bluuebunny/crossref_metadata_2025 huggingface dataset:
The CPNE Family and Their Role in Cancers
Authors: Tang Haicheng , Pang Pei , Qin Zhu , Zhao Zhangyan , Wu Qingguo , Song Shu , Li Feng
Published: July 2021

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite significant advances in cancer research and treatment, the overall prognosis of lung cancer patients remains poor. Therefore, the identification for novel therapeutic targets is critical for the diagnosis and treatment of lung cancer. CPNEs (copines) are a family of membrane-bound proteins that are highly conserved, soluble, ubiquitous, calcium dependent in a variety of eukaryotes. Emerging evidences have also indicated CPNE family members are involved in cancer development and progression as well. However, the expression patterns and clinical roles in cancer have not yet been well understood. In this review, we summarize recent advances concerning CPNE family members and provide insights into new potential mechanism involved in cancer development.
An Assessment of the Factors Influencing the Prediction Accuracy of Genomic Prediction Models Across Multiple Environments
Authors: Widener Sarah , Graef George , Lipka Alexander E. , Jarquin Diego
Published: July 2021

The effects of climate change create formidable challenges for breeders striving to produce sufficient food quantities in rapidly changing environments. It is therefore critical to investigate the ability of multi-environment genomic prediction (GP) models to predict genomic estimated breeding values (GEBVs) in extreme environments. Exploration of the impact of training set composition on the accuracy of such GEBVs is also essential. Accordingly, we examined the influence of the number of training environments and the use of environmental covariates (ECs) in GS models on four subsets of n = 500 lines of the soybean nested association mapping (SoyNAM) panel grown in nine environments in the US-North Central Region. The ensuing analyses provided insights into the influence of both of these factors for predicting grain yield in the most and the least extreme of these environments. We found that only a subset of the available environments was needed to obtain the highest observed prediction accuracies. The inclusion of ECs in the GP model did not substantially increase prediction accuracies relative to competing models, and instead more often resulted in negative prediction accuracies. Combined with the overall low prediction accuracies for grain yield in the most extreme environment, our findings highlight weaknesses in current GP approaches for prediction in extreme environments, and point to specific areas on which to focus future research efforts.
The Potential of Serum Exosomal hsa_circ_0028861 as the Novel Diagnostic Biomarker of HBV-Derived Hepatocellular Cancer
Authors: Wang Yuanxiao , Pei Lin , Yue Zhihong , Jia Mei , Wang Hui , Cao Lin-Lin
Published: July 2021

Hepatitis B virus (HBV)-derived hepatocellular cancer (HCC) is a serious threat to human health, especially in China. There is no highly sensitive and specific HCC biomarker at present, which makes it difficult to detect HCC at the early stage. Serum exosomal circular RNAs (circRNAs) have been reported as novel diagnostic and prognostic biomarkers of cancers. In the present study, we aimed to explore the diagnostic performance of serum exosomal circRNAs for HBV-derived HCC screening. At first, many circRNAs were found to be differentially expressed in the serum exosomes of HCC individuals by microarray analysis. The validation of dysregulated circRNAs by qRT-PCR revealed that serum exosomal hsa_circ_0028861 was decreased in HCC compared to chronic HBV and cirrhosis. Then, hsa_circ_0028861 was identified as a novel biomarker for HCC diagnosis with an area under the ROC curve (AUC) of 0.79 for discriminating HCC from chronic HBV and cirrhosis individuals. Hsa_circ_0028861 was capable of detecting small (AUC = 0.81), early-stage (AUC = 0.82) and AFP-negative [AFP (−)] (AUC = 0.78) tumors as well. The combination of hsa_circ_0028861 and AFP exhibited better diagnostic ability (AUC = 0.86 for discriminating HCC from chronic HBV and cirrhosis). Moreover, bioinformatics prediction suggested that hsa_circ_0028861 might influence HCC progression by regulating its targeted microRNAs (miRNAs) and downstream tumor-related signaling pathways. Collectively, our study reveals a novel diagnostic tool for HBV-derived HCC.
Mononormativity and Related Normative Bias in the UK Immigration System: The Experience of LGBTIQ+ Asylum Seekers
Authors: Gordon-Orr Rose
Published: July 2021

This article examines the impact that different normative understandings of sexuality and relationships have on LGBTIQ+ people’s experience of the UK Immigration System, with a particular focus on mononormative conceptions that privilege forms of coupledom. By examining legal regulations and case judgments, the mononormative bias is shown to disadvantage LGBTIQ+ asylum seekers and make it difficult for those not seen to be in long-term romantic relationships to have their sexuality acknowledged and their claims for asylum upheld. The article considers how mononormativity intersects with heteronormative stereotypes and narrow homonormative prescriptions of gay identity such as “coming out” or expressing particular lifestyle choices. Taken together these normativities combine in a culture of disbelief in the immigration system that negates the self-identification of LGBTIQ+ asylum seekers and refugees by requiring them conform to norms that do not reflect the diversity of queer lives and experiences.
Diagnostic and Therapeutic Approach in a Metastatic Vaginal Adenocarcinoma: A Case Report
Authors: Egger Eva Katharina , Ralser Damian J. , Lindner Kira , Recker Florian , Marinova Milka , Savchenko Oleksandre , Lau Jan-Frederic , Mustea Alexander
Published: July 2021

Background

Vaginal adenocarcinomas (VAC) are most often reported after intrauterine exposition to diethylstilbestrol (DES). Rarely, VACs are reported as a malignant transformation of vaginal adenosis or endometriosis, in the context of chromosomal abnormalities or malformations of the uterus or the vagina. VACs without DES exposition have a poor prognosis and a significantly worse outcome compared to vaginal squamous cell carcinomas or DES-associated VACs.

Objective

Here, we report the case of a primarily metastatic VAC, treated successfully with different lines of chemo-, antiangiogenic, antibody, and immunotherapy.

Case

The 49-year-old patient presented in 5/2018 with a primarily pulmonary metastatic VAC. Significant tumor reduction was seen after six cycles of carboplatin AUC5/paclitaxel 175 mg/m²/bevacizumab 15 mg/kg q3w. Bevacizumab maintenance therapy and later cisplatin mono 50 mg/m² q2w led to local and distant tumor progression. To identify a potential targeted therapy, new tumor biopsies were obtained. Immunohistochemistry revealed ERBB2 expression, and paclitaxel 80 mg/m² weekly plus trastuzumab 4 mg/m² respectively 2 mg/m² q3w was administered. Due to local and pulmonal tumor progression after 6 months and persistent ERBB2 positivity, the therapy was adjusted to trastuzumab emtansine (T-DM1) 3.6 mg/kg q3w; however, the patient remained locally progressive after three cycles of T-DM1 and additionally showed a new bone metastasis. The new tumor biopsies revealed a combined positive score (CPS) of 2 regarding PD-L1, and pembrolizumab 200 mg q3w was initiated. The bone metastasis was radiated and treated with denosumab 120 mg q4w. Extreme tumor regression followed by stable disease was maintained for 9 months. Due to a slow locoregional progress only with new inguinal lymph node and pararectal lymph node metastases, a new tumor biopsy was taken. Molecular profiling showed an ARID1A mutation, a mutational burden of 5.1 mutations per megabase, and no genfusions. Based on these findings, therapy with PD-L1 antibodies, PD-1 antibodies, gemcitabine, or dasatinib was suggested. Therefore, administration of pembrolizumab was continued and local radiation therapy was performed. This led to a decrease in local tumor manifestations and a stable systemic disease.

Conclusion

Our case demonstrates the diagnostic and therapeutic approach in a patient with primary metastatic vaginal adenocarcinoma. By tumorgenetic profiling, different lines of systemic therapy, namely, antiangiogenic therapy, monoclonal antibody therapy, immunotherapy, and local radiation therapy, were identified and successfully administered.
Identification of Disease-Associated Cryptococcal Proteins Reactive With Serum IgG From Cryptococcal Meningitis Patients
Authors: Gressler A. Elisabeth , Volke Daniela , Firacative Carolina , Schnabel Christiane L. , Müller Uwe , Krizsan Andor , Schulze-Richter Bianca , Brock Matthias , Brombacher Frank , Escandón Patricia , Hoffmann Ralf , Alber Gottfried
Published: July 2021

Cryptococcus neoformans, an opportunistic fungal pathogen ubiquitously present in the environment, causes cryptococcal meningitis (CM) mainly in immunocompromised patients, such as AIDS patients. We aimed to identify disease-associated cryptococcal protein antigens targeted by the human humoral immune response. Therefore, we used sera from Colombian CM patients, with or without HIV infection, and from healthy individuals living in the same region. Serological analysis revealed increased titers of anti-cryptococcal IgG in HIV-negative CM patients, but not HIV-positive CM patients, compared to healthy controls. In contrast, titers of anti-cryptococcal IgM were not affected by CM. Furthermore, we detected pre-existing IgG and IgM antibodies even in sera from healthy individuals. The observed induction of anti-cryptococcal IgG but not IgM during CM was supported by analysis of sera fromC. neoformans-infected mice. Stronger increase in IgG was found in wild type mice with high lung fungal burden compared to IL-4Rα-deficient mice showing low lung fungal burden. To identify the proteins targeted by human anti-cryptococcal IgG antibodies, we applied a quantitative 2D immunoproteome approach identifying cryptococcal protein spots preferentially recognized by sera from CM patients or healthy individuals followed by mass spectrometry analysis. Twenty-three cryptococcal proteins were recombinantly expressed and confirmed to be immunoreactive with human sera. Fourteen of them were newly described as immunoreactive proteins. Twelve proteins were classified as disease-associated antigens, based on significantly stronger immunoreactivity with sera from CM patients compared to healthy individuals. The proteins identified in our screen significantly expand the pool of cryptococcal proteins with potential for (i) development of novel anti-cryptococcal agents based on implications in cryptococcal virulence or survival, or (ii) development of an anti-cryptococcal vaccine, as several candidates lack homology to human proteins and are localized extracellularly. Furthermore, this study defines pre-existing anti-cryptococcal immunoreactivity in healthy individuals at a molecular level, identifying target antigens recognized by sera from healthy control persons.
Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease
Authors: Minaga Kosuke , Watanabe Tomohiro , Hara Akane , Yoshikawa Tomoe , Kamata Ken , Kudo Masatoshi
Published: July 2021

Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.
Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19
Authors: Solanich Xavier , Vargas-Parra Gardenia , van der Made Caspar I. , Simons Annet , Schuurs-Hoeijmakers Janneke , Antolí Arnau , del Valle Jesús , Rocamora-Blanch Gemma , Setién Fernando , Esteller Manel , van Reijmersdal Simon V. , Riera-Mestre Antoni , Sabater-Riera Joan , Capellá Gabriel , van de Veerdonk Frank L. , van der Hoven Ben , Corbella Xavier , Hoischen Alexander , Lázaro Conxi
Published: July 2021

Introduction

Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19.

Methods

We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants.

Results

TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect.

Conclusions

This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.
Combining Traditional Taxonomy and Metabarcoding: Assemblage Structure of Nematodes in the Shelf Sediments of the Eastern Antarctic Peninsula
Authors: Pantó Gabriella , Pasotti Francesca , Macheriotou Lara , Vanreusel Ann
Published: July 2021

This study provides a snapshot of the largely understudied meiobenthic and nematode communities in the Prince Gustav Channel (PGC) and Duse Bay (DB). We compared five stations sampled at different water depths along the shelf and investigated their meiobenthic community structure. We approached nematode biodiversity combining traditional taxonomic identification and high throughput sequencing (HTS), with the use of Amplicon Sequence Variants (ASVs). Additionally, we characterized the environment by primary production proxies, grain size and seasonal ice conditions. Our results suggest that the availability of organic matter and its freshness are responsible for the high densities found at all depths. However, potential factors influencing the high local and regional variability of meiofauna density and biodiversity are less clear. A bathymetric transect consisting of three stations in DB (200, 500, and 1,000 m depth) showed increasing pigment concentrations in the first centimeters of the sediment vertical profile with increasing water depth, whereas the meiofauna densities showed the opposite trend. The deepest station of DB seems to function as a sink for fine material as supported by the higher silt fraction and higher organic matter concentrations. When comparing the two basins in the PGC (1,000 and 1,250 m) and the one in DB (1,000 m), differences in terms of environmental variables, meiofaunal densities, and composition were observed. The deepest basin in PGC is located further South (closer to the highly unstable Larsen area), and marked differences with the other basins suggest that it might be experiencing different conditions as a result of its presence near the summer ice margin and its more elongated topography. Both, the shallowest and the deepest stations showed the highest number of unique sequences, suggesting a more biodiverse nematode assemblage. The morphological identification did not show significant differences in the biodiversity of all stations, differently from the ASVs approach. However, the lack of reference sequences in online databases and the thickness of nematode’s cuticule are still important issues to consider as they potentially lead to underestimations of biodiversity and functional traits.
Molecular Commerce on Coral Reefs: Using Metabolomics to Reveal Biochemical Exchanges Underlying Holobiont Biology and the Ecology of Coastal Ecosystems
Authors: Wegley Kelly Linda , Nelson Craig E. , Aluwihare Lihini I. , Arts Milou G. I. , Dorrestein Pieter C. , Koester Irina , Matsuda Shayle B. , Petras Daniel , Quinlan Zachary A. , Haas Andreas F.
Published: July 2021

The rapidly advancing field of metabolomics encompasses a diverse suite of powerful analytical and bioinformatic tools that can help to reveal the diversity and activity of chemical compounds in individual organisms, species interactions, and entire ecosystems. In this perspective we use examples from studies of coral reefs to illustrate ways in which metabolomics has been and can be applied to understand coastal ecosystems. Examples of new insights that can be provided by metabolomics include resolving metabolite exchange between plants, animals and their microbiota, identifying the relevant metabolite exchanges associated with the onset and maintenance of diverse, microbial mutualisms characterizing unknown molecules that act as cues in coral, reproduction, or defining the suites of compounds involved in coral-algal competition and microbialization of algal-dominated ecosystems. Here we outline sampling, analytical and informatic methods that marine biologists and ecologists can apply to understand the role of chemical processes in ecosystems, with a focus on open access data analysis workflows and democratized databases. Finally, we demonstrate how these metabolomics tools and bioinformatics approaches can provide scientists the opportunity to map detailed metabolic inventories and dynamics for a holistic view of the relationships among reef organisms, their symbionts and their surrounding marine environment.
A Drop in the Ocean: Patchy Evidence on the Societal Benefits of Marine Litter Reduction
Authors: Stoever Jana , Rehdanz Katrin , Okoli Ikechukwu Charles
Published: July 2021

The benefits of marine litter reduction to society, which are mostly non-market ones, need to be valued and quantified in monetary terms to be included in cost benefit analyses required by the EU Marine Strategy Framework Directive. This article investigates the extent to which these benefits can be derived from existing studies. We review the available empirical evidence and analyze its key characteristics based on descriptive statistics. Comparing the availability of estimates with the requirements for the EU Member States, we find a striking mismatch between the data available and the information required, which cannot be alleviated by benefit transfer. This finding is valid for both, ex-ante and ex-post, evaluation attempts. We conclude that the evidence available at present is too patchy to derive country-wide policy implications to the extent necessary to comprehensively conduct the evaluations required by the Directive.
Risk Factors for Band Keratopathy in Aphakic Eyes With Silicone Oil Tamponade for Open-Globe Injuries: A Multicenter Case-Control Study
Authors: He Kai , Liao Mengyu , Zhu Yun , Cui Bohao , Chen Haoyu , Wang Ting , Wu Nan , Xie Zhenggao , Luo Jing , Wei Yong , Wang Zhiliang , Zhou Heding , Shen Zhansheng , Yan Hua
Published: July 2021

Band keratopathy (BK) is a common complication in aphakic eyes with silicone oil tamponade for open-globe injury (OGI), characterized by the grayish-white opacities in the cornea, resulting in a significantly decreased vision when extending to the visual axis. To identify the risk factors for BK in aphakic eyes following vitreoretinal surgical treatment with silicone oil tamponade for OGIs, we performed a multicenter case-control study. The incidence of BK was 28% (28/100 eyes). The multivariate binary logistic regression revealed the silicone oil retention time (SORT) ≥6 months and zone III injury were significant risk factors for BK. From the hierarchical interaction, SORT ≥6 months had a significant risk for BK in eyes with rupture, aniridia, and zone III injury, while zone III injury had a significant risk for BK in eyes with rupture, incomplete/complete iris, and SORT ≥6 months. By using restricted cubic splines with three knots at the 25th, 50th, and 75th centiles to model the association of SORT with BK, we also found a marked increase in the risk for BK at ≥10 months and a slow increase after 6 months, but almost stable within 4–6 months.
Differential Association of Viral Dynamics With Disease Severity Depending on Patients’ Age Group in COVID-19
Authors: Kim Yuri , Cheon Shinhyea , Jeong Hyeongseok , Park Uni , Ha Na-Young , Lee Jooyeon , Sohn Kyung Mok , Kim Yeon-Sook , Cho Nam-Hyuk
Published: July 2021

Despite a clear association of patient’s age with COVID-19 severity, there has been conflicting data on the association of viral load with disease severity. Here, we investigated the association of viral load dynamics with patient’s age and severity of COVID-19 using a set of respiratory specimens longitudinally collected (mean: 4.8 times/patient) from 64 patients with broad distribution of clinical severity and age during acute phase. Higher viral burden was positively associated with inflammatory responses, as assessed by IL-6, C-reactive protein, and lactate dehydrogenase levels in patients’ plasma collected on the same day, primarily in the younger cohort (≤59 years old) and in mild cases of all ages, whereas these were barely detectable in elderly patients (≥60 years old) with critical disease. In addition, viral load dynamics in elderly patients were not significantly different between mild and critical cases, even though more enhanced inflammation was consistently observed in the elderly group when compared to the younger group during the acute phase of infection. The positive correlation of viral load with disease severity in younger patients may explain the increased therapeutic responsiveness to current antiviral drugs and neutralizing antibody therapies in younger patients compared to elderly patients. More careful intervention against aging-associated inflammation might be required to mitigate severe disease progression and reduce fatality in COVID-19 patients more than 60 years old.
Effects of an Enhanced Training on Primary Care Providers Knowledge, Attitudes, Service and Skills of Dementia Detection: A Cluster Randomized Trial
Authors: Lv Xiaozhen , Zhao Mei , Li Tao , Yuan Changzheng , Zhang Haifeng , Pu Chengcheng , Li Zhiying , Zhang Na , Yu Xin , Wang Huali
Published: July 2021

Background: Effective training programs for primary care providers (PCPs) to support dementia detection are needed, especially in developing countries. This study aimed to investigate the effect of an enhanced training on the competency and service of PCPs for dementia detection.

Methods: We conducted a cluster randomized trial in Beijing, China. Community healthcare centers (CHCs) located in Fengtai or Fangshan District were eligible. The enrolled CHCs in each district were randomly assigned to the standard or the enhanced training group at a 1:1 ratio. PCPs serving older adults in enrolled CHCs were eligible to participate. The standard training group received three-hour didactic lectures, three monthly supervisions, 3 months of online support and dementia screening packages. The enhanced training group additionally received three monthly face-to-face supervisions and 3 months of online support. The participants became aware of their group membership at the end of the standard training. The knowledge, attitudes, service, and skills regarding dementia detection were assessed using questionnaires and submitted dementia detection records, respectively.

Results: A total of 23 and 21 CHCs were randomly assigned to the standard and the enhanced training group, respectively, and 58 participants from 20 CHCs assigned to the standard training group and 48 from 16 CHCs assigned to the enhanced training group were included in the final analysis (mean age 37.5 years, and 67.0% women). A significant increase in the knowledge score was found in both groups, but the increase was similar in the two groups (P = 0.262). The attitude score remained stable in both groups, and no between-group difference was found. Compared with the baseline, both groups reported an increase in dementia detection service, especially the enhanced training group (24.1% to 31.0% in the standard training group and 14.6% to 45.8% in the enhanced training group). The completion rate and accuracy of submitted dementia detection records in the enhanced training group were both significantly higher than those in the standard training group (both P < 0.001).

Conclusion: The enhanced training had similar effect on the knowledge of PCPs comparing with the standard training, but was better on continuous service and skills of PCPs related to dementia detection.

Trial registration:www.ClinicalTrials.gov, identifier: NCT02782000. Registration date: May 2016. The trial was completed in July 2017.
Evaluation of Revascularization in Different Suzuki Stages of Ischemic Moyamoya Disease by Whole-Brain CT Perfusion
Authors: Han Qingdong , Yao Feirong , Zhang Zhengyu , Huang Yabo
Published: July 2021

Objective: This study compared the clinical features and hemodynamic characteristics of patients in different Suzuki stages of ischemic moyamoya disease (iMMD) before and after treatment with extracranial-intracranial (EC-IC) bypass surgery combined with encephalo-duro-myo-synangiosis and whole-brain computed tomography perfusion (WB-CTP).

Methods: A total of 126 patients in different Suzuki stages (II, III, IV, and V) of iMMD who underwent bypass surgery from April 2013 to August 2020 were included in this retrospective study. MIStar automatic analysis of Whole brain CT perfusion imaging software (WB-CTP, Apollo Medical Imaging Technology, Melbourne, Australia) was used. The patients also underwent WB-CTP 1 day before and 1 week and 3 months after the surgery. The relationships between hemodynamic parameters in WB-CTP including delay time (DT) > 3 s, relative cerebral blood flow (rCBF) < 30%, mismatch and mismatch ratio, and clinical outcomes were evaluated for different Suzuki stages, with comparisons between early (II and III) and late (IV and V) stages.

Results: Combined bypass surgery was performed in 161 hemispheres of 126 patients with iMMD. Brain volume with DT > 3 s was decreased 1 week (51.5 ± 11.8 ml, P < 0.05) and 3 months (41.5 ± 10.7 ml, P < 0.05) after bypass compared to 1 day before bypass (104.7 ± 15.1 ml) in early-stage patients. In late-stage patients, the volume was increased 1 week after bypass compared to the preoperative value (154.3 ± 14.7 vs. 118.3 ± 19.1 ml, P < 0.05). Preoperative brain volume with rCBF < 30% was lower (9.8 ± 3.9 vs. 33.5 ± 11.0 ml) whereas preoperative mismatch ratio was higher (11.2 ± 2.8 vs. 3.6 ± 1.6) in early-stage as compared to late-stage patients (both P < 0.05). A higher modified Rankin scale score (0–1) was achieved by early-stage patients than by those in the late stage (93.8 vs. 80.4%, P < 0.05) at the 3-month follow-up.

Conclusions: WB-CTP is useful for assessing the effectiveness of combined bypass/revascularization in different Suzuki stages of iMMD. Patients in the early stage of disease with higher preoperative brain volume with DT > 3 s and mismatch ratio show greater improvements in hemodynamic parameters and fewer postoperative complications associated with hemodynamic disturbance following bypass than patients in the late stage. Preoperative mismatch ratio can serve as a marker for assessing the status of collateral circulation in different Suzuki stages of iMMD.
Temporal Dynamics of Corticomuscular Coherence Reflects Alteration of the Central Mechanisms of Neural Motor Control in Post-Stroke Patients
Authors: Fauvet Maxime , Gasq David , Chalard Alexandre , Tisseyre Joseph , Amarantini David
Published: July 2021

The neural control of muscular activity during a voluntary movement implies a continuous updating of a mix of afferent and efferent information. Corticomuscular coherence (CMC) is a powerful tool to explore the interactions between the motor cortex and the muscles involved in movement realization. The comparison of the temporal dynamics of CMC between healthy subjects and post-stroke patients could provide new insights into the question of how agonist and antagonist muscles are controlled related to motor performance during active voluntary movements. We recorded scalp electroencephalography activity, electromyography signals from agonist and antagonist muscles, and upper limb kinematics in eight healthy subjects and seventeen chronic post-stroke patients during twenty repeated voluntary elbow extensions and explored whether the modulation of the temporal dynamics of CMC could contribute to motor function impairment. Concomitantly with the alteration of elbow extension kinematics in post-stroke patients, dynamic CMC analysis showed a continuous CMC in both agonist and antagonist muscles during movement and highlighted that instantaneous CMC in antagonist muscles was higher for post-stroke patients compared to controls during the acceleration phase of elbow extension movement. In relation to motor control theories, our findings suggest that CMC could be involved in the online control of voluntary movement through the continuous integration of sensorimotor information. Moreover, specific alterations of CMC in antagonist muscles could reflect central command alterations of the selectivity in post-stroke patients.
Brain and Retinal Abnormalities in the 5xFAD Mouse Model of Alzheimer's Disease at Early Stages
Authors: Zhang Mengrong , Zhong Liting , Han Xiu , Xiong Guoyin , Xu Di , Zhang Sensen , Cheng Haiyang , Chiu Kin , Xu Ying
Published: July 2021

One of the major challenges in treating Alzheimer's disease (AD) is its early diagnosis. Increasing data from clinical and animal research indicate that the retina may facilitate an early diagnosis of AD. However, a previous study on the 5xFAD (a fast AD model), showing retinal changes before those in the brain, has been questioned because of the involvement of the retinal degeneration allele Pde6brd1. Here, we tested in parallel, at 4 and 6 months of age, both the retinal and the brain structure and function in a 5xFAD mouse line that carries no mutation of rd1. In the three tested regions of the 5xFAD brain (hippocampus, visual cortex, and olfactory bulb), the Aβ plaques were more numerous than in wild-type (WT) littermates already at 4 months, but deterioration in the cognitive behavioral test and long-term potentiation (LTP) lagged behind, showing significant deterioration only at 6 months. Similarly in the retina, structural changes preceded functional decay. At 4 months, the retina was generally normal except for a thicker outer nuclear layer in the middle region than WT. At 6 months, the visual behavior (as seen by an optomotor test) was clearly impaired. While the full-field and pattern electroretinogram (ERG) responses were relatively normal, the light responses of the retinal ganglion cells (measured with multielectrode-array recording) were decreased. Structurally, the retina became abnormally thick with few more Aβ plaques and activated glia cells. In conclusion, the timeline of the degenerative processes in the retina and the brain is similar, supporting the use of non-invasive methods to test the retinal structure and function to reflect changes in the brain for early AD diagnosis.
Mesoscopic Mapping of Ictal Neurovascular Coupling in Awake Behaving Mice Using Optical Spectroscopy and Genetically Encoded Calcium Indicators
Authors: Yang Fan , Li Jing , Song Yan , Zhao Mingrui , Niemeyer James E. , Luo Peijuan , Li Dan , Lin Weihong , Ma Hongtao , Schwartz Theodore H.
Published: July 2021

Unambiguously identifying an epileptic focus with high spatial resolution is a challenge, especially when no anatomic abnormality can be detected. Neurovascular coupling (NVC)-based brain mapping techniques are often applied in the clinic despite a poor understanding of ictal NVC mechanisms, derived primarily from recordings in anesthetized animals with limited spatial sampling of the ictal core. In this study, we used simultaneous wide-field mesoscopic imaging of GCamp6f and intrinsic optical signals (IOS) to record the neuronal and hemodynamic changes during acute ictal events in awake, behaving mice. Similar signals in isoflurane-anesthetized mice were compared to highlight the unique characteristics of the awake condition. In awake animals, seizures were more focal at the onset but more likely to propagate to the contralateral hemisphere. The HbT signal, derived from an increase in cerebral blood volume (CBV), was more intense in awake mice. As a result, the “epileptic dip” in hemoglobin oxygenation became inconsistent and unreliable as a mapping signal. Our data indicate that CBV-based imaging techniques should be more accurate than blood oxygen level dependent (BOLD)-based imaging techniques for seizure mapping in awake behaving animals.
Characterization of Genetic Variants in the SLC5A5 Gene and Associations With Breast Milk Iodine Concentration in Lactating Women of African Descent: The NUPED Study
Authors: Siro Sicelosethu S. , Baumgartner Jeannine , Schoonen Maryke , Ngounda Jennifer , Malan Linda , Symington Elizabeth A. , Smuts Cornelius M. , Zandberg Lizelle
Published: July 2021

Background: The sodium iodide symporter is responsible for the transfer of iodine into breast milk and is encoded for by the SLC5A5 gene. The role of genetic variants in the SLC5A5 gene locus in relation to the transfer of iodine from plasma into breast milk in healthy lactating individuals has, to our knowledge, not been explored.

Objective: To identify and characterize possible genetic variants of the SLC5A5 gene in women of African descent living in urban South Africa, and to study associations with breast milk iodine concentrations (BMIC) in lactating women.

Methods: This study is affiliated to the Nutrition during Pregnancy and Early Development (NuPED) cohort study (n = 250 enrolled pregnant women). In a randomly selected sub-sample of 32 women, the SLC5A5 gene was sequenced to identify known and novel variants. Of the identified variants, genotyping of selected variants was performed in all pregnant women who gave consent for genetic analyses (n = 246), to determine the frequency of the variants in the study sample. Urinary iodine concentration (UIC) in spot urine samples and BMIC were measured to determine iodine status. Associations of SLC5A5 genetic variants with BMIC were studied in lactating women (n = 55).

Results: We identified 27 variants from sequencing of gene exomes and 10 variants were selected for further study. There was a significant difference in BMIC between the genotypes of the rs775249401 variant (P = 0.042), with the homozygous GG group having lower BMIC [86.8 (54.9–167.9) μg/L] compared to the (A) allele carriers rs775249401(AG+AA) [143.9 (122.4–169.3) μg/L] (P = 0.042). Of the rs775249401(GG), 49% had UIC <100 μg/L and 61% had BMIC <100 μg/L. On the other hand, 60% of the rs775249401(AG+AA) carriers had UIC <100 μg/L, and none had a BMIC <100 μg/L.

Conclusion: Our results suggest that A-allele carriers of rs775249401(AG+AA) are likely to have higher iodine transfer into breast milk compared to the homozygous GG counterparts. Thus, genetic variations in the SLC5A5 gene may play an important role in the transfer of iodine from plasma into breast milk and may partially explain inter-individual variability in BMIC.
Risk–Benefit Assessment of Consumption of Rice for Adult Men in China
Authors: Fang Haiqin , Zhang Quantao , Zhang Shengjie , Zhang Tongwei , Pan Feng , Cui Yufeng , Thomsen Sofie Theresa , Jakobsen Lea S. , Liu Aidong , Pires Sara M.
Published: July 2021

Objective: To evaluate the health impact of current and alternative patterns of rice consumption in Chinese adult men (40–79 years of age).

Methods: We applied a risk–benefit assessment (RBA) model that took into account the health effects of selenium (Se), cadmium (Cd), and inorganic arsenic (i-As). The health effects included the prevention of prostate cancer associated with exposure to Se, and an increased risk of lung, bladder, and skin cancer for i-As and chronic kidney disease (CKD) for Cd. We defined the baseline scenario (BS) as the current individual mean daily consumption of rice in the population of interest and two alternative scenarios (AS): AS1 = 50 g/day and AS2 = 200 g/day. We estimated the health impact for different age groups in terms of change in Disability-Adjusted Life Years (ΔDALY).

Results: The BS of rice consumption was 71.5–105.4 g/day in different age groups of adult men in China. We estimated that for AS1, the mean ΔDALY was −2.76 to 46.2/100,000 adult men of 40–79 years old. For AS2, the mean ΔDALY was 41.3 to 130.8/100,000 individuals in this population group.

Conclusion: Our results showed that, based on associated exposure to selenium, cadmium, and i-As in rice, the current consumption of rice does not pose a risk to adult men in China. Also, a lower (50 g/day) or higher (200 g/day) rice consumption will not bring larger beneficial effects.
GMFG Has Potential to Be a Novel Prognostic Marker and Related to Immune Infiltrates in Breast Cancer
Authors: Yang Yan , He Xin , Tang Qian-Qian , Shao You-Cheng , Song Wen-Jing , Gong Peng-Ju , Zeng Yi-Fan , Huang Si-Rui , Zhou Jiang-Yao , Wan Hui-Fang , Wei Lei , Zhang Jing-Wei
Published: July 2021

A growing amount of evidence has indicated immune genes perform a crucial position in the development and progression of breast cancer microenvironment. The purpose of our study was to identify immunogenic prognostic marker and explore potential regulatory mechanisms for breast cancer. We identified the genes related to ImmuneScore using ESTIMATE algorithm and WGCNA analysis, and we identified the differentially expressed gene (DEGs). Then, Glia maturation factor γ (GMFG) was determined as a predictive factor by intersecting immune-related genes with DEGs and survival analysis. We found the expression of GMFG was lower in breast cancer tissues compared with normal breast tissues, which was further verified by immunohistochemical (IHC). Moreover, the decreased expression of GMFG was significantly related to the poor prognosis. Besides, the expression of GMFG was related to the age, ER status, PR status, HER2 status and tumor size, which further suggested that the expression of GMFG was correlated with the subtype and the growth of tumor. The univariate and multivariate Cox regression analyses revealed that age, stage, the expression level of GMFG and radiotherapy were independent factors for predicting the prognosis of breast cancer patients. Subsequently, a prognostic model to predict the 3-year, 5-year and 10-year overall survival rate was developed based on the above four variables, and visualized as a nomogram. The values of area under the curve of the nomogram at 3-year, 5-year and 10-year were 0.897, 0.873 and 0.922, respectively, which was higher than stage in prognostic accuracy. In addition, we also found that GMFG expression level was correlated with sensitivity of some breast cancer chemotherapy drugs. Furthermore, the results of GSEA indicated immune-related pathways were mainly enriched in GMFG-high-expression group. CIBERSORT analysis for the proportion of tumor-infiltrating immune cells (TIICs) suggested that expression of GMFG was positively association with multiple kinds T-cell in BC. Among them, CD8+ T cells had the strongest correlation with GMFG expression, which revealed that GMFG might has an antitumor effect by increasing the infiltration of CD8+ T cells in breast cancer. Accordingly, GMFG has the potential to become a novel immune biomarker for the diagnosis and treatment of breast cancer.
Multi-Omic Analyses of the m5C Regulator ALYREF Reveal Its Essential Roles in Hepatocellular Carcinoma
Authors: Xue Chen , Zhao Yalei , Li Ganglei , Li Lanjuan
Published: July 2021

The ALYREF protein acts as a crucial epigenetic regulator in several cancers. However, the specific expression levels and functional roles of ALYREF in cancers are largely unknown, including for hepatocellular carcinoma (HCC). In a pan-cancer tissue analysis that included HCC, we assessed the expression of ALYREF compared to normal tissues using The Cancer Genome Atlas database. Associations between ALYREF gene expression and the clinical characteristics of HCC patient samples were assessed using the UALCAN database. Kaplan-Meier plots were performed to assess HCC patient prognosis, and the TIMER database was used to explore associations between ALYREF expression and immune-cell infiltrations. The same methods were used to assess eIF4A3 expression in HCC patient samples. In addition, ALYREF- and elF4A3-related differentially expressed genes (DEGs) were determined using LinkedOmics, associated protein functionalities were predicted for positively associated DEGs, and both the TargetScan and miRDB databases were used to predict potential upstream miRNAs for control of ALYREF and eIF4A3 expression. We found that ALYREF gene expression was dysregulated in several cancers and was significantly elevated in HCC patient tissue samples and HCC cell lines. The overexpression of ALYREF was significantly related to both advanced tumor-node-metastasis stages and poor HCC prognosis. Furthermore, we found that eIF4A3 expression was significantly correlated with ALYREF expression, and that upregulated eIF4A3 was significantly associated with poor HCC patient outcomes. In the protein-protein interaction network, we identified eight hub genes based on the positively associated DEGs in common between ALYREF and eIF4A3, and the high expression levels of these hub genes were positively associated with patient clinical outcomes. In addition, we identified miR-4666a-5p and miR-6124 as potential regulators of ALYREF and eIF4A3 expression. These findings suggest that increased ALYREF expression may function as a novel biomarker for both HCC diagnosis and prognosis predictions.
Harnessing Lactate Metabolism for Radiosensitization
Authors: Liu Kevin X. , Everdell Emily , Pal Sharmistha , Haas-Kogan Daphne A. , Milligan Michael G.
Published: July 2021

Cancer cells rewire their metabolism to promote cell proliferation, invasion, and metastasis. Alterations in the lactate pathway have been characterized in diverse cancers, correlate with outcomes, and lead to many downstream effects, including decreasing oxidative stress, promoting an immunosuppressive tumor microenvironment, lipid synthesis, and building chemo- or radio-resistance. Radiotherapy is a key modality of treatment for many cancers and approximately 50% of patients with cancer will receive radiation for cure or palliation; thus, overcoming radio-resistance is important for improving outcomes. Growing research suggests that important molecular controls of the lactate pathway may serve as novel therapeutic targets and in particular, radiosensitizers. In this mini-review, we will provide an overview of lactate metabolism in cancer, discuss three important contributors to lactate metabolism (lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier), and present data that inhibition of these three pathways can lead to radiosensitization. Future research is needed to further understand critical regulators of lactate metabolism and explore clinical safety and efficacy of inhibitors of lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier alone and in combination with radiation.
Targeting NUFIP1 Suppresses Growth and Induces Senescence of Colorectal Cancer Cells
Authors: Shen Aling , Wu Meizhu , Liu Liya , Chen Youqin , Chen Xiaoping , Zhuang Mingkai , Xie Qiurong , Cheng Ying , Li Jiapeng , Shen Zhiqing , Wei Lihui , Chu Jianfeng , Sferra Thomas J. , Zhang Xiuli , Xu Nanhui , Li Li , Peng Jun , Chen Fenglin
Published: July 2021

NUFIP1 is an RNA-binding protein that interacts with fragile X mental retardation protein (FMRP) in the messenger ribonucleoprotein particle (mRNP). We previously showed that NUFIP1 was upregulated in colorectal cancer (CRC), but how the protein may contribute to the disease and patient prognosis is unknown. Here we combine database analysis, microarray, quantitative PCR, and immunohistochemistry of patients’ samples to confirm our previous findings on NUFIP1 overexpression in CRC, and to reveal that increased expression of NUFIP1 in CRC tissues correlated with worse overall, recurrence-free, event-free and disease-free survival in patients, as well as with more advanced CRC clinicopathological stage. Loss of function analysis demonstrated that NUFIP1 knockdown suppressed cell growth in vitro and in vivo, inhibited cell viability and survival, and induced cell cycle arrest and apoptosis in vitro, as well as up-regulated Bax and down-regulated Bcl-2 protein expression. In addition, as a natural anticancer triterpene from various fruits and vegetables, ursolic acid (UA) treatment suppressed cell proliferation, down-regulated NUFIP1 protein expression, and further enhanced the effects of NUFIP1 knockdown in CRC cells in vitro. NUFIP1 knockdown up-regulated the expression of 136 proteins, down-regulated the expression of 41 proteins, and enriched multiple signaling pathways including the senescence-associated heterochromatin foci (SAHF) pathway. Furthermore, NUFIP1 knockdown enhanced the expression of senescence-associated-β-galactosidase (SA-β-gal), the SAHF markers HP1γ and trimethylation (H3k9me3), and the senescence-related protein HMGA2, as well as both p53 and its downstream p21 protein expression. Our findings suggest that NUFIP1 is overexpressed in CRC and correlates with disease progression and poor patient survival. NUFIP1 may exert oncogenic effects partly by altering senescence. UA may show potential to treat CRC by down-regulating NUFIP1.