bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Disturbed Expression and DNA Methylation of SCAP/SREBP Signaling in the Mouse Lung From Assisted Reproductive Technologies
Authors: Le Fang , Wang Ning , Wang Qijing , Yang Xinyun , Li Lejun , Wang Liya , Liu Xiaozhen , Hu Minhao , Jin Fan , Lou Hangying
Published: June 2021

Assisted reproductive technology (ART) has been linked to cholesterol metabolic and respiratory disorders later in life, but the mechanisms by which biosynthetic signaling remain unclear. Lung inflammatory diseases are tightly linked with the sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP), but this has not been shown in an ART offspring. Here, mouse models from a young to old age were established including in vitro fertilization (IVF), intracytoplasmic injection (ICSI), and in vivo fertilized groups. In our results, significantly higher plasma levels of CRP, IgM, and IgG were identified in the aged ICSI mice. Additionally, pulmonary inflammation was found in four aged ART mice. At three weeks, ART mice showed significantly downregulated levels of Scap, Srebp-1a, Srebp-1c, and Srebf2 mRNA in the lung. At the same time, significant differences in the DNA methylation rates of Scap-Srebfs and protein expression of nuclear forms of SREBPs (nSREBPs) were detected in the ART groups. Only abnormalities in the expression levels of Srebp-1a and Srebp-1c mRNA and nSREBP1 protein were found in the ART groups at 10 weeks. However, at 1.5 years old, aberrant expression levels and DNA methylation of SCAP, SREBP1, and SREBP2, and their associated target genes, were observed in the lung of the ART groups. Our results indicate that ART increases long-term alterations in SCAP/SREBP expression that may be associated with their aberrant methylation status in mouse.
A Computational Approach Identified Andrographolide as a Potential Drug for Suppressing COVID-19-Induced Cytokine Storm
Authors: Rehan Mohd , Ahmed Firoz , Howladar Saad M. , Refai Mohammed Y. , Baeissa Hanadi M. , Zughaibi Torki A. , Kedwa Khalid Mohammed , Jamal Mohammad Sarwar
Published: June 2021

Background

The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the coronavirus disease of 2019 (COVID-19) that killed more than 3.5 million people till now. The cytokine storm induced in severe COVID-19 patients causes hyper-inflammation, is the primary reason for respiratory and multi-organ failure and fatality. This work uses a rational computational strategy to identify the existing drug molecules to target host pathways to reduce the cytokine storm.

Results

We used a “host response signature network” consist of 36 genes induced by SARS-CoV-2 infection and associated with cytokine storm. In order to attenuate the cytokine storm, potential drug molecules were searched against “host response signature network”. Our study identified that drug molecule andrographolide, naturally present in a medicinal plant Andrographis paniculata, has the potential to bind with crucial proteins to block the TNF-induced NFkB1 signaling pathway responsible for cytokine storm in COVID-19 patients. The molecular docking method showed the binding of andrographolide with TNF and covalent binding with NFkB1 proteins of the TNF signaling pathway.

Conclusion

We used a rational computational approach to repurpose existing drugs targeting host immunomodulating pathways. Our study suggests that andrographolide could bind with TNF and NFkB1 proteins, block TNF-induced cytokine storm in COVID-19 patients, and warrant further experimental validation.
Normal Numbers of Stem Cell Memory T Cells Despite Strongly Reduced Naive T Cells Support Intact Memory T Cell Compartment in Ataxia Telangiectasia
Authors: Weitering Thomas J. , Melsen Janine E. , van Ostaijen-ten Dam Monique M. , Weemaes Corry M. R. , Schilham Marco W. , van der Burg Mirjam
Published: June 2021

Ataxia Telangiectasia (AT) is a rare inherited disorder characterized by progressive cerebellar ataxia, chromosomal instability, cancer susceptibility and immunodeficiency. AT is caused by mutations in the ATM gene, which is involved in multiple processes linked to DNA double strand break repair. Immunologically, ATM mutations lead to hampered V(D)J recombination and consequently reduced numbers of naive B and T cells. In addition, class switch recombination is disturbed resulting in antibody deficiency causing common, mostly sinopulmonary, bacterial infections. Yet, AT patients in general have no clinical T cell associated infections and numbers of memory T cells are usually normal. In this study we investigated the naive and memory T cell compartment in five patients with classical AT and compared them with five healthy controls using a 24-color antibody panel and spectral flow cytometry. Multidimensional analysis of CD4 and CD8 TCRαβ+ cells revealed that early naive T cell populations, i.e. CD4+CD31+ recent thymic emigrants and CD8+CCR7++CD45RA++ T cells, were strongly reduced in AT patients. However, we identified normal numbers of stem cell memory T cells expressing CD95, which are antigen-experienced T cells that can persist for decades because of their self-renewal capacity. We hypothesize that the presence of stem cell memory T cells explains why AT patients have an intact memory T cell compartment. In line with this novel finding, memory T cells of AT patients were normal in number and expressed chemokine receptors, activating and inhibitory receptors in comparable percentages as controls. Comparing memory T cell phenotypes by Boolean gating revealed similar diversity indices in AT compared to controls. We conclude that AT patients have a fully developed memory T cell compartment despite strongly reduced naive T cells. This could be explained by the presence of normal numbers of stem cell memory T cells in the naive T cell compartment, which support the maintenance of the memory T cells. The identification of stem cell memory T cells via our spectral flow cytometric approach is highly relevant for better understanding of T cell immunity in AT. Moreover, it provides possibilities for further research on this recently identified T cell population in other inborn errors of immunity.
Imaging Inflammation – From Whole Body Imaging to Cellular Resolution
Authors: Peñate Medina Tuula , Kolb Jan Philip , Hüttmann Gereon , Huber Robert , Peñate Medina Oula , Ha Linh , Ulloa Patricia , Larsen Naomi , Ferrari Arianna , Rafecas Magdalena , Ellrichmann Mark , Pravdivtseva Mariya S. , Anikeeva Mariia , Humbert Jana , Both Marcus , Hundt Jennifer E. , Hövener Jan-Bernd
Published: June 2021

Imaging techniques have evolved impressively lately, allowing whole new concepts like multimodal imaging, personal medicine, theranostic therapies, and molecular imaging to increase general awareness of possiblities of imaging to medicine field. Here, we have collected the selected (3D) imaging modalities and evaluated the recent findings on preclinical and clinical inflammation imaging. The focus has been on the feasibility of imaging to aid in inflammation precision medicine, and the key challenges and opportunities of the imaging modalities are presented. Some examples of the current usage in clinics/close to clinics have been brought out as an example. This review evaluates the future prospects of the imaging technologies for clinical applications in precision medicine from the pre-clinical development point of view.
Plasma Extracellular Vesicles Enhance HIV-1 Infection of Activated CD4+ T Cells and Promote the Activation of Latently Infected J-Lat10.6 Cells via miR-139-5p Transfer
Authors: Okoye Isobel , Xu Lai , Oyegbami Olaide , Shahbaz Shima , Pink Desmond , Gao Priscilla , Sun Xuejun , Elahi Shokrollah
Published: June 2021

HIV latency is a challenge to the success of antiretroviral therapy (ART). Hence patients may benefit from interventions that efficiently reactivate the latent virus to be eliminated by ARTs. Here we show that plasma extracellular vesicles (pEVs) can enhance HIV infection of activated CD4+ T cells and reactivate the virus in latently infected J-Lat 10.6 cells. Evaluation of the extravesicular miRNA cargo by a PCR array revealed that pEVs from HIV patients express miR-139-5p. Furthermore, we found that increased levels of miR-139-5p in J-Lat 10.6 cells incubated with pEVs corresponded with reduced expression of the transcription factor, FOXO1. pEV treatment also corresponded with increased miR-139-5p expression in stimulated PD1+ Jurkat cells, but with concomitant upregulation of FOXO1, Fos, Jun, PD-1 and PD-L1. However, J-Lat 10.6 cells incubated with miR-139-5p inhibitor-transfected pEVs from HIV ART-naïve and on-ART patients expressed reduced levels of miR-139-5p than cells treated with pEVs from healthy controls (HC). Collectively, our results indicate that pEV miR-139-5p belongs to a network of miRNAs that can promote cell activation, including latent HIV-infected cells by regulating the expression of FOXO1 and the PD1/PD-L1 promoters, Fos and Jun.
Effects of Citrus Fruit Juices and Their Bioactive Components on Inflammation and Immunity: A Narrative Review
Authors: Miles Elizabeth A. , Calder Philip C.
Published: June 2021

The immune system provides defence to the host against pathogenic organisms. A weak immune system increases susceptibility to infections and allows infections to become more severe. One component of the immune response is inflammation. Where inflammation is excessive or uncontrolled it can damage host tissues and cause pathology. Limitation of oxidative stress is one means of controlling inflammation. Citrus fruit juices are a particularly good source of vitamin C and folate, which both have roles in sustaining the integrity of immunological barriers and in supporting the function of many types of immune cell including phagocytes, natural killer cells, T-cells and B-cells. Vitamin C is an antioxidant and reduces aspects of the inflammatory response. Important bioactive polyphenols in citrus fruit juices include hesperidin, narirutin and naringin. Hesperidin is a glycoside of hesperetin while narirutin and naringin are glycosides of naringenin. Hesperidin, hesperetin, naringenin, naringin and narirutin have all been found to have anti-inflammatory effects in model systems, and human trials of hesperidin report reductions in inflammatory markers. In humans, orange juice was shown to limit the post-prandial inflammation induced by a high fat-high carbohydrate meal. Consuming orange juice daily for a period of weeks has been reported to reduce markers of inflammation, including C-reactive protein, as confirmed through a recent meta-analysis. A newly emerging topic is whether polyphenols from orange juice have direct anti-viral effects. In summary, micronutrients and other bioactives present in citrus fruit juices have established roles in controlling oxidative stress and inflammation and in supporting innate and acquired immune responses. Trials in humans demonstrate that orange juice reduces inflammation; its effects on innate and acquired immunity require further exploration in well-designed trials in appropriate population sub-groups such as older people.
Energy Evolution Law of Marble Failure Process Under Different Confining Pressures Based on Particle Discrete Element Method
Authors: Yang Yan-Shuang , Cheng Wei , Zhang Zhan-Rong , Tian Hao-Yuan , Li Kai-Yue , Huang Cai-Ping
Published: June 2021

The energy dissipation usually occurs during rock failure, which can demonstrate the meso failure process of rock in a relatively accurate way. Based on the results of conventional triaxial compression experiments on the Jinping marble, a numerical biaxial compression model was established by PFC2D to observe the development of the micro-cracks and energy evolution during the test, and then the laws of crack propagation, energy dissipation and damage evolution were analyzed. The numerical simulation results indicate that both the crack number and the total energy dissipated during the loading process increase with confining pressures, which is basically consistent with the experiment results. Two damage variables were presented in terms of the density from other researchers’ results and energy dissipation from numerical simulation, respectively. The energy-based damage variable varies with axial strain in the shape of “S,” and approaches one more closely than that based on density at the final failure period. The research in the rock failure from the perspective of energy may further understand the mechanical behavior of rocks.
The Characterisation of the Craniofacial Morphology of Infants Born With Zika Virus; Innovative Approach for Public Health Surveillance and Broad Clinical Applications
Authors: Ayoub Ashraf , de Freitas Silva Leonardo , Mossey Peter , Al-Rudainy Dhelal , de Mattos Adriana Marques , Garcia Júnior Idelmo Rangel , Quigley Alan , Ju Xiangyang
Published: June 2021

Background: This study was carried out in response to the Zika virus epidemic, which constituted a public health emergency, and to the 2019 WHO calling for strengthened surveillance for the early detection of related microcephaly. The main aim of the study was to phenotype the craniofacial morphology of microcephaly using a novel approach and new measurements, and relate the characteristics to brain abnormalities in Zika-infected infants in Brazil to improve clinical surveillance.

Methods: 3D images of the face and the cranial vault of 44 Zika-infected infants and matched healthy controls were captured using a 3D stereophotogrammetry system. The CT scans of the brain of the infected infants were analysed. Principal component analysis (PCA) was applied to characterise the craniofacial morphology. In addition to the head circumference (HC), a new measurement, head height (HH), was introduced to measure the cranial vault. The level of brain abnormality present in the CT scans was assessed; the severity of parenchymal volume loss and ventriculomegaly was quantified. Student's t-test and Spearman's Rho statistical test have been applied.

Findings: The PCA identified a significant difference (p < 0.001) between the cranial vaults and the face of the Zika infants and that of the controls. Spearman's rank-order correlation coefficients show that the head height (HH) has a strong correlation (0.87 in Zika infants; 0.82 in controls) with the morphology of the cranial vaults, which are higher than the correlation with the routinely used head circumference (HC). Also, the head height (HH) has a moderate negative correlation (−0.48) with the brain abnormalities of parenchymal volume loss.

Interpretation: It is discovered that the head height (HH) is the most sensitive and discriminatory measure of the severity of cranial deformity, which should be used for clinical surveillance of the Zika syndrome, evaluation of other craniofacial syndromes and assessment of various treatment modalities.
Bioinformatics Analysis Reveals Crosstalk Among Platelets, Immune Cells, and the Glomerulus That May Play an Important Role in the Development of Diabetic Nephropathy
Authors: Yao Xinyue , Shen Hong , Cao Fukai , He Hailan , Li Boyu , Zhang Haojun , Zhang Xinduo , Li Zhiguo
Published: June 2021

Diabetic nephropathy (DN) is the main cause of end stage renal disease (ESRD). Glomerulus damage is one of the primary pathological changes in DN. To reveal the gene expression alteration in the glomerulus involved in DN development, we screened the Gene Expression Omnibus (GEO) database up to December 2020. Eleven gene expression datasets about gene expression of the human DN glomerulus and its control were downloaded for further bioinformatics analysis. By using R language, all expression data were extracted and were further cross-platform normalized by Shambhala. Differentially expressed genes (DEGs) were identified by Student's t-test coupled with false discovery rate (FDR) (P < 0.05) and fold change (FC) ≥1.5. DEGs were further analyzed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to enrich the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. We further constructed a protein-protein interaction (PPI) network of DEGs to identify the core genes. We used digital cytometry software CIBERSORTx to analyze the infiltration of immune cells in DN. A total of 578 genes were identified as DEGs in this study. Thirteen were identified as core genes, in which LYZ, LUM, and THBS2 were seldom linked with DN. Based on the result of GO, KEGG enrichment, and CIBERSORTx immune cells infiltration analysis, we hypothesize that positive feedback may form among the glomerulus, platelets, and immune cells. This vicious cycle may damage the glomerulus persistently even after the initial high glucose damage was removed. Studying the genes and pathway reported in this study may shed light on new knowledge of DN pathogenesis.
The Significance of Duration of Exposure and Circulation of Fresh Air in SARS-CoV-2 Transmission Among Healthcare Workers
Authors: Vlacha Vasiliki , Feketea Gavriela , Petropoulou Athanasia , Trancá Sebastian Daniel
Published: June 2021

Background: The true risk of infection after exposure to SARS-CoV-2 of healthcare workers (HCWs) in the workplace has not yet been established. This descriptive study analyzes the exposure characteristics of HCWs to SARS-CoV-2.

Methods: In March 2020, at the beginning of the pandemic, a total of 58 HCWs in a regional hospital in Greece were exposed to three patients with symptomatic SARS-CoV-2 infection. These three index cases had taken part in an 8-day religious tour, during which 52 travelers spent 10 h every day in a tour bus. A study was made of the circumstances of the hospital exposure.

Results: Of the 52 travelers in the bus, 48 contracted SARS-CoV2. None of the 58 HCW contacts developed symptoms related to COVID-19, although, 43% were exposed to a SARS-CoV-2 infected patient for more than 15 min, and 74% were within a distance of <1 m, and half of the contacts were not wearing a surgical mask. Additional information was that 63% of the contacts were exposed in a room sized more than 15 m2, and in more than 80% of cases, the window or the door to the room was open during their exposure. In about one-third of the exposure events, the HCW contacts were not wearing a mask and were at a distance of <1 m, and just under half of them were exposed for more than 15 min. One-fourth of the contacts underwent RT-PCR testing, and 11% IgG/IgM antibody testing for SARS-CoV-2, all of which were negative. All observed quarantine at home for 14 days.

Conclusion: This observational study was made before the extent of the SARS-CoV-2 became apparent, and before routine preventive measures were observed by all HCWs. Comparing the conditions of exposure in the two different settings (bus vs. regional health facility), it is apparent that the duration of exposure and the small, enclosed nature of the bus are the distinguishing factors. In the healthcare setting, the elimination of both factors and the implementation of additional measures protected the exposed HCWs from contracting SARS-CoV-2 infection.
Correlation Between Electroretinogram and Visual Prognosis in Metallic Intraocular Foreign Body Injury
Authors: Mai Xiaoting , Ling Fangyi , Gong Yuting , Chen Jialin , Lin Hongjie , Chen Haoyu
Published: June 2021

Purpose: This study aims to investigate the correlation between electroretinogram (ERG) and visual outcome in eyes with metallic intraocular foreign body (IOFB) injury.

Methods: Cases with metallic IOFB injuries with preoperative ERG from January 2008 to May 2020 were reviewed retrospectively. Five ERG responses were recorded, including rod response, maximal response, oscillatory potentials, cone response, and 30-Hz flicker. The results were compared between the affected and the contralateral eyes. All patients received surgery to remove IOFBs. The correlation between amplitudes, implicit times, and grades of ERG with final best-corrected visual acuity (BCVA) was analyzed.

Results: A total of 33 eyes of 33 patients were included. The eyes with IOFB had generally delayed implicit time and reduced amplitude in all waves. The maximum change was found in oscillatory potentials S3 and N1 (0.42 ± 0.42 and 1.95 ± 1.97 of the fellow eyes, respectively, p < 0.05). All amplitudes were negatively correlated with the final BCVA (rs: −0.676 to −0.459, all p < 0.05). In contrast, all implicit times were positively correlated with final BCVA, although, some of them were not statistically significant (rs: 0.035 to 0.687). Among them, oscillatory potential P3 has the highest correlation coefficient (rs = 0.687, p < 0.001). All grades of ERG waves were statistically correlated with the final BCVA (rs: −0.596 to −0.664, all p < 0.001).

Conclusions: ERG can be used to assess visual outcome in metallic IOFB injury after surgery. Oscillatory potentials provided the most significant responses.
Shaping of the Present-Day Deep Biosphere at Chicxulub by the Impact Catastrophe That Ended the Cretaceous
Authors: Cockell Charles S. , Schaefer Bettina , Wuchter Cornelia , Coolen Marco J. L. , Grice Kliti , Schnieders Luzie , Morgan Joanna V. , Gulick Sean P. S. , Wittmann Axel , Lofi Johanna , Christeson Gail L. , Kring David A. , Whalen Michael T. , Bralower Timothy J. , Osinski Gordon R. , Claeys Philippe , Kaskes Pim , de Graaff Sietze J. , Déhais Thomas , Goderis Steven , Hernandez Becerra Natali , Nixon Sophie ,   IODP-ICDP Expedition 364 Scientists
Published: June 2021

We report on the effect of the end-Cretaceous impact event on the present-day deep microbial biosphere at the impact site. IODP-ICDP Expedition 364 drilled into the peak ring of the Chicxulub crater, México, allowing us to investigate the microbial communities within this structure. Increased cell biomass was found in the impact suevite, which was deposited within the first few hours of the Cenozoic, demonstrating that the impact produced a new lithological horizon that caused a long-term improvement in deep subsurface colonization potential. In the biologically impoverished granitic rocks, we observed increased cell abundances at impact-induced geological interfaces, that can be attributed to the nutritionally diverse substrates and/or elevated fluid flow. 16S rRNA gene amplicon sequencing revealed taxonomically distinct microbial communities in each crater lithology. These observations show that the impact caused geological deformation that continues to shape the deep subsurface biosphere at Chicxulub in the present day.
Lactobacillus casei Zhang Counteracts Blood-Milk Barrier Disruption and Moderates the Inflammatory Response in Escherichia coli-Induced Mastitis
Authors: Zheng Yuhui , Liu Gang , Wang Wei , Wang Yajing , Cao Zhijun , Yang Hongjian , Li Shengli
Published: June 2021

Escherichia coli is a common mastitis-causing pathogen that can disrupt the blood-milk barrier of mammals. Although Lactobacillus casei Zhang (LCZ) can alleviate mice mastitis, whether it has a prophylactic effect on E. coli-induced mastitis through intramammary infusion, as well as its underlying mechanism, remains unclear. In this study, E. coli-induced injury models of bovine mammary epithelial cells (BMECs) and mice in lactation were used to fill this research gap. In vitro tests of BMECs revealed that LCZ significantly inhibited the E. coli adhesion (p < 0.01); reduced the cell desmosome damage; increased the expression of the tight junction proteins claudin-1, claudin-4, occludin, and zonula occludens-1 (ZO-1; p < 0.01); and decreased the expression of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 (p < 0.01), thereby increasing trans-epithelial electric resistance (p < 0.01) and attenuating the lactate dehydrogenase release induced by E. coli (p < 0.01). In vivo tests indicated that LCZ significantly reduced the injury and histological score of mice mammary tissues in E. coli-induced mastitis (p < 0.01) by significantly promoting the expression of the tight junction proteins claudin-3, occludin, and ZO-1 (p < 0.01), which ameliorated blood-milk barrier disruption, and decreasing the expression of the inflammatory cytokines (TNF-α, IL-1β, and IL-6) in mice mammary tissue (p < 0.01). Our study suggested that LCZ counteracted the disrupted blood-milk barrier and moderated the inflammatory response in E. coli-induced injury models, indicating that LCZ can ameliorate the injury of mammary tissue in mastitis.
Antidiabetic Function of Lactobacillus fermentum MF423-Fermented Rice Bran and Its Effect on Gut Microbiota Structure in Type 2 Diabetic Mice
Authors: Ai Xiaojuan , Wu Cuiling , Yin Tingting , Zhur Olena , Liu Congling , Yan Xiaotao , Yi CuiPing , Liu Dan , Xiao Linhu , Li Wenkai , Xie Binbin , He Hailun
Published: June 2021

Rice bran is an industrial byproduct that exerts several bioactivities despite its limited bioavailability. In this study, rice bran fermented with Lactobacillus fermentum MF423 (FLRB) had enhanced antidiabetic effects both in vitro and in vivo. FLRB could increase glucose consumption and decrease lipid accumulation in insulin resistant HepG2 cells. Eight weeks of FLRB treatment significantly reduced the levels of blood glucose and lipids and elevated antioxidant activity in type 2 diabetic mellitus (T2DM) mice. H&E staining revealed alleviation of overt lesions in the livers of FLRB-treated mice. Moreover, high-throughput sequencing showed notable variation in the composition of gut microbiota in FLRB-treated mice, especially for short-chain fatty acids (SCFAs)-producing bacteria such as Dubosiella and Lactobacillus. In conclusion, our results suggested that rice bran fermentation products can modulate the intestinal microbiota and improve T2DM-related biochemical abnormalities, so they can be applied as potential probiotics or dietary supplements.
RNA Chaperones Hfq and ProQ Play a Key Role in the Virulence of the Plant Pathogenic Bacterium Dickeya dadantii
Authors: Leonard Simon , Villard Camille , Nasser William , Reverchon Sylvie , Hommais Florence
Published: June 2021

Dickeya dadantii is an important pathogenic bacterium that infects a number of crops including potato and chicory. While extensive works have been carried out on the control of the transcription of its genes encoding the main virulence functions, little information is available on the post-transcriptional regulation of these functions. We investigated the involvement of the RNA chaperones Hfq and ProQ in the production of the main D. dadantii virulence functions. Phenotypic assays on the hfq and proQ mutants showed that inactivation of hfq resulted in a growth defect, a modified capacity for biofilm formation and strongly reduced motility, and in the production of degradative extracellular enzymes (proteases, cellulase, and pectate lyases). Accordingly, the hfq mutant failed to cause soft rot on chicory leaves. The proQ mutant had reduced resistance to osmotic stress, reduced extracellular pectate lyase activity compared to the wild-type strain, and reduced virulence on chicory leaves. Most of the phenotypes of the hfq and proQ mutants were related to the low amounts of mRNA of the corresponding virulence factors. Complementation of the double mutant hfq-proQ by each individual protein and cross-complementation of each chaperone suggested that they might exert their effects via partially overlapping but different sets of targets. Overall, it clearly appeared that the two Hfq and ProQ RNA chaperones are important regulators of pathogenicity in D. dadantii. This underscores that virulence genes are regulated post-transcriptionally by non-coding RNAs.
Cadmium, an Environmental Contaminant, Exacerbates Alzheimer’s Pathology in the Aged Mice’s Brain
Authors: Ali Tahir , Khan Amjad , Alam Sayed Ibrar , Ahmad Sareer , Ikram Muhammad , Park Jun Sung , Lee Hyeon Jin , Kim Myeong Ok
Published: June 2021

Cadmium (Cd) is an environmental contaminant, which is a potential risk factor in the progression of aging-associated neurodegenerative diseases. Herein, we have assessed the effects of chronic administration of Cd on cellular oxidative stress and its associated Alzheimer’s disease (AD) pathologies in animal models. Two groups of mice were used, one group administered with saline and the other with Cd (1 mg/kg/day; intraperitoneally) for 3 months. After behavioral studies, molecular/biochemical (Immunoblotting, ELISAs, ROS, LPO, and GSH assays) and morphological analyses were performed. We observed an exacerbation of memory and synaptic deficits in chronic Cd-injected mice. Subacute and chronic Cd escalated reactive oxygen species (ROS), suppressed the master antioxidant enzymes, e.g., nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1, and evoked the stress kinase phospho-c-Jun N-terminal kinase 1 signaling pathways, which may escalate AD pathologies possibly associated with amyloidogenic processes. These findings suggest the regulation of oxidative stress/ROS and its associated amyloid beta pathologies for targeting the Cd-exacerbated AD pathogenesis. In addition, these preclinical animal studies represent a paradigm for epidemiological studies of the human population exposed to chronic and subacute administration of Cd, suggesting avoiding environmental contaminants.
Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
Authors: Feringa Femke M. , van der Kant Rik
Published: June 2021

While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer’s disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.
Active Inferants: An Active Inference Framework for Ant Colony Behavior
Authors: Friedman Daniel Ari , Tschantz Alec , Ramstead Maxwell J. D. , Friston Karl , Constant Axel
Published: June 2021

In this paper, we introduce an active inference model of ant colony foraging behavior, and implement the model in a series of in silico experiments. Active inference is a multiscale approach to behavioral modeling that is being applied across settings in theoretical biology and ethology. The ant colony is a classic case system in the function of distributed systems in terms of stigmergic decision-making and information sharing. Here we specify and simulate a Markov decision process (MDP) model for ant colony foraging. We investigate a well-known paradigm from laboratory ant colony behavioral experiments, the alternating T-maze paradigm, to illustrate the ability of the model to recover basic colony phenomena such as trail formation after food location discovery. We conclude by outlining how the active inference ant colony foraging behavioral model can be extended and situated within a nested multiscale framework and systems approaches to biology more generally.
Autonomic Modulation During Baseline and Recovery Sleep in Adult Sleepwalkers
Authors: Scavone Geneviève , Baril Andrée-Ann , Montplaisir Jacques , Carrier Julie , Desautels Alex , Zadra Antonio
Published: June 2021

Sleepwalking has been conceptualized as deregulation between slow-wave sleep and arousal, with its occurrence in predisposed patients increasing following sleep deprivation. Recent evidence showed autonomic changes before arousals and somnambulistic episodes, suggesting that autonomic dysfunctions may contribute to the pathophysiology of sleepwalking. We investigated cardiac autonomic modulation during slow-wave sleep in sleepwalkers and controls during normal and recovery sleep following sleep deprivation. Fourteen adult sleepwalkers (5M; 28.1 ± 5.8 years) and 14 sex- and age-matched normal controls were evaluated by video-polysomnography for one baseline night and during recovery sleep following 25 h of sleep deprivation. Autonomic modulation was investigated with heart rate variability during participants' slow-wave sleep in their first and second sleep cycles. 5-min electrocardiographic segments from slow-wave sleep were analyzed to investigate low-frequency (LF) and high-frequency (HF) components of heart rate spectral decomposition. Group (sleepwalkers, controls) X condition (baseline, recovery) ANOVAs were performed to compare LF and HF in absolute and normalized units (nLF and nHF), and LF/HF ratio. When compared to controls, sleepwalkers' recovery slow-wave sleep showed lower LF/HF ratio and higher nHF during the first sleep cycle. In fact, compared to baseline recordings, sleepwalkers, but not controls, showed a significant decrease in nLF and LF/HF ratio as well as increased nHF during recovery slow-wave sleep during the first cycle. Although non-significant, similar findings with medium effect sizes were observed for absolute values (LF, HF). Patterns of autonomic modulation during sleepwalkers' recovery slow-wave sleep suggest parasympathetic dominance as compared to baseline sleep values and to controls. This parasympathetic predominance may be a marker of abnormal neural mechanisms underlying, or interfere with, the arousal processes and contribute to the pathophysiology of sleepwalking.
Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers
Authors: Menozzi Elisa , Schapira Anthony H. V.
Published: June 2021

Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.
Getting on the Same Page: Consolidating Terminology to Facilitate Cross-Disciplinary Health-Related Blast Research
Authors: Belding Jennifer N. , Egnoto Michael , Englert Robyn M. , Fitzmaurice Shannon , Thomsen Cynthia J.
Published: June 2021

The consequences of blast exposure (including both high-level and low-level blast) have been a focal point of military interest and research for years. Recent mandates from Congress (e.g., National Defense Authorization Act for Fiscal Year 2018, section 734) have further accelerated these efforts, facilitating collaborations between research teams from a variety of disciplinary backgrounds. Based on findings from a recent scoping review, we argue that the scientific field of blast research is plagued by inconsistencies in both conceptualization of relevant constructs and terminology used to describe them. These issues hamper our ability to interpret study methods and findings, hinder efforts to integrate findings across studies to reach scientific consensus, and increase the likelihood of redundant efforts. We argue that multidisciplinary experts in this field require a universal language and clear, standardized terminology to further advance the important work of examining the effects of blast exposure on human health, performance, and well-being. To this end, we present a summary of descriptive conventions regarding the language scientists currently use when discussing blast-related exposures and outcomes based on findings from a recent scoping review. We then provide prescriptive conventions about how these terms should be used by clearly conceptualizing and explicitly defining relevant constructs. Specifically, we summarize essential concepts relevant to the study of blast, precisely distinguish between high-level blast and low-level blast, and discuss how the terms acute, chronic, exposure, and outcome should be used when referring to the health-related consequences of blast exposure.
Neural Network Training Acceleration With RRAM-Based Hybrid Synapses
Authors: Choi Wooseok , Kwak Myonghoon , Kim Seyoung , Hwang Hyunsang
Published: June 2021

Hardware neural network (HNN) based on analog synapse array excels in accelerating parallel computations. To implement an energy-efficient HNN with high accuracy, high-precision synaptic devices and fully-parallel array operations are essential. However, existing resistive memory (RRAM) devices can represent only a finite number of conductance states. Recently, there have been attempts to compensate device nonidealities using multiple devices per weight. While there is a benefit, it is difficult to apply the existing parallel updating scheme to the synaptic units, which significantly increases updating process’s cost in terms of computation speed, energy, and complexity. Here, we propose an RRAM-based hybrid synaptic unit consisting of a “big” synapse and a “small” synapse, and a related training method. Unlike previous attempts, array-wise fully-parallel learning is possible with our proposed architecture with a simple array selection logic. To experimentally verify the hybrid synapse, we exploit Mo/TiOx RRAM, which shows promising synaptic properties and areal dependency of conductance precision. By realizing the intrinsic gain via proportionally scaled device area, we show that the big and small synapse can be implemented at the device-level without modifications to the operational scheme. Through neural network simulations, we confirm that RRAM-based hybrid synapse with the proposed learning method achieves maximum accuracy of 97 %, comparable to floating-point implementation (97.92%) of the software even with only 50 conductance states in each device. Our results promise training efficiency and inference accuracy by using existing RRAM devices.
The Type 3 Deiodinase Is a Critical Modulator of Thyroid Hormone Sensitivity in the Fetal Brain
Authors: Martinez Maria Elena , Hernandez Arturo
Published: June 2021

Thyroid hormones (TH) are critical for the development and function of the central nervous system (CNS). Although their effects on the rodent brain peak within 2–3 weeks postnatally, the fetal brain has been found largely insensitive to exogenously administrated TH. To address this issue, here we examined gene expression in brains from mouse fetuses deficient in the type 3 deiodinase (DIO3), the selenoenzyme responsible for clearing TH. At embryonic day E18.5 qPCR determinations indicated a marked increase in the mRNA expression of T3-responsive genes Klf9 and Nrgn. The increased expression of these genes was confirmed by in situ hydridization in multiple areas of the cortex and in the striatum. RNA sequencing revealed 246 genes differentially expressed (70% up-regulated) in the brain of E18.5 Dio3−/− male fetuses. Differential expression of 13 of these genes was confirmed in an extended set of samples that included females. Pathway analyses of differentially expressed genes indicated enrichment in glycolysis and signaling related to axonal guidance, synaptogenesis and hypoxia inducible factor alpha. Additional RNA sequencing identified 588 genes differentially expressed (35% up-regulated) in the brain of E13.5 Dio3−/− male fetuses. Differential expression of 13 of these genes, including Klf9, Hr, and Mgp, was confirmed in an extended set of samples including females. Although pathway analyses of differentially expressed genes at E13.5 also revealed significant enrichment in axonal guidance and synaptogenesis signaling, top enrichment was found for functions related to the cell cycle, aryl hydrocarbon receptor signaling, PCP and kinetochore metaphase signaling pathways and mitotic roles of polo-like kinase. Differential expression at E13.5 was confirmed by qPCR for additional genes related to collagen and extracellular matrix and for selected transcription factors. Overall, our results demonstrate that the rodent fetal brain is sensitive to TH as early as E13.5 of gestational age, and suggest that TH distinctly affects brain developmental programs in early and late gestation. We conclude that DIO3 function is critical to ensure an adequate timing for TH action in the developing brain and is probably the main factor underlying the lack of effects on the fetal brain observed in previous studies after TH administration.
Exocrine Pancreatic Maturation in Pre-term and Term Piglets Supplemented With Bovine Colostrum
Authors: Arévalo Sureda Ester , Pierzynowska Kateryna , Weström Björn , Sangild Per Torp , Thymann Thomas
Published: June 2021

Pre-term infants have an immature digestive system predisposing to short- and long-term complications including feeding intolerance, maldigestion and necrotizing enterocolitis (NEC). Optimal feeding strategies are required to promote maturation of the gut including the exocrine pancreas. Little is known about age- and diet-related development of pancreatic exocrine enzymes following pre-term birth. Currently, bovine colostrum supplementation is investigated in clinical trials on pre-term infants. Using pigs as models for infants, we hypothesized that pancreatic enzyme content is (1) immature following pre-term birth, (2) stimulated by early colostrum supplementation, and (3) stimulated by later colostrum fortification. Thus, using piglets as models for infants, we measured trypsin, amylase, lipase and total protein in pancreatic tissue collected from piglets delivered by cesarean section either pre-term (90% gestation) or close to term. Experiment 1:Pre-term and term pigs were compared at birth and 11 days. Experiment 2: Pre-term and term pigs were either enterally supplemented with bovine colostrum or fed total parenteral nutrition for 5 days, followed by exclusive milk feeding until day 26. Experiment 3: Pre-term pigs were fed bovine's milk with or without colostrum fortification until 19 days. The results showed that pancreatic trypsin, amylase and total protein contents were reduced in pre-term vs. term pigs. Trypsin mainly increased with advancing post-conceptional age (2-fold), while amylase was affected predominantly by advancing post-natal age, and mostly in pre-term pigs from birth to 11 or 26 days. Colostrum feeding in both term and pre-term piglets decreased trypsin and increased amylase contents. Lipase activity decreased with advancing gestational age at birth and post-natal age, with no consistent responses to colostrum feeding, with lipase activities decreasing relative to total pancreatic protein content. In summary, key pancreatic enzymes, amylase and trypsin, are immature following pre-term birth, potentially contributing to reduced digestive capacity in pre-term neonates. Rapid post-natal increases occurs within few weeks of pre-term birth, partly stimulated by enteral colostrum intake, reflecting a marked adaptation capacity. Alternatively, lipase is less affected by pre-/post-natal age and feeding. Thus, there is a highly enzyme-specific and asymmetric perinatal development of the exocrine pancreas.
Prognosis and Concurrent Genomic Alterations in Patients With Advanced NSCLC Harboring MET Amplification or MET Exon 14 Skipping Mutation Treated With MET Inhibitor: A Retrospective Study
Authors: Liu Li , Kalyani Farhin Shaheed , Yang Haiyan , Zhou Chunhua , Xiong Yi , Zhu Songlin , Yang Nong , Qu Jingjing
Published: June 2021

Background

MET amplification or METex14 skipping mutations are uncommon oncogenic events in NSCLC patients. Clinicopathological characteristics, concurrent gene alterations, and prognosis of MET TKIs in these patients are yet to be elucidated.

Methods

We retrospectively analyzed the genomic profiles of 43 MET amplifications or 31 METex14 skipping mutations in NSCLC patients with no previous treatment with EGFR TKIs. Survival outcomes were analyzed in evaluable patients receiving MET TKI treatment: MET amplification cohort (n = 29) and METex14 skipping mutation cohort (n = 29).

Results

Among evaluable patients, a shorter PFS was observed in the MET amplification cohort than in the METex14 skipping mutation cohort (7.0 months vs. 11.0 months, P = 0.043). Concurrent mutations in both cohorts resulted in a statistically significant shorter PFS (MET amplification: 3.5 months versus 8.0 months, P = 0.038, METex14 skipping mutation: 7.0 versus NR months, P = 0.022). However, a statistically significant OS (17.0 months versus 20.0 months, P = 0.044) was only observed in the MET amplification cohort. TP53, the most common concurrent mutation in both cohorts, was associated with worse survival outcomes as compared to the wild type. The MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%).

Conclusion

MET TKIs could be a better treatment option for patients with METex14 skipping mutations. Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. PIK3CA mutations may confer primary resistance to MET TKIs in patients with MET amplification.
FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration
Authors: Li Sisi , Huang Xiao-ting , Wang Meng-yao , Chen Dong-ping , Li Ming-yi , Zhu Yan-yi , Yu Yi , Zheng Lu , Qi Bin , Liu Jin-quan
Published: June 2021

Radiotherapy is one of the standard treatments for cervical cancer and head and neck cancer. However, the clinical efficacy of this treatment is limited by radioresistance. The discovery of effective prognostic biomarkers and the identification of new therapeutic targets have helped to overcome the problem of radioresistance. In this study, we show that in the context of PIK3CA mutation or amplification, high expression of fascin actin-bundling protein 1 (FSCN1) (using the median as the cut-off value) is associated with poor prognosis and radiotherapy response in cancer patients. Silencing FSCN1 enhances radiosensitivity and promotes apoptosis in cancer cells with PIK3CA alterations, and this process may be associated with the downregulation of YWHAZ. These results reveal that FSCN1 may be a key regulator of radioresistance and could be a potential target for improving radiotherapy efficacy in cervical cancer and head and neck cancer patients with PIK3CA alterations.