bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response
Authors: Gilkerson Robert , De La Torre Patrick , St. Vallier Shaynah
Published: March 2021

Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially,opticatrophy-1(OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨm) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨmis lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1’s role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.
High Ambient Temperature Aggravates Experimental Autoimmune Uveitis Symptoms
Authors: Pan Su , Tan Handan , Chang Rui , Wang Qingfeng , Zhu Ying , Chen Lin , Li Hongxi , Su Guannan , Zhou Chunjiang , Cao Qingfeng , Kijlstra Aize , Yang Peizeng
Published: March 2021

Whether ambient temperature influences immune responses leading to uveitis is unknown. We thus tested whether ambient temperature affects the symptoms of experimental autoimmune uveitis (EAU) in mice and investigated possible mechanisms. C57BL/6 mice were kept at a normal (22°C) or high temperature (30°C) housing conditions for 2 weeks and were then immunized with human interphotoreceptor retinoid-binding protein (IRBP651–670) peptide to induce EAU. Histological changes were monitored to evaluate the severity of uveitis. Frequency of Th1 cells and Th17 cells was measured by flow cytometry (FCM). The expression of IFN-γ and IL-17A mRNA was measured by real-time qPCR. The generation of neutrophil extracellular traps (NETs) was quantified by enzyme-linked immunosorbent assay (ELISA). Differential metabolites in the plasma of the mice kept in the aforementioned two ambient temperatures were measured via ultra-high-performance liquid chromatography triple quadrupole mass spectrometry quadrupole time of flight mass spectrometry (UHPLC-QQQ/MS). The differential metabolites identified were used to evaluate their effects on differentiation of Th1 and Th17 cells and generation of NETs in vitro. The results showed that EAU mice kept at high temperature experienced a more severe histopathological manifestation of uveitis than mice kept at a normal temperature. A significantly increased frequency of Th1 and Th17 cells in association with an upregulated expression of IFN-γ and IL-17A mRNA was observed in the splenic lymphocytes and retinas of EAU mice in high temperature. The expression of NETs as evidenced by myeloperoxidase (MPO) and neutrophil elastase (NE), was significantly elevated in serum and supernatants of neutrophils from EAU mice kept at high temperature compared to the normal temperature group. The metabolites in the plasma from EAU mice, fumaric acid and succinic acid, were markedly increased in the high temperature group and could induce the generation of NETs via the NADPH oxidase-dependent pathway, but did not influence the frequency of Th1 and Th17 cells. Our findings suggest that an increased ambient temperature is a risk factor for the development of uveitis. This is associated with the induction of Th1 and Th17 cells as well as the generation of NETs which could be mediated by the NADPH oxidase-dependent pathway.
Adipose-Derived Stromal Cell-Sheets Sandwiched, Book-Shaped Acellular Dermal Matrix Capable of Sustained Release of Basic Fibroblast Growth Factor Promote Diabetic Wound Healing
Authors: Shi Xin , Jiang Liyuan , Zhao Xin , Chen Bei , Shi Wei , Cao Yanpeng , Chen Yaowu , Li Xiying , He Yusheng , Li Chengjie , Liu Xiaoren , Li Xing , Lu Hongbin , Chen Can , Liu Jun
Published: March 2021

The management of diabetic wounds is a therapeutic challenge in clinical settings. Current tissue engineering strategies for diabetic wound healing are insufficient, owing to the lack of an appropriate scaffold that can load a large number of stem cells and induce the interaction of stem cells to form granulation tissue. Herein we fabricated a book-shaped decellularized dermal matrix (BDDM), which shows a high resemblance to native dermal tissue in terms of its histology, microstructure, and ingredients, is non-cytotoxic and low-immunogenic, and allows adipose-derived stromal cell (ASC) attachment and proliferation. Then, a collagen-binding domain (CBD) capable of binding collagen was fused into basic fibroblast growth factor (bFGF) to synthetize a recombinant growth factor (termed as CBD–bFGF). After that, CBD–bFGF was tethered onto the collagen fibers of BDDM to improve its endothelial inducibility. Finally, a functional scaffold (CBD–bFGF/BDDM) was fabricated. In vitro and in vivo experiments demonstrated that CBD–bFGF/BDDM can release tethered bFGF with a sustained release profile, steadily inducing the interaction of stem cells down to endothelial differentiation. ASCs were cultured to form a cell sheet and then sandwiched by CBD–bFGF/BDDM, thus enlarging the number of stem cells loaded into the scaffold. Using a rat model, the ASC sheets sandwiched with CBD–bFGF/BDDM (ASCs/CBD–bFGF/BDDM) were capable of enhancing the formation of granulation tissue, promoting angiogenesis, and facilitating collagen deposition and remodeling. Therefore, the findings of this study demonstrate that ASCs/CBD–bFGF/BDDM could be applicable for diabetic wound healing.
How Malaria Parasites Acquire Nutrients From Their Host
Authors: Counihan Natalie A. , Modak Joyanta K. , de Koning-Ward Tania F.
Published: March 2021

Plasmodiumparasites responsible for the disease malaria reside within erythrocytes. Inside this niche host cell, parasites internalize and digest host hemoglobin to source amino acids required for protein production. However, hemoglobin does not contain isoleucine, an amino acid essential forPlasmodiumgrowth, and the parasite cannot synthesize itde novo. The parasite is also more metabolically active than its host cell, and the rate at which some nutrients are consumed exceeds the rate at which they can be taken up by erythrocyte transporters. To overcome these constraints,Plasmodiumparasites increase the permeability of the erythrocyte membrane to isoleucine and other low-molecular-weight solutes it requires for growth by forming new permeation pathways (NPPs). In addition to the erythrocyte membrane, host nutrients also need to cross the encasing parasitophorous vacuole membrane (PVM) and the parasite plasma membrane to access the parasite. This review outlines recent advances that have been made in identifying the molecular constituents of the NPPs, the PVM nutrient channel, and the endocytic apparatus that transports host hemoglobin and identifies key knowledge gaps that remain. Importantly, blocking the ability ofPlasmodiumto source essential nutrients is lethal to the parasite, and thus, components of these key pathways represent potential antimalaria drug targets.
CircRNA_100395 Carried by Exosomes From Adipose-Derived Mesenchymal Stem Cells Inhibits the Malignant Transformation of Non-Small Cell Lung Carcinoma Through the miR-141-3p-LATS2 Axis
Authors: Zhang Chong , Cao Jinlin , Lv Wang , Mou Haibo
Published: March 2021

Objective: The specific purpose of this study is to investigate the impact exosomes from adipose-derived mesenchymal stem cell (AMSC) has on non-small cell lung carcinoma (NSCLC) and the relative applications. Methods: circ_100395, miR-141-3p, and LATS2 were expressed and detected in NSCLC and paracancerous tissues as well as NSCLC cell lines. Pearson correlation analysis, Dual-Luciferase Reporter Assay and RNA pull-down assay were used to validate their expression and interaction, respectively. After isolation and culture of AMSCs, exosomes were extracted and identified. EdU, epithelial-mesenchymal transition (EMT), and cell colony formation assay were used to distinguish the biological activity of the cells. Expression Hippo/YAP signalling pathway-related proteins were measured by western blotting. Subsequently, tumour volume and weight were confirmed based on xenograft nude mice models, Ki-67 and LATS2 expression was observed by immunohistochemistry. Results: circ_100395 was lowly expressed in NSCLC tissues or cells. The negative correlations and interactions were confirmed between circ_100395 and miR-141-3p, miR-141-3p, and LATS2. AMSC-derived exosomes with overexpression of circ_100395 (exo-circ_100395) significantly inhibited the biological activity as well as EMT of H1650 cells and Hippo/YAP signalling pathway activity. In addition, exo-circ_100395 markedly reduced tumour volume and weight as well as Ki-67 and LASP1 expression in vivo. However, overexpressed miR-141-3p or knocked down LATS2 alleviated the above effects. Conclusion: Exo-circ_100395 can increase LATS2 expression by sponging miR-141-3p to regulate Hippo/YAP signalling pathway, thereby inhibiting NSCLC malignant transformation.
The Benefits of Unnatural Amino Acid Incorporation as Protein Labels for Single Molecule Localization Microscopy
Authors: Laxman Pooja , Ansari Shirin , Gaus Katharina , Goyette Jesse
Published: March 2021

Single Molecule Localization Microscopy (SMLM) is an imaging method that allows for the visualization of structures smaller than the diffraction limit of light (~200 nm). This is achieved through techniques such as stochastic optical reconstruction microscopy (STORM) and photoactivated localization microscopy (PALM). A large part of obtaining ideal imaging of single molecules is the choice of the right fluorescent label. An upcoming field of protein labeling is incorporating unnatural amino acids (UAAs) with an attached fluorescent dye for precise localization and visualization of individual molecules. For this technique, fluorescent probes are conjugated to UAAs and are introduced into the protein of interest (POI) as a label. Here we contrast this labeling method with other commonly used protein-based labeling methods such as fluorescent proteins (FPs) or self-labeling tags such as Halotag, SNAP-tags, and CLIP-tags, and highlight the benefits and shortcomings of the site-specific incorporation of UAAs coupled with fluorescent dyes in SMLM.
Epidemiology of Leishmania Carriers in Tan Chang County, Gansu Province, China
Authors: Han Shuai , Chen Sheng-bang , Yang Zhang-hong , Feng Yu , Wu Wei-ping
Published: March 2021

Background

Leishmaniasis is a regional infectious disease caused by the bite of Leishmania-carrying sandflies. The clinical symptoms include prolonged fever, spleen enlargement, anemia, emaciation, leukopenia, and increased serum globulin levels. If not appropriately treated, patients may die of complications caused by leishmaniasis within 1–2 years after the onset of the illness. Therefore, further investigation of the mechanisms of infection by this pathogen is required. Here, an epidemiological study of Leishmania carriers was conducted. The potential mechanism of infection through domestic animals as carriers of the parasite was investigated to identify potential reservoir hosts for Leishmania.

Methods

The rK-39 strip test was performed on blood samples from previously infected patients. Blood samples were collected from the patients and their families. The blood, liver, spleen, and diaphragm muscle samples were collected from livestock. To perform nested polymerase chain reaction (PCR), DNA was extracted and the internal transcribed spacer sequence was used. The amplified products were then subjected to restriction fragment length polymorphism and phylogenetic analyses.

Results

Among previously infected patients, 40% (12/30) showed positive results in the rK-39 strip test. The nested PCR positive rates for previously infected patients/relatives and livestock samples were 86% (77/90) and 80% (8/10), respectively. Moreover, the phylogenetic analysis showed that the pathogen was Leishmania infantum. Dogs, patients, and domesticated animals carrying Leishmania were found to be a potential source of infection for leishmaniasis.

Conclusions

The results of this study provide a basis for developing disease prevention and control strategies for leishmaniasis.
The Impact of Ancient Landscape Changes on the City Arrangement of the Early Shang Dynasty Capital Zhengzhou, Central China
Authors: Chen Panpan , Lu Peng , Yang Shugang , Storozum Michael , Yang Ruixia , Tian Yan , Wang Hui , Wu Qian , Xu Junjie , Wang Xia , Yan Lijie , Zhai Haiguo
Published: March 2021

Buried underneath modern Zhengzhou city in Henan Province, China, lies the archeological remains of one of the ancient capital cities of the Shang dynasty (1766 – 1122 BCE). Although it is likely that people planned this Shang capital city according to the demands of the surrounding environment, there is no clear relationship between the current environment, such as the hydrology and topography, and the ancient city’s layout. To better understand the relationship between planning principles used during the Shang dynasty and the nearby environment at Zhengzhou, we measured and sampled stratigraphic exposures at excavation locations throughout Zhengzhou. Through these excavations we obtained both absolute and relative chronological data from each culture layer, enabling us to use geospatial interpolation and analysis methods to reconstruct the ancient landscape. The results show that ancient city’s different activity areas had a close relationship with their environmental context. For example, the Shang dynasty palace was located on high ground and workshops were located down below along the courses of ancient rivers. In conclusion, we argue that research that merges geomorphology and archeology is a necessary prerequisite for understanding the development of urban areas.
Evidence-Based Use of Cognitive Testing for Academic Interventions: A Critical Appraisal of Meta-Analytic Methodologies
Authors: Decker Scott L. , Luedke Jessica C.
Published: March 2021

Research suggests Specific Learning Disabilities (SLD) are directly linked to specific neurocognitive deficits that result in unexpected learning delays in academic domains for children in schools. However, meta-analytic studies have failed to find supporting evidence for using neurocognitive tests and, consequently, have discouraged their inclusion in SLD identification policies. The current study critically reviews meta-analytic findings and the methodological validity of over 200 research studies used in previous meta-analytic studies to estimate the causal effect of neurocognitive tests on intervention outcomes. Results suggest that only a very small percentage (6–12%) of studies used in previous meta-analytic studies were methodologically valid to estimate a direct effect of cognitive tests on academic intervention outcomes, with the majority of studies having no causal link between neurocognitive tests and intervention outcomes. Additionally, significant reporting discrepancies and inaccurate effect size estimates were found that warranted legitimate concerns for conclusions and policy recommendations provided in several meta-analytic studies. Given the lack of methodological rigor linking cognitive testing to academic interventions in current research, removing neurocognitive testing from learning disability evaluations may be premature. Suggestions for future studies evaluating the impact of neurocognitive tests on intervention outcomes as well as guidelines for synthesizing meta-analytic findings are discussed.
Energy Investment Risk Assessment for Nations Via Seq2seq Model
Authors: Liang Panning , Yu Mingyang , Jiang Lincheng
Published: March 2021

China’s “Belt & Road Initiative” has been proposed for several years, which has stimulated the economic and financial development of the countries alongside the “Belt & Road”. For a world’s leading energy consuming country, China tries to secure the energy supply from the resource-rich countries via oversea energy investment. In this paper, we propose a sequence to sequence (seq2seq) model to evaluate the energy investment risk of 50 countries alongside the “Belt & Road Initiative”. Specifically, we first build an indicator system mainly containing six factors. Then we adopt Bi-long-short term memory (Bi-LSTM) as encoder to process the historical statistics. Afterward, we use self-attention mechanism to assign the weights on the six factors of the indicator system. Finally we use a hierarchical convolution neural network decoder to generate the assessment results. Our findings indicate that resource potential and Chinese factor are the most important indicators. And through our thorough investigation, we find that Russia, Kazakhstan, Pakistan, United Arab Emirates, Saudi Arabia, Malaysia and Indonesia are the most recommended target countries for China’s oversea energy investment.
The Fish Family Poeciliidae as a Model to Study the Evolution and Diversification of Regenerative Capacity in Vertebrates
Authors: Safian Diego , Wiegertjes Geert F. , Pollux Bart J. A.
Published: March 2021

The capacity of regenerating a new structure after losing an old one is a major challenge in the animal kingdom. Fish have emerged as an interesting model to study regeneration due to their high and diverse regenerative capacity. To date, most efforts have focused on revealing the mechanisms underlying fin regeneration, but information on why and how this capacity evolves remains incomplete. Here, we propose the livebearing fish family Poeciliidae as a promising new model system to study the evolution of fin regeneration. First, we review the current state of knowledge on the evolution of regeneration in the animal kingdom, with a special emphasis on fish fins. Second, we summarize recent advances in our understanding of the mechanisms behind fin regeneration in fish. Third, we discuss potential evolutionary pressures that may modulate the regenerative capacity of fish fins and propose three new theories for how natural and sexual selection can lead to the evolution of fin regeneration: (1) signaling-driven fin regeneration, (2) predation-driven fin regeneration, and (3) matrotrophy-suppressed fin regeneration. Finally, we argue that fish from the family Poeciliidae are an excellent model system to test these theories, because they comprise of a large variety of species in a well-defined phylogenetic framework that inhabit very different environments and display remarkable variation in reproductive traits, allowing for comparative studies of fin regeneration among closely related species, among populations within species or among individuals within populations. This new model system has the potential to shed new light on the underlying genetic and molecular mechanisms driving the evolution and diversification of regeneration in vertebrates.
Different Effects of Mineral Versus Vegetal Granular Activated Carbon Filters on the Microbial Community Composition of a Drinking Water Treatment Plant
Authors: Bruno Antonia , Sandionigi Anna , Magnani Davide , Bernasconi Marzia , Pannuzzo Bruno , Consolandi Clarissa , Camboni Tania , Labra Massimo , Casiraghi Maurizio
Published: March 2021

Drinking water quality and safety is strictly regulated and constantly monitored, but little is known about the microorganisms inhabiting drinking water treatment plants (DWTPs). This lack of knowledge prevents optimization of designs and operational controls. Here we investigated the drinking water microbial community harbored by a groundwater-derived DWTP, involving mineral and vegetal granular activated carbon filters (GACs). We used 16S rRNA gene sequencing to analyze water microbiome variations through the potabilization process, considering (i) different GAC materials and (ii) time from GAC regeneration. Our results revealed the predominance of Cand. Patescibacteria, uncultivable bacteria with limited metabolic capacities and small genomes, from source to downstream water. Microbial communities clustered per sampling date, with the noteworthy exception of groundwater samples. If the groundwater microbiome showed no significant variations over time, the community structure of water downstream GACs (both mineral and vegetal) seemed to be affected by time from GAC regeneration. Looking at a finer scale, different GAC material affected microbiome assembly over time with significant variation in the relative abundances of specific taxa. The significance of our research is in identifying the environmental microorganisms intrinsic of deep groundwater and the community shift after the perturbations induced by potabilization processes. Which microorganisms colonize different GACs and become abundant after GACs regeneration and over time is a first step toward advanced control of microbial communities, improving drinking water safety and management of operational costs.
Associations of Mitochondrial Variants With Lipidomic Traits in a Chinese Cohort With Coronary Artery Disease
Authors: Wang Zixian , Chen Hui , Qin Min , Liu Chen , Ma Qilin , Chen Xiaoping , Zhang Ying , Lai Weihua , Zhang Xiaojuan , Zhong Shilong
Published: March 2021

Plasma lipids have been at the center stage of the prediction and prevention strategies for cardiovascular diseases (CVDs), and novel lipidomic traits have been recognized as reliable biomarkers for CVD risk prediction. The mitochondria serve as energy supply sites for cells and can synthesize a variety of lipids autonomously. Therefore, investigating the relationships between mitochondrial single nucleotide polymorphism (SNPs) and plasma lipidomic traits is meaningful. Here, we enrolled a total of 1,409 Han Chinese patients with coronary artery disease from three centers and performed linear regression analyses on the SNPs of mitochondrial DNA (mtDNA) and lipidomic traits in two independent groups. Sex, age, aspartate aminotransferase, estimated glomerular filtration rate, antihypertensive drugs, hypertension, and diabetes were adjusted. We identified three associations, namely, D-loopm.16089T>C with TG(50:4) NL-16:0, D-loopm.16145G>A with TG(54:5) NL-18:0, and D-loopm.16089T>C with PC(16:0_16:1) at the statistically significant threshold of FDR < 0.05. Then, we explored the relationships between mitochondrial genetic variants and traditional lipids, including triglyceride, total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and high-density lipoprotein cholesterol. Two significant associations were found, namely MT-ND6m.14178T>C with TC and D-loopm.215A>G with LDLC. Furthermore, we performed linear regression analysis to determine on the SNPs of mtDNA and left ventricular ejection fraction (LVEF) and found that the SNP D-loopm.16145G>A was nominally significantly associated with LVEF (P = 0.047). Our findings provide insights into the lipidomic context of mtDNA variations and highlight the importance of studying mitochondrial genetic variants related to lipid species.
Profiles of Immune Cell Infiltration in Carotid Artery Atherosclerosis Based on Gene Expression Data
Authors: Wang Long , Gao Beibei , Wu Mingyue , Yuan Wei , Liang Ping , Huang Jinyu
Published: March 2021

Since immune infiltration is closely associated with the progression and prognosis of atherosclerosis, we aimed to describe the abundance of 24 immune cell types within atherosclerotic tissues. In the current study, we used the Immune Cell Abundance Identifier (ImmuCellAI), a web-based tool, to estimate the abundance of 24 immune cells based on the microarray profiles of atherosclerotic carotid artery samples to analyze the proportions and the dysregulation of immune cell types within carotid atherosclerosis. We found that atherosclerotic immune cells had a diverse landscape dominated by T cells and myeloid cells and that macrophages and dendritic cells (DCs) showed different abundance in normal and atherosclerotic tissues. Moreover, the expression of macrophages was closely related to the level of the expression of DCs and of exhausted T cells, while the expression of T-helper type 1 (Th1) cells was strongly correlated with the expression of T-helper type 2 (Th2) cells and effector memory cells. Our data confirm a distinct profile of atherosclerosis-infiltrating immune cell subpopulations, which may inspire an immunological direction for research on atherosclerosis.
Structural Basis of VSIG3: The Ligand for VISTA
Authors: Xie Xiaoxue , Chen Caiping , Chen Wenting , Jiang Jingwei , Wang Lanlan , Li Tingting , Sun Hongbin , Liu Jun
Published: March 2021

B7 family members and their receptors play key roles in regulating T cell responses, and constitute very attractive targets for developing immunotherapeutic drugs. V-Set and Immunoglobulin domain containing 3 (VSIG3), a ligand for the novel B7 family immune checkpoint V-domain immunoglobulin suppressor of T cell activation (VISTA), can significantly inhibit T cell functions. Inhibitors targeting the VISTA/VSIG3 pathway are of great significance in tumor immunology. Here, we show the crystal structure of the extracellular domain (ECD) of the human VSIG3 protein at 2.64 angstrom resolution, and we produce recombinant human VSIG-3 ECD in both CHO cells and E. coli. Furthermore, we demonstrated the interaction of VISTA and VSIG3 by coimmunoprecipitation (Co-IP). Based on protein-protein docking for VISTA and VSIG3, we report a small molecule inhibitor of VSIG3 K284-3046 and evaluate its biological activities in vitro. This study was the first to reveal the crystal structure of VSIG3, and provides the structural basis for designing antibodies or compounds for the unique VSIG3/VISTA coinhibitory pathway in the treatment of cancers, autoimmune diseases and may be beneficial of designing vaccines.
Association of Isocitrate Dehydrogenase (IDH) Status With Edema to Tumor Ratio and Its Correlation With Immune Infiltration in Glioblastoma
Authors: Dubinski Daniel , Won Sae-Yeon , Rauch Maximilian , Behmanesh Bedjan , Ngassam Lionel D. C. , Baumgarten Peter , Senft Christian , Harter Patrick N. , Bernstock Joshua D. , Freiman Thomas M. , Seifert Volker , Gessler Florian
Published: March 2021

Purpose

The extent of preoperative peritumoral edema in glioblastoma (GBM) has been negatively correlated with patient outcome. As several ongoing studies are investigating T-cell based immunotherapy in GBM, we conducted this study to assess whether peritumoral edema with potentially increased intracranial pressure, disrupted tissue homeostasis and reduced local blood flow has influence on immune infiltration and affects survival.

Methods

A volumetric analysis of preoperative imaging (gadolinium enhanced T1 weighted MRI sequences for tumor size and T2 weighted sequences for extent of edema (including the infiltrative zone, gliosis etc.) was conducted in 144 patients using the Brainlab® software. Immunohistochemical staining was analyzed for lymphocytic- (CD 3+) and myelocytic (CD15+) tumor infiltration. A retrospective analysis of patient-, surgical-, and molecular characteristics was performed using medical records.

Results

The edema to tumor ratio was neither associated with progression-free nor overall survival (p=0.90, p=0.74). However, GBM patients displaying IDH-1 wildtype had significantly higher edema to tumor ratio than patients displaying an IDH-1 mutation (p=0.01). Immunohistopathological analysis did not show significant differences in lymphocytic or myelocytic tumor infiltration (p=0.78, p=0.74) between these groups.

Conclusion

In our cohort, edema to tumor ratio had no significant correlation with immune infiltration and outcome. However, patients with an IDH-1wildtype GBM had a significantly higher edema to tumor ratio compared to their IDH-1 mutated peer group. Further studies are necessary to elucidate the underlying mechanisms.
Plasma Biomarkers of Risk of Tuberculosis Recurrence in HIV Co-Infected Patients From South Africa
Authors: Pillay Kimesha , Lewis Lara , Rambaran Santhuri , Yende-Zuma Nonhlanhla , Archary Derseree , Gengiah Santhanalakshmi , Govender Dhineshree , Hassan-Moosa Razia , Samsunder Natasha , Abdool Karim Salim S. , McKinnon Lyle R. , Padayatchi Nesri , Naidoo Kogieleum , Sivro Aida
Published: March 2021

There is an urgent need to identify immunological markers of tuberculosis (TB) risk in HIV co-infected individuals. Previously we have shown that TB recurrence in HIV co-infected individuals on ART was associated with markers of systemic inflammation (IL-6, IL1β and IL-1Rα). Here we examined the effect of additional acute inflammation and microbial translocation marker expression on risk of TB recurrence. Stored plasma samples were drawn from the TB Recurrence upon Treatment with HAART (TRuTH) study, in which individuals with previously treated pulmonary TB were screened for recurrence quarterly for up to 4 years. Recurrent TB cases (n = 37) were matched to controls (n = 102) by original trial study arm assignment and ART start date. Additional subsets of HIV infected (n = 41) and HIV uninfected (n = 37) individuals from Improving Recurrence Success (IMPRESS) study were sampled at active TB and post successful treatment completion. Plasma concentrations of soluble adhesion molecules (sMAdCAM, sICAM and sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor-beta (TGF-β1, TGF-β2, TGF-β3) were measured by multiplex immunoassays and ELISA. Cytokine data was square root transformed in order to reduce variability. Multivariable analysis adjusted for a number of potential confounders measured at sample time-point: age, BMI, CD4 count, viral load (VL) and measured at baseline: presence or absence of lung cavities, previous history of TB, and WHO disease stage (4 vs 3). The following analytes were associated with increased risk of TB recurrence in the multivariable model: sICAM (aOR 1.06, 95% CI: 1.02-1.12, p = 0.009), LBP (aOR 8.78, 95% CI: 1.23-62.66, p = 0.030) and TGF-β3 (aOR 1.44, 95% CI 1.01-2.05, p = 0.044). Additionally, we observed a positive correlation between LBP and sICAM (r= 0.347, p<0.0001), and LBP and IL-6, identified to be one of the strongest predictors of TB risk in our previous study (r=0.623, p=0.03). These data show that increased risk of TB recurrence in HIV infected individuals on ART is likely associated with HIV mediated translocation of microbial products and the resulting chronic immune activation.
Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective
Authors: Kanellopoulos Jean M. , Almeida-da-Silva Cássio Luiz Coutinho , Rüütel Boudinot Sirje , Ojcius David M.
Published: March 2021

Extracellular nucleotides are important mediators of activation, triggering various responses through plasma membrane P2 and P1 receptors. P2 receptors are further subdivided into ionotropic P2X receptors and G protein-coupled P2Y receptors. P2X4 is an ATP-gated cation channel broadly expressed in most tissues of the body. Within the P2X family, P2X4 has a unique subcellular distribution, being preferentially localized in lysosomes. In these organelles, high ATP concentrations do not trigger P2X4 because of the low pH. However, when the pH increases to 7.4, P2X4 can be stimulated by intra-lysosomal ATP, which is in its active, tetra-anionic form. Elucidation of P2X4, P2X3 and P2X7 structures has shed some light on the functional differences between these purinergic receptors. The potential interaction between P2X4 and P2X7 has been extensively studied. Despite intensive effort, it has not been possible yet to determine whether P2X4 and P2X7 interact as heterotrimers or homotrimers at the plasma membrane. However, several publications have shown that functional interactions between P2X4 and P2X7 do occur. Importantly, these studies indicate that P2X4 potentiates P2X7-dependent activation of inflammasomes, leading to increased release of IL-1β and IL-18. The role of P2X4 in various diseases could be beneficial or deleterious even though the pathophysiological mechanisms involved are still poorly defined. However, in diseases whose physiopathology involves activation of the NLRP3 inflammasome, P2X4 was found to exacerbate severity of disease. The recent production of monoclonal antibodies specific for the human and mouse P2X4, some of which are endowed with agonist or antagonist properties, raises the possibility that they could be used therapeutically. Analysis of single nucleotide polymorphisms of the human P2RX4 gene has uncovered the association of P2RX4 gene variants with susceptibility to several human diseases.
Human Herpesviruses 6A and 6B in Reproductive Diseases
Authors: Komaroff Anthony L. , Rizzo Roberta , Ecker Jeffrey L.
Published: March 2021

Human herpesviruses 6A (HHV-6A) and human herpesvirus 6B (HHV-6B)—collectively, HHV-6A/B—are recently-discovered but ancient human viruses. The vast majority of people acquire one or both viruses, typically very early in life, producing an ineradicable lifelong infection. The viruses have been linked to several neurological, pulmonary and hematological diseases. In early human history, the viruses on multiple occasions infected a germ cell, and integrated their DNA into a human chromosome. As a result, about 1% of humans are born with the full viral genome present in every cell, with uncertain consequences for health. HHV-6A may play a role in 43% of cases of primary unexplained infertility. Both the inherited and acquired viruses may occasionally trigger several of the factors that are important in the pathogenesis of preeclampsia. Transplacental infection occurs in 1-2% of pregnancies, with some evidence suggesting adverse health consequences for the child. While emerging knowledge about these viruses in reproductive diseases is not sufficient to suggest any changes in current practice, we write this review to indicate the need for further research that could prove practice-changing.
Protective or Harmful: The Dual Roles of Autophagy in Diabetic Retinopathy
Authors: Gong Qiaoyun , Wang Haiyan , Yu Ping , Qian Tianwei , Xu Xun
Published: March 2021

Autophagy is a self-degradative pathway involving intracellular substance degradation and recycling. Recently, this process has attracted a great deal of attention for its fundamental effect on physiological processes in cells, tissues, and the maintenance of organismal homeostasis. Dysregulation of autophagy occurs in some diseases, including immune disease, cancer, and neurodegenerative conditions. Diabetic retinopathy (DR), as a serious microvascular complication of diabetes, is the main cause of visual loss in working-age adults worldwide. The pathogenic mechanisms of DR are thought to be associated with accumulation of oxidative stress, retinal cell apoptosis, inflammatory response, endoplasmic reticulum (ER) stress, and nutrient starvation. These factors are closely related to the regulation of autophagy under pathological conditions. Increasing evidence has demonstrated the potential role of autophagy in the progression of DR through different pathways. However, to date this role is not understood, and whether the altered level of autophagy flux protects DR, or instead aggravates the progression, needs to be explored. In this review, we explore the alterations and functions of autophagy in different retinal cells and tissues under DR conditions, and explain the mechanisms involved in DR progression. We aim to provide a basis on which DR associated stress-modulated autophagy may be understood, and to suggest novel targets for future therapeutic intervention in DR.
Detection of Parkinson's Disease Through Automated Pupil Tracking of the Post-illumination Pupillary Response
Authors: Tabashum Thasina , Zaffer Adnaan , Yousefzai Raman , Colletta Kalea , Jost Mary Beth , Park Youngsook , Chawla Jasvinder , Gaynes Bruce , Albert Mark V. , Xiao Ting
Published: March 2021

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, but it is often diagnosed after the majority of dopaminergic cells are already damaged. It is critical to develop biomarkers to identify the disease as early as possible for early intervention. PD patients appear to have an altered pupillary response consistent with an abnormality in photoreceptive retinal ganglion cells. Tracking the pupil size manually is a tedious process and offline automated systems can be prone to errors that may require intervention; for this reason in this work we describe a system for pupil size estimation with a user interface to allow rapid adjustment of parameters and extraction of pupil parameters of interest for the present study. We implemented a user-friendly system designed for clinicians to automate the process of tracking the pupil diameter to measure the post-illumination pupillary response (PIPR), permit manual corrections when needed, and continue automation after correction. Tracking was automated using a Kalman filter estimating the pupil center and diameter over time. The resulting system was tested on a PD classification task in which PD subjects are known to have similar responses for two wavelengths of light. The pupillary response is measured in the contralateral eye to two different light stimuli (470 and 610 nm) for 19 PD and 10 control subjects. The measured Net PIPR indicating different responsiveness to the wavelengths was 0.13 mm for PD subjects and 0.61 mm for control subjects, demonstrating a highly significant difference (p < 0.001). Net PIPR has the potential to be a biomarker for PD, suggesting further study to determine clinical validity.
Audiometric Phenotypes of Noise-Induced Hearing Loss by Data-Driven Cluster Analysis and Their Relevant Characteristics
Authors: Wang Qixuan , Qian Minfei , Yang Lu , Shi Junbo , Hong Yingying , Han Kun , Li Chen , Lin James , Huang Zhiwu , Wu Hao
Published: March 2021

Background: The definition of notched audiogram for noise-induced hearing loss (NIHL) is presently based on clinical experience, but audiometric phenotypes of NIHL are highly heterogeneous. The data-driven clustering of subtypes could provide refined characteristics of NIHL, and help identify individuals with typical NIHL at diagnosis.

Methods: This cross-sectional study initially recruited 12,218 occupational noise-exposed employees aged 18–60 years from two factories of a shipyard in Eastern China. Of these, 10,307 subjects with no history of otological injurie or disease, family history of hearing loss, or history of ototoxic drug use were eventually enrolled. All these subjects completed health behavior questionnaires, cumulative noise exposure (CNE) measurement, and pure-tone audiometry. We did data-driven cluster analysis (k-means clustering) in subjects with hearing loss audiograms (n = 6,599) consist of two independent datasets (n = 4,461 and n = 2,138). Multinomial logistic regression was performed to analyze the relevant characteristics of subjects with different audiometric phenotypes compared to those subjects with normal hearing audiograms (n = 3,708).

Results: A total of 10,307 subjects (9,165 males [88.9%], mean age 34.5 [8.8] years, mean CNE 91.2 [22.7] dB[A]) were included, 3,708 (36.0%) of them had completely normal hearing, the other 6,599 (64.0%) with hearing loss audiograms were clustered into four audiometric phenotypes, which were replicable in two distinct datasets. We named the four clusters as the 4–6 kHz sharp-notched, 4–6 kHz flat-notched, 3–8 kHz notched, and 1–8 kHz notched audiogram. Among them, except for the 4–6 kHz flat-notched audiogram which was not significantly related to NIHL, the other three phenotypes with different relevant characteristics were strongly associated with noise exposure. In particular, the 4–6 kHz sharp-notched audiogram might be a typical subtype of NIHL.

Conclusions: By data-driven cluster analysis of the large-scale noise-exposed population, we identified three audiometric phenotypes associated with distinct NIHL subtypes. Data-driven sub-stratification of audiograms might eventually contribute to the precise diagnosis and treatment of NIHL.
Remediation of Chromium-Contaminated Soil Based on Bacillus cereus WHX-1 Immobilized on Biochar: Cr(VI) Transformation and Functional Microbial Enrichment
Authors: Chen Youyuan , Wu Haixia , Sun Ping , Liu Jiaxin , Qiao Shixuan , Zhang Dakuan , Zhang Zhiming
Published: March 2021

Microorganisms are applied to remediate chromium (Cr)-contaminated soil extensively. Nevertheless, the microbial loss and growth inhibition in the soil environment restrain the application of this technology. In this study, a Cr(VI)-reducing strain named Bacillus cereus WHX-1 was screened, and the microbial aggregates system was established via immobilizing the strain on Enteromorpha prolifera biochar to enhance the Cr(VI)-reducing activity of this strain. The mechanism of the system on Cr(VI) transformation in Cr-contaminated soil was illuminated. Pot experiments indicated that the microbial aggregates system improved the physicochemical characteristics of Cr-contaminated soil obviously by increasing organic carbon content and cation exchange capacity, as well as decreasing redox potential and bulk density of soil. Moreover, 94.22% of Cr(VI) was transformed into Cr(III) in the pot, and the content of residue fraction Cr increased by 63.38% compared with control check (CK). Correspondingly, the physiological property of Ryegrass planted on the Cr-contaminated soil was improved markedly and the main Cr(VI)-reducing microbes, Bacillus spp., were enriched in the soil with a relative abundance of 28.43% in the microbial aggregates system. Considering more active sites of biochar for microbial aggregation, it was inferred that B. cereus WHX-1 could be immobilized by E. prolifera biochar, and more Cr(VI) was transformed into residue fraction. Cr stress was decreased and the growth of plants was enhanced. This study would provide a new perspective for Cr-contaminated soil remediation.
Anethole Attenuates Enterotoxigenic Escherichia coli-Induced Intestinal Barrier Disruption and Intestinal Inflammation via Modification of TLR Signaling and Intestinal Microbiota
Authors: Yi Qingyuan , Liu Jiaxin , Zhang Yufeng , Qiao Hanzhen , Chen Fang , Zhang Shihai , Guan Wutai
Published: March 2021

This study aimed to investigate the effects of dietary anethole supplementation on the growth performance, intestinal barrier function, inflammatory response, and intestinal microbiota of piglets challenged with enterotoxigenic Escherichia coli K88. Thirty-six weaned piglets (24 ± 1 days old) were randomly allocated into four treatment groups: (1) sham challenge (CON); (2) Escherichia coli K88 challenge (ETEC); (3) Escherichia coli K88 challenge + antibiotics (ATB); and (4) Escherichia coli K88 challenge + anethole (AN). On day 12, the piglets in the ETEC, ATB, and AN group were challenged with 10 mL E. coli K88 (5 × 109 CFU/mL), whereas the piglets in the CON group were orally injected with 10 mL nutrient broth. On day 19, all the piglets were euthanized for sample collection. The results showed that the feed conversion ratio (FCR) was increased in the Escherichia coli K88-challenged piglets, which was reversed by the administration of antibiotics or anethole (P < 0.05). The duodenum and jejunum of the piglets in ETEC group exhibited greater villous atrophy and intestinal morphology disruption than those of the piglets in CON, ATB, and AN groups (P < 0.05). Administration of anethole protected intestinal barrier function and upregulated mucosal layer (mRNA expression of mucin-1 in the jejunum) and tight junction proteins (protein abundance of ZO-1 and Claudin-1 in the ileum) of the piglets challenged with Escherichia coli K88 (P < 0.05). In addition, administration of antibiotics or anethole numerically reduced the plasma concentrations of IL-1β and TNF-α (P < 0.1) and decreased the mRNA expression of TLR5, TLR9, MyD88, IL-1β, TNF-α, IL-6, and IL-10 in the jejunum of the piglets after challenge with Escherichia coli K88 (P < 0.05). Dietary anethole supplementation enriched the abundance of beneficial flora in the intestines of the piglets. In summary, anethole can improve the growth performance of weaned piglets infected by ETEC through attenuating intestinal barrier disruption and intestinal inflammation.
A Neural Network Model for Learning 3D Object Representations Through Haptic Exploration
Authors: Yan Xiaogang , Mills Steven , Knott Alistair
Published: March 2021

Humans initially learn about objects through the sense of touch, in a process called “haptic exploration.” In this paper, we present a neural network model of this learning process. The model implements two key assumptions. The first is that haptic exploration can be thought of as a type of navigation, where the exploring hand plays the role of an autonomous agent, and the explored object is this agent's “local environment.” In this scheme, the agent's movements are registered in the coordinate system of the hand, through slip sensors on the palm and fingers. Our second assumption is that the learning process rests heavily on a simple model of sequence learning, where frequently-encountered sequences of hand movements are encoded declaratively, as “chunks.” The geometry of the object being explored places constraints on possible movement sequences: our proposal is that representations of possible, or frequently-attested sequences implicitly encode the shape of the explored object, along with its haptic affordances. We evaluate our model in two ways. We assess how much information about the hand's actual location is conveyed by its internal representations of movement sequences. We also assess how effective the model's representations are in a reinforcement learning task, where the agent must learn how to reach a given location on an explored object. Both metrics validate the basic claims of the model. We also show that the model learns better if objects are asymmetrical, or contain tactile landmarks, or if the navigating hand is articulated, which further constrains the movement sequences supported by the explored object.