bluuebunny/crossref_metadata_2025 huggingface dataset:
TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury
Authors: Liu Lu , Chen Manli , Lin Kun , Xiang Xuwu , Yang Jing , Zheng Yueying , Xiong Xiaoxing , Zhu Shengmei
Published: February 2021

Transient receptor potential canonical 6 (TRPC6) channel is an important non-selective cation channel with a variety of physiological roles in the central nervous system. Evidence has shown that TRPC6 is involved in the process of experimental stroke; however, the underlying mechanisms remain unclear. In the present study, the role of astrocytic TRPC6 was investigated in an oxygen–glucose deprivation cell model and middle cerebral artery occlusion (MCAO) mouse model of stroke. HYP9 (a selective TRPC6 agonist) and SKF96365 (SKF; a TRPC antagonist) were used to clarify the exact functions of TRPC6 in astrocytes after ischemic stroke. TRPC6 was significantly downregulated during ischemia/reperfusion (IR) injury in cultured astrocytes and in cortices of MCAO mice. Application of HYP9 in vivo alleviated the brain infarct lesion, astrocytes population, apoptosis, and interleukin-6 (IL-6) and IL-1β release in mouse cortices after ischemia. HYP9 dose-dependently inhibited the downregulation of TRPC6 and reduced astrocytic apoptosis, cytotoxicity and inflammatory responses in IR insult, whereas SKF aggravated the damage in vitro. In addition, modulation of TRPC6 channel diminished IR-induced Ca2+ entry in astrocytes. Furthermore, decreased Ca2+ entry due to TRPC6 contributed to reducing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) nuclear translocation and phosphorylation. Overexpression of astrocytic TRPC6 also attenuated apoptosis, cytotoxicity, inflammatory responses, and NF-κB phosphorylation in modeled ischemia in astrocytes. The results of the present study indicate that the TRPC6 channel can act as a potential target to reduce both inflammatory responses and apoptosis in astrocytes during IR injury, subsequently attenuating ischemic brain damage. In addition, we provide a novel view of stroke therapy by targeting the astrocytic TRPC6 channel.
STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
Authors: Vigont Vladimir A. , Grekhnev Dmitriy A. , Lebedeva Olga S. , Gusev Konstantin O. , Volovikov Egor A. , Skopin Anton Yu. , Bogomazova Alexandra N. , Shuvalova Lilia D. , Zubkova Olga A. , Khomyakova Ekaterina A. , Glushankova Lyubov N. , Klyushnikov Sergey A. , Illarioshkin Sergey N. , Lagarkova Maria A. , Kaznacheyeva Elena V.
Published: February 2021

Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neurons modeling a juvenile form of HD (HD76). We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development.
Adaptive Cardiac Metabolism Under Chronic Hypoxia: Mechanism and Clinical Implications
Authors: Su Zhanhao , Liu Yiwei , Zhang Hao
Published: February 2021

Chronic hypoxia is an essential component in many cardiac diseases. The heart consumes a substantial amount of energy and it is important to maintain the balance of energy supply and demand when oxygen is limited. Previous studies showed that the heart switches from fatty acid to glucose to maintain metabolic efficiency in the adaptation to chronic hypoxia. However, the underlying mechanism of this adaptive cardiac metabolism remains to be fully characterized. Moreover, how the altered cardiac metabolism affects the heart function in patients with chronic hypoxia has not been discussed in the current literature. In this review, we summarized new findings from animal and human studies to illustrate the mechanism underlying the adaptive cardiac metabolism under chronic hypoxia. Clinical focus is given to certain patients that are subject to the impact of chronic hypoxia, and potential treatment strategies that modulate cardiac metabolism and may improve the heart function in these patients are also summarized.
The Multifaceted Roles of Primary Cilia in the Development of the Cerebral Cortex
Authors: Hasenpusch-Theil Kerstin , Theil Thomas
Published: February 2021

The primary cilium, a microtubule based organelle protruding from the cell surface and acting as an antenna in multiple signaling pathways, takes center stage in the formation of the cerebral cortex, the part of the brain that performs highly complex neural tasks and confers humans with their unique cognitive capabilities. These activities require dozens of different types of neurons that are interconnected in complex ways. Due to this complexity, corticogenesis has been regarded as one of the most complex developmental processes and cortical malformations underlie a number of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and epilepsy. Cortical development involves several steps controlled by cell–cell signaling. In fact, recent findings have implicated cilia in diverse processes such as neurogenesis, neuronal migration, axon pathfinding, and circuit formation in the developing cortex. Here, we will review recent advances on the multiple roles of cilia during cortex formation and will discuss the implications for a better understanding of the disease mechanisms underlying neurodevelopmental disorders.
Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
Authors: Das Yannick , Swinkels Daniëlle , Kocherlakota Sai , Vinckier Stefan , Vaz Frédéric M. , Wever Eric , van Kampen Antoine H. C. , Jun Bokkyoo , Do Khanh V. , Moons Lieve , Bazan Nicolas G. , Van Veldhoven Paul P. , Baes Myriam
Published: February 2021

Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
Metagenomic Analysis of the Gut Microbiota of Wild Mice, a Newly Identified Reservoir of Campylobacter
Authors: Song Hyokeun , Kim Junhyung , Guk Jae-Ho , Kim Woo-Hyun , Nam Hajin , Suh Jun Gyo , Seong Je Kyung , Cho Seongbeom
Published: February 2021

Campylobacter, the most common etiologic agent of zoonotic gastroenteritis in humans, is present in many reservoirs including livestock animals, wildlife, soil, and water. Previously, we reported a novel Campylobacter jejuni strain SCJK02 (MLST ST-8388) from the gut of wild mice (Micromys minutus) using culture-dependent methods. However, due to fastidious growth conditions and the presence of viable but non-culturable Campylobacter spp., it is unclear whether M. minutus is a Campylobacter reservoir. This study aimed to: 1) determine the distribution and proportion of Campylobacter spp. in the gut microbiota of wild mice using culture-independent methods and 2) investigate the gut microbiota of wild mice and the relationship of Campylobacter spp. with other gut microbes. The gut microbiota of 38 wild mice captured from perilla fields in Korea and without any clinical symptoms (18 M. minutus and 20 Mus musculus) were analyzed. Metagenomic analysis showed that 77.8% (14 of 18) of the captured M. minutus harbored Campylobacter spp. (0.24–32.92%) in the gut metagenome, whereas none of the captured M. musculus carried Campylobacter spp. in their guts. Notably, 75% (6 of 8) of M. minutus determined to be Campylobacter-negative using culture-dependent methods showed a high proportion of Campylobacter through metagenome analysis. The results of metagenome analysis and the absence of clinical symptoms suggest that Campylobacter may be a component of the normal gut flora of wild M. minutus. Furthermore, linear discriminant analysis (LDA) showed that Campylobacter was the most enriched genus in the gut microbiota of M. minutus (LDA score, 5.37), whereas Lactobacillus was the most enriched genus in M. musculus (LDA score, −5.96). The differences in the presence of Campylobacter between the two species of wild mice may be attributed to the differential abundance of Campylobacter and Lactobacillus in their respective gut microbiota. In conclusion, the results indicate that wild M. minutus may serve as a potential Campylobacter reservoir. This study presents the first metagenomics analysis of the M. minutus gut microbiota to explore its possible role as an environmental Campylobacter reservoir and provides a basis for future studies using culture-independent methods to determine the role of environmental reservoirs in Campylobacter transmission.
Microvascular Angiopathic Consequences of COVID-19
Authors: Nalugo Margaret , Schulte Linda J. , Masood Muhammad F. , Zayed Mohamed A.
Published: February 2021

The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first appeared in Wuhan, China in December, 2019. Ever increasing data is continuing to emerge about the impact of COVID-19 on cardiovascular tissue and other organ system. Clinical features associated with COVID-19 suggest that endothelial cell dysfunction and microvascular thrombosis are to a large extent contributing to resultant multi-organ complications. This review is aimed at highlighting the critical aspects associated with COVID-19 and its presumed microvascular angiopathic consequences on the cardiovascular system leading to multi-organ dysfunction.
Exploring the Influences of Temperature on “H-Shaped” Glycerol Dialkyl Glycerol Tetraethers in a Stratigraphic Context: Evidence From Two Peat Cores Across the Late Quaternary
Authors: Tang Xiaotong , Naafs B. David A. , Pancost Richard D. , Liu Zhao , Fan Tongyu , Zheng Yanhong
Published: February 2021

Unusual “H-Shaped” branched and isoprenoidal glycerol monoalkyl glycerol tetraethers (GMGTs, or H-GDGTs) have been found in peat, lake, and ocean sediments. A survey of recent samples from a modern global peat database suggested that there is a relationship between the abundance of H-GDGTs relative to regular GDGTs and temperature. However, this relationship has not been widely explored, including in a historical, stratigraphic or geological context. Here, we report the abundance and distribution of H-iso- and H-brGDGTs in two (Hani and Gushantun) peat cores from northeastern China through the late Quaternary (last 15 kyr) to examine whether the relationship between temperature and the relative abundance of H-GDGTs is preserved downcore. The results indicate that high relative abundances of H-brGDGTs are associated with high (or increasing) reconstructed mean annual air temperature (MAATpeat), albeit with considerable divergence in some intervals. On the other hand, high relative abundances of H-isoGDGTs are generally associated with low (or decreasing) MAATpeat. These findings are partly inconsistent with the observations from the modern database of globally distributed peats, which showed that the abundance of both (br- and iso-) H-GDGTs is positively correlated with temperature. The deviation in the relationship between H-isoGDGTs and temperature suggests that additional factors, for example pH and shifts in archaeal community related to hydrology, exert an influence on the abundance of H-isoGDGTs on the long-term.
Computational Screening of Doped Graphene Electrodes for Alkaline CO2 Reduction
Authors: Verma Anand M. , Honkala Karoliina , Melander Marko M.
Published: February 2021

The electrocatalytic CO2 reduction reaction (CO2RR) is considered as one of the most promising approaches to synthesizing carbonaceous fuels and chemicals without utilizing fossil resources. However, current technologies are still in the early phase focusing primarily on identifying optimal electrode materials and reaction conditions. Doped graphene-based materials are among the best CO2RR electrocatalysts and in the present work we have performed a computational screening study to identify suitable graphene catalysts for CO2RR to CO under alkaline conditions. Several types of modified-graphene frameworks doped with metallic and non-metallic elements were considered. After establishing thermodynamically stable electrodes, the electrochemical CO2RR to CO is studied in the alkaline media. Both concerted proton-coupled electron transfer (PCET) and decoupled proton and electron transfer (ETPT) mechanisms were considered by developing and using a generalization of the computational hydrogen electrode approach. It is established that the CO2 electrosorption and associated charge transfer along the ETPT pathway are of utmost importance and significantly impact the electrochemical thermodynamics of CO2RR. Our study suggests an exceptional performance of metal-doped nitrogen-coordinated graphene electrodes, especially 3N-coordinated graphene electrodes.
China’s Energy Transition Policy Expectation and Its CO2 Emission Reduction Effect Assessment
Authors: Wang Di , Liu Xue , Yang Xiaodi , Zhang Zhiyuan , Wen Xinchen , Zhao Yueying
Published: February 2021

Measuring the expected impact of China’s energy transition on carbon dioxide (CO2) mitigation and identifying the key influencing factors in different economic sectors will help to provide better policy recommendations for CO2 emission reduction. Based on the prediction results of China’s CO2 emissions in 2030 under the baseline scenario and the target scenario, this study constructs the control group and the treatment group of the energy transition policy quasinatural experiment and then uses the difference in difference (DID) model to evaluate the CO2 emission reduction effect of China’s energy transition policy. The results reveal that the energy transition policy has a significant impact on CO2 emission reduction and helps to achieve China’s 2030 carbon emission reduction target. The impact of energy structure transition on CO2 emission reduction has significant sectoral heterogeneity, which has a positive reduction effect in the industry sector, wholesale and retail sectors, and accommodation and catering sectors, but its reduction effect is not obvious in transportation, storage, and postal sectors. It is suggested that China should implement the sector-differentiated CO2 mitigation strategy, focus on improving the industrial sector’s energy efficiency, and promote the clean, low-carbon transition of energy consumption structure in construction, transportation, storage, and postal industries.
Distributive Justice and Sustainability Goals in Transboundary Rivers: Case of the Nile Basin
Authors: Yalew S. G. , Kwakkel J. , Doorn N.
Published: February 2021

The importance of cooperation on transboundary waters is stated as a target in the United Nations 2030 Agenda for Sustainable Development Goals (SDG6: water). Cooperation on transboundary water management is critical, particularly because it concerns issues across multiple states, SDGs and targets regarding agriculture, energy, ecosystems, climate adaptation, health, and peace and security. The percentage of transboundary basin area within a country that has an “operational arrangement” for water cooperation is used as the main indicator of such cooperation in the SDGs for “equitable and reasonable use“ of water resources (SDG 6.5.2). However, no clear criteria and explanation are available for what exactly constitutes an “equitable and reasonable use” in any such “operational arrangements.” Furthermore, it is understandable that any such arrangements may be shaped by differences in historical, legal, and political contexts and hence may be inherently unjust. Here, we highlight the limitations of SDG indicators, particularly SDG 6.5.2, to monitor equity of resource sharing in transboundary river systems. Using Walzer’s theory of morality of the state and cosmopolitanism as a framework, we examine the Nile basin as a case study to demonstrate the shortcomings of current SDG criteria and indicators. Our article contributes ideas of “operationalizing” theoretical justice toward a more equitable water management in transboundary rivers.
Hierarchical Approach for Comparing Collective Behavior Across Scales: Cellular Systems to Honey Bee Colonies
Authors: Davidson Jacob D. , Vishwakarma Medhavi , Smith Michael L.
Published: February 2021

How individuals in a group lead to collective behavior is a fundamental question across biological systems, from cellular systems, to animal groups, to human organizations. Recent technological advancements have enabled an unprecedented increase in our ability to collect, quantify, and analyze how individual responses lead to group behavior. However, despite a wealth of data demonstrating that collective behavior exists across biological scales, it is difficult to make general statements that apply in different systems. In this perspective, we present a cohesive framework for comparing groups across different levels of biological organization, using an intermediate link of “collective mechanisms” that connects individual responses to group behavior. Using this approach we demonstrate that an effective way of comparing different groups is with an analysis hierarchy that asks complementary questions, including how individuals in a group implement various collective mechanisms, and how these various mechanisms are used to achieve group function. We apply this framework to compare two collective systems—cellular systems and honey bee colonies. Using a case study of a response to a disturbance, we compare and contrast collective mechanisms used in each system. We then discuss how inherent differences in group structure and physical constraints lead to different combinations of collective mechanisms to solve a particular problem. Together, we demonstrate how a hierarchical approach can be used to compare and contrast different systems, lead to new hypotheses in each system, and form a basis for common research questions in collective behavior.
C-Kit, a Double-Edged Sword in Liver Regeneration and Diseases
Authors: Wang Weina , Shui Liyan , Liu Yanning , Zheng Min
Published: February 2021

Previous studies have reported an important role of c-kit in embryogenesis and adulthood. Activation of the SCF/KIT signal transduction pathway is customarily linked to cell proliferation, migration and survival thus influence hematopoiesis, pigmentation, and spermatogenesis. The role of c-kit in the liver is controversial, it is however argued that it is a double-edged sword in liver regeneration and diseases. First, liver c-kit+ cells, including oval cells, bile epithelial cells, and part of hepatocytes, participate in liver tissue repair by regenerating target cells according to the type of liver injury. At the same time, c-kit+ mast cells, act as immature progenitors in circulation, playing a critical role in liver fibrosis. Furthermore, c-kit is also a proto-oncogene. Notably, c-kit overexpression regulates gastrointestinal stromal tumors. Various studies have explored on c-kit and hepatocellular carcinoma, nevertheless, the intricate roles of c-kit in the liver are largely understudied. Herein, we extensively summarize previous studies geared toward providing hints for future clinical and basic research.
Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors
Authors: Liu Wenhui , Wang Ying , Luo Jianquan , Liu Mouze , Luo Zhiying
Published: February 2021

Cancer is an important threat to public health because of its high morbidity and mortality. In recent decades, immune checkpoint inhibitors (ICIs) have ushered a new therapeutic era in clinical oncology. The rapid development of immune checkpoint therapy is due to its inspiring clinical efficacy in a group of cancer types. Metformin, an effective agent for the management of type 2 diabetes mellitus (T2DM), has shown beneficial effects on cancer prevention and cancer treatment. Emerging studies have suggested that metformin in combination with ICI treatment could improve the anticancer effects of ICIs. Hence, we conducted a review to summarize the effects of metformin on ICI therapy. We also review the pleiotropic mechanisms of metformin combined with ICIs in cancer therapy, including its direct and indirect effects on the host immune system.
Relevance of QuantiFERON-TB Gold Plus and Heparin-Binding Hemagglutinin Interferon-γ Release Assays for Monitoring of Pulmonary Tuberculosis Clearance: A Multicentered Study
Authors: Chedid Carole , Kokhreidze Eka , Tukvadze Nestani , Banu Sayera , Uddin Mohammad Khaja Mafij , Biswas Samanta , Russomando Graciela , Acosta Chyntia Carolina Díaz , Arenas Rossana , Ranaivomanana Paulo PR. , Razafimahatratra Crisca , Herindrainy Perlinot , Rakotonirina Julio , Raherinandrasana Antso Hasina , Rakotosamimanana Niaina , Hamze Monzer , Ismail Mohamad Bachar , Bayaa Rim , Berland Jean-Luc , De Maio Flavio , Delogu Giovanni , Endtz Hubert , Ader Florence , Goletti Delia , Hoffmann Jonathan
Published: February 2021

Background

Tuberculosis (TB) is a leading infectious cause of death. To improve treatment efficacy, quicker monitoring methods are needed. The objective of this study was to monitor the response to a heparin-binding hemagglutinin (HBHA) interferon-γ (IFN-γ) release assay (IGRA) and QuantiFERON-TB Gold Plus (QFT-P) and to analyze plasma IFN-γ levels according to sputum culture conversion and immune cell counts during treatment.

Methods

This multicentered cohort study was based in Bangladesh, Georgia, Lebanon, Madagascar, and Paraguay. Adult, non-immunocompromised patients with culture-confirmed pulmonary TB were included. Patients were followed up at baseline (T0), after two months of treatment (T1), and at the end of therapy (T2). Clinical data and blood samples were collected at each timepoint. Whole blood samples were stimulated with QFT-P antigens or recombinant methylated Mycobacterium tuberculosis HBHA (produced in Mycobacterium smegmatis; rmsHBHA). Plasma IFN-γ levels were then assessed by ELISA.

Findings

Between December 2017 and September 2020, 132 participants completed treatment, including 28 (21.2%) drug-resistant patients. rmsHBHA IFN-γ increased significantly throughout treatment (0.086 IU/ml at T0 vs. 1.03 IU/ml at T2, p < 0.001) while QFT-P IFN-γ remained constant (TB1: 0.53 IU/ml at T0 vs. 0.63 IU/ml at T2, p = 0.13). Patients with low lymphocyte percentages (<14%) or high neutrophil percentages (>79%) at baseline had significantly lower IFN-γ responses to QFT-P and rmsHBHA at T0 and T1. In a small group of slow converters (patients with positive cultures at T1; n = 16), we observed a consistent clinical pattern at baseline (high neutrophil percentages, low lymphocyte percentages and BMI, low TB1, TB2, and MIT IFN-γ responses) and low rmsHBHA IFN-γ at T1 and T2. However, the accuracy of the QFT-P and rmsHBHA IGRAs compared to culture throughout treatment was low (40 and 65% respectively). Combining both tests improved their sensitivity and accuracy (70–80%) but not their specificity (<30%).

Conclusion

We showed that QFT-P and rmsHBHA IFN-γ responses were associated with rates of sputum culture conversion. Our results support a growing body of evidence suggesting that rmsHBHA IFN-γ discriminates between the different stages of TB, from active disease to controlled infection. However, further work is needed to confirm the specificity of QFT-P and rmsHBHA IGRAs for treatment monitoring.
Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy
Authors: Jiang Weiqin , He Yinjun , He Wenguang , Wu Guosheng , Zhou Xile , Sheng Qinsong , Zhong Weixiang , Lu Yimin , Ding Yongfeng , Lu Qi , Ye Feng , Hua Hanju
Published: February 2021

Tumor-specific CD8+T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8+T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8+T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.
Tenascin-W: Discovery, Evolution, and Future Prospects
Authors: Degen Martin , Scherberich Arnaud , Tucker Richard P.
Published: February 2021

Of the four tenascins found in bony fish and tetrapods, tenascin-W is the least understood. It was first discovered in the zebrafish and later in mouse, where it was mistakenly named tenascin-N. Tenascin-W is expressed primarily in developing and mature bone, in a subset of stem cell niches, and in the stroma of many solid tumors. Phylogenetic studies show that it is the most recent tenascin to evolve, appearing first in bony fishes. Its expression in bone and the timing of its evolutionary appearance should direct future studies to its role in bone formation, in stem cell niches, and in the treatment and detection of cancer.
Stability Evaluation and Mechanism of Asphalts Modified With Various Rubber Powder Contents
Authors: Xue Hengxiao , Cao Yuanbo , Liu Qi , Zhang Hongfei , Zhang Mingliang
Published: February 2021

Ground tires are one of the main sources of urban solid waste. Rubber powder-modified asphalt provides an effective method to solve the problem, and it presents good high- and low-temperature performance in sustainable pavement construction. However, the storage properties of rubber powder-modified asphalts prepared from the traditional low-temperature shear mixing method are unstable, which restricts their application. In this study, four test methods (the softening-point test; the dynamic shear rheological test; the Laboratory Asphalt Stability Test; and fluorescence image analysis) and six evaluation indexes (the softening-point difference Sdiff, the segregation percentage Sp, the segregation index Ise, the segregation rate Rs, the degradation rate Rd, and the stability index Ist) were employed to analyze the storage abilities of asphalts modified by various activated rubber powder contents. The results show that the storage properties have a positive correlation with rubber powder content in the modified asphalt, and a rubber powder content of 60% is proven to be the optimum mixing amount. The rubber powders can distribute uniformly in the asphalt matrix when mixed below the optimum mixing amount; otherwise a rubber powder agglomeration is formed. The quantitative morphology analysis results are in good agreement with the laboratory test conclusions. The activated rubber powder shows better compatibility compared with ordinary rubber powders and presents a promising method to treat waste ground tires.
YF-H-2015005, a CXCR4 Antagonist, for the Mobilization of Hematopoietic Stem Cells in Non-Hodgkin Lymphoma Patients: A Randomized, Controlled, Phase 3 Clinical Trial
Authors: Liu Weiping , Li Yufu , Wang Quanshun , Su Hang , Ding Kaiyang , Shuang Yuerong , Gao Sujun , Zou Dehui , Jing Hongmei , Chai Ye , Zhang Yicheng , Liu Lihong , Wang Chunling , Liu Hui , Lin Jinying , Zhu Haiyan , Yao Chen , Yan Xiaoyan , Shang Meixia , Wang Shufang , Chang Fengyuan , Wang Xiaopei , Zhu Jun , Song Yuqin
Published: February 2021

Background: YF-H-2015005, a novel CXCR4 antagonist, has been proven to increase the quantities of circulating hematopoietic stem cells (HSCs), which results in an adequate collection of HSCs in non-Hodgkin lymphoma (NHL) patients.

Methods: This was a multicenter, double-blind, randomized (1:1), placebo-controlled phase III clinical trial. All patients received granulocyte colony-stimulating factor (G-CSF) for up to 8 consecutive days. YF-H-2015005 or placebo was administrated on the evening of day 4 and continued daily for up to 4 days. Apheresis was conducted 9–10 h after each dose of YF-H-2015005 or placebo. The primary endpoint was the proportion of NHL patients procuring ≥5 × 106/kg CD34+ HSCs within ≤4 apheresis sessions.

Results: In total, 101 patients with NHL were enrolled. The proportions of patients achieving primary endpoint were 57 and 12% in YF-H-2015005 and placebo groups, respectively (P < 0.001). Moreover, a higher proportion of YF-H-2015005-treated patients reached a minimum target collection of ≥2 × 106/kg CD34+ HSCs in ≤4 apheresis days compared to placebo-treated patients (86 vs. 38%, P < 0.001). Furthermore, the median time to collect ≥2 or 5 × 106/kg CD34+ HSCs were 1 and 3 days in YF-H-2015005-treated patients, but 4 days and not reached in placebo-treated patients, respectively. No severe treatment emergent adverse events were observed in both YF-H-2015005 treatment and placebo groups.

Conclusions: YF-H-2015005 plus G-CSF regimen was a tolerable combination with high efficacy, which might be used to rapidly mobilize and collect HSCs in NHL patients.
Early Drug Development and Evaluation of Putative Antitubercular Compounds in the -Omics Era
Authors: Minias Alina , Żukowska Lidia , Lechowicz Ewelina , Gąsior Filip , Knast Agnieszka , Podlewska Sabina , Zygała Daria , Dziadek Jarosław
Published: February 2021

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. According to the WHO, the disease is one of the top 10 causes of death of people worldwide. Mycobacterium tuberculosis is an intracellular pathogen with an unusually thick, waxy cell wall and a complex life cycle. These factors, combined with M. tuberculosis ability to enter prolonged periods of latency, make the bacterium very difficult to eradicate. The standard treatment of TB requires 6–20months, depending on the drug susceptibility of the infecting strain. The need to take cocktails of antibiotics to treat tuberculosis effectively and the emergence of drug-resistant strains prompts the need to search for new antitubercular compounds. This review provides a perspective on how modern -omic technologies facilitate the drug discovery process for tuberculosis treatment. We discuss how methods of DNA and RNA sequencing, proteomics, and genetic manipulation of organisms increase our understanding of mechanisms of action of antibiotics and allow the evaluation of drugs. We explore the utility of mathematical modeling and modern computational analysis for the drug discovery process. Finally, we summarize how -omic technologies contribute to our understanding of the emergence of drug resistance.
Nutrients Bioaccessibility and Anti-inflammatory Features of Fermented Bee Pollen: A Comprehensive Investigation
Authors: Filannino Pasquale , Di Cagno Raffaella , Vincentini Olimpia , Pinto Daniela , Polo Andrea , Maialetti Francesca , Porrelli Annalisa , Gobbetti Marco
Published: February 2021

We compared raw bee-collected pollen (Raw-BCP), spontaneously fermented BCP (Unstarted-BCP), and BCP fermented with selected microbial starters (Started-BCP) to deepen whether fermentation may favorably affect the nutrients bioaccessibility and functional features of BCP. Underin vitrogastrointestinal batches, the highest serum-availability of phenolic compounds was found in Started-BCP, highlighting the positive effect exerted by selected microbial starters. The same effect was not found in spontaneously fermented BCP. In colon adenocarcinoma cell line-2 (Caco-2) cells stressed by a pro-inflammatory stimulus, the treatment with Started-BCP halted the increase of pro-inflammatory mediator’s level. Started-BCP counteracted efficiently the deleterious effects of inflammatory stimuli on the integrity of the Caco-2 cells monolayer and its barrier function. Started-BCP successfully counteracted the H2O2-induced intracellular accumulation of reactive oxygen species (ROS) in Caco-2 cells. A protective role against lipopolysaccharide (LPS)-induced inflammation was exerted by Started-BCP in human keratinocytes. The same protective effects on Caco-2 and keratinocyte cell lines were negligible after treatments with Raw-BCP or Unstarted-BCP.
Identification and Immunocorrelation of Prognosis-Related Genes Associated With Development of Muscle-Invasive Bladder Cancer
Authors: Li Jingxian , Lou Yantao , Li Shuai , Sheng Fei , Liu Shuaibing , Du E. , Zhang Zhihong
Published: February 2021

Improved understanding of the molecular mechanisms and immunoregulation of muscle-invasive bladder cancer (MIBC) is essential to predict prognosis and develop new targets for therapies. In this study, we used the cancer genome atlas (TCGA) MIBC and GSE13507 datasets to explore the differential co-expression genes in MIBC comparing with adjacent non-carcinoma tissues. We firstly screened 106 signature genes by Weighted Gene Co-expression Network Analysis (WGCNA) and further identified 15 prognosis-related genes of MIBC using the univariate Cox progression analysis. Then we systematically analyzed the genetic alteration, molecular mechanism, and clinical relevance of these 15 genes. We found a different expression alteration of 15 genes in MIBC comparing with adjacent non-carcinoma tissues and normal tissues. Meanwhile, the biological functions and molecular mechanisms of them were also discrepant. Among these, we observed the ANLN was highly correlated with multiple cancer pathways, molecular function, and cell components, revealing ANLN may play a pivotal role in MIBC development. Next, we performed a consensus clustering of 15 prognosis-related genes; the results showed that the prognosis, immune infiltration status, stage, and grade of MIBC patients were significantly different in cluster1/2. We further identified eight-genes risk signatures using the least absolute shrinkage and selection operator (LASSO) regression analysis based on the expression values of 15 prognosis-related genes, and also found a significant difference in the prognosis, immune infiltration status, stage, grade, and age in high/low-risk cohort. Moreover, the expression of PD-1, PD-L1, and CTLA4 was significantly up-regulated in cluster1/high-risk-cohort than that in cluster2/low-risk-cohort. High normalized enrichment score of the Mitotic spindle, mTORC1, Complement, and Apical junction pathway suggested that they might be involved in the distinct tumor immune microenvironment (TIME) of cluster1/2 and high-/low-risk-cohort. Our study identified 15 prognosis-related genes of MIBC, provided a feasible stratification method to help for the future immunotherapy strategies of MIBC patients.
Lifestyle Modifications to Help Prevent Headache at a Developmental Age
Authors: Raucci Umberto , Boni Alessandra , Evangelisti Melania , Della Vecchia Nicoletta , Velardi Margherita , Ursitti Fabiana , Terrin Gianluca , Di Nardo Giovanni , Reale Antonino , Villani Alberto , Parisi Pasquale
Published: February 2021

Headache is the world's seventh most significant cause of disability-adjusted-life in people aged between 10 and 14 years. Therapeutic management is based on pharmacological approaches and lifestyle recommendations. Many studies show associations between each migraine-promoting lifestyle, behavioral triggers, frequency, and intensity of headaches. Nevertheless, the overall aspects of this topic lack any definitive evidence. Educational programs advise that pediatric patients who suffer from migraines follow a correct lifestyle and that this is of the utmost importance in childhood, as it will improve quality of life and assist adult patients in avoiding headache chronicity, increasing general well-being. These data are important due to the scarcity of scientific evidence on drug therapy for prophylaxis during the developmental age. The “lifestyle recommendations” described in the literature include a perfect balance between regular sleep and meal, adequate hydration, limited consumption of caffeine, tobacco, and alcohol, regular physical activity to avoid being overweight as well as any other elements causing stress. The ketogenic diet is a possible new therapeutic strategy for the control of headache in adults, however, the possible role of dietary factors requires more specific studies among children and adolescents. Educational programs advise that the improvement of lifestyle as a central element in the management of pediatric headache will be of particular importance in the future to improve the quality of life of these patients and reduce the severity of cephalalgic episodes and increase their well-being in adulthood. The present review highlights how changes in different aspects of daily life may determine significant improvements in the management of headaches in people of developmental age.
The Effect of Perturbation-Based Balance Training and Conventional Intensive Balance Training on Reactive Stepping Ability in Individuals With Incomplete Spinal Cord Injury or Disease: A Randomized Clinical Trial
Authors: Unger Janelle , Chan Katherine , Lee Jae W. , Craven B. Catharine , Mansfield Avril , Alavinia Mohammad , Masani Kei , Musselman Kristin E.
Published: February 2021

Introduction: Impaired balance leads to falls in individuals with motor incomplete spinal cord injury or disease (iSCI/D). Reactive stepping is a strategy used to prevent falls and Perturbation-based Balance Training (PBT) can improve this ability.

Objective: The objective of this study was to determine if PBT results in greater improvements in reactive stepping ability than frequency-matched Conventional Intensive Balance Training (CIBT) in adults with iSCI/D.

Design: Randomized clinical trial.

Setting: Tertiary SCI/D rehabilitation center.

Participants: Twenty-one adults with chronic (>1 year) iSCI/D were randomized. Due to one drop out 20 participants completed the study.

Methods: Participants were randomly allocated to complete either PBT or CIBT three times per week for 8 weeks. Both programs included challenging static and dynamic balance tasks, but the PBT group also experienced manual external balance perturbations.

Main Outcome Measures: Assessments of reactive stepping ability using the Lean-and-Release test were completed at baseline, and after 4 and 8 weeks of training, and 3 and 6 months after training completion. A blinded assessor evaluated secondary outcomes.

Results: Twenty-five participants were screened and 21 consented; one withdrew. Ten PBT and 10 CIBT participants were included in analyses. Across all participants there were improvements in reactive stepping ability (p = 0.049), with retention of improvements at follow up assessments. There were no differences in reactive stepping ability between groups [median (interquartile range): PBT 0.08 (0.68); CIBT 0.00 (0.22)]. One participant in the PBT group experienced a non-injurious fall during training.

Conclusions: Balance training is beneficial for individuals with iSCI/D, but the addition of manual perturbations (i.e., PBT) did not prove advantageous for performance on a measure of reactive stepping ability.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02960178.
Harnessing Neuroimaging to Reduce Socioeconomic Disparities in Chronic Disease: A Conceptual Framework for Improving Health Messaging
Authors: Brosso Samantha N. , Sheeran Paschal , Lazard Allison J. , Muscatell Keely A.
Published: February 2021

Socioeconomic status (SES)-related health disparities persist for numerous chronic diseases, with lower-SES individuals exhibiting greater risk of morbidity and mortality compared to their higher-SES counterparts. One likely contributor is disparities in health messaging efforts, which are currently less effective for motivating health behavior change among those lower in SES. Drawing on communication neuroscience and social neuroscience research, we describe a conceptual framework to improve health messaging effectiveness in lower SES communities. The framework is based on evidence that health-message-induced activity in the ventral striatum (VS) and subdivisions of the medial pre-frontal cortex (MPFC) predicts behavior change. Additionally, we draw from social neuroscience work showing that activity in these regions during valuation and the processing of self-related vs. social information, differs as a function of SES. Bringing together these previously disparate lines of work, we argue that health messages emphasizing the benefits to close others (vs. the self) of engaging in behavior change will be more effective among lower SES individuals. We also outline a research agenda based on our framework. Ultimately, we hope that this framework utilizing a “brain-as-predictor” approach generates novel insights about the neural underpinnings of message-induced behavior change among lower SES individuals, and helps to close the gap in SES-based health disparities by harnessing the power of neuroimaging.
A Study Protocol for a Parallel-Designed Trial Evaluating the Impact of Plant-Based Diets in Comparison to Animal-Based Diets on Health Status and Prevention of Non-communicable Diseases—The Nutritional Evaluation (NuEva) Study
Authors: Dawczynski Christine
Published: February 2021

Background and Aims: Currently, there is a continuing upward trend for plant-based lifestyles in Germany and Europe. The implementation of vegetarian and vegan lifestyles is characterized by omitting defined food groups such as fish, meat, sausage (vegetarians), or dairy products and honey (vegans). This carries the risk of an undersupply of valuable nutrients. The NuEva study is designed to examine this hypothesis and to evaluate the impact of plant-based diets on health status and disease risk.

Methods: The NuEva study is a parallel-designed trial with at least 55 participants for each diet (vegetarian, vegan, flexitarian [rare meat/sausage consumption, once or twice per week]), and participants who consume a traditional Western diet as the control group. In the screening period critical nutrients are identified for the studied diets by analysis of a broad spectrum of nutrients in the human samples (fatty acids, vitamins, minerals, trace elements, nutrient metabolites).

Results: Based on the data from the screening period, defined menu plans, ensuring an adequate nutrient intake in accordance with the nutritional guidelines are prepared for each group. The plans are adapted and personalized to individual energy requirements based on the basal metabolic rate and physical activity level. The compliance with the NuEva concept and their impact on nutrient status and cardiovascular risk factors are validated during the intervention period of the NuEva study over 1 year. To investigate the impact of the studied diets on the microbiome, feces samples are collected at the beginning and after the 12 months intervention period (follow up: 12 months).

Conclusion: The NuEva study is designed to investigate the impact of common diets on health and disease status, with focus on prevention of cardiovascular diseases. In addition, the effectiveness of the prepared nutritional coaching strategy, ensuring optimal nutrient intake in accordance with the guidelines, is validated during the intervention period of the NuEva study.

Clinical Trial Registration: Registered under ClinicalTrials.gov Identifier no. NCT03582020.
LncRNA DNAJC3-AS1 Regulates Fatty Acid Synthase via the EGFR Pathway to Promote the Progression of Colorectal Cancer
Authors: Tang Yanyan , Tang Rui , Tang Mengtian , Huang Ping , Liao Zhiqiang , Zhou Jumei , Zhou Lianqing , Su Min , Chen Pan , Jiang Jiarui , Hu Yingbin , Zhou Yujuan , Liao QianJin , Zeng Zhaoyang , Xiong Wei , Chen Junhong , Nie Shaolin
Published: February 2021

Colorectal cancer (CRC) is one of the most common cancers worldwide. Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in tumorigenesis and the development of CRC. By constructing a differential lncRNA expression profile, we screened gene chips and found that DNAJC3-AS1 was highly expressed in CRC tissues and was associated with poor prognosis in patients with CRC. Further, we proved through assays such as wound healing, colony formation, and Cell Counting Kit-8 (CCK8) that interfering with DNAJC3-AS1 could reduce the proliferation, migration, and invasion of CRC cells. Mechanically, we found that DNAJC3-AS1 regulates fatty acid synthase to promote the progression of CRC via the epidermal growth factor receptor/phosphatidylinositol 3-kinase/protein kinase B/nuclear factor κB signaling pathway. Therefore, DNAJC3-AS1 may be a new target for the diagnosis and therapy of CRC.