bluuebunny/crossref_metadata_2025 huggingface dataset:
Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer
Authors: Zhang Yueming , Lin Anqi , Li Yonghe , Ding Weimin , Meng Hui , Luo Peng , Zhang Jian
Published: December 2020

The immunosuppressive tumor microenvironment plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSC). Compared to traditional chemoradiotherapy, immune checkpoint inhibitors (ICIs) have become increasingly important in HNSC therapy. Prior studies linked the efficacy of ICIs to PD-L1, microsatellite instability (MSI), HPV infection, tumor mutation burden (TMB), and tumor lymphocyte infiltration in patients with HNSC, but further verification is needed. Additional predictors are needed to recognize HNSC patients with a good response to ICIs. We collected the clinical information and mutation data of HNSC patients from Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA) databases to generate two clinical cohorts. The MSKCC cohort was used to recognize predictors related to the efficacy of ICIs, and the TCGA cohort was used to further examine the immune microenvironment features and signaling pathways that are significantly enriched in the subgroups of predictors. Multivariate Cox regression analysis indicated that age (HR = 0.50,p= 0.014) and ARID1A (HR = 0.13,p= 0.048), PIK3CA (HR = 0.45,p= 0.021), and TP53 (HR = 1.82,p= 0.035) mutations were potential predictors for ICI efficacy in HNSC patients. Age > 65 years and ARID1A or PIK3CA mutations correlated with good overall survival (OS). TP53 mutant-type (MT) patients experienced a worse prognosis than TP53 wild-type (WT) patients. The subgroups associated with a good prognosis (age > 65 years, ARID1A-MT, and PIK3CA-MT) universally had a high TMB and increased expression of immune checkpoint molecules. Although TP53-MT was associated with a high TMB, the expression of most immune checkpoint molecules and immune-related genes was lower in TP53-MT patients than TP53-WT patients, which may reflect low immunogenicity. Pathways related to the immunosuppressive tumor microenvironment were mostly enriched in the subgroups associated with a poor prognosis (age ≤ 65 years, low TMB, ARID1A-WT, PIK3CA-WT, and TP53-MT). In conclusion, the factors age > 65 years, PIK3CA-MT, and ARID1A-MT predicted favorable efficacy for ICI treatment in HNSC patients, and TP53 mutation was a negative predictor.
Coronavirus Disease (COVID-19) Caused by (SARS-CoV-2) Infections: A Real Challenge for Human Gut Microbiota
Authors: Vodnar Dan-Cristian , Mitrea Laura , Teleky Bernadette-Emoke , Szabo Katalin , Călinoiu Lavinia-Florina , Nemeş Silvia-Amalia , Martău Gheorghe-Adrian
Published: December 2020

The current COVID-19 pandemic is a great challenge for worldwide researchers in the human microbiota area because the mechanisms and long-term effects of the infection at the GI level are not yet deeply understood. In the current review, scientific literature including original research articles, clinical studies, epidemiological reports, and review-type articles concerning human intestinal infection with SARS-CoV-2 and the possible consequences on the microbiota were reviewed. Moreover, the following aspects pertaining to COVID-19 have also been discussed: transmission, resistance in the human body, the impact of nutritional status in relation to the intestinal microbiota, and the impact of comorbid metabolic disorders such as inflammatory bowel disease (IBS), obesity, and type two diabetes (T2D). The articles investigated show that health, age, and nutritional status are associated with specific communities of bacterial species in the gut, which could influence the clinical course of COVID-19 infection. Fecal microbiota alterations were associated with fecal concentrations of SARS-CoV-2 and COVID-19 severity. Patients suffering from metabolic and gastrointestinal (GI) disorders are thought to be at a moderate-to-high risk of infection with SARS-CoV-2, indicating the direct implication of gut dysbiosis in COVID-19 severity. However, additional efforts are required to identify the initial GI symptoms of COVID-19 for possible early intervention.
Evaluation of Microbiological Performance and the Potential Clinical Impact of the ePlex® Blood Culture Identification Panels for the Rapid Diagnosis of Bacteremia and Fungemia
Authors: Bryant Sabrina , Almahmoud Iyad , Pierre Isabelle , Bardet Julie , Touati Saber , Maubon Daniele , Cornet Muriel , Richarme Claire , Maurin Max , Pavese Patricia , Caspar Yvan
Published: December 2020

Molecular rapid diagnostic assays associated with antimicrobial stewardship have proven effective for the early adaptation of empiric therapy in bloodstream infections. The ePlex® BCID (GenMark Diagnostics) Panels allow identification of 56 bacteria and fungi and 10 resistance genes in 90 min directly from positive blood cultures. We prospectively evaluated 187 sepsis episodes at Grenoble University Hospital and retrospectively analyzed the cases to measure the potential clinical impact of the ePlex BCID results. Identification of all pathogens was obtained for 164/187 (88%) bloodstream infections with 100% detection of antimicrobial resistance genes (17 blaCTX-M, 1 vanA, and 17 mecA genes). Only 15/209 (7%) strains were not covered by the panels. Sensitivity for detection of micro-organisms targeted by the RUO BCID-GP, BCID-GN, and BCID-FP Panels was respectively 84/84 (100%), 103/107 (96%), and 14/14 (100%). Interestingly, accurate identification of all pathogens was achieved in 15/17 (88%) polymicrobial samples. Retrospective analysis of medical records showed that a modification of antimicrobial treatment would have been done in 45% of the patients. Treatment modifications would have been an optimization of empiric therapy, a de-escalation or an escalation in respectively 16, 17, and 11% of the patients. Moreover, 11% of the samples were classified as contaminants or not clinically relevant and would have led to early de-escalation or withdrawal of any antibiotic. Detection of resistance genes in addition to identification alone increased escalation rate from 4 to 11% of the patients. Absence of the ePlex result was considered a lost opportunity for therapy modiﬁcation in 28% of patients.
Telemedicine in Heart Failure During COVID-19: A Step Into the Future
Authors: Tersalvi Gregorio , Winterton Dario , Cioffi Giacomo Maria , Ghidini Simone , Roberto Marco , Biasco Luigi , Pedrazzini Giovanni , Dauw Jeroen , Ameri Pietro , Vicenzi Marco
Published: December 2020

During the Coronavirus Disease 2019 worldwide pandemic, patients with heart failure are a high-risk group with potential higher mortality if infected. Although lockdown represents a solution to prevent viral spreading, it endangers regular follow-up visits and precludes direct medical assessment in order to detect heart failure progression and optimize treatment. Furthermore, lifestyle changes during quarantine may trigger heart failure decompensations. During the pandemic, a paradoxical reduction of heart failure hospitalization rates was observed, supposedly caused by patient reluctance to visit emergency departments and hospitals. This may result in an increased patient mortality and/or in more complicated heart failure admissions in the future. In this scenario, different telemedicine strategies can be implemented to ensure continuity of care to patients with heart failure. Patients at home can be monitored through dedicated apps, telephone calls, or devices. Virtual visits and forward triage screen the patients with signs or symptoms of decompensated heart failure. In-hospital care may benefit from remote communication platforms. After discharge, patients may undergo remote follow-up or telerehabilitation to prevent early readmissions. This review provides a comprehensive appraisal of the many possible applications of telemedicine for patients with heart failure during Coronavirus disease 2019 and elucidates practical limitations and challenges regarding specific telemedicine modalities.
Insights Into the Internal Dynamics of Natural Lahars From Analysis of 3-Component Broadband Seismic Signals at Volcán de Colima, Mexico
Authors: Walsh Braden , Coviello Velio , Capra Lucia , Procter Jonathan , Márquez-Ramirez Victor
Published: December 2020

Lahar monitoring on active volcanoes is challenging, and the ever changing environment leads to inconsistent results that hamper a warning systems ability to characterize the flow event properly. Therefore, more data, new methods, and the use of different sensors needs to be tested, which could lead to improvements in warning capabilities. Here, we present data from a 3-component broadband seismometer and video camera installed 3 m from the Lumbre channel on Volcán de Colima, Mexico to understand rheology differences within multiple lahar events that occurred in late 2016. We examine differences in frequency and directionality from each seismic component. Results indicate an increase in peak frequency above background in each component when a lahar nears the sensor, and a decrease in overall peak frequency when transitioning from a streamflow to a higher concentration flow. The seismic frequency distribution for the cross-channel component for the streamflow has a wider range compared with the lahar events. In contrast, the peak spectral frequency of the streamflow is narrower in comparison to the lahar events in the flow parallel and vertical directions. Estimated directionality ratios (cross-channel signal divided by flow parallel signal) yielded further evidence for a rheologic change between streamflow and lahars. Directionality ratios >1 were calculated for each lahar, and <1 for streamflow. Finally, we demonstrate from component analyses that channelization or freedom of movement in the cross-channel, bedload transport in the flow parallel, and bed composition in the vertical directions are possibly the main drivers in the peak spectral frequency output of lahars. The results described here indicate that using all three components may provide important information about lahar dynamics, which may be useful for automatic detection and warning systems, and using all three components should be encouraged.
Dexamethasone Stimulation Test in the Diagnostic Work-Up of Growth Hormone Deficiency in Childhood: Clinical Value and Comparison With Insulin-Induced Hypoglycemia
Authors: Cattoni Alessandro , Molinari Silvia , Medici Francesco , De Lorenzo Paola , Valsecchi Maria Grazia , Masera Nicoletta , Adavastro Marta , Biondi Andrea
Published: December 2020

Context

dexamethasone has been demonstrated to elicit GH secretion in adults, but few data are available about its effectiveness as a provocative stimulus in the diagnostic work-up of GH deficiency (GHD) in childhood.

Objective

to assess the clinical value of dexamethasone stimulation test (DST) as a diagnostic tool for pediatric GHD.

Design and setting

retrospective single-center analysis. The study population included 166 patients with a pathological response to arginine stimulation test (AST, first-line test) and subsequently tested with either insulin tolerance test (ITT) or DST as a second-line investigation between 2008 and 2019.

Main outcome measures

comparison between GH peaks and secretory curves induced by ITT and DST; degree of agreement between DST and AST versus ITT and AST.

Results

the pathological response to AST (GH peak < 8 ng/mL) was confirmed by an ITT in 80.2% (89/111) of patients and by a DST in 76.4% (42/55), with no statistical difference between the two groups (p value 0.69). Mean GH peaks achieved after ITT and DST were entirely comparable (6.59 ± 3.59 versus 6.50 ± 4.09 ng/ml, respectively, p 0.97) and statistically higher than those elicited by arginine (p < 0.01 for both), irrespectively of the average GH peaks recorded for each patient (Bland-Altman method). Dexamethasone elicited a longer lasting and later secretory response than AST and ITT. No side effects were recorded after DST.

Conclusions

DST and ITT confirmed GHD in a superimposable percentage of patients with a pathological first-line test. DST and ITT share a similar secretagogue potency, overall greater than AST.
Clinical Application of AMH Measurement in Assisted Reproduction
Authors: Li Hang Wun Raymond , Nelson Scott M.
Published: December 2020

Anti-Müllerian hormone reflects the continuum of the functional ovarian reserve, and as such can predict ovarian response to gonadotropin stimulation and be used to individualize treatment pathways to improve efficacy and safety. However, consistent with other biomarkers and age-based prediction models it has limited ability to predict live birth and should not be used to refuse treatment, but rather to inform counselling and shared decision making. The use of absolute clinical thresholds to stratify patient phenotypes, assess discordance and individualize treatment protocols in non-validated algorithms combined with the lack of standardization of assays may result in inappropriate classification and sub-optimal clinical decision making. We propose that holistic baseline phenotyping, incorporating antral follicle count and other patient characteristics is critical. Treatment decisions driven by validated algorithms that use ovarian reserve biomarkers as continuous measures, reducing the risk of misclassification, are likely to improve overall outcomes for our patients.
Investment Planning Methodology for Complex Urban Energy Systems Applied to a Hospital Site
Authors: Bornand Bastien , Girardin Luc , Belfiore Francesca , Robineau Jean-Loup , Bottallo Stéphane , Maréchal François
Published: December 2020

Industrial process integration based on mixed integer linear programming has been used for decades to design and improve industrial processes. The technique has later been extended to solve multi-period and multi-scale problems for the design of urban energy systems. Assistance is indeed required for the elaboration of coordinated investment scheduling strategies to promote renewable and efficient urban energy infrastructure shaping the future energy context for the next decades. Major energy consumers, such as hospital complexes, airports, or educational campuses can act as a driving force for the development of renewable energy cities by attracting profitable large-scale energy networks and infrastructure. The proposed methodology generates optimal alternatives for the replacement, in a long-term perspective, of the various energy supply units and systems considering the evolution of the energy demand and the availability of the energy resources. Energy integration techniques are coupled to a parametric multi-objective optimization routine to select and size the energy equipment with both financial profitability and CO2 emission reduction as objectives. The originality of the developed method lies in the integration of a multi-period mixed integer linear programming formulation to generate long-term investment planning scenarios. The method has been demonstrated on a complex of eight hospitals totaling 466,000 m2 and an operating budget of 1.85 billion USD per year. The energy integration of new centralized and decentralized equipment has been evaluated on a monthly basis over four periods until the year 2035. The results show that among the four scenarios identified, the most optimistic alternative allows to decrease the final energy consumption of about 36%, cut the CO2 emissions by a half, multiply the renewable energy share by a factor 3.5 while reducing the annual total cost by 24%. This scenario considers mainly the integration of a very low temperature district heating with decentralized heat pumps to satisfy the heat requirements below 75°C, as well as heat recovery systems and the refurbishment of about 33% of the building stock.
Evaluation of the FLake Model in ERA5 for Lake Champlain
Authors: Betts Alan K. , Reid Daniel , Crossett Caitlin
Published: December 2020

Global model reanalyses of temperature and radiation are used for many purposes because of their spatial and temporal homogeneity. However, they use sub-models for lakes that are smaller than the model grid. This paper compares the simplified small-lake model, known as FLake, used in the European Centre global reanalysis known as ERA5, with observations made in and near Lake Champlain in northern Vermont. Lake Champlain is a challenging test for the ERA5 FLake model. The lake, which extends over several grid cells, is the lowest region at 30 m above sea level within complex mountain topography. The smoothing of the adjacent mountain topography means that the ERA5 grid cells containing the lake have higher mean elevations then 30 m, and this contributes to a small cool bias in FLake mid-summer temperatures. The seasonal cycle of FLake temperatures has a sharper peak than the observed lake temperatures. In winter, lake temperatures are close to 3°C, while the 30 m deep FLake mixed layer (ML) is near freezing. In May and June, FLake maintains a deep ML, while lake profiles are generally strongly stratified with peak temperatures near the surface several degrees above the model ML. One possible contributing reason is that inflowing river temperatures that are not considered by FLake are as much as 5°C above the lake surface temperature from April to June. The lake does develop a ML structure as it cools from the temperature peak in August, but the FLake ML cools faster and grows deeper in fall. We conclude that the vertical mixing in the FLake ML is stronger than the vertical mixing in Lake Champlain.
Early Phases of COVID-19 Are Characterized by a Reduction in Lymphocyte Populations and the Presence of Atypical Monocytes
Authors: Lombardi Andrea , Trombetta Elena , Cattaneo Alessandra , Castelli Valeria , Palomba Emanuele , Tirone Mario , Mangioni Davide , Lamorte Giuseppe , Manunta Maria , Prati Daniele , Ceriotti Ferruccio , Gualtierotti Roberta , Costantino Giorgio , Aliberti Stefano , Scaravilli Vittorio , Grasselli Giacomo , Gori Andrea , Porretti Laura , Bandera Alessandra
Published: December 2020

Background

Severe acute respiratory syndrome coronavirus 2 is a recently discovered pathogen responsible of coronavirus disease 2019 (COVID-19). The immunological changes associated with this infection are largely unknown.

Methods

We evaluated the peripheral blood mononuclear cells profile of 63 patients with COVID-19 at diagnosis. We also assessed the presence of association with inflammatory biomarkers and the 28-day mortality.

Results

Lymphocytopenia was present in 51 of 63 (80.9%) patients, with a median value of 720 lymphocytes/µl (IQR 520-1,135). This reduction was mirrored also on CD8+ (128 cells/µl, IQR 55-215), natural killer (67 cells/µl, IQR 35–158) and natural killer T (31 cells/µl, IQR 11–78) cells. Monocytes were preserved in total number but displayed among them a subpopulation with a higher forward and side scatter properties, composed mainly of cells with a reduced expression of both CD14 and HLA-DR. Patients who died in the 28 days from admission (N=10, 15.9%), when compared to those who did not, displayed lower mean values of CD3+ (337.4 cells/µl vs 585.9 cells/µl; p=0.028) and CD4+ cells (232.2 cells/µl vs 381.1 cells/µl; p=0.042) and an higher percentage of CD8+/CD38+/HLA-DR+ lymphocytes (13.5% vs 7.6%; p=0.026).

Discussion

The early phases of COVID-19 are characterized by lymphocytopenia, predominance of Th2-like lymphocytes and monocytes with altered immune profile, which include atypical mononuclear cells.
TLR4 Response to LPS Is Reinforced by Urokinase Receptor
Authors: Kiyan Yulia , Tkachuk Sergey , Rong Song , Gorrasi Anna , Ragno Pia , Dumler Inna , Haller Hermann , Shushakova Nelli
Published: December 2020

GPI-anchored uPAR is the receptor for the extracellular serine protease urokinase-type plasminogen activator (uPA). Though uPAR role in inflammatory processes is documented, underlying mechanisms are not fully understood. In this study we demonstrate that uPAR is a part of Toll-like receptor 4 (TLR4) interactome. Downregulation of uPAR expression resulted in diminished LPS-induced TLR4 signaling, less activation of NFκB, and decreased secretion of inflammatory mediators in myeloid and non-myeloid cells in vitro. In vivo uPAR−/− mice demonstrated better survival, strongly diminished inflammatory response and better organ functions in cecal ligation and puncture mouse polymicrobial sepsis model. Mechanistically, GPI-uPAR and soluble uPAR colocalized with TLR4 on the cell membrane and interacted with scavenger receptor CD36. Our data show that uPAR can interfere with innate immunity response via TLR4 and this mechanism represents a potentially important target in inflammation and sepsis therapy.
Interferon Regulatory Factor 5 Mediates Lipopolysaccharide-Induced Neuroinflammation
Authors: Fan Ziqi , Zhao Shuai , Zhu Yueli , Li Zheyu , Liu Zhirong , Yan Yaping , Tian Jun , Chen Yanxing , Zhang Baorong
Published: December 2020

Background

Activated microglia play a vital role in neuroinflammation in the central nervous system (CNS), which is associated with the pathogenesis and the progression of neurological diseases. Interferon regulatory factor 5 (IRF5) has been well established participating in inflammatory responses and is highly expressed in M1 macrophage in the periphery, the role of which in the CNS remains elusive.

Methods

Lipopolysaccharide (LPS) was employed to induce neuroinflammation. Down-regulation of IRF5 in C57/BL6 mice and BV2 microglial cells were achieved by IRF5 siRNA transfection. The levels of pro-inflammatory cytokines were evaluated by ELISA and quantitative real-time PCR. The expression levels of IRF5 were examined by immunofluorescence and Western blot.

Results

LPS induced significantly elevated expression of IRF5 in mouse brain, which co-localized with CD11b-positive microglia. Down-regulation of IRF5 quenched the pro-inflammatory responses. The levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were up-regulated at 4 h after LPS treatment, which were significantly down-regulated with the knockdown of IRF5. LPS-induced pro-inflammatory responses were transient, which were comparable to control group at 24 h after LPS treatment. However, LPS did not up-regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS-induced inflammation in BV2 cells does not involve IRF5 signaling.

Conclusions

IRF5 mediates the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. LPS-induced inflammation does not involve IRF5 signaling in BV2 microglia.
All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes
Authors: Yang Emily , Li Melody M. H.
Published: December 2020

Interferon (IFN) signaling induces the expression of a wide array of genes, collectively referred to as IFN-stimulated genes (ISGs) that generally function to inhibit viral replication. RNA viruses are frequently targeted by ISGs through recognition of viral replicative intermediates and molecular features associated with viral genomes, or the lack of molecular features associated with host mRNAs. The ISGs reviewed here primarily inhibit viral replication in an RNA-centric manner, working to sense, degrade, or repress expression of viral RNA. This review focuses on dissecting how these ISGs exhibit multiple antiviral mechanisms, often through use of varied co-factors, highlighting the complexity of the type I IFN response. Specifically, these ISGs can mediate antiviral effects through viral RNA degradation, viral translation inhibition, or both. While the OAS/RNase L pathway globally degrades RNA and arrests translation, ISG20 and ZAP employ targeted RNA degradation and translation inhibition to block viral replication. Meanwhile, SHFL targets translation by inhibiting -1 ribosomal frameshifting, which is required by many RNA viruses. Finally, a number of E3 ligases inhibit viral transcription, an attractive antiviral target during the lifecycle of negative-sense RNA viruses which must transcribe their genome prior to translation. Through this review, we aim to provide an updated perspective on how these ISGs work together to form a complex network of antiviral arsenals targeting viral RNA processes.
Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
Authors: Yang Mingya , Wang Lei , Ni Ming , Neuber Brigitte , Wang Sanmei , Gong Wenjie , Sauer Tim , Sellner Leopold , Schubert Maria-Luisa , Hückelhoven-Krauss Angela , Hong Jian , Zhu Lixin , Kleist Christian , Eckstein Volker , Müller-Tidow Carsten , Dreger Peter , Schmitt Michael , Schmitt Anita
Published: December 2020

Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of anti-apoptotic Bcl-2 family proteins, overexpressed in most cancer cells. In this study we investigated the combination of 3rd-generation CD19.CAR-T cells and the BH3 mimetics venetoclax, a Bcl-2 inhibitor, or S63845, a Mcl-1 inhibitor, under three different treatment conditions: pre-sensitization of cancer cells with BH3 mimetics followed by CAR-T cell treatment, simultaneous combination therapy, and the administration of BH3 mimetics after CAR-T cell treatment. Our results showed that administration of CAR-T cells and BH3 mimetics had a significant effect on the quantity and quality of CD19.CAR-T cells. The administration of BH3 mimetics prior to CAR-T cell therapy exerted an enhanced cytotoxic efficacy by upregulating the CD19 expression and pro-apoptotic proteins in highly sensitive tumor cells, and thereby improving both CD19.CAR-T cell cytotoxicity and persistence. In simultaneous and post-treatment approaches, however, the quantity of CAR-T cells was adversely affected. Our findings indicate pre-sensitization of highly sensitive tumor cells with BH3 mimetics could enhance the cytotoxic efficacy of CAR-T cell treatment.
Effect of Short-Term Rotifer Enrichment With Marine Phospholipids on Growth, Survival, and Composition of Meager (Argyrosomus regius) Larvae
Authors: Ghaderpour Sirwe , Estevez Alicia
Published: December 2020

Larval rearing and ongrowing of meager have experienced a great advance during the last years and nowadays this species is considered as one of the most important new species in Mediterranean aquaculture. However, larval nutrition in meager still needs some improvements especially regarding live prey enrichment and fatty acid composition. In this study, a trial for larval rearing of meager (Argyrosomus regius) using different commercial products for rotifer enrichment (Multigain, Red Pepper and concentrated microalgae) with and without phospholipids (PL), and with a different fatty acid composition, especially regarding DHA, have been used to assess the growth and survival of the larvae and check the effect of PLs in larval growth. Lipid class composition was the same among the larvae whereas % DHA was always higher in larvae fed Multigain and Red Pepper enriched rotifers. The dominant fatty acids in the PL of the larvae and PL of the diets were well-correlated and the results suggested a close relationship between the composition of dominant PL fatty acids in the rotifer and in the larvae, especially in the case of DHA and 16:0 that show a high correlation.
Prevalence of and Risk Factors for Community-Based Osteoporosis and Associated Fractures in Beijing: Study Protocol for a Cross-Sectional and Prospective Study
Authors: Sun Menghua , Zhang Yili , Shen Hao , Sun Kai , Qi Baoyu , Yu Chenchen , Zhi Yingjie , Zhang Ranxing , Jiang Junjie , Chai Yan , Wei Xu , Xie Yanming
Published: December 2020

Background: Osteoporosis (OP) patients are usually asymptomatic until osteoporotic fractures occur, which makes early diagnosis and prevention difficult, and the associated fractures secondary to OP could be preventable with appropriate management. Therefore, early identification and relevant evidence-based management of OP could guide the prevention of subsequent fractures. This study will investigate the prevalence of OP and the incidence of osteoporotic fractures in Beijing community residents to further explore the related risk factors and put forward suggestions for people aged 45–80 years old.

Methods: Over 2 years, this study will conduct an OP screening and a prospective follow-up in the Beijing community to investigate the incidence of osteoporotic fractures. The study will undertake bone mineral density detection, collect biological samples, and record information via questionnaires.

Discussion: The study aims to investigate the potential risk factors for osteoporosis and explore syndromes from traditional Chinese medicine that are associated with this condition based on large samples from the Beijing community. Data on the incidence of osteoporotic fractures among community dwellers in Beijing over the two-years will be available on the Chinese clinical trial registry: ChiCTR-SOC-17013090.
Normal-Appearing Salivary Gland Ultrasonography Identifies a Milder Phenotype of Primary Sjögren's Syndrome
Authors: Zandonella Callegher Sara , Zabotti Alen , Giovannini Ivan , Treppo Elena , Quartuccio Luca , De Vita Salvatore
Published: December 2020

Objective: Salivary gland ultrasound (SGUS) is emerging as a valid tool in the management of primary Sjögren's syndrome (pSS). This study aimed to investigate whether pSS patients with normal-appearing or pathological SGUS findings showed different clinical, laboratory, and pathologic pSS-related features, and to compare the results by using two different SGUS scores.

Methods: Consecutive pSS patients, according to the ACR-EULAR classification criteria, were evaluated. Salivary glands were scored using the early 1992 score by De Vita et al. and the latest 2019 OMERACT score, both being semiquantitative 0–3 scoring systems focused on ultrasonographic parenchymal inhomogeneity (grades 0 and 1, normal-appearing; grades 2 and 3, pathological). The patients were then divided into two groups: “SGUS normal-appearing” if all the salivary glands had normal-appearing parenchyma (grade 0 or 1), or “SGUS pathological” if the grade was 2 or 3 in at least one salivary gland. The associations between SGUS and pSS-related clinical, laboratory, and pathological features were then investigated in the two groups.

Results: One hundred pSS patients were evaluated, the mean age (±SD) was 60.9 ± 12.0 years, and mean disease duration was 11.7 ± 7.2 years. Twenty-nine out of 100 (29%) patients were in the “SGUS normal-appearing” group and 71/100 (71%) were in the “SGUS pathological” group. A normal-appearing SGUS was significantly associated with the absence of anti-La/SSB antibodies (p < 0.001) and normal unstimulated salivary flow rate (p = 0.02) by both univariate and multivariate analyses. By univariate analysis, a normal-appearing SGUS was significantly associated also with the absence of rheumatoid factor (p = 0.002) and of serum monoclonal component (p = 0.003), ESSDAI < 5 (p = 0.03), and with a negative lip biopsy (p = 0.029). No associations were found with other items, including anti-Ro/SSA (p = 0.145), Schirmer's test (p = 0.793), ESSPRI (p = 0.47), and demographic data. No differences in these results were observed by using the two SGUS scoring systems.

Conclusion: The SGUS allowed the identification of different phenotypes of pSS, and different SGUS scores focused on salivary gland inhomogeneity may be effective to this end.
Integrated Transcriptomic and Proteomic Analyses Reveal the Role of NprR in Bacillus anthracis Extracellular Protease Expression Regulation and Oxidative Stress Responses
Authors: Wang Yanchun , Jiang Na , Wang Bowen , Tao Haoxia , Zhang Xin , Guan Qing , Liu Chunjie
Published: December 2020

NprR is a protein of Bacillus anthracis that exhibits moonlighting functions as either a phosphatase or a neutral protease regulator that belongs to the RNPP family. We previously observed that the extracellular protease activity of an nprR deletion mutant significantly decreased within in vitro cultures. To identify the genes within the regulatory network of nprR that contribute to its protease activity, integrated transcriptomic and proteomic analyses were conducted here by comparing the nprR deletion mutant and parent strains. A total of 366 differentially expressed genes (DEGs) between the strains were observed via RNA-seq analysis. In addition, label-free LC-MS/MS analysis revealed 503 differentially expressed proteins (DEPs) within the intracellular protein fraction and 213 extracellular DEPs with significant expressional differences between the strains. The majority of DEGs and DEPs were involved in environmental information processing and metabolism. Integrated transcriptomic and proteomic analyses indicated that oxidation-reduction-related GO terms for intracellular DEPs and endopeptidase-related GO terms for extracellular DEPs were significantly enriched in the mutant strain. Notably, many genes involved in protease activity were largely downregulated in the nprR deletion mutant cultures. Moreover, western blot analysis revealed that the major extracellular neutral protease Npr599 was barely expressed in the nprR deletion mutant strain. The mutant also exhibited impaired degradation of protective antigen, which is a major B. anthracis toxin component, thereby resulting in higher protein yields. Concomitantly, another global transcriptional regulator, SpxA1, was also dramatically downregulated in the nprR deletion mutant, resulting in higher sensitivity to oxidative and disulfide stress. These data consequently indicate that NprR is a transcriptional regulator that controls genes whose products function as extracellular proteases and also is involved in oxidative stress responses. This study thus contributes to a more comprehensive understanding of the biological function of NprR, and especially in the middle growth stages of B. anthracis.
Nanomedicine & Nanotoxicology Future Could Be Reshaped Post-COVID-19 Pandemic
Authors: Al-Ahmady Zahraa S. , Ali-Boucetta Hanene
Published: December 2020

Since its first emergence in December 2019, the coronavirus-2 infection has quickly spread around the world and the severity of the pandemic has already re-shaped our lives. This review highlights the role of nanotechnology in the fight against this pandemic with a focus on the design of effective nano-based prevention and treatment options that overcome the limitations associated with conventional vaccines and other therapies. How nanotechnology could be utilized to understand the pathology of the ongoing pandemic is also discussed as well as how our knowledge about SARS-CoV-2 cellular uptake and toxicity could influence future nanotoxicological considerations and nanomedicine design of safe yet effective nanomaterials.
Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons
Authors: Rousset Francis , B. C. Kokje Vivianne , Sipione Rebecca , Schmidbauer Dominik , Nacher-Soler German , Ilmjärv Sten , Coelho Marta , Fink Stefan , Voruz François , El Chemaly Antoun , Marteyn Antoine , Löwenheim Hubert , Krause Karl-Heinz , Müller Marcus , Glückert Rudolf , Senn Pascal
Published: December 2020

Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro. However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing–thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.
Validation and Diagnostic Performance of a CFD-Based Non-invasive Method for the Diagnosis of Aortic Coarctation
Authors: Lu Qiyang , Lin Weiyuan , Zhang Ruichen , Chen Rui , Wei Xiaoyu , Li Tingyu , Du Zhicheng , Xie Zhaofeng , Yu Zhuliang , Xie Xinzhou , Liu Hui
Published: December 2020

Purpose: The clinical diagnosis of aorta coarctation (CoA) constitutes a challenge, which is usually tackled by applying the peak systolic pressure gradient (PSPG) method. Recent advances in computational fluid dynamics (CFD) have suggested that multi-detector computed tomography angiography (MDCTA)-based CFD can serve as a non-invasive PSPG measurement. The aim of this study was to validate a new CFD method that does not require any medical examination data other than MDCTA images for the diagnosis of CoA.

Materials and methods: Our study included 65 pediatric patients (38 with CoA, and 27 without CoA). All patients underwent cardiac catheterization to confirm if they were suffering from CoA or any other congenital heart disease (CHD). A series of boundary conditions were specified and the simulated results were combined to obtain a stenosis pressure-flow curve. Subsequently, we built a prediction model and evaluated its predictive performance by considering the AUC of the ROC by 5-fold cross-validation.

Results: The proposed MDCTA-based CFD method exhibited a good predictive performance in both the training and test sets (average AUC: 0.948 vs. 0.958; average accuracies: 0.881 vs. 0.877). It also had a higher predictive accuracy compared with the non-invasive criteria presented in the European Society of Cardiology (ESC) guidelines (average accuracies: 0.877 vs. 0.539).

Conclusion: The new non-invasive CFD-based method presented in this work is a promising approach for the accurate diagnosis of CoA, and will likely benefit clinical decision-making.
Morphometric Changes to Corneal Dendritic Cells in Individuals With Mild Cognitive Impairment
Authors: Dehghani Cirous , Frost Shaun , Jayasena Rajiv , Fowler Christopher , Masters Colin L. , Kanagasingam Yogesan , Jiao Haihan , Lim Jeremiah K. H. , Chinnery Holly R. , Downie Laura E.
Published: December 2020

Purpose

There has been increasing interest in identifying non-invasive, imaging biomarkers for neurodegenerative disorders of the central nervous system (CNS). The aim of this proof-of-concept study was to investigate whether corneal sensory nerve and dendritic cell (DC) parameters, captured using in vivo confocal microscopy (IVCM), are altered in individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

Methods

Fifteen participants were recruited from the Australian Imaging Biomarkers and Lifestyle (AIBL) study in Melbourne, VIC, Australia. The cohort consisted of cognitively normal (CN) individuals (n = 5), and those with MCI (n = 5) and AD (n = 5). Participants underwent a slit lamp examination of the anterior segment, followed by corneal imaging using laser-scanning in vivo confocal microscopy (IVCM) of the central and inferior whorl regions. Corneal DC density, field area, perimeter, circularity index, aspect ratio, and roundness were quantified using Image J. Quantitative data were derived for corneal nerve parameters, including nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and diameter.

Results

Corneal DC field area and perimeter were greater in individuals with MCI, relative to CN controls, in both the central and inferior whorl regions (p < 0.05 for all comparisons). In addition, corneal DCs in the whorl region of MCI eyes had lower circularity and roundness indices and a higher aspect ratio relative to CNs (p < 0.05 for all comparisons). DC density was similar across participant groups in both corneal regions. There was a trend toward lower quantitative parameters for corneal nerve architecture in the AD and MCI groups compared with CN participants, however, the inter-group differences did not reach statistical significance. Central corneal nerve diameters were similar between groups.

Conclusion

This study is the first to report morphological differences in corneal DCs in humans with MCI. These differences were evident in both the central and mid-peripheral cornea, and in the absence of significant nerve abnormalities or a difference in DC density. These findings justify future large-scale studies to assess the utility of corneal IVCM and DC analysis for identifying early stage pathology in neurodegenerative disorders of the CNS.
Abnormal Regional Spontaneous Brain Activity and Its Indirect Effect on Spasm Ratings in Patients With Hemifacial Spasm
Authors: Luo Fei-Fei , Xu Hui , Zhang Ming , Wang Yuan
Published: December 2020

Purpose

Three classical methods of resting-state functional magnetic resonance imaging (rs-fMRI) were employed to explore the local functional abnormalities and their effect on spasm ratings in hemifacial spasm (HFS) patients.

Methods

Thirty HFS patients and 30 matched healthy controls (HCs) were recruited. Rs-fMRI data, neurovascular compression (NVC) degree and spasm severity were collected in each subject. Fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated in the whole brain voxels. Two samplet-tests were performed to investigate group differences of fALFF, ReHo, and DC. Correlation analysis was performed to assess the relationships between the regional brain abnormalities and clinical variables in HFS.

Results

Compared with HCs, HFS patients exhibited increased fALFF in the left precuneus and right posterior cingulate cortex (PCC), together with increased ReHo in the bilateral PCC and bilateral precuneus. Decreased ReHo was observed in the right middle occipital gyrus (MOG), right superior occipital gyrus (SOG), right cuneus, and right angular gyrus (AG) in HFS patients. Moreover, ReHo in the right PCC were positively correlated with NVC degree and spasm severity in HFS patients, respectively. Mediation analysis revealed that increased ReHo in the right PCC regulated the neurovascular compression degree, and further resulted in increased spasm ratings.

Conclusion

Our study revealed regional brain dysfunctions from different perspectives and an indirect effect of ReHo in right PCC on spasm ratings predominantly through the alteration of NVC.
AChR β-Subunit mRNAs Are Stabilized by HuR in a Mouse Model of Congenital Myasthenic Syndrome With Acetylcholinesterase Deficiency
Authors: Karmouch Jennifer , Delers Perrine , Semprez Fannie , Soyed Nouha , Areias Julie , Bélanger Guy , Ravel-Chapuis Aymeric , Dobbertin Alexandre , Jasmin Bernard J. , Legay Claire
Published: December 2020

Collagen Q (COLQ) is a specific collagen that anchors acetylcholinesterase (AChE) in the synaptic cleft of the neuromuscular junction. So far, no mutation has been identified in the ACHE human gene but over 50 different mutations in the COLQ gene are causative for a congenital myasthenic syndrome (CMS) with AChE deficiency. Mice deficient for COLQ mimic most of the functional deficit observed in CMS patients. At the molecular level, a striking consequence of the absence of COLQ is an increase in the levels of acetylcholine receptor (AChR) mRNAs and proteins in vivo and in vitro in murine skeletal muscle cells. Here, we decipher the mechanisms that drive AChR mRNA upregulation in cultured muscle cells deficient for COLQ. We show that the levels of AChR β-subunit mRNAs are post-transcriptionally regulated by an increase in their stability. We demonstrate that this process results from an activation of p38 MAPK and the cytoplasmic translocation of the nuclear RNA-binding protein human antigen R (HuR) that interacts with the AU-rich element located within AChR β-subunit transcripts. This HuR/AChR transcript interaction induces AChR β-subunit mRNA stabilization and occurs at a specific stage of myogenic differentiation. In addition, pharmacological drugs that modulate p38 activity cause parallel modifications of HuR protein and AChR β-subunit levels. Thus, our study provides new insights into the signaling pathways that are regulated by ColQ-deficiency and highlights for the first time a role for HuR and p38 in mRNA stability in a model of congenital myasthenic syndrome.
Comparative Profiling of Volatile Compounds in Popular South Indian Traditional and Modern Rice Varieties by Gas Chromatography–Mass Spectrometry Analysis
Authors: Ashokkumar Kaliyaperumal , Govindaraj Mahalingam , Vellaikumar Sampathrajan , Shobhana V. G. , Karthikeyan Adhimoolam , Akilan Manoharan , Sathishkumar Jeyaraman
Published: December 2020

Rice (Oryza sativa L.) is one of the major cereal crops cultivated across the world, particularly in Southeast Asia with 95% of global production. The present study was aimed to evaluate the total phenolic content (TPC) and to profile all the volatile organic compounds (VOCs) of eight popular traditional and two modern rice varieties cultivated in South India. Thirty-one VOCs were estimated by gas chromatography–mass spectrometry (GC-MS). The identified volatile compounds in the 10 rice varieties belong to the chemical classes of fatty acids, terpenes, alkanes, alkenes, alcohols, phenols, esters, amides, and others. Interestingly, most of the identified predominant components were not identical, which indicate the latent variation among the rice varieties. Significant variations exist for fatty acids (46.9–76.2%), total terpenes (12.6–30.7%), total phenols (0.9–10.0%), total aliphatic alcohols (0.8–5.9%), total alkanes (0.5–5.1%), and total alkenes (1.0–4.9%) among the rice varieties. Of all the fatty acid compounds, palmitic acid, elaidic acid, linoleic acid, and oleic acid predominantly varied in the range of 11.1–33.7, 6.1–31.1, 6.0–28.0, and 0.7–15.1%, respectively. The modern varieties recorded the highest palmitic acid contents (28.7–33.7%) than the traditional varieties (11.1–20.6%). However, all the traditional varieties had higher linoleic acid (10.0–28.0%) than the modern varieties (6.0–8.5%). Traditional varieties had key phenolic compounds, stearic acid, butyric acid, and glycidyl oleate, which are absent in the modern varieties. The traditional varieties Seeraga samba and Kichilli samba had the highest azulene and oleic acid, respectively. All these indicate the higher variability for nutrients and aroma in traditional varieties. These varieties can be used as potential parents to improve the largely cultivated high-yielding varieties for the evolving nutritional market. The hierarchical cluster analysis showed three different clusters implying the distinctness of the traditional and modern varieties. This study provided a comprehensive volatile profile of traditional and modern rice as a staple food for energy as well as for aroma with nutrition.