bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing Tsunami Inundation Maps for Evacuation Planning in Italy
Authors: Tonini Roberto , Di Manna Pio , Lorito Stefano , Selva Jacopo , Volpe Manuela , Romano Fabrizio , Basili Roberto , Brizuela Beatriz , Castro Manuel J. , de la Asunción Marc , Di Bucci Daniela , Dolce Mauro , Garcia Alexander , Gibbons Steven J. , Glimsdal Sylfest , González-Vida José M. , Løvholt Finn , Macías Jorge , Piatanesi Alessio , Pizzimenti Luca , Sánchez-Linares Carlos , Vittori Eutizio
Published: March 2021

Inundation maps are a fundamental tool for coastal risk management and in particular for designing evacuation maps and evacuation planning. These in turn are a necessary component of the tsunami warning systems’ last-mile. In Italy inundation maps are informed by a probabilistic tsunami hazard model. Based on a given level of acceptable risk, Italian authorities in charge for this task recommended to consider, as design hazard intensity, the average return period of 2500 years and the 84th percentile of the hazard model uncertainty. An available, regional-scale tsunami hazard model was used that covers the entire Italian coastline. Safety factors based on analysis of run-up variability and an empirical coastal dissipation law on a digital terrain model (DTM) were applied to convert the regional hazard into the design run-up and the corresponding evacuation maps with a GIS-based approach. Since the regional hazard cannot fully capture the local-scale variability, this simplified and conservative approach is considered a viable and feasible practice to inform local coastal risk management in the absence of high-resolution hazard models. The present work is a first attempt to quantify the uncertainty stemming from such procedure. We compare the GIS-based inundation maps informed by a regional model with those obtained from a local high-resolution hazard model. Two locations on the coast of eastern Sicily were considered, and the local hazard was addressed with the same seismic model as the regional one, but using a higher-resolution DTM and massive numerical inundation calculations with the GPU-based Tsunami-HySEA nonlinear shallow water code. This study shows that the GIS-based inundation maps used for planning deal conservatively with potential hazard underestimation at the local scale, stemming from typically unmodeled uncertainties in the numerical source and tsunami evolution models. The GIS-based maps used for planning fall within the estimated “error-bar” due to such uncertainties. The analysis also demonstrates the need to develop local assessments to serve very specific risk mitigation actions to reduce the uncertainty. More in general, the presented case-studies highlight the importance to explore ways of dealing with uncertainty hidden within the high-resolution numerical inundation models, e.g., related to the crude parameterization of the bottom friction, or the inaccuracy of the DTM.
Case Report and Literature Review: Ectopic Thyrotropin-Secreting Pituitary Adenoma in the Suprasellar Region
Authors: Li Xiaoxu , Zhao Binghao , Hou Bo , Wang Jing , Zhu Jianyu , Yao Yong , Lian Xiaolan
Published: March 2021

Ectopic thyrotropin-secreting pituitary adenoma (ectopic TSH-oma) is a rare disorder that is easily misdiagnosed in clinical work. We report one patient who presented with hyperthyroidism and a suprasellar mass. In this case, preoperative diagnosis of suprasellar ectopic thyrotropin-secreting pituitary adenoma was challenging. A literature review revealed that a total of 11 patients with ectopic TSH-oma were previously reported, and only our one case was diagnosed in the microadenoma stage. Most of the patients with TSH-oma or ectopic TSH-oma were middle-aged. We described ectopic TSH-oma in a child at length. We recommend that ectopic TSH-oma should be considered in the differential diagnosis of thyrotoxicosis syndrome to achieve an accurate, early diagnosis. The somatostatin suppression test and imaging examinations, such as magnetic resonance imaging and positron emission tomography/magnetic resonance imaging, could contribute to the diagnosis. Once the diagnosis was highly suspected, tumor resection could achieve a satisfying long-term outcome in ectopic TSH-oma.
The Centrality of Obesity in the Course of Severe COVID-19
Authors: Liu Danfei , Zhang Tongyue , Wang Yijun , Xia Limin
Published: March 2021

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global public health challenge. Most patients do not experience severe complications, but approximately 25% of patients progress to acute respiratory distress syndrome (ARDS), and the mortality rate is approximately 5–7%. Clinical findings have determined several risk factors for severe complications and mortality in COVID-19 patients, such as advanced age, smoking, obesity, and chronic diseases. Obesity is a common and serious health problem worldwide that initiates a cascade of disorders, including hypertension, cardiovascular disease (CVD), diabetes mellitus, and chronic kidney disease (CKD). The presence of these disorders is linked to a more severe course of COVID-19. Given the “epidemic” of obesity worldwide and the importance of obesity in the progression of COVID-19, we investigated the mechanisms through which obesity increases the susceptibility to and severity of COVID-19 to support the selection of more appropriate therapies for individuals with obesity.
The Complex World of Regulation of Pituitary Growth Hormone Secretion: The Role of Ghrelin, Klotho, and Nesfatins in It
Authors: Devesa Jesús
Published: March 2021

The classic concept of how pituitary GH is regulated by somatostatin and GHRH has changed in recent years, following the discovery of peripheral hormones involved in the regulation of energy homeostasis and mineral homeostasis. These hormones are ghrelin, nesfatins, and klotho. Ghrelin is an orexigenic hormone, released primarily by the gastric mucosa, although it is widely expressed in many different tissues, including the central nervous system and the pituitary. To be active, ghrelin must bind to an n-octanoyl group (n = 8, generally) on serine 3, forming acyl ghrelin which can then bind and activate a G-protein-coupled receptor leading to phospholipase C activation that induces the formation of inositol 1,4,5-triphosphate and diacylglycerol that produce an increase in cytosolic calcium that allows the release of GH. In addition to its direct action on somatotrophs, ghrelin co-localizes with GHRH in several neurons, facilitating its release by inhibiting somatostatin, and acts synergistically with GHRH stimulating the synthesis and secretion of pituitary GH. Gastric ghrelin production declines with age, as does GH. Klotho is an anti-aging agent, produced mainly in the kidneys, whose soluble circulating form directly induces GH secretion through the activation of ERK1/2 and inhibits the inhibitory effect that IGF-I exerts on GH. Children and adults with untreated GH-deficiency show reduced plasma levels of klotho, but treatment with GH restores them to normal values. Deletions or mutations of the Klotho gene affect GH production. Nesfatins 1 and 2 are satiety hormones, they inhibit food intake. They have been found in GH3 cell cultures where they significantly reduce the expression of gh mRNA and that of pituitary-specific positive transcription factor 1, consequently acting as inhibitors of GH production. This is a consequence of the down-regulation of the cAMP/PKA/CREB signaling pathway. Interestingly, nesfatins eliminate the strong positive effect that ghrelin has on GH synthesis and secretion. Throughout this review, we will attempt to broadly analyze the role of these hormones in the complex world of GH regulation, a world in which these hormones already play a very important role.
Carbon and Beyond: The Biogeochemistry of Climate in a Rapidly Changing Amazon
Authors: Covey Kristofer , Soper Fiona , Pangala Sunitha , Bernardino Angelo , Pagliaro Zoe , Basso Luana , Cassol Henrique , Fearnside Philip , Navarrete Diego , Novoa Sidney , Sawakuchi Henrique , Lovejoy Thomas , Marengo Jose , Peres Carlos A. , Baillie Jonathan , Bernasconi Paula , Camargo Jose , Freitas Carolina , Hoffman Bruce , Nardoto Gabriela B. , Nobre Ismael , Mayorga Juan , Mesquita Rita , Pavan Silvia , Pinto Flavia , Rocha Flavia , de Assis Mello Ricardo , Thuault Alice , Bahl Alexis Anne , Elmore Aurora
Published: March 2021

The Amazon Basin is at the center of an intensifying discourse about deforestation, land-use, and global change. To date, climate research in the Basin has overwhelmingly focused on the cycling and storage of carbon (C) and its implications for global climate. Missing, however, is a more comprehensive consideration of other significant biophysical climate feedbacks [i.e., CH4, N2O, black carbon, biogenic volatile organic compounds (BVOCs), aerosols, evapotranspiration, and albedo] and their dynamic responses to both localized (fire, land-use change, infrastructure development, and storms) and global (warming, drying, and some related to El Niño or to warming in the tropical Atlantic) changes. Here, we synthesize the current understanding of (1) sources and fluxes of all major forcing agents, (2) the demonstrated or expected impact of global and local changes on each agent, and (3) the nature, extent, and drivers of anthropogenic change in the Basin. We highlight the large uncertainty in flux magnitude and responses, and their corresponding direct and indirect effects on the regional and global climate system. Despite uncertainty in their responses to change, we conclude that current warming from non-CO2 agents (especially CH4 and N2O) in the Amazon Basin largely offsets—and most likely exceeds—the climate service provided by atmospheric CO2 uptake. We also find that the majority of anthropogenic impacts act to increase the radiative forcing potential of the Basin. Given the large contribution of less-recognized agents (e.g., Amazonian trees alone emit ~3.5% of all global CH4), a continuing focus on a single metric (i.e., C uptake and storage) is incompatible with genuine efforts to understand and manage the biogeochemistry of climate in a rapidly changing Amazon Basin.
A Novel Six-mRNA Signature Predicts Survival of Patients With Glioblastoma Multiforme
Authors: Liu Zhentao , Zhang Hao , Hu Hongkang , Cai Zheng , Lu Chengyin , Liang Qiang , Qian Jun , Wang Chunhui , Jiang Lei
Published: March 2021

Glioblastoma multiforme (GBM) is a devastating brain tumor and displays divergent clinical outcomes due to its high degree of heterogeneity. Reliable prognostic biomarkers are urgently needed for improving risk stratification and survival prediction. In this study, we analyzed genome-wide mRNA profiles in GBM patients derived from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify mRNA-based signatures for GBM prognosis with survival analysis. Univariate Cox regression model was used to evaluate the relationship between the expression of mRNA and the prognosis of patients with GBM. We established a risk score model that consisted of six mRNA (AACS, STEAP1, STEAP2, G6PC3, FKBP9, and LOXL1) by the LASSO regression method. The six-mRNA signature could divide patients into a high-risk and a low-risk group with significantly different survival rates in training and test sets. Multivariate Cox regression analysis confirmed that it was an independent prognostic factor in GBM patients, and it has a superior predictive power as compared with age, IDH mutation status, MGMT, and G-CIMP methylation status. By combining this signature and clinical risk factors, a nomogram can be established to predict 1-, 2-, and 3-year OS in GBM patients with relatively high accuracy.
A New Model for Caries Risk Prediction in Teenagers Using a Machine Learning Algorithm Based on Environmental and Genetic Factors
Authors: Pang Liangyue , Wang Ketian , Tao Ye , Zhi Qinghui , Zhang Jianming , Lin Huancai
Published: March 2021

Dental caries is a multifactorial disease that can be caused by interactions between genetic and environmental risk factors. Despite the availability of caries risk assessment tools, caries risk prediction models incorporating new factors, such as human genetic markers, have not yet been reported. The aim of this study was to construct a new model for caries risk prediction in teenagers, based on environmental and genetic factors, using a machine learning algorithm. We performed a prospective longitudinal study of 1,055 teenagers (710 teenagers for cohort 1 and 345 teenagers for cohort 2) aged 13 years, of whom 953 (633 teenagers for cohort 1 and 320 teenagers for cohort 2) were followed for 21 months. All participants completed an oral health questionnaire, an oral examination, biological (salivary and cariostate) tests, and single nucleotide polymorphism sequencing analysis. We constructed a caries risk prediction model based on these data using a random forest with an AUC of 0.78 in cohort 1 (training cohort). We further verified the discrimination and calibration abilities of this caries risk prediction model using cohort 2. The AUC of the caries risk prediction model in cohort 2 (testing cohort) was 0.73, indicating high discrimination ability. Risk stratification revealed that our caries risk prediction model could accurately identify individuals at high and very high caries risk but underestimated risks for individuals at low and very low caries risk. Thus, our caries risk prediction model has the potential for use as a powerful community-level tool to identify individuals at high caries risk.
The Molecular Function of PURA and Its Implications in Neurological Diseases
Authors: Molitor Lena , Bacher Sabrina , Burczyk Sandra , Niessing Dierk
Published: March 2021

In recent years, genome-wide analyses of patients have resulted in the identification of a number of neurodevelopmental disorders. Several of them are caused by mutations in genes that encode for RNA-binding proteins. One of these genes is PURA, for which in 2014 mutations have been shown to cause the neurodevelopmental disorder PURA syndrome. Besides intellectual disability (ID), patients develop a variety of symptoms, including hypotonia, metabolic abnormalities as well as epileptic seizures. This review aims to provide a comprehensive assessment of research of the last 30 years on PURA and its recently discovered involvement in neuropathological abnormalities. Being a DNA- and RNA-binding protein, PURA has been implicated in transcriptional control as well as in cytoplasmic RNA localization. Molecular interactions are described and rated according to their validation state as physiological targets. This information will be put into perspective with available structural and biophysical insights on PURA’s molecular functions. Two different knock-out mouse models have been reported with partially contradicting observations. They are compared and put into context with cell biological observations and patient-derived information. In addition to PURA syndrome, the PURA protein has been found in pathological, RNA-containing foci of patients with the RNA-repeat expansion diseases such as fragile X-associated tremor ataxia syndrome (FXTAS) and amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) spectrum disorder. We discuss the potential role of PURA in these neurodegenerative disorders and existing evidence that PURA might act as a neuroprotective factor. In summary, this review aims at informing researchers as well as clinicians on our current knowledge of PURA’s molecular and cellular functions as well as its implications in very different neuronal disorders.
Genome-Wide DNA Methylation and Transcriptome Analyses Reveal Epigenetic and Genetic Mechanisms Underlying Sex Maintenance of Adult Chinese Alligator
Authors: Lin Jian-Qing , Yu Jun , Sun Li , Fang Sheng-Guo
Published: March 2021

The sexes of Chinese alligators are determined during embryonic development and remain fixed thereafter. In this study, we investigated the genetic and epigenetic mechanisms underlying sex maintenance in Chinese alligators through RNA sequencing and bisulfite sequencing data analyses of the adult gonads. We identified the genes and pathways (e. g., DMRT1-SOX9-AMH pathway for males and oocyte meiotic maturation pathway for females) involved in male and female sex maintenance and gonadal development of adult Chinese alligators. In contrast to their expression patterns in the embryo, both DMRT1 and the steroid hormone biosynthesis related genes showed a male-biased expression in adult gonads. The overall DNA methylation density and level were higher in testes than in ovaries. Hypermethylation in the gene bodies enhanced the expression of male-biased genes (such as DMRT1-SOX9-AMH and steroid hormone biosynthesis related genes) in the testis, as opposed to the normalization of gene expression. Our results provide insights into the genetic and epigenetic mechanisms underlying sex maintenance in adult Chinese alligators, and are expected to contribute to the development of scientific programs for the successful conservation of this endangered species.
The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial
Authors: Sangaleti Carine Teles , Katayama Keyla Yukari , De Angelis Kátia , Lemos de Moraes Tércio , Araújo Amanda Aparecida , Lopes Heno F. , Camacho Cleber , Bortolotto Luiz Aparecido , Michelini Lisete Compagno , Irigoyen Maria Cláudia , Olofsson Peder S. , Barnaby Douglas P. , Tracey Kevin J. , Pavlov Valentin A. , Consolim Colombo Fernanda Marciano
Published: March 2021

Background: The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS.

Trial Design and Methods: The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment.

Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39–2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34–1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46–1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 μmol/mg protein, [95% CI 0.57–1.20], P = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment.

Conclusion: Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.
OX40L/OX40 Signal Promotes IL-9 Production by Mucosal MAIT Cells During Helicobacter pylori Infection
Authors: Ming Siqi , Zhang Mei , Liang Zibin , Li Chunna , He Jianzhong , Chen Peiyu , Zhang Shunxian , Niu Xiaoli , Deng Shimei , Geng Lanlan , Zhang Guoliang , Gong Sitang , Wu Yongjian
Published: March 2021

Mucosal associated invariant T (MAIT) cells play a critical role in Helicobacter pylori (H. pylori)-induced gastritis by promoting mucosal inflammation and aggravating mucosal injuries (1, 2). However, the underlying mechanism and key molecules involved are still uncertain. Here we identified OX40, a co-stimulatory molecule mainly expressed on T cells, as a critical regulator to promote proliferation and IL-9 production by MAIT cells and facilitate mucosal inflammation in H. pylori-positive gastritis patients. Serum examination revealed an increased level of IL-9 in gastritis patients. Meanwhile, OX40 expression was increased in mucosal MAIT cells, and its ligand OX40L was also up-regulated in mucosal dendritic cells (DCs) of gastritis patients, compared with healthy controls. Further results demonstrated that activation of the OX40/OX40L pathway promoted IL-9 production by MAIT cells, and MAIT cells displayed a highly-activated phenotype after the cross-linking of OX40 and OX40L. Moreover, the level of IL-9 produced by MAIT cells was positively correlated with inflammatory indexes in the gastric mucosa, suggesting the potential role of IL-9-producing MAIT cells in mucosal inflammation. Taken together, we elucidated that OX40/OX40L axis promoted mucosal MAIT cell proliferation and IL-9 production in H. pylori-induced gastritis, which may provide potential targeting strategies for gastritis treatment.
The Contact Allergen NiSO4 Triggers a Distinct Molecular Response in Primary Human Dendritic Cells Compared to Bacterial LPS
Authors: Höper Tessa , Siewert Katherina , Dumit Verónica I. , von Bergen Martin , Schubert Kristin , Haase Andrea
Published: March 2021

Dendritic cells (DC) play a central role in the pathogenesis of allergic contact dermatitis (ACD), the most prevalent form of immunotoxicity in humans. However, knowledge on allergy-induced DC maturation is still limited and proteomic studies, allowing to unravel molecular effects of allergens, remain scarce. Therefore, we conducted a global proteomic analysis of human monocyte-derived dendritic cells (MoDC) treated with NiSO4, the most prominent cause of ACD and compared proteomic alterations induced by NiSO4 to the bacterial trigger lipopolysaccharide (LPS). Both substances possess a similar toll-like receptor (TLR) 4 binding capacity, allowing to identify allergy-specific effects compared to bacterial activation. MoDCs treated for 24 h with 2.5 μg/ml LPS displayed a robust immunological response, characterized by upregulation of DC activation markers, secretion of pro-inflammatory cytokines and stimulation of T cell proliferation. Similar immunological reactions were observed after treatment with 400 μM NiSO4 but less pronounced. Both substances triggered TLR4 and triggering receptor expressed on myeloid cells (TREM) 1 signaling. However, NiSO4 also activated hypoxic and apoptotic pathways, which might have overshadowed initial signaling. Moreover, our proteomic data support the importance of nuclear factor erythroid 2-related factor 2 (Nrf2) as a key player in sensitization since many Nrf2 targets genes were strongly upregulated on protein and gene level selectively after treatment with NiSO4. Strikingly, NiSO4 stimulation induced cellular cholesterol depletion which was counteracted by the induction of genes and proteins relevant for cholesterol biosynthesis. Our proteomic study allowed for the first time to better characterize some of the fundamental differences between NiSO4 and LPS-triggered activation of MoDCs, providing an essential contribution to the molecular understanding of contact allergy.
Ceratothoa oestroides Infection in European Sea Bass: Revealing a Long Misunderstood Relationship
Authors: Piazzon M. Carla , Mladineo Ivona , Dirks Ron P. , Santidrián Yebra-Pimentel Elena , Hrabar Jerko , Sitjà-Bobadilla Ariadna
Published: March 2021

Ceratothoa oestroides(Cymothoidea, Isopoda) is a generalist crustacean parasite that negatively affects the economic sustainability of European sea bass (Dicentrarchus labrax) aquaculture in the North-East Mediterranean. While mortalities are observed in fry and fingerlings, infection in juvenile and adult fish result in approximately 20% growth delay. A transcriptomic analysis (PCR array, RNA-Seq) was performed on organs (tongue, spleen, head kidney, and liver) from infected vs.Ceratothoa-free sea bass fingerlings. Activation of local and systemic immune responses was detected, particularly in the spleen, characterized by the upregulation of cytokines (also in the tongue), a general reshaping of the immunoglobulin (Ig) response and suppression of T-cell mediated responses. Interestingly, starvation and iron transport and metabolism genes were strongly downregulated, suggesting that the parasite feeding strategy is not likely hematophagous. The regulation of genes related to growth impairment and starvation supported the growth delay observed in infected animals. Most differentially expressed (DE) transcripts were exclusive of a specific organ; however, only in the tongue, the difference between infected and uninfected fish was significant. At the attachment/feeding site, the pathways involved in muscle contraction and intercellular junction were the most upregulated, whereas the pathways involved in fibrosis (extracellular matrix organization, collagen formation, and biosynthesis) were downregulated. These results suggest that parasite-inflicted damage is successfully mitigated by the host and characterized by regenerative processes that prevail over the reparative ones.
T Cell Activation, Highly Armed Cytotoxic Cells and a Shift in Monocytes CD300 Receptors Expression Is Characteristic of Patients With Severe COVID-19
Authors: Zenarruzabeitia Olatz , Astarloa-Pando Gabirel , Terrén Iñigo , Orrantia Ane , Pérez-Garay Raquel , Seijas-Betolaza Iratxe , Nieto-Arana Javier , Imaz-Ayo Natale , Pérez-Fernández Silvia , Arana-Arri Eunate , Borrego Francisco
Published: March 2021

COVID-19 manifests with a wide diversity of clinical phenotypes characterized by dysfunctional and exaggerated host immune responses. Many results have been described on the status of the immune system of patients infected with SARS-CoV-2, but there are still aspects that have not been fully characterized or understood. In this study, we have analyzed a cohort of patients with mild, moderate and severe disease. We performed flow cytometric studies and correlated the data with the clinical characteristics and clinical laboratory values of the patients. Both conventional and unsupervised data analyses concluded that patients with severe disease are characterized, among others, by a higher state of activation in all T cell subsets (CD4, CD8, double negative and T follicular helper cells), higher expression of perforin and granzyme B in cytotoxic cells, expansion of adaptive NK cells and the accumulation of activated and immature dysfunctional monocytes which are identified by a low expression of HLA-DR and an intriguing shift in the expression pattern of CD300 receptors. More importantly, correlation analysis showed a strong association between the alterations in the immune cells and the clinical signs of severity. These results indicate that patients with severe COVID-19 have a broad perturbation of their immune system, and they will help to understand the immunopathogenesis of COVID-19.
Biological Impact of Ocean Acidification in the Canadian Arctic: Widespread Severe Pteropod Shell Dissolution in Amundsen Gulf
Authors: Niemi Andrea , Bednaršek Nina , Michel Christine , Feely Richard A. , Williams William , Azetsu-Scott Kumiko , Walkusz Wojciech , Reist James D.
Published: March 2021

Increasing atmospheric CO2, cold water temperatures, respiration, and freshwater inputs all contribute to enhanced acidification in Arctic waters. However, ecosystem effects of ocean acidification (derived from anthropogenic and/or natural sources) in the Arctic Ocean are highly uncertain. Zooplankton samples and oceanographic data were collected in August 2012–2014 and again in August 2017 to investigate the pelagic sea snail,Limacina helicina, a biological indicator of the presence and potential impact of acidified waters in the Canadian Beaufort Sea. Between 2012 and 2014L. helicinaabundance ranged from <1 to 1942 Ind. m–2, with highest abundances occurring at stations on the Canadian Beaufort Shelf in 2012. The majority of individuals (66%) were located between 25 and 100 m depth, corresponding to upper halocline water of Pacific origin. In both 2014 and 2017, >85% ofL. helicinaassessed (n= 134) from the Amundsen Gulf region displayed shell dissolution and advanced levels of dissolution occurred at all stations. The severity of dissolution was not significantly different between 2014 and 2017 despite the presence of larger individuals that are less prone to dissolution, and higher food availability that can provide some physiological benefits in 2014. Corrosive water conditions were not widespread in the Amundsen Gulf at the time of sampling in 2017, and aragonite undersaturation (Ωar< 1) occurred primarily at depths >150 m. The majority of dissolution was observed on the first whorl of the shells strongly indicating that damage was initiated during the larval stage of growth in May or early June when sea ice is still present. Evidence of shell modification was present in 2014, likely supported by abundant food availability in 2014 relative to 2017. The proportion of damagedL. helicinacollected from coastal embayments and offshore stations is higher than in other Arctic and temperate locations indicating that exposure to corrosive waters is spatially widespread in the Amundsen Gulf region, and periods of exposure are extreme enough to impact the majority of the population.
ESBL and AmpC β-Lactamase Encoding Genes in E. coli From Pig and Pig Farm Workers in Vietnam and Their Association With Mobile Genetic Elements
Authors: Hounmanou Yaovi Mahuton Gildas , Bortolaia Valeria , Dang Son Thi Thanh , Truong Duong , Olsen John E. , Dalsgaard Anders
Published: March 2021

Animals are considered important sources of ESBL/AmpC-producing bacteria in humans. We analyzed indications of transfer of ESBL/AmpC genes between pigs and pig farmers in Vietnam by analyzing whole genome sequences of 114 ESBL/AmpC-producing E. coli isolated from the two hosts, and performed conjugation experiments and plasmid profiling to confirm that such transfer could have happened. ESBL-encoding genes detected in pigs and pig farmers included blaCTX–M-55, blaCTX-M-27, blaCTX-M-65, blaCTX-M-15, blaCTX-M-14, blaCTX-M-3, blaCTX-M-24, and blaCARB-2, and AmpC β-lactamases included blaCMY-2, blaDHA-1, and blaCMY-42. The most frequent ESBL gene, blaCTX-M-55, was carried on plasmid with replicons types IncF, IncX, IncH, IncN, IncR, and IncP. The insertion transposases downstream of the blaCTX-M-55 gene were different in plasmids carried by different strains. The second most detected gene, blaCTX-M-27, is found in a stable genetic arrangement with the same flanking transposons seen across strains, and the gene was located on similar conjugal IncF plasmid types, suggesting a horizontal spread of these plasmids. In three strains, we observed a novel blaCTX-M-27 harboring IncF type of plasmid which had not been reported before. Its closest reference in NCBI was the non-ESBL Salmonella Typhimurium plasmid pB71 that might have experienced an insertion of blaCTX-M-27. Our data also point to an emergence of plasmids co-carrying ESBL genes, mcr genes, quinolones and other antimicrobials resistance determinants, and such plasmids require special attention. Plasmids phylogeny confirmed that the blaCTX-M-55 encoding plasmids varied considerably, while those encoding blaCTX-M-27 were closely related. Plasmids harboring both ESBL genes were confirmed to be conjugative and not to differ in transfer efficacy. The isolates carrying the plasmids, even those with plasmids of similar types, showed wide genetic variation with high number of SNPs, suggesting horizontal spread of plasmids into different clonal lines. Their virulence profiles did not confirm to known pathotypes, suggesting that unrelated commensals are a main reservoir for ESBL and AmpC β-lactamases in both humans and pigs. Overall, despite evidence of transferability of plasmids in the analyzed strains, our findings do not support that ESBL-producing E. coli from pigs or their ESBL/AmpC encoding plasmids are commonly spread to workers in close contact with the animals.
H2S Persulfidated and Increased Kinase Activity of MPK4 to Response Cold Stress in Arabidopsis
Authors: Du Xinzhe , Jin Zhuping , Liu Zhiqiang , Liu Danmei , Zhang Liping , Ma Xiaoli , Yang Guangdong , Liu Sha , Guo Yarong , Pei Yanxi
Published: March 2021

Hydrogen sulfide (H2S) is a gasotransmitter along with nitric oxide and carbon oxide, which is involved in plant growth and development as well as biotic and abiotic stress resistance. In a previous study, we reported that mitogen-activated protein kinases, especially MPK4, are important downstream components of H2S involved in alleviating cold stress; however the underlying mechanism is unclear. In this study, we determined that the ability of H2S to alleviate cold stress is impaired in mpk4 mutants, but not in the upstream mek2 and crlk1 mutants. MPK4 was basically persulfidated, and NaHS (H2S donor) further increased the persulfidation level of MPK4. MEK2 was not persulfidated by H2S. NaHS treatments increased the MPK4 activity level nearly tenfold. The persulfidation signal of MPK4 did not disappear after eight cystein residues in MPK4 were site-mutated, respectively. Above all, our results suggested that H2S alleviates cold stress directly by persulfidating MPK4 and increasing the MPK4 kinase activity.
A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration
Authors: Pellegrini Camilla , Pirazzini Chiara , Sala Claudia , Sambati Luisa , Yusipov Igor , Kalyakulina Alena , Ravaioli Francesco , Kwiatkowska Katarzyna M. , Durso Danielle F. , Ivanchenko Mikhail , Monti Daniela , Lodi Raffaele , Franceschi Claudio , Cortelli Pietro , Garagnani Paolo , Bacalini Maria Giulia
Published: March 2021

Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.
Serum Uric Acid Levels Predict Mortality Risk in Male Amyotrophic Lateral Sclerosis Patients
Authors: Xu Liu-Qing , Hu Wei , Guo Qi-Fu , Xu Guo-Rong , Wang Ning , Zhang Qi-Jie
Published: March 2021

Objective: To explore the associations between serum uric acid levels with survival in male and female ALS patients.

Methods: A longitudinal cohort study was carried out including 313 sporadic and 16 familial ALS patients with repeated serum uric acid measurements. Multivariate Cox regression models were used to evaluate the survival-related factors.

Results: There were 207 male and 122 female, and the mean age of onset was 55.7 ± 11.2 years old. The male patients had significantly higher baseline uric acid levels than that in female patients (342.4 ± 91.4 vs. 279.3 ± 71.4 μmol/L; p < 0.0001). The uric acid levels were inversely associated with the decline rate of ALSFRS-R per month (ΔALSFRS-R). After multivariate Cox regression analysis, a survival advantage was found in male, but not female, with higher serum uric acid levels. In males, a shorter diagnostic delay (≤10 m), lower BMI at baseline (≤18.70 kg/m2), faster disease progression (ΔALSFRS-R > 0.63), and lower baseline uric acid levels (≤292 μmol/L, HR: 1.936; 95% CI: 1.334–2.810) were associated with a shorter survival. During follow-up, the serum uric acid levels were not significantly altered over time.

Conclusion: There is an inverse correlation between baseline serum uric acid levels and risk of death, prominently in male ALS patients.
Artifact Reduction in Simultaneous EEG-fMRI: A Systematic Review of Methods and Contemporary Usage
Authors: Bullock Madeleine , Jackson Graeme D. , Abbott David F.
Published: March 2021

Simultaneous electroencephalography-functional MRI (EEG-fMRI) is a technique that combines temporal (largely from EEG) and spatial (largely from fMRI) indicators of brain dynamics. It is useful for understanding neuronal activity during many different event types, including spontaneous epileptic discharges, the activity of sleep stages, and activity evoked by external stimuli and decision-making tasks. However, EEG recorded during fMRI is subject to imaging, pulse, environment and motion artifact, causing noise many times greater than the neuronal signals of interest. Therefore, artifact removal methods are essential to ensure that artifacts are accurately removed, and EEG of interest is retained. This paper presents a systematic review of methods for artifact reduction in simultaneous EEG-fMRI from literature published since 1998, and an additional systematic review of EEG-fMRI studies published since 2016. The aim of the first review is to distill the literature into clear guidelines for use of simultaneous EEG-fMRI artifact reduction methods, and the aim of the second review is to determine the prevalence of artifact reduction method use in contemporary studies. We find that there are many published artifact reduction techniques available, including hardware, model based, and data-driven methods, but there are few studies published that adequately compare these methods. In contrast, recent EEG-fMRI studies show overwhelming use of just one or two artifact reduction methods based on literature published 15–20 years ago, with newer methods rarely gaining use outside the group that developed them. Surprisingly, almost 15% of EEG-fMRI studies published since 2016 fail to adequately describe the methods of artifact reduction utilized. We recommend minimum standards for reporting artifact reduction techniques in simultaneous EEG-fMRI studies and suggest that more needs to be done to make new artifact reduction techniques more accessible for the researchers and clinicians using simultaneous EEG-fMRI.
The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat): Driving Multicentric Research and Implementation Science
Authors: Ibanez Agustin , Yokoyama Jennifer S. , Possin Katherine L. , Matallana Diana , Lopera Francisco , Nitrini Ricardo , Takada Leonel T. , Custodio Nilton , Sosa Ortiz Ana Luisa , Avila-Funes José Alberto , Behrens Maria Isabel , Slachevsky Andrea , Myers Richard M. , Cochran J. Nicholas , Brusco Luis Ignacio , Bruno Martin A. , Brucki Sonia M. D. , Pina-Escudero Stefanie Danielle , Okada de Oliveira Maira , Donnelly Kehoe Patricio , Garcia Adolfo M. , Cardona Juan Felipe , Santamaria-Garcia Hernando , Moguilner Sebastian , Duran-Aniotz Claudia , Tagliazucchi Enzo , Maito Marcelo , Longoria Ibarrola Erika Mariana , Pintado-Caipa Maritza , Godoy Maria Eugenia , Bakman Vera , Javandel Shireen , Kosik Kenneth S. , Valcour Victor , Miller Bruce L.
Published: March 2021

Dementia is becoming increasingly prevalent in Latin America, contrasting with stable or declining rates in North America and Europe. This scenario places unprecedented clinical, social, and economic burden upon patients, families, and health systems. The challenges prove particularly pressing for conditions with highly specific diagnostic and management demands, such as frontotemporal dementia. Here we introduce a research and networking initiative designed to tackle these ensuing hurdles, the Multi-partner consortium to expand dementia research in Latin America (ReDLat). First, we present ReDLat's regional research framework, aimed at identifying the unique genetic, social, and economic factors driving the presentation of frontotemporal dementia and Alzheimer's disease in Latin America relative to the US. We describe ongoing ReDLat studies in various fields and ongoing research extensions. Then, we introduce actions coordinated by ReDLat and the Latin America and Caribbean Consortium on Dementia (LAC-CD) to develop culturally appropriate diagnostic tools, regional visibility and capacity building, diplomatic coordination in local priority areas, and a knowledge-to-action framework toward a regional action plan. Together, these research and networking initiatives will help to establish strong cross-national bonds, support the implementation of regional dementia plans, enhance health systems' infrastructure, and increase translational research collaborations across the continent.
Reduction of Pressure Pain Sensitivity as Novel Non-pharmacological Therapeutic Approach to Type 2 Diabetes: A Randomized Trial
Authors: Faber Jens , Eldrup Ebbe , Selmer Christian , Pichat Caroline , Hecquet Sofie Korsgaard , Watt Torquil , Kreiner Svend , Karpatschof Benny , Gyntelberg Finn , Ballegaard Søren , Gjedde Albert
Published: March 2021

Background

Autonomic nervous system dysfunction (ANSD) is known to affect glucose metabolism in the mammalian body. Tradition holds that glucose homeostasis is regulated by the peripheral nervous system, and contemporary therapeutic intervention reflects this convention.

Objectives

The present study tested the role of cerebral regulation of ANSD as consequence of novel understanding of glucose metabolism and treatment target in type 2 diabetes (T2D), suggested by the claim that the pressure pain sensitivity (PPS) of the chest bone periosteum may be a measure of cerebral ANSD.

Design

In a randomized controlled trial of 144 patients with T2D, we tested the claim that 6 months of this treatment would reduce PPS and improve peripheral glucose metabolism.

Results

In the active treatment group, mean glycated hemoglobin A1c (HbA1c) declined from 53.8 to 50.5 mmol/mol (intragroup p = 0.001), compared with the change from 53.8 to 53.4 mmol/mol in the control group, with the same level of diabetes treatment but not receiving the active treatment (between group p = 0.036). Mean PPS declined from 76.6 to 56.1 units (p < 0.001) in the active treatment group and from 77.5 to 72.8 units (p = 0.02; between group p < 0.001) in the control group. Changes of PPS and HbA1c were correlated (r = 0.37; p < 0.001).

Conclusion

We conclude that the proposed approach to treatment of T2D is a potential supplement to conventional therapy.

Clinical Trial Registration:

www.clinicaltrials.gov (NCT 03576430).
Altered Functional Connectivity Within and Between Salience and Sensorimotor Networks in Patients With Functional Constipation
Authors: Duan Shijun , Liu Lei , Li Guanya , Wang Jia , Hu Yang , Zhang Wenchao , Tan Zongxin , Jia Zhenzhen , Zhang Lei , von Deneen Karen M. , Zhang Yi , Nie Yongzhan , Cui Guangbin
Published: March 2021

Functional constipation (FCon) is a common functional gastrointestinal disorder. A considerable portion of patients with FCon is associated with anxiety/depressive status (FCAD). Previous neuroimaging studies mainly focused on patients with FCon without distinguishing FCAD from FCon patients without anxiety/depressive status (FCNAD). Differences in brain functions between these two subtypes remain unclear. Thus, we employed resting-state functional magnetic resonance imaging (RS-fMRI) and graph theory method to investigate differences in brain network connectivity and topology in 41 FCAD, 42 FCNAD, and 43 age- and gender-matched healthy controls (HCs). FCAD/FCNAD showed significantly lower normalized clustering coefficient and small-world-ness. Both groups showed altered nodal degree/efficiency mainly in the rostral anterior cingulate cortex (rACC), precentral gyrus (PreCen), supplementary motor area (SMA), and thalamus. In the FCAD group, nodal degree in the SMA was negatively correlated with difficulty of defecation, and abdominal pain was positively correlated with nodal degree/efficiency in the rACC, which had a lower within-module nodal degree. The salience network (SN) exhibited higher functional connectivity (FC) with the sensorimotor network (SMN) in FCAD/FCNAD, and FC between these two networks was negatively correlated with anxiety ratings in FCAD group. Additionally, FC of anterior insula (aINS)–rACC was only correlated with constipation symptom (i.e., abdominal pain) in the FCNAD group. In the FCAD group, FCs of dorsomedial prefrontal cortex–rACC, PreCen–aINS showed correlations with both constipation symptom (i.e., difficulty of defecation) and depressive status. These findings indicate the differences in FC of the SN–SMN between FCAD and FCNAD and provide neuroimaging evidence based on brain function, which portrays important clues for improving new treatment strategies.