bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic Changes of Porcine Oocytes After Vitrification and Subsequent in vitro Maturation: A Tandem Mass Tag-Based Quantitative Analysis
Authors: Jia Baoyu , Xiang Decai , Fu Xiangwei , Shao Qingyong , Hong Qionghua , Quan Guobo , Wu Guoquan
Published: December 2020

Cryopreservation of immature germinal vesicle (GV) oocytes is a promising strategy in pigs but still results in reduced oocyte quality due to inevitable cryodamages. Recently, there has been more focus on the molecular changes of oocytes after vitrification, but the alteration in the proteome level remains elusive. The aim of this study therefore was to decipher the proteomic characteristics of porcine GV oocytes following vitrification and in vitro maturation (IVM) by using tandem mass tag (TMT)-based quantitative approach and bioinformatics analysis. A total of 4,499 proteins were identified, out of which 153 presented significant difference. There were 94 up-regulated and 59 down-regulated proteins expressed differentially in the vitrified oocytes. Functional classification and enrichment analyses revealed that many of these proteins were involved in metabolism, signal transduction, response to stimulus, immune response, complement, coagulation cascades, and so on. Moreover, a parallel reaction monitoring technique validated the reliability of TMT data through quantitative analysis for 10 candidate proteins. In conclusion, our results provided a novel perspective of proteomics to comprehend the quality change in the vitrified porcine GV oocytes after IVM.
Determining the Fate of Neurons in SCA3: ATX3, a Rising Decision Maker in Response to DNA Stresses and Beyond
Authors: Tu Yingfeng , Li Xiaoling , Zhu Xuefei , Liu Xiaokang , Guo Caixia , Jia Da , Tang Tie-Shan
Published: December 2020

DNA damage response (DDR) and apoptosis are reported to be involved in the pathogenesis of many neurodegenerative diseases including polyglutamine (polyQ) disorders, such as Spinocerebellar ataxia type 3 (SCA3) and Huntington's disease (HD). Consistently, an increasing body of studies provide compelling evidence for the crucial roles of ATX3, whose polyQ expansion is defined as the cause of SCA3, in the maintenance of genome integrity and regulation of apoptosis. The polyQ expansion in ATX3 seems to affect its physiological functions in these distinct pathways. These advances have expanded our understanding of the relationship between ATX3's cellular functions and the underlying molecular mechanism of SCA3. Interestingly, dysregulated DDR pathways also contribute to the pathogenesis of other neurodegenerative disorder such as HD, which presents a common molecular mechanism yet distinct in detail among different diseases. In this review, we provide a comprehensive overview of the current studies about the physiological roles of ATX3 in DDR and related apoptosis, highlighting the crosslinks between these impaired pathways and the pathogenesis of SCA3. Moreover, whether these mechanisms are shared in other neurodegenerative diseases are analyzed. Finally, the preclinical studies targeting DDR and related apoptosis for treatment of polyQ disorders including SCA3 and HD are also summarized and discussed.
Application of In Silico and HTS Approaches to Identify Nuclear Import Inhibitors for Venezuelan Equine Encephalitis Virus Capsid Protein: A Case Study
Authors: Shechter Sharon , Thomas David R. , Jans David A.
Published: December 2020

The development of new drugs is costly and time-consuming, with estimates of over $US1 billion and 15 years for a product to reach the market. As understanding of the molecular basis of disease improves, various approaches have been used to target specific molecular interactions in the search for effective drugs. These include high-throughput screening (HTS) for novel drug identification and computer-aided drug design (CADD) to assess the properties of putative drugs before experimental work begins. We have applied conventional HTS and CADD approaches to the problem of identifying antiviral compounds to limit infection by Venezuelan equine encephalitis virus (VEEV). Nuclear targeting of the VEEV capsid (CP) protein through interaction with the host nuclear import machinery has been shown to be essential for viral pathogenicity, with viruses incapable of this interaction being greatly attenuated. Our previous conventional HTS and in silico structure-based drug design (SBDD) screens were successful in identifying novel inhibitors of CP interaction with the host nuclear import machinery, thus providing a unique opportunity to assess the relative value of the two screening approaches directly. This focused review compares and contrasts the two screening approaches, together with the properties of the inhibitors identified, as a case study for parallel use of the two approaches to identify antivirals. The utility of SBDD screens, especially when used in parallel with traditional HTS, in identifying agents of interest to target the host–pathogen interface is highlighted.
Intracellular Porphyromonas gingivalis Promotes the Proliferation of Colorectal Cancer Cells via the MAPK/ERK Signaling Pathway
Authors: Mu Wenxin , Jia Yiqun , Chen Xiaobing , Li Haoyu , Wang Zhi , Cheng Bin
Published: December 2020

Porphyromonas gingivalis(P. gingivalis) is a keystone pathogen in periodontitis. However, several clinical studies have revealed an enrichment ofP. gingivalisin the stool samples and colorectal mucosa of colorectal cancer patients. Thus, the goal of this study was to determine whetherP. gingivaliscan promote colorectal cancer progressionin vitro. We established an acute infection model (24 h, multiplicity of infection =100) ofP. gingivalisinvasion of colorectal cancer cells to study the alterations induced byP. gingivalisin the proliferation and cell cycle of colorectal cancer cells. We observed thatP. gingivaliscan adhere and invade host cells a few hours after infection. Once invaded,P. gingivalissignificantly promoted colorectal cancer cell proliferation, and the percentage of S phase cells was increased in the cell cycle assay. However, KDP136, a gingipain-deficient mutant ofP. gingivalis33277, showed a decreased ability to promote colorectal cancer cell proliferation, indicating that gingipain is associated with colorectal cancer cell proliferation. Furthermore, we extracted RNA from colorectal cancer cells for high-throughput sequencing analysis and reconfirmed the results by quantitative polymerase chain reaction and western blot analyses. The results suggested that the MAPK/ERK signaling pathway is significantly activated byP. gingivalis, while these changes were not observed for KDP136. In conclusion,P. gingivaliscan invade cells and promote the proliferation of colorectal cancer cells by activating the MAPK/ERK signaling pathway. Gingipain is an essential virulence factor in this interaction.
Impact of Data Transformation: An ECG Heartbeat Classification Approach
Authors: Liang Yongbo , Hussain Ahmed , Abbott Derek , Menon Carlo , Ward Rabab , Elgendi Mohamed
Published: December 2020

Cardiovascular diseases continue to be a significant global health threat. The electrocardiogram (ECG) signal is a physiological signal that plays a major role in preventing severe and even fatal heart diseases. The purpose of this research is to explore a simple mathematical feature transformation that could be applied to ECG signal segments in order to improve the detection accuracy of heartbeats, which could facilitate automated heart disease diagnosis. Six different mathematical transformation methods were examined and analyzed using 10s-length ECG segments, which showed that a reciprocal transformation results in consistently better classification performance for normal vs. atrial fibrillation beats and normal vs. atrial premature beats, when compared to untransformed features. The second best data transformation in terms of heartbeat detection accuracy was the cubic transformation. Results showed that applying the logarithmic transformation, which is considered the go-to data transformation, was not optimal among the six data transformations. Using the optimal data transformation, the reciprocal, can lead to a 35.6% accuracy improvement. According to the overall comparison tested by different feature engineering methods, classifiers, and different dataset sizes, performance improvement also reached 4.7%. Therefore, adding a simple data transformation step, such as the reciprocal or cubic, to the extracted features can improve current automated heartbeat classification in a timely manner.
Testing the Reliability of Sedimentary Paleomagnetic Datasets for Paleogeographic Reconstructions
Authors: Dallanave Edoardo , Kirscher Uwe
Published: December 2020

Paleogeographic reconstructions largely rely on paleomagnetic data, mostly in the form of paleomagnetic poles. Compilations of poles are used to determine so called apparent polar wander paths (APWPs), which capture the motion through time of a particular location with respect to an absolute reference frame such as the Earth’s spin axis. Paleomagnetic datasets from sedimentary rocks are particularly relevant, because of their spatial distribution and temporal continuity. Several criteria have been proposed through the years to assess the reliability of paleomagnetic datasets. Among these, the latitudinal-dependent elongation of a given paleomagnetic directions distribution, predicted by a widely accepted paleosecular variations model, has been applied so far only to investigate inclination flattening commonly observed in sedimentary rocks. We show in this work that this concept can be generalized to detect “contamination” of paleomagnetic data derived from tectonic strain, which is not always detected by field observation only. After generating different sets of simulated geomagnetic directions at different latitudes, we monitored the variations in the shape of the distributions after applying deformation tensors that replicate the effect of increasing tectonic strain. We show that, in most cases, the “deformation” of the dataset can be detected by elongation vs. inclination ratios not conforming to the values predicted by the paleosecular variations model. Recently acquired paleomagnetic directions and anisotropy of magnetic susceptibility (AMS; a parameter very sensitive to tectonic strain) data from New Caledonia verifies the results of these simulations and highlights the importance of measuring AMS when using sedimentary paleomagnetic data for paleogeographic reconstruction. We suggest to include always AMS measurement and analysis of the distribution shape to assess sedimentary paleomagnetic data used for paleogeographic reconstructions.
Uncovering the Role of p38 Family Members in Adipose Tissue Physiology
Authors: Leiva Magdalena , Matesanz Nuria , Pulgarín-Alfaro Marta , Nikolic Ivana , Sabio Guadalupe
Published: December 2020

The complex functions of adipose tissue have been a focus of research interest over the past twenty years. Adipose tissue is not only the main energy storage depot, but also one of the largest endocrine organs in the body and carries out crucial metabolic functions. Moreover, brown and beige adipose depots are major sites of energy expenditure through the activation of adaptive, non-shivering thermogenesis. In recent years, numerous signaling molecules and pathways have emerged as critical regulators of adipose tissue, in both homeostasis and obesity-related disease. Among the best characterized are members of the p38 kinase family. The activity of these kinases has emerged as a key contributor to the biology of the white and brown adipose tissues, and their modulation could provide new therapeutic approaches against obesity. Here, we give an overview of the roles of the distinct p38 family members in adipose tissue, focusing on their actions in adipogenesis, thermogenic activity, and secretory function.
Harnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis
Authors: Chakravarthy Manu V. , Siddiqui Mohammad S. , Forsgren Mikael F. , Sanyal Arun J.
Published: December 2020

Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, affecting an estimated one-quarter of the world’s adult population. Multiple organ systems have been implicated in the pathophysiology of NAFLD; however, the role of skeletal muscle has until recently been largely overlooked. A growing body of evidence places skeletal muscle—via its impact on insulin resistance and systemic inflammation—and the muscle-liver axis at the center of the NAFLD pathogenic cascade. Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum in that it is tightly linked to an increased risk of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis, all independent of obesity and insulin resistance. Longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Adverse muscle composition, comprising both low muscle volume and high muscle fat infiltration (myosteatosis), is highly prevalent in patients with NAFLD. The risk of functional disability conferred by low muscle volume in NAFLD is further exacerbated by the presence of myosteatosis, which is twice as common in NAFLD as in other chronic liver diseases. Crosstalk between muscle and liver is influenced by several factors, including obesity, physical inactivity, ectopic fat deposition, oxidative stress, and proinflammatory mediators. In this perspective review, we discuss key pathophysiological processes driving sarcopenia in NAFLD: anabolic resistance, insulin resistance, metabolic inflexibility and systemic inflammation. Interventions that modify muscle quantity (mass), muscle quality (fat), and physical function by simultaneously engaging multiple targets and pathways implicated in muscle-liver crosstalk may be required to address the multifactorial pathogenesis of NAFLD/NASH and provide effective and durable therapies.
DNA-PKcs: A Multi-Faceted Player in DNA Damage Response
Authors: Yue Xiaoqiao , Bai Chenjun , Xie Dafei , Ma Teng , Zhou Ping-Kun
Published: December 2020

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a member of the phosphatidylinositol 3-kinase related kinase family, which can phosphorylate more than 700 substrates. As the core enzyme, DNA-PKcs forms the active DNA-PK holoenzyme with the Ku80/Ku70 heterodimer to play crucial roles in cellular DNA damage response (DDR). Once DNA double strand breaks (DSBs) occur in the cells, DNA-PKcs is promptly recruited into damage sites and activated. DNA-PKcs is auto-phosphorylated and phosphorylated by Ataxia-Telangiectasia Mutated at multiple sites, and phosphorylates other targets, participating in a series of DDR and repair processes, which determine the cells’ fates: DSBs NHEJ repair and pathway choice, replication stress response, cell cycle checkpoints, telomeres length maintenance, senescence, autophagy, etc. Due to the special and multi-faceted roles of DNA-PKcs in the cellular responses to DNA damage, it is important to precisely regulate the formation and dynamic of its functional complex and activities for guarding genomic stability. On the other hand, targeting DNA-PKcs has been considered as a promising strategy of exploring novel radiosensitizers and killing agents of cancer cells. Combining DNA-PKcs inhibitors with radiotherapy can effectively enhance the efficacy of radiotherapy, offering more possibilities for cancer therapy.
Zooplankton Biomass Depletion Event Reveals the Importance of Small Pelagic Fish Top-Down Control in the Western Mediterranean Coastal Waters
Authors: Yebra Lidia , Espejo Estefanía , Putzeys Sébastien , Giráldez Ana , Gómez-Jakobsen Francisco , León Pablo , Salles Soluna , Torres Pedro , Mercado Jesús M.
Published: December 2020

The influence of hydrochemistry and trophic conditions on the coastal zooplankton community’s biomass and metabolic activities was investigated along the Spanish Mediterranean coastal waters, from Algeciras Bay to Barcelona, from autumn 2011 to autumn 2012. Two hydrographic regions were differentiated: NW Alboran (ALB) and W Mediterranean (MED). Zooplankton metabolism was assessed from measurements of the electron transport system (ETS) and aminoacyl-tRNA synthetases (AARS) activities, as proxies for potential respiration and somatic growth, respectively. Zooplankton showed three to fivefold higher biomass in ALB than in MED during autumn 2011 and spring 2012. However, in autumn 2012, a drastic decrease in biomass standing stock was observed in ALB, with no significant differences between the two regions. This biomass depletion event was not associated with environmental variables, food availability or zooplankton metabolic rates, but coincided with a twofold peak of Sardina pilchardus landings in ALB. A reduced standing stock coupled with high zooplankton growth rates suggests mortality by predation as the main cause for the low zooplankton biomass typically observed in MED, and in ALB during autumn 2012.
Morphologic Features of Myopic Choroidal Neovascularization in Pathologic Myopia on Swept-Source Optical Coherence Tomography
Authors: Xie Jiamin , Chen Qiuying , Yu Jiayi , Zhou Hao , He Jiangnan , Wang Weijun , Fan Ying , Xu Xun
Published: December 2020

Purpose: To investigate the morphologic features and identify the risk factors of myopic choroidal neovascularization (CNV).

Methods: Eighty-eight eyes of 69 consecutive patients with myopic CNV were included in this study. About 109 eyes of 78 pathologic myopia patients without myopic CNV were randomly selected as the control group. Morphologic features and parameters including scleral thickness (ST), choroidal thickness (CT), posterior staphyloma height and the presence of scleral perforating vessels were obtained and measured by swept-source optical coherence tomography (SS-OCT). Binary logistic regression analysis was performed to identify the risk factors for myopic CNV.

Results: Patients with myopic CNV had relatively shorter axial length (P < 0.001) and thicker sclera (P < 0.001) compared to those without. After adjusting age, gender and axial length, thick sclera (OR = 1.333, P < 0.001 per 10-μm increase) and thin choroid (OR = 0.509, P < 0.001 per 10-μm increase) were associated with the presence of myopic CNV. Scleral perforating vessels were detected in the area of myopic CNV in 78.67% of the subjects.

Conclusions: A relatively thicker sclera and a thinner choroid are the biological indicators for myopic CNV on SS-OCT. Scleral perforating vessels may also play a pivotal role in the formation of myopic CNV.
Role of Complement and Histones in Sepsis
Authors: Zetoune Firas S. , Ward Peter A.
Published: December 2020

The wide use of the mouse model of polymicrobial sepsis has provided important evidence for events occurring in infectious sepsis involving septic mice and septic humans. Nearly 100 clinical trials in humans with sepsis have been completed, yet there is no FDA-approved drug. Our studies of polymicrobial sepsis have highlighted the role of complement activation products (especially C5a anaphylatoxin and its receptors C5aR1 and C5aR2) in adverse effects of sepsis. During sepsis, the appearance of these complement products is followed by appearance of extracellular histones in plasma, which have powerful proinflammatory and prothrombotic activities that cause cell injury and multiorgan dysfunction in septic mice. Similar responses occur in septic humans. Histone appearance in plasma is related to complement activation and appearance of C5a and its interaction with its receptors. Development of the cardiomyopathy of sepsis also depends on C5a, C5a receptors and histones. Neutralization of C5a with antibody or absence of C5aR1 blocks appearance of extracellular histones and cell and organ failure in sepsis. Survival rates in septic mice are greatly improved after blockade of C5a with antibody. We also review the various strategies in sepsis that greatly reduce the development of life-threatening events of sepsis.
Comparison of Two Sampling Techniques for Evaluating Ruminal Fermentation and Microbiota in the Planktonic Phase of Rumen Digesta in Dairy Cows
Authors: de Assis Lage Camila Flavia , Räisänen Susanna Elizabeth , Melgar Audino , Nedelkov Krum , Chen Xianjiang , Oh Joonpyo , Fetter Molly Elizabeth , Indugu Nagaraju , Bender Joseph Samuel , Vecchiarelli Bonnie , Hennessy Meagan Leslie , Pitta Dipti , Hristov Alexander Nikolov
Published: December 2020

The objective of this experiment was to compare ruminal fluid samples collected through rumen cannula (RC) or using an oral stomach tube (ST) for measurement of ruminal fermentation and microbiota variables. Six ruminally cannulated lactating Holstein cows fed a standard diet were used in the study. Rumen samples were collected at 0, 2, 4, 6, 8, and 12 h after the morning feeding on two consecutive days using both RC and ST techniques. Samples were filtered through two layers of cheesecloth and the filtered ruminal fluid was used for further analysis. Compared with RC, ST samples had 7% greater pH; however, the pattern in pH change after feeding was similar between sampling methods. Total volatile fatty acids (VFA), acetate and propionate concentrations in ruminal fluid were on average 23% lower for ST compared with RC. There were no differences between RC and ST in VFA molar proportions (except for isobutyrate), ammonia and dissolved hydrogen (dH2) concentrations, or total protozoa counts, and there were no interactions between sampling technique and time of sampling. Bacterial ASV richness was higher in ST compared with RC samples; however, no differences were observed for Shannon diversity. Based on Permanova analysis, bacterial community composition was influenced by sampling method and there was an interaction between sampling method and time of sampling. A core microbiota comprised of Prevotella, S24-7, unclassified Bacteroidales and unclassified Clostridiales, Butyrivibrio, unclassified Lachnospiraceae, unclassified Ruminococcaceae, Ruminococcus, and Sharpea was present in both ST and RC samples, although their relative abundance varied and was influenced by an interaction between sampling time and sampling method. Overall, our results suggest that ruminal fluid samples collected using ST (at 180 to 200 cm depth) are not representative of rumen pH, absolute values of VFA concentrations, or bacterial communities >2 h post-feeding when compared to samples of ruminal fluid collected using RC. However, ST can be a feasible sampling technique if the purpose is to study molar proportions of VFA, protozoa counts, dH2, and ammonia concentrations.
Molecular Docking Studies on the Anti-viral Effects of Compounds From Kabasura Kudineer on SARS-CoV-2 3CLpro
Authors: Vincent Savariar , Arokiyaraj Selvaraj , Saravanan Muthupandian , Dhanraj Manoj
Published: December 2020

The COVID-19 has now been declared a global pandemic by the World Health Organization. No approved drug is currently available; therefore, an urgent need has been developed for any antiviral therapy for COVID-19. Main protease 3CLproof this novel Coronavirus (SARS-CoV-2) play a critical role in the disease propagation, and hence represent a crucial target for the drug discovery. Herein, we have applied a bioinformatics approach for drug repurposing to identify the possible potent inhibitors of SARS-CoV-2 main proteases 3CLpro(6LU7). In search of the anti-COVID-19 compound, we selected 145 phyto-compounds from Kabasura kudineer (KK), a poly-herbal formulation recommended by AYUSH for COVID-19 which are effective against fever, cough, sore throat, shortness of breath (similar to SARS-CoV2-like symptoms). The present study aims to identify molecules from natural products which may inhibit COVID-19 by acting on the main protease (3CLpro). Obtained results by molecular docking showed that Acetoside (−153.06), Luteolin 7 -rutinoside (−134.6) rutin (−133.06), Chebulagic acid (−124.3), Syrigaresinol (−120.03), Acanthoside (−122.21), Violanthin (−114.9), Andrographidine C (−101.8), myricetin (−99.96), Gingerenone -A (−93.9), Tinosporinone (−83.42), Geraniol (−62.87), Nootkatone (−62.4), Asarianin (−79.94), and Gamma sitosterol (−81.94) are main compounds from KK plants which may inhibit COVID-19 giving the better energy score compared to synthetic drugs. Based on the binding energy score, we suggest that these compounds can be tested against Coronavirus and used to develop effective antiviral drugs.
Comparison of Three Motor Subtype Classifications in de novo Parkinson's Disease Patients
Authors: Ren Jingru , Hua Ping , Li Yuqian , Pan Chenxi , Yan Lei , Yu Cuiyu , Zhang Li , Xu Pingyi , Zhang Minming , Liu Weiguo
Published: December 2020

Objective: The aims of this study were to compare the characteristics of three motor subtype classifications in patients with de novo Parkinson's disease (PD) and to find the most suitable motor subtype classification for identifying non-motor symptoms (NMSs).

Methods: According to previous studies, a total of 256 patients with de novo PD were classified using the tremor-dominant/mixed/akinetic-rigid (TD/mixed/AR), TD/indeterminate/postural instability and gait disturbance (PIGD), and predominantly TD/predominantly PIGD (p-TD/p-PIGD) classification systems.

Results: Among the TD/mixed/AR subgroups, the patients with the AR subtype obtained more severe motor scores than the patients with the TD subtype. Among the TD/indeterminate/PIGD subgroups and between the p-TD and p-PIGD subgroups, the patients with the PIGD/p-PIGD subtype obtained more severe scores related to activities of daily living (ADL), motor and non-motor symptoms, including depression, anxiety, and sleep impairment, than the patients with the TD/p-TD subtype. Furthermore, symptoms in the cardiovascular, gastrointestinal, and miscellaneous domains of the Non-motor Questionnaire (NMSQuest) were more prevalent in the patients with the PIGD/p-PIGD subtypes than the patients with the TD/p-TD subtypes.

Conclusions: The PIGD/p-PIGD subtypes had more severe ADL, motor and non-motor symptoms than the TD/p-TD subtypes. We disclosed for the first time that the TD/indeterminate/PIGD classification seems to be the most suitable classification among the three motor subtype classifications for identifying NMSs in PD.
Aberrant Metabolic Patterns Networks in Insular Epilepsy
Authors: Zhao Baotian , Seguin Caio , Ai Lin , Sun Tao , Hu Wenhan , Zhang Chao , Wang Xiu , Liu Chang , Wang Yao , Mo Jiajie , Zalesky Andrew , Zhang Kai , Zhang Jianguo
Published: December 2020

Introduction: Insular epilepsy is clinically challenging. This study aimed to map cerebral metabolic networks in insular epilepsy and investigate their graph-theoretic properties, with the goal of elucidating altered metabolic network architectures that underlie interictal hypometabolism.

Aims: Fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) imaging was performed in 17 individuals with a stereoelectroencephalography (SEEG) confirmed diagnosis of insula epilepsy and 14 age- and sex-matched healthy comparison individuals. Metabolic covariance networks were mapped for each group and graph theoretical analyses of these networks were undertaken. For each pair of regions comprising a whole-brain parcellation, regionally-averaged FDG uptake values were correlated across individuals to estimate connection weights.

Results: Correlation in regionally-averaged FDG uptake values in the insular epilepsy group was substantially increased for several pairs of regions compared to the healthy comparison group, particularly for the opercular cortex and subcortical structures. This effect was less prominent in brainstem structures. Metabolic covariance networks in the epilepsy group showed reduced small-worldness as well as altered nodal properties in the ipsilateral hemisphere, compared to the healthy comparison group.

Conclusions: Cerebral glucose metabolism in insular epilepsy is marked by a lack of normal regional heterogeneity in metabolic patterns, resulting in metabolic covariance networks that are more tightly coupled between regions than healthy comparison individuals. Metabolic networks in insular epilepsy exhibit altered topological properties and evidence of potentially compensatory formation of aberrant local connections. Taken together, these results demonstrate that insular epilepsy is a systemic neurological disorder with widespread disruption to cerebral metabolic networks.
Caenorhabditis elegans, a Host to Investigate the Probiotic Properties of Beneficial Microorganisms
Authors: Poupet Cyril , Chassard Christophe , Nivoliez Adrien , Bornes Stéphanie
Published: December 2020

Caenorhabditis elegans, a non-parasitic nematode emerges as a relevant and powerful candidate as anin vivomodel for microorganisms-microorganisms and microorganisms-host interactions studies. Experiments have demonstrated the probiotic potential of bacteria since they can provide to the worm a longer lifespan, an increased resistance to pathogens and to oxidative or heat stresses. Probiotics are used to prevent or treat microbiota dysbiosis and associated pathologies but the molecular mechanisms underlying their capacities are still unknown. Beyond safety and healthy aspects of probiotics,C. elegansrepresents a powerful way to design large-scale studies to explore transkingdom interactions and to solve questioning about the molecular aspect of these interactions. Future challenges and opportunities would be to validateC. elegansas anin vivotool for high-throughput screening of microorganisms for their potential probiotic use on human health and to enlarge the panels of microorganisms studied as well as the human diseases investigated.
Breast Cancer During Pregnancy: A Marked Propensity to Triple-Negative Phenotype
Authors: Allouch Soumaya , Gupta Ishita , Malik Shaza , Al Farsi Halema F. , Vranic Semir , Al Moustafa Ala-Eddin
Published: December 2020

Breast and cervical cancers comprise 50% of all cancers during pregnancy. In particular, gestational breast cancer is considered one of the most aggressive types of cancers, which is a rare but fatal disease. However, the incidence of this type of cancer is increasing over the years and its prevalence is expected to rise further as more women delay childbearing. Breast cancer occurring after pregnancy is generally triple negative with specific characterizations of a poorer prognosis and outcome. On the other hand, it has been pointed out that this cancer is associated with a specific group of genes which can be used as precise targets to manage this deadly disease. Indeed, combination therapies consisting of gene-based agents with other cancer therapeutics is presently under consideration. We herein review recent progress in understanding the development of breast cancer during pregnancy and their unique subtype of triple negative which is the hallmark of this type of breast cancer.
Connexins in Lung Cancer and Brain Metastasis
Authors: Luo Kai-Jun , Chen Chang-Xu , Yang Jia-Peng , Huang Yun-Chao , Cardenas Eduardo R. , Jiang Jean X.
Published: December 2020

Connexins (Cxs) are involved in the brain metastasis of lung cancer cells. Thus, it is necessary to determine whether gap junction-forming Cxs are involved in the communication between lung cancer cells and the host cells, such as endothelial cells, forming the brain–blood-barrier, and cells in the central nervous system. Data from multiple studies support that Cxs function as tumor suppressors during lung cancer occurrence. However, recent evidence suggests that during metastasis to the brain, cancer cells establish communication with the host. This review discusses junctional or non-junctional hemichannel studies in lung cancer development and brain metastasis, highlighting important unanswered questions and controversies.
HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer
Authors: Ji Ce , Sun Li-Sha , Xing Fei , Niu Nan , Gao Hong-Li , Dai Jing-Wei , Zhou Nan , Jiang Ben-Chun
Published: December 2020

HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02–2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08–2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14–2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021–2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079–2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140–2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFβ pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.
FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies
Authors: Kennedy Vanessa E. , Smith Catherine C.
Published: December 2020

The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.
Mechanisms of Drug Desensitization: Not Only Mast Cells
Authors: Vultaggio Alessandra , Matucci Andrea , Nencini Francesca , Bormioli Susanna , Vivarelli Emanuele , Maggi Enrico
Published: December 2020

Drug desensitization (DD) allows transient clinical tolerance to the drug in reactive patients and it is frequently and successfully used in the management of both IgE and non IgE-mediated hypersensitivity reactions (HRs). The underlying mechanisms behind this process is not well understood. The desensitization procedure is associated with the inhibition of mast cells degranulation and cytokine production, that, is attributable, at least partially, to the abrogation of Ca2+ mobilization; in vitro findings and in vivo mouse models of rapid desensitization show that the organization and spatial distribution of actin is critical for Ca2+ mobilization. Some clinical observations may suggest the induction of a longer memory of tolerance by DD and they raise the suspicion that other cells and mechanisms are involved in DD. Some data are emerging about the modifications of immune responses during DD in patients with previous immediate HRs. In particular, an increase of regulatory cytokines, mainly represented by IL-10, has been shown, and more importantly, the appearance of IL-35 producing T regulatory cells has been described during DD. The release of controlled cellular mediators by mast cells over time and the development of the antigen-specific regulation of adaptive response allow to safely and successfully reach the target dose of a first line drug during DD.
The Role(s) of Eicosanoids and Exosomes in Human Parturition
Authors: Mosaad Eman , Peiris Hassendrini N. , Holland Olivia , Morean Garcia Isabella , Mitchell Murray D.
Published: December 2020

The roles that eicosanoids play during pregnancy and parturition are crucial to a successful outcome. A better understanding of the regulation of eicosanoid production and the roles played by the various end products during pregnancy and parturition has led to our view that accurate measurements of a panel of those end products has exciting potential as diagnostics and prognostics of preterm labor and delivery. Exosomes and their contents represent an exciting new area for research of movement of key biological factors circulating between tissues and organs akin to a parallel endocrine system but involving key intracellular mediators. Eicosanoids and enzymes regulating their biosynthesis and metabolism as well as regulatory microRNAs have been identified within exosomes. In this review, the regulation of eicosanoid production, abundance and actions during pregnancy will be explored. Additionally, the functional significance of placental exosomes will be discussed.
Mitochondrial Calcium Uniporter Deficiency in Zebrafish Causes Cardiomyopathy With Arrhythmia
Authors: Langenbacher Adam D. , Shimizu Hirohito , Hsu Welkin , Zhao Yali , Borges Alexandria , Koehler Carla , Chen Jau-Nian
Published: December 2020

Mitochondrial Ca2 + uptake influences energy production, cell survival, and Ca2 + signaling. The mitochondrial calcium uniporter, MCU, is the primary route for uptake of Ca2 + into the mitochondrial matrix. We have generated a zebrafish MCU mutant that survives to adulthood and exhibits dramatic cardiac phenotypes resembling cardiomyopathy and sinus arrest. MCU hearts contract weakly and have a smaller ventricle with a thin compact layer and reduced trabecular density. Damaged myofibrils and swollen mitochondria were present in the ventricles of MCU mutants, along with gene expression changes indicative of cell stress and altered cardiac structure and function. Using electrocardiography, we found that MCU hearts display conduction system defects and abnormal rhythm, with extended pauses resembling episodes of sinus arrest. Together, our findings suggest that proper mitochondrial Ca2 + homeostasis is crucial for maintaining a healthy adult heart, and establish the MCU mutant as a useful model for understanding the role of mitochondrial Ca2 + handling in adult cardiac biology.
Effects of Combined Balance and Strength Training on Measures of Balance and Muscle Strength in Older Women With a History of Falls
Authors: Zouita Sghaier , Zouhal Hassane , Ferchichi Habiba , Paillard Thierry , Dziri Catherine , Hackney Anthony C. , Laher Ismail , Granacher Urs , Ben Moussa Zouita Amira
Published: December 2020

Objective

We investigated the effects of combined balance and strength training on measures of balance and muscle strength in older women with a history of falls.

Methods

Twenty-seven older women aged 70.4 ± 4.1 years (age range: 65 to 75 years) were randomly allocated to either an intervention (IG, n = 12) or an active control (CG, n = 15) group. The IG completed 8 weeks combined balance and strength training program with three sessions per week including visual biofeedback using force plates. The CG received physical therapy and gait training at a rehabilitation center. Training volumes were similar between the groups. Pre and post training, tests were applied for the assessment of muscle strength (weight-bearing squat [WBS] by measuring the percentage of body mass borne by each leg at different knee flexions [0°, 30°, 60°, and 90°], sit-to-stand test [STS]), and balance. Balance tests used the modified clinical test of sensory interaction (mCTSIB) with eyes closed (EC) and opened (EO), on stable (firm) and unstable (foam) surfaces as well as spatial parameters of gait such as step width and length (cm) and walking speed (cm/s).

Results

Significant group × time interactions were found for different degrees of knee flexion during WBS (0.0001 < p < 0.013, 0.441 < d < 0.762). Post hoc tests revealed significant pre-to-post improvements for both legs and for all degrees of flexion (0.0001 < p < 0.002, 0.697 < d < 1.875) for IG compared to CG. Significant group × time interactions were found for firm EO, foam EO, firm EC, and foam EC (0.006 < p < 0.029; 0.302 < d < 0.518). Post hoc tests showed significant pre-to-post improvements for both legs and for all degrees of oscillations (0.0001 < p < 0.004, 0.753 < d < 2.097) for IG compared to CG. This study indicates that combined balance and strength training improved percentage distribution of body weight between legs at different conditions of knee flexion (0°, 30°, 60°, and 90°) and also decreased the sway oscillation on a firm surface with eyes closed, and on foam surface (with eyes opened or closed) in the IG.

Conclusion

The higher positive effects of training seen in standing balance tests, compared with dynamic tests, suggests that balance training exercises including lateral, forward, and backward exercises improved static balance to a greater extent in older women.
Anthropometric Prediction of DXA-Measured Percentage of Fat Mass in Athletes With Unilateral Lower Limb Amputation
Authors: Cavedon Valentina , Sandri Marco , Venturelli Massimo , Zancanaro Carlo , Milanese Chiara
Published: December 2020

To date there is no anthropometric equation specific to athletes with unilateral lower limb amputation to estimate the percentage of fat mass (%FM). This study investigated the accuracy of a set of anthropometric equations validated on able-bodied populations to predict the %FM assessed by-means of dual-energy x-ray absorptiometry (DXA) in athletes with unilateral lower limb amputation. Furthermore, a predictive anthropometric equation specific to athletes with unilateral lower limb amputation was developed from skinfold thickness measurements using DXA as the reference method for the estimation of the %FM. Twenty-nine white male athletes with unilateral lower limb amputation underwent a DXA scan and an anthropometric assessment on the same day. The %FM, calculated through several existing anthropometric equations validated upon able-bodied populations, was compared with the DXA-measured %FM (%FM_DXA). Accuracy and agreement between the two methods was computed with two-tailed paired-sample t-test, concordance correlation coefficient, reduced major axis regression and Bland-Altman analysis. A stepwise multiple regression analysis with the %FM_DXA as the dependent variable and age and nine skinfold thicknesses as potential predictors was carried out and validated using a repeated 10-fold cross-validation. A linear regression analysis with the sum of nine skinfolds as the independent variable was also carried out and validated using a repeated 10-fold cross-validation. The results showed that the anthropometric equations validated on able-bodied populations are inaccurate in the estimation of %FM_DXA with an average bias ranging from 0.51 to −13.70%. Proportional bias was also found revealing that most of the anthropometric equations considered, tended to underestimate/overestimate the %FM_DXA as body fat increased. Regression analysis produced two statistically significant models (P < 0.001 for both) which were able to predict more than 93% of total variance of %FM_DXA from the values of four skinfold measurements (i.e., thigh, abdominal, subscapular and axillary skinfold measurements) or from the sum of 9 skinfolds. Repeated cross-validation analysis highlighted a good predictive performance of the proposed equations. The predictive equations proposed in this study represent a useful tool for clinicians, nutritionists, and physical conditioners to evaluate the physical and nutritional status of athletes with unilateral lower limb amputation directly in the field.
Co-Immunoprecipitation Reveals Interactions Between Amelogenin and Ameloblastin via Their Self-Assembly Domains
Authors: Bapat Rucha Arun , Su Jingtan , Moradian-Oldak Janet
Published: December 2020

Macromolecular assembly of extracellular enamel matrix proteins (EMPs) is intimately associated with the nucleation, growth, and maturation of highly organized hydroxyapatite crystals giving rise to healthy dental enamel. Although the colocalization of two of the most abundant EMPs amelogenin (Amel) and ameloblastin (Ambn) in molar enamel has been established, the evidence toward their interaction is scarce. We used co-immunoprecipitation (co-IP) to show evidence of direct molecular interactions between recombinant and native Amel and Ambn. Ambn fragments containing Y/F-x-x-Y/L/F-x-Y/F self-assembly motif were isolated from the co-IP column and characterized by mass spectroscopy. We used recombinant Ambn (rAmbn) mutants with deletion of exons 5 and 6 as well as Ambn derived synthetic peptides to demonstrate that Ambn binds to Amel via its previously identified Y/F-x-x-Y/L/F-x-Y/F self-assembly motif at the N-terminus of its exon 5 encoded region. Using an N-terminal specific anti-Ambn antibody, we showed that Ambn N-terminal fragments colocalized with Amel from secretory to maturation stages of enamel formation in a single section of developing mouse incisor, and closely followed mineral patterns in enamel rod interrod architecture. We conclude that Ambn self-assembly motif is involved in its interaction with Amel in solution and that colocalization between the two proteins persists from secretory to maturation stages of amelogenesis. Our in vitro and in situ data support the notion that Amel and Ambn may form heteromolecular assemblies that may perform important physiological roles during enamel formation.