, the sub-foveal choroidal thickness (p = 0.039) was also reduced in RE patients. The vessel density of the GCC (R2 = 0.643) and DVP (R2 = 0.777) had a significant positive correlation with high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) and had a significant negative correlation with age (GCC: HDL-C, β = 29.89, p = 0.005; ApoA1, β = 78.92, p = 0.002; age, β = −0.886, p = 0.001; DVP: HDL-C, β = 40.09, p = 0.003; ApoA1, β = 62.65, p = 0.013; age, β = −1.31, p = 0.001). The vessel density of the GCC also had a significant negative correlation with apolipoprotein B (ApoB) (β = −32.18, p = 0.006). In the VF, MD had a significant positive correlation with the vessel density inside disc (R2 = 0.241, β = 0.304, p = 0.045), whereas PSD showed a significant negative correlation with the vessel density inside disc and the average GCC thickness, respectively (R2 = 0.437; vessel density inside disc, β = −0.358, p = 0.004; average GCC thickness, β = −0.510, p < 0.001).

Conclusion: With the aid of OCTA, we found that neurovascular alterations of the retina may exist in RE patients with normal-ranged visual acuity. Herein, we suggest the implementation of OCTA to assist ophthalmologists in the early detection and consistent monitoring of radiation-related eye diseases to avoid delayed diagnosis.
Pediatric Behçet's Disease
Authors: Yildiz Mehmet , Haslak Fatih , Adrovic Amra , Sahin Sezgin , Koker Oya , Barut Kenan , Kasapcopur Ozgur
Published: February 2021

Behçet's Disease (BD) is a systemic vasculitis firstly described as a disorder causing aphthous lesion in oral and genital mucosae and uveitis. The disease has an extremely unique distribution characterized by the highest incidence in communities living along the historical Silk road. Although our understanding of the etiopathogenesis of BD has expanded over time, there are still lots of unidentified points in the underlying mechanisms of the disease. The accepted opinion in the light of the current knowledge is that various identified and/or unidentified infectious and/or environmental triggers can take a role as a trigger in individuals with genetic susceptibility. Although the disease usually develops in young adulthood, it is reported that about 15–20% of all Behçet's patients develop in childhood. Pediatric BD differs from adult BD not only with the age of onset but also in the frequency and distribution of clinical findings, disease severity and outcome. While gastrointestinal system involvement, neurological findings, arthralgia and positive family history are more common in children, genital lesions and vascular lesions are more common in adult patients. In addition, a better disease outcome with lower severity score and activity index has been reported in children. The diagnosis of the disease is made according to clinical findings. It can be challenging to diagnose the disease due to the absence of a specific diagnostic test, and the long time interval from the first finding of the disease to the full-blown disease phenotype in pediatric cases. Therefore, many classification criteria have been proposed so far. The widely accepted ones are proposed by the International Study Group. The new sets of classification criteria which is the only one for pediatric BD were also developed for pediatric cases by the PEDBD group. The primary goal for the treatment is preventing the organ damages by suppressing the ongoing inflammation and forestalling the disease flares. The treatment of the BD can be onerous due to its multisystemic nature and a multidisciplinary approach is essential for the management of the patients. In this review article, the definition, clinical findings, epidemiology, etiopathogenesis, and treatment will be discussed.
Two Novel Endornaviruses Co-infecting a Phytophthora Pathogen of Asparagus officinalis Modulate the Developmental Stages and Fungicide Sensitivities of the Host Oomycete
Authors: Uchida Keiko , Sakuta Kohei , Ito Aori , Takahashi Yumi , Katayama Yukie , Omatsu Tsutomu , Mizutani Tetsuya , Arie Tsutomu , Komatsu Ken , Fukuhara Toshiyuki , Uematsu Seiji , Okada Ryo , Moriyama Hiromitsu
Published: February 2021

Two novel endornaviruses, Phytophthora endornavirus 2 (PEV2) and Phytophthora endornavirus 3 (PEV3) were found in isolates of a Phytophthora pathogen of asparagus collected in Japan. A molecular phylogenetic analysis indicated that PEV2 and PEV3 belong to the genus Alphaendornavirus. The PEV2 and PEV3 genomes consist of 14,345 and 13,810 bp, and they contain single open reading frames of 4,640 and 4,603 codons, respectively. Their polyproteins contain the conserved domains of an RNA helicase, a UDP-glycosyltransferase, and an RNA-dependent RNA polymerase, which are conserved in other alphaendornaviruses. PEV2 is closely related to Brown algae endornavirus 2, whereas PEV3 is closely related to Phytophthora endornavirus 1 (PEV1), which infects a Phytophthora sp. specific to Douglas fir. PEV2 and PEV3 were detected at high titers in two original Phytophthora sp. isolates, and we found a sub-isolate with low titers of the viruses during subculture. We used the high- and low-titer isolates to evaluate the effects of the viruses on the growth, development, and fungicide sensitivities of the Phytophthora sp. host. The high-titer isolates produced smaller mycelial colonies and much higher numbers of zoosporangia than the low-titer isolate. These results suggest that PEV2 and PEV3 inhibited hyphal growth and stimulated zoosporangium formation. The high-titer isolates were more sensitive than the low-titer isolate to the fungicides benthiavalicarb-isopropyl, famoxadone, and chlorothalonil. In contrast, the high-titer isolates displayed lower sensitivity to the fungicide metalaxyl (an inhibitor of RNA polymerase I) when compared with the low-titer isolate. These results indicate that persistent infection with PEV2 and PEV3 may potentially affect the fungicide sensitivities of the host oomycete.
Homology Model of a Catalytically Competent Bifunctional Rel Protein
Authors: Civera Monica , Sattin Sara
Published: February 2021

Bacteria have developed different bet hedging strategies to survive hostile environments and stressful conditions with persistency being maybe the most elegant yet still poorly understood one. Persisters’ temporary tolerance to antibiotic treatment hints at their role not only in chronic and recurrent infections but also in the insurgence of resistant strains. Therefore, hampering persisters formation might represent an innovative strategy in the quest for new effective antimicrobial compounds. Among the molecular mechanisms postulated for the persister phenotypic switch, we decided to focus our attention on the stringent response and, in particular, on the upstream triggering step that is the accumulation of guanosine tetra- and pentaphosphate, collectivity called (p)ppGpp. Intracellular levels of (p)ppGpp are regulated by a superfamily of enzymes called RSH (RelA/SpoT homologue) that are able to promote its synthesis via pyrophosphate transfer from an ATP molecule to the 3’ position of either GDP or GTP. These enzymes are classified based on the structural domain(s) present (only synthetase, only hydrolase, or both). Here we present our work on RelSeq (from S. equisimilis), still the only bifunctional Rel protein for which a GDP-bound “synthetase-ON” structure is available. Analysis of the synthetase site, occupied only by GDP, revealed a partially active state, where the supposed ATP binding region is not conformationally apt to accommodate it. In order to achieve a protein model that gets closer to a fully active state, we generated a chimera structure of RelSeq by homology modeling, starting from the crystal structure of the catalytically competent state of RelP, a smaller, single-domain, Rel protein from S. aureus. Molecular dynamics simulations allowed verifying the stability of the generated chimera model. Virtual screening and ligand design studies are underway.
Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature
Authors: Hu Chaoping , Xu Qiong , Shen Jin , Wang Yi
Published: February 2021

Background: As one of the assembly factors of complex I in the mitochondrial respiratory chain, FOXRED1 plays an important role in mitochondrial function. However, only a few patients with mitochondrial encephalopathy due to FOXRED1 defects have been reported.

Methods: Two Chinese patients with mitochondrial encephalopathy due to mutations in FOXRED1 were identified through trio whole-exome sequencing. The clinical presentation, laboratory data, brain imaging findings, and genetic results were collected and reviewed. All previously reported cases with FOXRED1-related mitochondrial encephalopathy were collected using a PubMed search, and their data were reviewed.

Results: Two patients presented with severe neurodevelopmental delay, epilepsy, high lactic acid levels, and remarkable diffuse brain atrophy and polycystic encephalomalacia during early infancy. Trio whole-exome sequencing revealed compound heterozygous variants in both patients: one case harbored a c.606_607delAG frameshift variant and a c.1054C>T (p.R352W) variant. At the same time, the other carried a novel c.352C>T (p.Q118X) variant and a reported c.1054C>T (p.R352W) variant. To date, nine patients have been reported with FOXRED1 defects, including our two cases. The most common presentations were neurodevelopment delay (100%), epilepsy (80%), poor feeding (30%), and vision loss (20%). Multisystem involvement comprised cardiovascular dysfunction (30%), abnormal liver function (20%), and hypoglycemia (10%). The neuroimaging results ranged from normal to severe cerebral atrophy and polycystic encephalomalacia in early infancy. Eleven pathogenic variants in FOXRED1 have been reported, comprising six missense variants, two non-sense variants, two frameshift variants, and one splice variant; among these the c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) variants are more common.

Conclusion:FOXRED1-related mitochondrial disorders have high clinical and genetic heterogeneity. Our study expanded the clinical and genetic spectrum of FOXRED1 defects. Early infantile onset and progressive encephalopathy are the most common clinical presentations, while the variants c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) may be critical founder mutations.
Use of Functional Near Infrared Spectroscopy to Assess Syntactic Processing by Monolingual and Bilingual Adults and Children
Authors: Ding Guoqin , Mohr Kathleen A. J. , Orellana Carla I. , Hancock Allison S. , Juth Stephanie , Wada Rebekah , Gillam Ronald B.
Published: February 2021

This exploratory study assessed the use of functional Near Infrared Spectroscopy (fNIRS) to examine hemodynamic response patterns during sentence processing. Four groups of participants: monolingual English children, bilingual Chinese-English children, bilingual Chinese-English adults and monolingual English adults were given an agent selection syntactic processing task. Bilingual child participants were classified as simultaneous or sequential bilinguals to examine the impact of first language, age of second-language acquisition (AoL2A), and the length of second language experience on behavioral performance and cortical activation. Participants were asked to select the agent of four types of sentences: subject-verb-object (SVO), passive (PAS), subject-extracted relative clause (SR), and object-extracted relative clause (OR) adopted from the “Whatdunit” task by Montgomery et al. (2016). Semantic cues were removed by using inanimate nouns for agents and patients, which constrained participants to make decisions based on syntactic knowledge. Behavioral results showed greater accuracy for canonical SVO and SR sentence types than for noncanonical OR and PAS sentence types, which aligns with prior studies. Neuroimaging results revealed greater hemodynamic responses to relative clauses (i.e., SR and OR sentences) than to simple sentences (SVO and PAS), especially for Chinese-English bilinguals suggesting first-language transfer influencing sentence processing in English. The effects AoL2A and the length of second language experience showed no significant differences between simultaneous and sequential bilinguals or between bilingual adults and children for identifying the correct agent in each sentence. However, neuroimaging results demonstrated greater hemodynamic responses in right dorsolateral prefrontal cortex (DLPFC) and left inferior parietal lobule (IPL) in simultaneous bilinguals compared to sequential bilinguals and greater hemodynamic responses in left and right DLPFC and left IPL among bilingual adults. Different behavioral and neural hemodynamic response patterns afford new insights into the effects of syntactic knowledge on sentence processing.
Brain Hemispheres Swap Dominance for Processing Semantically Meaningful Pitch
Authors: Wang Xiao-Dong , Xu Hong , Yuan Zhen , Luo Hao , Wang Ming , Li Hua-Wei , Chen Lin
Published: February 2021

The question of what determines brain laterality for auditory cognitive processing is unresolved. Here, we demonstrate a swap of hemisphere dominance from right to left during semantic interpretation of Chinese lexical tones in native speakers using simultaneously recorded mismatch negativity response and behavioral reaction time during dichotic listening judgment. The mismatch negativity, which is a brain wave response and indexes auditory processing at an early stage, indicated right hemisphere dominance. In contrast, the behavioral reaction time, which reflects auditory processing at a later stage, indicated a right ear listening advantage, or left hemisphere dominance. The observed swap of hemisphere dominance would not occur when the lexical tone was substituted with a meaningless pure tone. This swap reveals dependence of hemisphere labor division initially on acoustic and then on functional cues of auditory inputs in the processing from sound to meaning.
Phenotypic Resemblance to Neuropsychiatric Disorder and Altered mRNA Profiles in Cortex and Hippocampus Underlying IL15Rα Knockout
Authors: He Yi , Yu Yuxin , Li Yanan , Duan Weicheng , Sun Zuoli , Yang Jian , Kastin Abba J. , Pan Weihong , Zhang Yan , Wang Kang
Published: February 2021

Background

Previous studies of the functions of IL15Rα have been limited to immune activities and skeletal muscle development. Immunological factors have been identified as one of the multiple causes of psychosis, and neurological symptoms have been described in IL15Rα knockout (KO) mice. Seeking to explore possible mechanisms for this in the IL15Rα–/– mouse brain, we analyzed gene expression patterns in the cortex and hippocampus using the RNA-seq technique.

Methods

IL15Rα KO mice were generated and littermate wildtype (WT) mice were used as a control group. A Y-maze was used to assess behavior differences between the two groups. The cortex and hippocampus of 3-month-old male mice were prepared and RNA-seq and transcriptome analysis were performed by gene set enrichment analysis (GSEA).

Results

Compared with the WT group, IL15Rα KO animals showed higher speed in the novel arm and more entrance frequency in the old arm in the Y-maze experiment. GSEA indicated that 18 pathways were downregulated and 13 pathways upregulated in both cortex and hippocampus from the GO, KEGG, and Hallmark gene sets. The downregulated pathways formed three clusters: respiratory chain and electron transport, regulation of steroid process, and skeletal muscle development.

Conclusion

IL15Rα KO mice exhibit altered expression of multiple pathways, which could affect many functions of the brain. Lipid biosynthesis and metabolism in the central nervous system (CNS) should be investigated to provide insights into the effect of IL15Rα on psychosis in this murine model.
S100A8 Promotes Inflammation via Toll-Like Receptor 4 After Experimental Traumatic Brain Injury
Authors: He Guo-Yuan , Zhao Chen-Hui , Wu De-Gang , Cheng Hao , Sun Le-An , Zhang De-Long , Yang Xin-Jie , Fan Xi-Ran , Di Guang-Fu , Jiang Xiao-Chun
Published: February 2021

Introduction

S100 calcium-binding protein A8 (S100A8) is also known as macrophage-related protein 8, which is involved in various pathological processes in the central nervous system post-traumatic brain injury (TBI), and plays a critical role in inducing inflammatory cytokines. Accumulating evidences have indicated that toll-like receptor 4 (TLR4) is considered to be involved in inflammatory responses post TBI. The present study was designed to analyze the hypothesis that S100A8 is the key molecule that induces inflammation via TLR4 in TBI.

Methods

The weight-drop TBI model was used and randomly implemented on mice that were categorized into six groups: Sham, NS, S100A8, S100A8+TAK-242, TBI, and TBI+TAK-242 groups. In the S100A8+TAK-242 and TBI+TAK-242 groups, at half an hour prior to the intracerebroventricular administration of S100A8 or TBI, mice were intraperitoneally treated with TAK-242 that acts as a selective antagonist and inhibitor of TLR4. Furthermore, the protein recombinant of S100A8 was injected into the lateral ventricle of the brain of mice in the S100A8 and S100A8+TAK-242 groups. Sterile normal saline was injected into the lateral ventricle in the NS group. To evaluate the association between S100A8 and TLR4, Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Nissl staining were employed. Simultaneously, the neurological score and brain water content were assessed. In the in vitro analysis, BV-2 microglial cells were stimulated with lipopolysaccharide LPS or S100A8 recombinant protein, with or without TAK-242. The expression of the related proteins was subsequently detected by Western blot or enzyme-linked immunosorbent assay.

Results

The levels of S100A8 protein and pro-inflammatory cytokines were significantly elevated after TBI. There was a reduction in the neurological scores of non-TBI animals with remarkable severe brain edema after the intracerebroventricular administration of S100A8. Furthermore, the TLR4, p-p65, and myeloid differentiation factor 88 (MyD88) levels were elevated after the administration of S100A8 or TBI, which could be restored by TAK-242. Meanwhile, in the in vitro analysis, due to the stimulation of S100A8 or LPS, there was an upregulation of p-p65 and MyD88, which could also be suppressed by TAK-242.

Conclusion

The present study demonstrated that the TLR4-MyD88 pathway was activated by S100A8, which is essential for the development of inflammation in the brain after TBI.
The Impact of Preoperative Radiomics Signature on the Survival of Breast Cancer Patients With Residual Tumors After NAC
Authors: Zhang Ling , Jiang Xinhua , Xie Xiaoming , Wu Yaopan , Zheng Shaoquan , Tian Wenwen , Xie Xinhua , Li Li
Published: February 2021

Background

Residual cancer cells remaining after chemotherapy may have more aggressive behavior that promotes recurrence or metastasis, and which patients would benefit from subsequent additional treatment is controversial. The purpose of our study was to evaluate the prognostic value of the preoperative radiomics features of computed tomography (CT) imaging in breast cancer (BC) patients with residual tumors after neoadjuvant chemotherapy (NAC).

Methods

Post-NAC CT images were reviewed from 114 patients who had received breast surgery and had residual breast tumors. The association of the 110 radiomics features derived from CT images with 5-year disease-free survival (DFS) was assessed by log-rank test in the training cohort, resulting in 13 prognostic radiomics features.

Results

We constructed a radiomics signature consisting of four selected features by using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, which performed well in the discrimination with an area under the curve (AUC) of 0.78 (95% CI, 0.67–0.89) and 0.73 (95% CI, 0.59–0.87) in the training and validation cohorts, respectively. Radiomics nomogram, incorporating the radiomics signature with the conventional clinical variables, also performed well in the two cohorts (training cohort: AUC, 0.84; validation cohort: AUC, 0.82). Moreover, we found that the high-risk patients determined by our radiomics nomogram could benefit from postoperative adjuvant chemotherapy, while the low-risk and total patient groups could not.

Conclusions

Our novel radiomics nomogram is a promising and favorable prognostic biomarker for preoperatively predicting survival outcomes and may aid in clinical decision-making in BC patients with residual tumors after NAC.
Beyond Andromeda: Improving Therapy for Light Chain Amyloidosis
Authors: Kaufman Gregory P. , Cerchione Claudio
Published: February 2021

Therapy for light chain amyloidosis (AL) continues to evolve, and a new standard of care for the disease is rapidly forming. The risk of early death however, mainly from cardiac complications, remains an important benchmark yet to be definitively improved upon. This brief review explores recent advances in plasma cell directed therapy for AL, highlighting unique factors specific to these patients and AL biology driving differences in treatment strategies and clinical development compared with multiple myeloma. Improving upon proteasome inhibitor based upfront therapy combinations with the addition of anti-CD38 antibodies has shown promise with improved response rates in the ANDROMEDA (NCT03201965) study. Though depth and kinetics of achieving deep hematologic response as well as rates of biomarker defined organ response were improved with the addition of daratumumab to the combination of bortezomib, cyclophosphamide, and dexamethasone, death rates in each arm remained similar. Evaluation of other targeted and novel therapies in AL is ongoing, and we highlight efforts evaluating B-cell maturation antigen (BCMA) directed therapy, BCL-2 family inhibitors, and other novel agents in the field. We also look ahead to efforts to reimagine the clinical development of anti-fibrillar therapies after late phase study failures. Upcoming anti-amyloid fibril antibody studies explore opportunities to improve outcomes for the sickest AL patients with advanced cardiac disease, focusing on improving overall patient survival and reducing the risk of early death in this uniquely frail population.
The Cancer Rehabilitation Medicine Metrics Consortium: A Path to Enhanced, Multi-Site Outcome Assessment to Enhance Care and Demonstrate Value
Authors: Smith Sean R. , Vargo Mary , Zucker David S. , Henderson Maryanne , Shahpar Samman , Wisotzky Eric M. , Custodio Christian , Basford Jeffrey , Jay Gina , Gerber Lynn , Cheville Andrea
Published: February 2021

Purpose

A primary objective stated at the Cancer Rehabilitation Symposium at the National Institutes of Health was to improve outcome measurement. The purpose of this project was for the Cancer Rehabilitation Medicine Metrics Consortium (CRMMC) to develop an assessment tool to evaluate function in cancer patients via a data-driven and methodologically sound process. There is no agreed-upon measure of physical and cognitive function for cancer patients, making it difficult to demonstrate the value of rehabilitation interventions. Cancer patients are a particularly challenging population, with many tumor- and treatment-related variables impacting function.

Methods

Investigators from nine different cancer rehabilitation programs participated in a modified-Delphi process to delineate necessary aspects of an ideal patient assessment tool, including instrument type, domains evaluated, applicability across a range of patient traits, clinical feasibility, and item response characteristics. This involved numerous meetings, data review, and analysis of items involved in patient assessment.

Results

The CRMMC developed a 21-item patient-reported outcome measure based on item response theory. The process by which the short form was developed was documented and provides a framework for other clinicians to follow.

Conclusion

This document provides a framework for rehabilitation providers to follow when developing an assessment tool. This process is described in a stepwise fashion for reproducibility even in different, non-cancer populations.
Emerging Role of Long Non-Coding RNAs in the Pathobiology of Glioblastoma
Authors: Rezaei Omidvar , Tamizkar Kasra Honarmand , Sharifi Guive , Taheri Mohammad , Ghafouri-Fard Soudeh
Published: February 2021

Glioblastoma is the utmost aggressive diffuse kind of glioma which is originated from astrocytes, neural stem cells or progenitors. This malignant tumor has a poor survival rate. A number of genetic aberrations and somatic mutations have been associated with this kind of cancer. In recent times, the impact of long non-coding RNAs (lncRNAs) in glioblastoma has been underscored by several investigations. Up-regulation of a number of oncogenic lncRNAs such as H19, MALAT1, SNHGs, MIAT, UCA, HIF1A-AS2 and XIST in addition to down-regulation of other tumor suppressor lncRNAs namely GAS5, RNCR3 and NBAT1 indicate the role of these lncRNAs in the pathogenesis of glioblastoma. Several in vitro and a number of in vivo studies have demonstrated the contribution of these transcripts in the regulation of cell proliferation and apoptosis, cell survival, invasion and metastasis of glioblastoma cells. Moreover, some lncRNAs such as SBF2-AS1 are involved in conferring resistance to temozolomide. Finally, few circularRNAs have been identified that influence the evolution of glioblastoma. In this paper, we discuss the impacts of lncRNAs in the pathogenesis of glioblastoma, their applications as markers and their implications in the therapeutic responses in this kind of cancer.