bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying Biomarkers from Transcriptomic Signatures in Renal Allograft Biopsies Using Deceased and Living Donors
Authors: Yang Bin , Sylvius Nicolas , Luo Jinli , Yang Cheng , Da Zhanyun , Crotty Charlottelrm , Nicholson Michael L.
Published: July 2021

The survival of transplant kidneys using deceased donors (DD) is inferior to living donors (LD). In this study, we conducted a whole-transcriptome expression analysis of 24 human kidney biopsies paired at 30 minutes and 3 months post-transplantation using DD and LD. The transcriptome profile was found significantly different between two time points regardless of donor types. There were 446 differentially expressed genes (DEGs) between DD and LD at 30 minutes and 146 DEGs at 3 months, with 25 genes common to both time points. These DEGs reflected donor injury and acute immune responses associated with inflammation and cell death as early as at 30 minutes, which could be a precious window of potential intervention. DEGs at 3 months mainly represented the changes of adaptive immunity, immunosuppressive treatment, remodeling or fibrosis via different networks and signaling pathways. The expression levels of 20 highly DEGs involved in kidney diseases and 10 genes dysregulated at 30 minutes were found correlated with renal function and histology at 12 months, suggesting they could be potential biomarkers. These genes were further validated by quantitative polymerase chain reaction (qPCR) in 24 samples analysed by microarray, as well as in a validation cohort of 33 time point unpaired allograft biopsies. This analysis revealed that SERPINA3, SLPI and CBF were up-regulated at 30 minutes in DD compared to LD, while FTCD and TASPN7 were up-regulated at both time points. At 3 months, SERPINA3 was up-regulated in LD, but down-regulated in DD, with increased VCAN and TIMP1, and decreased FOS, in both donors. Taken together, divergent transcriptomic signatures between DD and LD, and changed by the time post-transplantation, might contribute to different allograft survival of two type kidney donors. Some DEGs including FTCD and TASPN7 could be novel biomarkers not only for timely diagnosis, but also for early precise genetic intervention at donor preservation, implantation and post-transplantation, in particular to effectively improve the quality and survival of DD.
Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells
Authors: Matsuda Yoshiko , Watanabe Takeshi , Li Xiao-Kang
Published: July 2021

Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.
Prognostic Value of Tumor-Infiltrating Lymphocytes and Tertiary Lymphoid Structures in Epstein-Barr Virus-Associated and -Negative Gastric Carcinoma
Authors: Cheng Na , Li Peng , Cheng Huanhuan , Zhao Xiaoxiao , Dong Min , Zhang Yiwang , Zhao Peizhen , Chen Jianning , Shao Chunkui
Published: July 2021

Background

Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response against cancer and tertiary lymphoid structures (TLS) may contribute to lymphocytes recruitment. Both of them have been reported as potential prognostic parameters in some human malignancies. However, the roles of TILs, TLS, and their correlation in Epstein-Barr Virus-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC) are largely unknown.

Methods

To observe the correlation among TILs, TLS, and clinicopathological characteristics and their prognostic significance in EBVaGC and EBVnGC, respectively. TILs and TLS were assessed by morphology and/or immunohistochemistry, and accompanied by clinicopathological analysis from 846 gastric cancer patients in multiple institutions.

Results

Forty-two (5.0%) cases of EBVaGC and 804 cases of EBVnGC were identified byin situhybridization, respectively. For EBVnGC, higher TILs grade was correlated with TLS-present. EBVnGC patients with high TILs grade and TLS-present exhibited survival benefits. TILs (P= 0.001) and TLS (P= 0.003), especially TILs & TLS (P< 0.001) were independent prognostic factors in EBVnGC. A nomogram was constructed and validated for predicting the probability of overall survival and performed well with a good calibration. No significant prognostic value was detected in EBVaGC.

Conclusion

TILs and TLS, especially TILs & TLS were promising prognostic indicators for overall survival in EBVnGC. TILs and TLS were highly overlapping in their extent and prognostic abilities, and may be considered as a coindicator of prognosis of gastric cancer. The evaluations of TILs and TLS are simple and can be assessed routinely in pathological diagnosis.
Detection of Immune Checkpoint Receptors – A Current Challenge in Clinical Flow Cytometry
Authors: Shibru Benjamin , Fey Katharina , Fricke Stephan , Blaudszun André-René , Fürst Friederike , Weise Max , Seiffert Sabine , Weyh Maria Katharina , Köhl Ulrike , Sack Ulrich , Boldt Andreas
Published: July 2021

Immunological therapy principles are increasingly determining modern medicine. They are used to treat diseases of the immune system, for tumors, but also for infections, neurological diseases, and many others. Most of these therapies base on antibodies, but small molecules, soluble receptors or cells and modified cells are also used. The development of immune checkpoint inhibitors is amazingly fast. T-cell directed antibody therapies against PD-1 or CTLA-4 are already firmly established in the clinic. Further targets are constantly being added and it is becoming increasingly clear that their expression is not only relevant on T cells. Furthermore, we do not yet have any experience with the long-term systemic effects of the treatment. Flow cytometry can be used for diagnosis, monitoring, and detection of side effects. In this review, we focus on checkpoint molecules as target molecules and functional markers of cells of the innate and acquired immune system. However, for most of the interesting and potentially relevant parameters, there are still no test kits suitable for routine use. Here we give an overview of the detection of checkpoint molecules on immune cells in the peripheral blood and show examples of a possible design of antibody panels.
Lipopolysaccharide Derived From the Lymphoid-Resident Commensal Bacteria Alcaligenes faecalis Functions as an Effective Nasal Adjuvant to Augment IgA Antibody and Th17 Cell Responses
Authors: Wang Yunru , Hosomi Koji , Shimoyama Atsushi , Yoshii Ken , Nagatake Takahiro , Fujimoto Yukari , Kiyono Hiroshi , Fukase Koichi , Kunisawa Jun
Published: July 2021

Alcaligenes spp., including A. faecalis, is a gram-negative facultative bacterium uniquely residing inside the Peyer’s patches. We previously showed that A. faecalis-derived lipopolysaccharides (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 to activate dendritic cells and shows adjuvant activity by enhancing IgG and Th17 responses to systemic vaccination. Here, we examined the efficacy of Alcaligenes LPS as a nasal vaccine adjuvant. Nasal immunization with ovalbumin (OVA) plus Alcaligenes LPS induced follicular T helper cells and germinal center formation in the nasopharynx-associated lymphoid tissue (NALT) and cervical lymph nodes (CLNs), and consequently enhanced OVA-specific IgA and IgG responses in the respiratory tract and serum. In addition, nasal immunization with OVA plus Alcaligenes LPS induced OVA-specific T cells producing IL-17 and/or IL-10, whereas nasal immunization with OVA plus cholera toxin (CT) induced OVA-specific T cells producing IFN-γ and IL-17, which are recognized as pathogenic type of Th17 cells. In addition, CT, but not Alcaligenes LPS, promoted the production of TNF-α and IL-5 by T cells. Nasal immunization with OVA plus CT, but not Alcaligenes LPS, led to increased numbers of neutrophils and eosinophils in the nasal cavity. Together, these findings indicate that the benign nature of Alcaligenes LPS is an effective nasal vaccine adjuvant that induces antigen-specific mucosal and systemic immune responses without activation of inflammatory cascade after nasal administration.
Circulating Plasmacytoid and Conventional Dendritic Cells Are Numerically and Functionally Deficient in Patients With Scrub Typhus
Authors: Kang Seung-Ji , Park Ki-Jeong , Jin Hye-Mi , Cho Young-Nan , Oh Tae Hoon , Kim Seong Eun , Kim Uh Jin , Park Kyung-Hwa , Jung Sook-In , Kim Tae-Ok , Kim Hyo Shin , Jo Young-Goun , Ju Jae Kyun , Kee Seung-Jung , Park Yong-Wook
Published: July 2021

Background

Dendritic cells (DCs) are specialized antigen-presenting cells known to bridge innate and adaptive immune reactions. However, the relationship between circulating DCs and Orientia tsutsugamushi infection is unclear. Therefore, this study aimed to examine the level and function of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), two subsets of circulating DCs, in scrub typhus patients.

Methods

The study included 35 scrub typhus patients and 35 healthy controls (HCs). pDC and cDC levels, CD86 and CD274 expression, and cytokine levels were measured using flow cytometry.

Results

Circulating pDC and cDC levels were found to be significantly reduced in scrub typhus patients, which were correlated with disease severity. The patients displayed increased percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs in the peripheral blood. The alterations in the levels and surface phenotypes of pDCs and cDCs were recovered in the remission state. In addition, the production of interferon (IFN)-α and tumor necrosis factor (TNF)-α by circulating pDCs, and interleukin (IL)-12 and TNF-α by circulating cDCs was reduced in scrub typhus patients. Interestingly, our in vitro experiments showed that the percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs were increased in cultures treated with cytokines including IFN-γ, IL-12, and TNF-α.

Conclusions

This study demonstrates that circulating pDCs and cDCs are numerically deficient and functionally impaired in scrub typhus patients. In addition, alterations in the expression levels of surface phenotypes of pDCs and cDCs could be affected by pro-inflammatory cytokines.
Summertime Amino Acid and Carbohydrate Patterns in Particulate and Dissolved Organic Carbon Across Fram Strait
Authors: Grosse Julia , Nöthig Eva-Maria , Torres-Valdés Sinhué , Engel Anja
Published: July 2021

Amino acids (AA) and carbohydrates (CHO) are important components of the marine organic carbon cycle. Produced mainly by phytoplankton as part of the particulate organic carbon (POC) fraction, these compounds can be released into the outer medium where they become part of the dissolved organic carbon (DOC) pool and are rapidly taken up by heterotrophs (e.g., bacteria). We investigated the quantity and quality of POC and DOC, AA and CHO composition in both pools in three different water masses in the Fram Strait (Arctic Ocean) in summer 2017. Polar Waters and Atlantic Waters showed similar concentrations of particulate and dissolved AA and CHO, despite Polar Waters showing the highest DOC concentrations. In Mixed Waters, where the two water masses mix with each other and with melting sea ice, the concentrations of particulate and dissolved AA and CHO were highest. AA and CHO composition differed substantially between the particulate and dissolved fractions. The particulate fraction (>0.7 μm) was enriched in essential AA and the CHO galactose, xylose/mannose, and muramic acid. In the dissolved fraction non-essential AA, several neutral CHO, and acidic and amino CHO were enriched. We further investigated different size fractions of the particulate matter using a separate size fractionation approach (0.2–0.7 μm, 0.7–10 μm and >10 μm). The chemical composition of the 0.2–0.7 μm size-fraction had a higher contribution of non-essential AA and acidic and amino sugars, setting them apart from the 0.7–10 μm and >10 μm fractions, which showed the same composition. We suggest that the relative differences observed between different size fractions and DOC with regards to AA and CHO composition can be used to evaluate the state of organic matter processing and evaluate the contribution of autotrophic phytoplankton or more heterotrophic biomass. In the future, changing conditions in the Central Arctic Ocean (Atlantification, warming, decreasing ice concentrations) may increase primary production and consequently degradation. The AA and CHO signatures left behind after production and/or degradation processes occurred, could be used as tracers after the fact to infer changes in microbial loop processes and food web interactions.
The Application of 3D-Printing and Nanotechnology for the Targeted Treatment of Osteosarcoma
Authors: Suleman Ayesha , Kondiah Pierre P. D. , Mabrouk Mostafa , Choonara Yahya E.
Published: July 2021

Osteosarcoma is a malignant bone neoplasm prevalent in adolescents. Current therapies include chemotherapy and surgery. Surgical resection of osteosarcoma induces a large bone defect which may be overcome by employing scaffolds for bone tissue engineering. This review details the polymers and bioceramics that may be used to fabricate 3D printed scaffolds for bone regeneration and the nanotechnology strategies that may be incorporated into such scaffolds. Natural polymers discussed include chitosan, alginate, collagen, gelatin, and silk fibroin. Synthetic polymers discussed include polycaprolactone, polyurethane, poly(lactic)acid and poly(vinyl) alcohol. Bioceramics that are utilized in bone regeneration such as calcium phosphate, calcium silicate and bioglass are elaborated on. Furthermore, comparison data between different types of 3D printed scaffolds for bone regeneration are presented. A discussion on Photo-responsive and magneto-responsive 3D printed scaffolds that have been fabricated for bone regeneration is included. Research concerning drug-loaded scaffolds as well as the incorporation of nanocarriers into scaffolds for bone regeneration is provided. Chemotherapy utilized in osteosarcoma therapy has severe adverse effects due to being non-selective between healthy cells and tumor cells. A possible way to overcome this is to utilize nanotechnology. Therefore, research detailing other types of nanocarriers that have the potential to be incorporated into 3D printed scaffolds for localized adjuvant therapy is presented.
Analysis of Long-Term Durability Monitoring Data of High-Piled Wharf with Anode-Ladder Sensors Embedded in Concrete
Authors: Liu Hongbiao , Zhang Baohua , Liu Haicheng , Ji Zifan
Published: July 2021

The structural durability monitoring (SDM) system for a high-piled wharf in the Tianjin Port of China is devised and deployed with an anode ladder sensor, which provides a means to monitor the state of steel corrosion for the wharf. In this project, the anode-ladder sensors are installed on the reinforced concrete components of the front platforms. After the installation, the monitoring data from the anode-ladder sensor was collected for 40 months. Based on the monitoring data for 40 months, it is proven that the resistance of concrete will be significantly affected by the change in temperature, and the increase in temperature will cause the drop in concrete resistance. Furthermore, the data of the anode-ladder sensor set in the track beam of the front platform shows that the current in anode A1 and A2 relative to the cathode exceeded 15 μA during the four-month period, which is abnormal. The main reason is the influence of concrete temperature and humidity. Therefore, the monitoring data for current, voltage, resistance, and temperature should be combined to determine the activation state of the anode, and cannot be determined simply using the current value.
The Application of Induced Pluripotent Stem Cells Against Liver Diseases: An Update and a Review
Authors: Zhang Lei , Pu Ke , Liu Xiaojun , Bae Sarah Da Won , Nguyen Romario , Bai Suyang , Li Yi , Qiao Liang
Published: July 2021

Liver diseases are a major health concern globally, and are associated with poor survival and prognosis of patients. This creates the need for patients to accept the main alternative treatment of liver transplantation to prevent progression to end-stage liver disease. Investigation of the molecular mechanisms underpinning complex liver diseases and their pathology is an emerging goal of stem cell scope. Human induced pluripotent stem cells (hiPSCs) derived from somatic cells are a promising alternative approach to the treatment of liver disease, and a prospective model for studying complex liver diseases. Here, we review hiPSC technology of cell reprogramming and differentiation, and discuss the potential application of hiPSC-derived liver cells, such as hepatocytes and cholangiocytes, in refractory liver-disease modeling and treatment, and drug screening and toxicity testing. We also consider hiPSC safety in clinical applications, based on genomic and epigenetic alterations, tumorigenicity, and immunogenicity.
Awake Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: Which Clinical Issues Should Be Taken Into Consideration
Authors: Yu Xin , Gu Sichao , Li Min , Zhan Qingyuan
Published: July 2021

With the goal of protecting injured lungs and extrapulmonary organs, venovenous extracorporeal membrane oxygenation (VV-ECMO) has been increasingly adopted as a rescue therapy for patients with severe acute respiratory distress syndrome (ARDS) when conventional mechanical ventilation failed to provide effective oxygenation and decarbonation. In recent years, it has become a promising approach to respiratory support for awake, non-intubated, spontaneously breathing patients with respiratory failure, referred to as awake ECMO, to avoid possible detrimental effects associated with intubation, mechanical ventilation, and the adjunctive therapies. However, several complex clinical issues should be taken into consideration when initiating and implementing awake ECMO, such as selecting potential patients who appeared to benefit most; techniques to facilitating cannulation and maintain stable ECMO blood flow; approaches to manage pain, agitation, and delirium; and approaches to monitor and modulate respiratory drive. It is worth mentioning that there had also been some inherent disadvantages and limitations of awake ECMO compared to the conventional combination of ECMO and invasive mechanical ventilation. Here, we review the use of ECMO in awake, spontaneously breathing patients with severe ARDS, highlighting the issues involving bedside clinical practice, detailing some of the technical aspects, and summarizing the initial clinical experience gained over the past years.
Advanced-Glycation End-Products Induce Podocyte Injury and Contribute to Proteinuria
Authors: Nishad Rajkishor , Tahaseen Vazeeha , Kavvuri Rajesh , Motrapu Manga , Singh Ashish K , Peddi Kiranmayi , Pasupulati Anil K
Published: July 2021

The prevalence of diabetes reaches epidemic proportions. Diabetes is the leading cause of end-stage kidney disease (ESKD) since 30–40% of diabetic patients develop diabetic nephropathy. Albuminuria and glomerular filtration rate used to assess kidney function are considered surrogate outcomes of chronic kidney disease. The search for a biomarker that predicts progression to diabetic kidney disease is intense. We analyzed the association of serum advanced glycation end-products (AGEs) index (AGI) with impaired kidney function in poorly controlled type II diabetic patients. We observed an association between AGI and impaired kidney function in microalbuminuria patients with hyperglycemia. A significant association between AGEs, particularly carboxymethyl lysine (CML), and impaired kidney function were observed. Administration of AGEs to mice showed heavy proteinuria and glomerular abnormalities. Reduced podocyte number in mice administered with AGEs could be attributed to the epithelial-mesenchymal transition of podocytes. Our study suggests CML could be independently related to the podocyte injury and the risk of DN progression to ESKD in patients with microalbuminuria. AGEs in general or CML could be considered a prognostic marker to assess diabetic kidney disease.
Optical Coherence Tomography Evaluation of Peripapillary and Macular Structure Changes in Pre-perimetric Glaucoma, Early Perimetric Glaucoma, and Ocular Hypertension: A Systematic Review and Meta-Analysis
Authors: Tong Yuxin , Wang Tiantian , Zhang Xinyu , He Yi , Jiang Bing
Published: July 2021

Background: This study aimed to assess the differences in the average and sectoral peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell plus inner plexiform layer (mGCIPL), and macular ganglion cell complex (mGCC) thickness using optical coherence tomography (OCT) in patients with pre-perimetric glaucoma (PPG) compared to those with early perimetric glaucoma (EG) and ocular hypertension (OHT).

Methods: A comprehensive literature search of the PubMed database, the Cochrane Library, and Embase was performed from inception to March 2021. The weighted mean difference (WMD) with the 95% confidence interval (CI) was pooled for continuous outcomes.

Results: Twenty-three cross-sectional studies comprising 2,574 eyes (1,101 PPG eyes, 1,233 EG eyes, and 240 OHT eyes) were included in the systematic review and meta-analysis. The pooled results demonstrated that the average pRNFL (WMD = 8.22, 95% CI = 6.32–10.12, P < 0.00001), mGCIPL (WMD = 4.83, 95% CI = 3.43–6.23, P < 0.00001), and mGCC (WMD = 7.19, 95% CI = 4.52–9.85, P < 0.00001) were significantly thinner in patients with EG than in those with PPG. The sectoral thickness of pRNFL, mGCIPL, and mGCC were also significantly lower in the EG eyes. In addition, the average pRNFL and mGCC were significantly thinner in the PPG eyes than those in the OHT eyes (pRNFL: WMD = −8.57, 95% CI = −9.88 to −7.27, P < 0.00001; mGCC: WMD = −3.23, 95% CI = −6.03 to −0.44, P = 0.02). Similarly, the sectoral pRNFL and mGCC were also significantly thinner in the PPG eyes than those in the OHT eyes.

Conclusion: OCT-based measurements of peripapillary and macular structural alterations can be used to distinguish PPG from EG and OHT, which can help understand the pathophysiology of glaucoma at earlier stages. Studies that employ clock hour classification methods and longitudinal studies are needed to verify our findings.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=239798 CRD42021239798
Clinical Outcomes of Severe COVID-19 Patients Admitted to an Intermediate Respiratory Care Unit
Authors: Suarez-Cuartin Guillermo , Gasa Merce , Bermudo Guadalupe , Ruiz Yolanda , Hernandez-Argudo Marta , Marin Alfredo , Trias-Sabria Pere , Cordoba Ana , Cuevas Ester , Sarasate Mikel , Ariza Albert , Sabater Joan , Romero Nuria , Subirana Cristina , Molina-Molina Maria , Santos Salud
Published: July 2021

Introduction: Many severe COVID-19 patients require respiratory support and monitoring. An intermediate respiratory care unit (IMCU) may be a valuable element for optimizing patient care and limited health-care resources management. We aim to assess the clinical outcomes of severe COVID-19 patients admitted to an IMCU.

Methods: Observational, retrospective study including patients admitted to the IMCU due to COVID-19 pneumonia during the months of March and April 2020. Patients were stratified based on their requirement of transfer to the intensive care unit (ICU) and on survival status at the end of follow-up. A multivariable Cox proportional hazards method was used to assess risk factors associated with mortality.

Results: A total of 253 patients were included. Of them, 68% were male and median age was 65 years (IQR 18 years). Ninety-two patients (36.4%) required ICU transfer. Patients transferred to the ICU had a higher mortality rate (44.6 vs. 24.2%; p < 0.001). Multivariable proportional hazards model showed that age ≥65 years (HR 4.14; 95%CI 2.31–7.42; p < 0.001); chronic respiratory conditions (HR 2.34; 95%CI 1.38–3.99; p = 0.002) and chronic kidney disease (HR 2.96; 95%CI 1.61–5.43; p < 0.001) were independently associated with mortality. High-dose systemic corticosteroids followed by progressive dose tapering showed a lower risk of death (HR 0.15; 95%CI 0.06–0.40; p < 0.001).

Conclusions: IMCU may be a useful tool for the multidisciplinary management of severe COVID-19 patients requiring respiratory support and non-invasive monitoring, therefore reducing ICU burden. Older age and chronic respiratory or renal conditions are associated with worse clinical outcomes, while treatment with systemic corticosteroids may have a protective effect on mortality.
Discovery and Characterization of a Novel Bipartite Botrexvirus From the Phytopathogenic Fungus Botryosphaeria dothidea
Authors: Yang Mengmeng , Xu Wenxing , Zhou Xiaoqi , Yang Zuokun , Wang Yanxiang , Xiao Feng , Guo Yashuang , Hong Ni , Wang Guoping
Published: July 2021

In this study, we describe a novel positive, single-stranded (+ss) RNA mycovirus, named Botryosphaeria dothidea botrexvirus 1 (BdBV1), from a phytopathogenic fungus Botryosphaeria dothidea showing abnormal morphology and attenuated virulence. BdBV1 is phylogenetically related to Botrytis virus X (BotVX) and is the second potential member of the proposed genus Botrexvirus in the family Alphaflexiviridae. However, it differs from the monopartite BotVX in that BdBV1 possesses a bipartite genome comprised of two ssRNA segments (RNA1 and RNA2 with lengths of 5,035 and 1,063 nt, respectively). BdBV1 RNA1 and RNA2 encode putative RNA-dependent RNA polymerase (RdRp) and coat protein (CP) genes, which share significant identity with corresponding genes in both fungal and plant viruses. Moreover, open reading frames (ORFs) 2–4 of BdBV1 RNA1 shared no detectable identity with any known viral proteins. Immunosorbent electron microscopy (ISEM) analysis using an antibody against the virus CP generated in vitro revealed that BdBV1 is encapsidated in filamentous particles. A comparison of the biological effects of BdBV1 infection on symptoms and growth in isogenic lines of virus-free and virus-infected B. dothidea revealed that BdBV1 is probably involved in reduced growth and virulence of the host fungus. This study describes and characterizes a novel bipartite botrexvirus, which is closely related to uni- and multi-partite fungal and plant viruses and contributes useful information to a better understanding of virus evolution.
ANLN Enhances Triple-Negative Breast Cancer Stemness Through TWIST1 and BMP2 and Promotes its Spheroid Growth
Authors: Maryam Alishba , Chin Y. Rebecca
Published: July 2021

ANLN is frequently upregulated in triple-negative breast cancer (TNBC) and its high expression in tumors are significantly associated with poor survival and recurrence, thereby it has been proposed to function as a prognostic marker for breast cancer. However, the specific function and molecular mechanisms by which ANLN promotes TNBC tumorigenesis remain elusive. Using multiomic profiling, we recently uncovered ANLN as a TNBC-specific gene driven by super-enhancer. Here, by Crispr/Cas9 editing, we showed that knockout of ANLN inhibits spheroid growth of TNBC. Interestingly, its effect on cell proliferation in 2D cultures is minimal. ANLN depletion inhibits mammosphere formation and clonogenicity potently, suggesting its important function in regulating cancer stem cells (CSCs). We screened a panel of stem cell-related genes and uncovered several CSC genes regulated by ANLN. We further identify TWIST1 and BMP2 as essential genes that mediate ANLN’s function in stemness but not spheroid growth. These findings may contribute to search for effective targeted therapies to treat TNBC.
Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome
Authors: Chen Xu-Qiao , Xing Zhuo , Chen Quang-Di , Salvi Richard J. , Zhang Xuming , Tycko Benjamin , Mobley William C. , Yu Y. Eugene
Published: July 2021

Down syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increasedAPPgene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (β-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact ofAPPtriplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.
Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Authors: Derk Julia , Jones Hannah E. , Como Christina , Pawlikowski Bradley , Siegenthaler Julie A.
Published: July 2021

The meninges are the fibrous covering of the central nervous system (CNS) which contain vastly heterogeneous cell types within its three layers (dura, arachnoid, and pia). The dural compartment of the meninges, closest to the skull, is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, as well as immune cells which are distinct from the CNS. Segregating the outer and inner meningeal compartments is the epithelial-like arachnoid barrier cells, connected by tight and adherens junctions, which regulate the movement of pathogens, molecules, and cells into and out of the cerebral spinal fluid (CSF) and brain parenchyma. Most proximate to the brain is the collagen and basement membrane-rich pia matter that abuts the glial limitans and has recently be shown to have regional heterogeneity within the developing mouse brain. While the meninges were historically seen as a purely structural support for the CNS and protection from trauma, the emerging view of the meninges is as an essential interface between the CNS and the periphery, critical to brain development, required for brain homeostasis, and involved in a variety of diseases. In this review, we will summarize what is known regarding the development, specification, and maturation of the meninges during homeostatic conditions and discuss the rapidly emerging evidence that specific meningeal cell compartments play differential and important roles in the pathophysiology of a myriad of diseases including: multiple sclerosis, dementia, stroke, viral/bacterial meningitis, traumatic brain injury, and cancer. We will conclude with a list of major questions and mechanisms that remain unknown, the study of which represent new, future directions for the field of meninges biology.
Dizziness and Driving From a Patient Perspective
Authors: van Leeuwen Roeland B. , Schermer Tjard R. , Colijn Carla , Bruintjes Tjasse D.
Published: July 2021

Background: People with dizziness may experience driving-related limitations. Few data are available about the impact of dizziness on driving.

Aim: The aim of this study is to investigate the impact of dizziness on driving, factors related to impairment (age, gender, and type of diagnosis), and the potential consequences for patients' ability to work. We also investigated whether the patients expected and actually received information about their dizziness-related fitness to drive from their physician.

Methods: A cross-sectional, observational study was conducted in the Apeldoorn Dizziness Centre, a tertiary care referral centre for patients with dizziness. A consecutive cohort of patients was asked to complete a study-specific questionnaire about driving.

Results: Between January 1, 2020, and December 20, 2020, 432 patients were included. Fifty-six percent of the patients in this group were female. The average age of patients was 58.3 years (SD 16). Overall, 191 of the 432 patients (44%) experienced limitations related to driving, and 40% of the patients who experienced limitations also experienced limitations to work related to their inability to drive. The subject of fitness to drive had not been discussed with their physician in 92% of the patients, and 24% of the whole patient group indicated that they would have liked to discuss this topic. The following factors, independently from each other, increased the chance of experiencing driving-related limitations: younger age, female sex, and the diagnosis of Meniere's disease.

Conclusion: Dizzy patients, especially younger patients, women, and patients with Meniere's disease, regularly experience limitations related to driving, and this often means that they are unable to work. Driving is hardly ever discussed during a medical consultation. In our opinion, the topic of driving and dizziness should always be addressed during medical consultations in dizzy patients.
Cognitive Deficits, Apathy, and Hypersomnolence Represent the Core Brain Symptoms of Adult-Onset Myotonic Dystrophy Type 1
Authors: Miller Jacob N. , Kruger Alison , Moser David J. , Gutmann Laurie , van der Plas Ellen , Koscik Timothy R. , Cumming Sarah A. , Monckton Darren G. , Nopoulos Peggy C.
Published: July 2021

Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults, and is primarily characterized by muscle weakness and myotonia, yet some of the most disabling symptoms of the disease are cognitive and behavioral. Here we evaluated several of these non-motor symptoms from a cross-sectional time-point in one of the largest longitudinal studies to date, including full-scale intelligence quotient, depression, anxiety, apathy, sleep, and cerebral white matter fractional anisotropy in a group of 39 adult-onset myotonic dystrophy type 1 participants (27 female) compared to 79 unaffected control participants (46 female). We show that intelligence quotient was significantly associated with depression (P < 0.0001) and anxiety (P = 0.018), but not apathy (P < 0.058) or hypersomnolence (P = 0.266) in the DM1 group. When controlling for intelligence quotient, cerebral white matter fractional anisotropy was significantly associated with apathy (P = 0.042) and hypersomnolence (P = 0.034), but not depression (P = 0.679) or anxiety (P = 0.731) in the myotonic dystrophy type 1 group. Finally, we found that disease duration was significantly associated with apathy (P < 0.0001), hypersomnolence (P < 0.001), IQ (P = 0.038), and cerebral white matter fractional anisotropy (P < 0.001), but not depression (P = 0.271) or anxiety (P = 0.508). Our results support the hypothesis that cognitive deficits, hypersomnolence, and apathy, are due to the underlying neuropathology of myotonic dystrophy type 1, as measured by cerebral white matter fractional anisotropy and disease duration. Whereas elevated symptoms of depression and anxiety in myotonic dystrophy type 1 are secondary to the physical symptoms and the emotional stress of coping with a chronic and debilitating disease. Results from this work contribute to a better understanding of disease neuropathology and represent important therapeutic targets for clinical trials.
Possibilistic Clustering-Promoting Semi-Supervised Learning for EEG-Based Emotion Recognition
Authors: Dan Yufang , Tao Jianwen , Fu Jianjing , Zhou Di
Published: July 2021

The purpose of the latest brain computer interface is to perform accurate emotion recognition through the customization of their recognizers to each subject. In the field of machine learning, graph-based semi-supervised learning (GSSL) has attracted more and more attention due to its intuitive and good learning performance for emotion recognition. However, the existing GSSL methods are sensitive or not robust enough to noise or outlier electroencephalogram (EEG)-based data since each individual subject may present noise or outlier EEG patterns in the same scenario. To address the problem, in this paper, we invent a Possibilistic Clustering-Promoting semi-supervised learning method for EEG-based Emotion Recognition. Specifically, it constrains each instance to have the same label membership value with its local weighted mean to improve the reliability of the recognition method. In addition, a regularization term about fuzzy entropy is introduced into the objective function, and the generalization ability of membership function is enhanced by increasing the amount of sample discrimination information, which improves the robustness of the method to noise and the outlier. A large number of experimental results on the three real datasets (i.e., DEAP, SEED, and SEED-IV) show that the proposed method improves the reliability and robustness of the EEG-based emotion recognition.
The Molecular Basis of Depression: Implications of Sex-Related Differences in Epigenetic Regulation
Authors: Kawatake-Kuno Ayako , Murai Toshiya , Uchida Shusaku
Published: July 2021

Major depressive disorder (MDD) is a leading cause of disability worldwide. Although the etiology and pathophysiology of MDD remain poorly understood, aberrant neuroplasticity mediated by the epigenetic dysregulation of gene expression within the brain, which may occur due to genetic and environmental factors, may increase the risk of this disorder. Evidence has also been reported for sex-related differences in the pathophysiology of MDD, with female patients showing a greater severity of symptoms, higher degree of functional impairment, and more atypical depressive symptoms. Males and females also differ in their responsiveness to antidepressants. These clinical findings suggest that sex-dependent molecular and neural mechanisms may underlie the development of depression and the actions of antidepressant medications. This review discusses recent advances regarding the role of epigenetics in stress and depression. The first section presents a brief introduction of the basic mechanisms of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs. The second section reviews their contributions to neural plasticity, the risk of depression, and resilience against depression, with a particular focus on epigenetic modulators that have causal relationships with stress and depression in both clinical and animal studies. The third section highlights studies exploring sex-dependent epigenetic alterations associated with susceptibility to stress and depression. Finally, we discuss future directions to understand the etiology and pathophysiology of MDD, which would contribute to optimized and personalized therapy.
Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation
Authors: Kiyohara Arlene C. P. , Torres Daniel J. , Hagiwara Ayaka , Pak Jenna , Rueli Rachel H. L. H. , Shuttleworth C. William R. , Bellinger Frederick P.
Published: July 2021

Selenoprotein P (SELENOP1) is a selenium-rich antioxidant protein involved in extracellular transport of selenium (Se). SELENOP1 also has metal binding properties. The trace element Zinc (Zn2+) is a neuromodulator that can be released from synaptic terminals in the brain, primarily from a subset of glutamatergic terminals. Both Zn2+ and Se are necessary for normal brain function. Although these ions can bind together with high affinity, the biological significance of an interaction of SELENOP1 with Zn2+ has not been investigated. We examined changes in brain Zn2+ in SELENOP1 knockout (KO) animals. Timm-Danscher and N-(6-methoxy-8-quinolyl)-p-toluenesulphonamide (TSQ) staining revealed increased levels of intracellular Zn2+ in the SELENOP1−/− hippocampus compared to wildtype (WT) mice. Mass spectrometry analysis of frozen whole brain samples demonstrated that total Zn2+ was not increased in the SELENOP1−/− mice, suggesting only local changes in Zn2+ distribution. Unexpectedly, live Zn2+ imaging of hippocampal slices with a selective extracellular fluorescent Zn2+ indicator (FluoZin-3) showed that SELENOP1−/− mice have impaired Zn2+ release in response to KCl-induced neuron depolarization. The zinc/metal storage protein metallothionein 3 (MT-3) was increased in SELENOP1−/− hippocampus relative to wildtype, possibly in response to an elevated Zn2+ content. We found that depriving cultured cells of selenium resulted in increased intracellular Zn2+, as did inhibition of selenoprotein GPX4 but not GPX1, suggesting the increased Zn2+ in SELENOP1−/− mice is due to a downregulation of antioxidant selenoproteins and subsequent release of Zn2+ from intracellular stores. Surprisingly, we found increased tau phosphorylation in the hippocampus of SELENOP1−/− mice, possibly resulting from intracellular zinc changes. Our findings reveal important roles for SELENOP1 in the maintenance of synaptic Zn2+ physiology and preventing tau hyperphosphorylation.
Associations of Whole Grain and Refined Grain Consumption With Metabolic Syndrome. A Meta-Analysis of Observational Studies
Authors: Guo Hongbin , Ding Jun , Liang Jieyu , Zhang Yi
Published: July 2021

Background: The associations of whole grain and refined grain consumption with metabolic syndrome (MetS) has been evaluated in several epidemiological studies with conflicting results. This meta-analysis was therefore employed to further investigate the above associations.

Method: We searched the PubMed, Web of Science and Embase database until March 2021 (without restriction for inclusion time), for observational studies on the associations of whole grain and refined grain consumption with MetS. The pooled relative risk (RR) of MetS for the highest vs. lowest category of whole grain and refined grain consumption, as well as their corresponding 95% confidence interval (CI) were calculated.

Results: A total of 14 observational studies, which involved seven cross-sectional and seven prospective cohort studies, were identified. Specifically, nine studies were related to whole grain consumption, and the overall multi-variable adjusted RR demonstrated that the whole grain consumption was inversely associated with MetS (RR = 0.80, 95%CI: 0.67–0.97; P = 0.021). With regard to refined grain consumption, 13 studies were included. The overall multi-variable adjusted RR indicated that refined grain consumption was positively associated with MetS (RR = 1.37, 95%CI: 1.02–1.84; P = 0.036).

Conclusions: The existing evidence suggests that whole grain consumption is negatively associated with MetS, whereas refined grain consumption is positively associated with MetS. Our result might be helpful to better consider the diet effect on MetS. However, more well-designed prospective cohort studies are needed to elaborate the concerned issues further.
Is Routine Gastroscopy/Colonoscopy Reasonable in Patients With Suspected Ovarian Cancer: A Retrospective Study
Authors: Liu Guochen , Yan Junping , Long Shanshan , Liu Zhimin , Gu Haifeng , Tu Hua , Li Jundong
Published: July 2021

Objective

To evaluate the value of routine preoperative gastroscopy/colonoscopy in patients with suspected ovarian cancer for differential diagnosis and judgment of bowel resection.

Methods

All women diagnosed with suspected ovarian cancer who underwent gastroscopy/colonoscopy before surgery in our center were retrospectively identified. Gastroscopy/colonoscopy results and clinical pathology, imaging, and surgical findings were analyzed.

Results

389 patients were included. Among them, 40 (including 13 gastric and 9 colonic malignancy) were ovarian metastasis. Compared with imaging, gastrointestinal endoscopy showed no statistical advantage in the specificity and sensitivity (99.4% vs. 99.7%, P=1.0; 55.0% vs. 45.2%, P=0.057; respectively). All patients with gastric/colonic cancer metastasize except for one had indicative imaging or tumor marker abnormalities. Three patients with colonic cancer metastases underwent optimal surgery and alive with no recurrence, the other 19 patients experienced palliative chemotherapy. There is no significant difference in the sensitivity of colonoscopy and imaging in predicting intestinal incision (61.5% vs. 43.8%, P=0.804), whereas the latter had higher specificity (87.8% vs. 74.3%, P=0.001).

Conclusions

For patients with suspected ovarian cancer, the incidence of gastrointestinal metastases is low, routine gastroscopy/colonoscopy before treatment is less efficient. Gastroscopy/colonoscopy has limited power to predict the need for gastrointestinal resection before ovarian cancer surgery.
Chemoresistance and Metastasis in Breast Cancer Molecular Mechanisms and Novel Clinical Strategies
Authors: Cao Jun , Zhang Mengdi , Wang Bin , Zhang Long , Zhou Fangfang , Fang Meiyu
Published: July 2021

Breast cancer is the most common malignant tumor in females worldwide. Chemotherapy is the standard breast cancer treatment; however, chemoresistance is often seen in patients with metastatic breast cancer. Owing to high heterogeneity, the mechanisms of breast cancer chemoresistance and metastasis have not been fully investigated. The possible molecular mechanisms of chemoresistance in breast cancer include efflux transporters, signaling pathways, non-coding RNAs, and cancer stem cells. However, to overcome this hurdle, the use of novel clinical strategies such as drug carriers, immunotherapy, and autophagy regulation, are being investigated. The goal of this review is to summarize the current data about the molecular mechanisms of breast cancer chemoresistance and the novel clinical strategies; thus, providing a useful clinical tool to explore optimal treatment for breast cancer.