bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying Priorities for the Protection of Deep Mediterranean Sea Ecosystems Through an Integrated Approach
Authors: Fanelli Emanuela , Bianchelli Silvia , Foglini Federica , Canals Miquel , Castellan Giorgio , Güell-Bujons Queralt , Galil Bella , Goren Menachem , Evans Julian , Fabri Marie-Claire , Vaz Sandrine , Ciuffardi Tiziana , Schembri Patrick J. , Angeletti Lorenzo , Taviani Marco , Danovaro Roberto
Published: July 2021

Benthic habitats of the deep Mediterranean Sea and the biodiversity they host are increasingly jeopardized by increasing human pressures, both direct and indirect, which encompass fisheries, chemical and acoustic pollution, littering, oil and gas exploration and production and marine infrastructures (i.e., cable and pipeline laying), and bioprospecting. To this, is added the pervasive and growing effects of human-induced perturbations of the climate system. International frameworks provide foundations for the protection of deep-sea ecosystems, but the lack of standardized criteria for the identification of areas deserving protection, insufficient legislative instruments and poor implementation hinder an efficient set up in practical terms. Here, we discuss the international legal frameworks and management measures in relation to the status of habitats and key species in the deep Mediterranean Basin. By comparing the results of a multi-criteria decision analysis (MCDA) and of expert evaluation (EE), we identify priority deep-sea areas for conservation and select five criteria for the designation of future protected areas in the deep Mediterranean Sea. Our results indicate that areas (1) with high ecological relevance (e.g., hosting endemic and locally endangered species and rare habitats),(2) ensuring shelf-slope connectivity (e.g., submarine canyons), and (3) subject to current and foreseeable intense anthropogenic impacts, should be prioritized for conservation. The results presented here provide an ecosystem-based conservation strategy for designating priority areas for protection in the deep Mediterranean Sea.
Testing a Novel Aggregated Methodology to Assess Hydrodynamic Impacts on a High-Resolution Marine Turtle Trajectory
Authors: Quattrocchi Giovanni , Cucco Andrea , Cerritelli Giulia , Mencacci Resi , Comparetto Giorgia , Sammartano Daniela , Ribotti Alberto , Luschi Paolo
Published: July 2021

We designed a novel aggregated methodology to infer the impact of ocean motions on the movements of satellite-tracked marine turtles adopting available oceanographic observations and validated products of a numerical oceanographic forecasting system. The method was tested on an 11-months trajectory of a juvenile loggerhead turtle (LT) wandering in the Tyrrhenian Sea (Mediterranean Sea) that was reconstructed with a high-resolution GPS tracking system. The application of ad-hoc designed metrics revealed that the turtle’s route shape, ground speed and periodicities of its explained variance mimic the inertial motions of the sea, showing that this methodology is able to reveal important details on the relation between turtle movements and oceanographic features. Inertial motions were also identified in the observed trajectory of a surface drifting buoy sampling the Tyrrhenian Sea in a common period. At each sampling point of the turtle trajectory, the sea current eddy kinetic energy (EKE) and a Sea Current Impact index were computed from a validated set of high-resolution ocean modeling products and their analysis showed the relevant effects of the highly variable local sea currents mechanical action. Specifically, the metric we adopted revealed that the turtle trajectory was favorably impacted by the encountered sea current advection for about 70% of its length. The presented oceanographic techniques in conjunction with high-resolution tracking system provide a practicable approach to study marine turtle movements, leading the way to discover further insights on turtle behavior in the ocean.
Challenges and Opportunities in Relation to Sargassum Events Along the Caribbean Sea
Authors: Robledo Daniel , Vázquez-Delfín Erika , Freile-Pelegrín Yolanda , Vásquez-Elizondo Román Manuel , Qui-Minet Zujaila Nohemy , Salazar-Garibay Adán
Published: July 2021

Mass blooms and stranding of pelagic Sargassum spp. in the Atlantic, termed Sargassum events are becoming more frequent in response to several factors: nutrient enrichment, increased temperature, changes in climatological patterns, but some causes remain unknown. The magnitude of Sargassum events in the Caribbean Sea since 2011 make us aware of the necessity to tackle these events, and macroalgal blooms generally, not only locally but on a regional scale. At least three pelagic species of Sargassum have been dominant in the blooms that have occurred along Caribbean coastlines in great quantities. Due to the regional scale of these events and its complexity, its management should be based on basic and applied information generated by different collaborative actors (national and international) through interdisciplinary and transdisciplinary work. To address this, we propose different phases (exploratory, valorization, and management) and the approach for their study should include detection, collection, stabilization and experimentation. This information will help identify the potential applications and/or ecological services to develop for the exploitation and mitigation strategies in the region. Relevant challenges and opportunities are discussed, remarking on the necessity to evaluate the spatiotemporal variation in the abundance and chemical composition of floating and stranded biomass. The above-mentioned will provide management strategies and economic opportunities as possible solutions to their extensive impact in the Caribbean.
Systematic Review of the Effect of a Zero-Markup Policy for Essential Drugs on Healthcare Costs and Utilization in China, 2015–2021
Authors: Liu Wen-Yi , Hsu Chia-Hsien , Liu Ting-Jun , Chen Pei-En , Zheng Boyuan , Chien Ching-Wen , Tung Tao-Hsin
Published: July 2021

Objective: This systematic review aimed to discuss the effects of a zero-markup policy for essential drugs (ZPED) on healthcare costs and utilization in China in the years 2015–2021.

Methods: We searched the PubMed, Embase, Scopus, and CINAHL databases for all associated studies carried out from January 1, 2015, to May 31, 2021, without any limitations regarding the language the studies were written in. To prevent selection bias, gray documents were tackled by other means. The methodological approaches were assessed by applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Newcastle-Ottawa Scale (NOS) collaboration tool.

Results: Forty studies were selected at first and then 15 studies that met the inclusion criterion. Most of the studies showed a considerable decrease in total medical spending and drug spending in both outpatient and inpatient services. After the implementation of ZPED, studies showed that the medical services increased and total hospital income sustained, despite a decrease in drug revenue. Minimal or no government subsidy is required from a financial perspective.

Conclusions: Although, the government could implement ZEPD with lower medical cost and drug cost to patients, and sustained income for health facilities, we have limited understanding of whether the increase in medical services was induced by the provider or was a response to unmet needs in the population. Further, studies using rigorous and advanced methods to study health policy, patient behaviors, provider behaviors, and government decisions are warranted.
Exploration of the Relationship Among Key Risk Factors of Acute Kidney Injury for Elderly Patients Considering Covid-19
Authors: Chuang Yen-Ching , Tung Tao-Hsin , Chen Jau-Yuan , Chien Ching-Wen , Shen Kao-Yi
Published: July 2021

Background: Previous systematic reviews and meta-analyses supported the relationship between frailty and risk of acute kidney injury (AKI) in elderly patients. However, few studies evaluated proactive management to wear down AKI risk in such frail populations.

Purpose: To understand how AKI risk factors might influence each other and to identify the source factors for clinical decision aids.

Methods: This study uses the decision-making trial and evaluation laboratory (DEMATEL) method to establish influential network-relationship diagrams (INRDs) to form the AKI risk assessment model for the elderly.

Results: Based on the DEMATEL approach, the results of INRD identified the six key risk factors: comorbidity, malignancy, diabetes, creatinine, estimated glomerular filtration rate, and nutritional assessment. (The statistical significance confidence is 98.423%, which is higher than 95%; the gap error is 1.577%, which is lower than 5%). After considering COVID-19 as an additional risk factor in comorbidity, the INRD revealed a similar influential relationship among the essential aspects.

Conclusion: While evaluating the geriatric population, physicians need to pay attention to patients' comorbidities and nutritional assessment; also, they should note patients' creatinine values and glomerular filtration rate. Physicians could establish a preliminary observation index and then design a series of preventive guidelines to reduce the incidence of AKI risk for the elderly.
Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease
Authors: Drobny Alice , Ngo Phuong A. , Neurath Markus F. , Zunke Friederike , López-Posadas Rocío
Published: July 2021

Intestinal symptoms, such as nausea, vomiting, and constipation, are common in Parkinson's disease patients. These clinical signs normally appear years before the diagnosis of the neurodegenerative disease, preceding the occurrence of motor manifestations. Moreover, it is postulated that Parkinson's disease might originate in the gut, due to a response against the intestinal microbiota leading to alterations in alpha-synuclein in the intestinal autonomic nervous system. Transmission of this protein to the central nervous system is mediated potentially via the vagus nerve. Thus, deposition of aggregated alpha-synuclein in the gastrointestinal tract has been suggested as a potential prodromal diagnostic marker for Parkinson's disease. Interestingly, hallmarks of chronic intestinal inflammation in inflammatory bowel disease, such as dysbiosis and increased intestinal permeability, are also observed in Parkinson's disease patients. Additionally, alpha-synuclein accumulations were detected in the gut of Crohn's disease patients. Despite a solid association between neurodegenerative diseases and gut inflammation, it is not clear whether intestinal alterations represent cause or consequence of neuroinflammation in the central nervous system. In this review, we summarize the bidirectional communication between the brain and the gut in the context of Parkinson's disease and intestinal dysfunction/inflammation as present in inflammatory bowel disease. Further, we focus on the contribution of intestinal epithelium, the communication between intestinal epithelial cells, microbiota, immune and neuronal cells, as well as mechanisms causing alterations of epithelial integrity.
Development of a Novel Simple Model to Predict Mortality in Patients With Systemic Lupus Erythematosus Admitted to the Intensive Care Unit
Authors: Guo Jinyan , Huang Zhen , Huang Maoxin , He Yujie , Han Bing , Ma Ning , Yu Zujiang , Liu Shengyun , Ren Zhigang
Published: July 2021

Background: Patients with systemic lupus erythematosus (SLE) may sometimes require admission to the intensive care unit (ICU), and the outcome is poor. The aim of this study was to explore the clinical features of patients with SLE in the ICU, identify prognostic factors, and develop and evaluate a prognostic model to predict in-ICU mortality of patients with SLE.

Patients and Methods: This was a single center retrospective study in a tertiary medical institution in China. A total of 480 SLE patients with 505 ICU admissions from 2010 to 2019 were screened, and 391 patients were enrolled. The clinical feature and outcomes of the patients were analyzed. According to the random number table, patients were divided into two mutually exclusively groups named derivation (n = 293) and validation (n = 98). Prognostic factors were identified by a Cox model with Markov Chain Monte Carlo simulation and evaluated by latent analysis. The risk score was developed based on the derivation group and evaluated using the validation group.

Results: Among the 391 patients, 348 (89.0%) patients were females. The median age of patients was 34 years, and the median course of SLE was 6 months. The median APACHE II and SLEDAI were 17 and 10, respectively. The average in-ICU mortality was 53.4% (95% CI, 48.5–58.4%). A total of 186 patients were admitted to the ICU due to infection. Pneumonia (320/391, 81.8%) was the most common clinical manifestation, followed by renal disease (246/391, 62.9%). Nine prognostic factors were identified. The model had C statistic of 0.912 (95% CI, 0.889–0.948) and 0.807 (95% CI 0.703–0.889), with predictive range of 5.2–98.3% and 6.3–94.7% for the derivation and validation groups, respectively. Based on distribution of the risk score, 25.3, 49.5, and 25.2% of patients were stratified into the high, average, and low-risk groups, with corresponding in-ICU mortality of 0.937, 0.593, and 0.118, respectively.

Conclusion: Nine prognostic factors including age, white blood cell count, alanine transaminase, uric acid, intracranial infection, shock, intracranial hemorrhage, respiratory failure, and cyclosporin A/tacrolimus usage were identified. A prognostic model was developed and evaluated to predict in-ICU mortality of patients with SLE. These findings may help clinicians to prognostically stratify patients into different risk groups of in-ICU mortality, and provide patients with intensive and targeted management.
The Value of Quantitative Faecal Immunochemical Testing as a Prioritisation Tool for the Endoscopic Investigation of Patients With Iron Deficiency
Authors: Clackett William , Barclay Stephen T. , Stanley Adrian J. , Cahill Aidan
Published: July 2021

Difficulty in providing endoscopy for patients with iron deficiency anaemia (IDA) during the COVID-19 pandemic has highlighted the requirement for a prioritisation tool. We aimed to test the validity of qFIT as a prioritisation tool in patients with iron deficiency and its ability to identify patients with advanced neoplastic lesions (ANLs). Data collected from patients referred with biochemically proven iron deficiency (ferritin ≤ 15 μg/L) and synchronous qFIT who underwent full gastrointestinal investigation within NHS Greater Glasgow and Clyde was analysed retrospectively. Patients who did not undergo full investigation, defined as gastroscopy and colonoscopy or CT colonography, were excluded. ANLs were defined as defined as upper GI cancer, colorectal adenoma ≥ 1 cm or colorectal cancer. Area under the curve (AUC) analysis was performed on qFIT results and outcome, defined as the presence of an ANL. AUC analysis guided cut-off scores for qFIT. Patients with a qFIT of <10, 10–200, >200, were allocated a score of 1, 2, and 3, respectively. A total of 575 patients met criteria for inclusion into the study. Overall, qFIT results strongly predicted the presence of ANLs (AUC 0.87, CI 0.81–0.92; P < 0.001). The prevalence of ANLs in patients with scores 1–3 was 1.2, 13.5, and 38.9% respectfully. When controlled for other significant variables, patients with a higher qFIT score were statistically more likely to have an ANL (qFIT score = 2; OR 12.8; P < 0.001, qFIT score = 3, OR 50.0; P < 0.001). A negative qFIT had a high NPV for the presence of ANLs (98.8%, CI 97.0–99.5%). These results strongly suggest that qFIT has validity as a prioritisation tool in patients with iron deficiency; both allowing for a more informed decision of investigation of patients with very low risk of malignancy, and in identifying higher risk patients who may benefit from more urgent endoscopy.
Quality of a Supporting Mobile App for Rheumatic Patients: Patient-Based Assessment Using the User Version of the Mobile Application Scale (uMARS)
Authors: Lambrecht Antonia , Vuillerme Nicolas , Raab Christina , Simon David , Messner Eva-Maria , Hagen Melanie , Bayat Sara , Kleyer Arnd , Aubourg Timothée , Schett Georg , Hueber Axel , Knitza Johannes
Published: July 2021

Introduction: Mobile applications promise to improve current health care. However, current mobile app quality ratings are mostly physician-based. The aim of this study was (1) to assess the quality of the self-management app Rheuma Auszeit using the validated uMARS (User Version of the Mobile App Rating Scale) app quality assessment tool and (2) to evaluate the association between uMARS scores and patients' characteristics.

Materials and Methods: Consecutive patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis were seen at the rheumatology clinic at university hospital Erlangen, Germany. They were asked to test Rheuma Auszeit, evaluate its quality using uMARS and complete a paper-based survey evaluating the individual preferences, attitudes and ehealth literacy. The association between uMARS scores and patients' characteristics was further explored.

Results: Between December 2018 and January 2019, a total of 126 patients evaluated Rheuma Auszeit using uMARS and filled out the paper-based survey. The median uMARS score was 3.9, IQR 0.7. Functionality was the domain with the highest rating (median 4.8, IQR 0.8), followed by aesthetics (median 4.0, IQR 0.7), information (median 3.5, IQR 0.8), and engagement (median 3.2, IQR 1.0). Subjective quality was average (median 3.0, IQR 1.0). The lowest scoring individual item was customization with a median of 2.5/5. Lower functionality scores were reported among older female rheumatic patients (P < 0.004). Older male rheumatic patients reported a higher subjective quality score (P < 0.024). Perceived disease activity and disease duration did not significantly correlate with any uMARS subdomain scores. eHealth literacy significantly correlated with functionality uMARS subdomain ratings (Rho = 0.18; P < 0.042). Preferred time of app usage significantly correlated with engagement (Rho = 0.20; P < 0.024), functionality (Rho = 0.19; P < 0.029), total uMARS score (Rho = 0.21; P < 0.017) and subjective quality score (Rho = 0.21; P < 0.017). The vast majority of rheumatic patients would consider recommending Rheuma Auszeit to other patients (117/126; 92.9%).

Conclusion: Rheuma Auszeit was well-accepted by German patients suffering from rheumatoid arthritis, psoriatic arthritis and ankylosing spondyloarthritis. Lacking customization could lead to low app compliance and should be improved. Lower functionality scores among older female rheumatic patients highlight the need for patient education. The study underlines the potential and feasibility of therapeutic complementary digital solutions in rheumatology.
Clostridium botulinum Type B Isolated From a Wound Botulism Case Due to Injection Drug Use Resembles Other Local Strains Originating From Hawaii
Authors: Halpin Jessica L. , Foltz Victoria , Dykes Janet K. , Chatham-Stephens Kevin , Lúquez Carolina
Published: July 2021

Clostridium botulinum produces botulinum neurotoxin (BoNT), which can lead to death if untreated. In the United States, over 90% of wound botulism cases are associated with injection drug use of black tar heroin. We sought to determine the phylogenetic relatedness of C. botulinum isolated from an injection drug use wound botulism case and isolates from endogenous infant botulism cases in Hawaii. Nineteen C. botulinum type B isolates from Hawaii and one type B isolate from California were analyzed by whole-genome sequencing. The botulinum toxin gene (bont) subtype was determined using CLC Genomics Workbench, and the seven-gene multi-locus sequence type (MLST) was identified by querying PubMLST. Mashtree and pairwise average nucleotide identity were used to find nearest neighbors, and Lyve-SET approximated a phylogeny. Eighteen of the isolates harbored the bont/B5 gene: of those, 17 were classified as sequence type ST36 and one was classified as ST104. A single isolate from Hawaii harbored bont/B1 and was determined to belong to ST110, and the isolate from California harbored bont/B1 and belonged to ST30. A tree constructed with Lyve-SET showed a high degree of homology among all the Hawaiian C. botulinum isolates that harbor the bont/B5 gene. Our results indicate that the bont/B-expressing isolates recovered from Hawaii are closely related to each other, suggesting local contamination of the drug paraphernalia or the wound itself with spores rather than contamination of the drug at manufacture or during transport. These findings may assist in identifying interventions to decrease wound botulism among persons who inject drugs.
Ribosome Biogenesis in Archaea
Authors: Londei Paola , Ferreira-Cerca Sébastien
Published: July 2021

Making ribosomes is a major cellular process essential for the maintenance of functional ribosome homeostasis and to ensure appropriate gene expression. Strikingly, although ribosomes are universally conserved ribonucleoprotein complexes decoding the genetic information contained in messenger RNAs into proteins, their biogenesis shows an intriguing degree of variability across the tree of life. In this review, we summarize our knowledge on the least understood ribosome biogenesis pathway: the archaeal one. Furthermore, we highlight some evolutionary conserved and divergent molecular features of making ribosomes across the tree of life.
Generating Chromosome Geometries in a Minimal Cell From Cryo-Electron Tomograms and Chromosome Conformation Capture Maps
Authors: Gilbert Benjamin R. , Thornburg Zane R. , Lam Vinson , Rashid Fatema-Zahra M. , Glass John I. , Villa Elizabeth , Dame Remus T. , Luthey-Schulten Zaida
Published: July 2021

JCVI-syn3A is a genetically minimal bacterial cell, consisting of 493 genes and only a single 543 kbp circular chromosome. Syn3A’s genome and physical size are approximately one-tenth those of the model bacterial organismEscherichia coli’s, and the corresponding reduction in complexity and scale provides a unique opportunity for whole-cell modeling. Previous work established genome-scale gene essentiality and proteomics data along with its essential metabolic network and a kinetic model of genetic information processing. In addition to that information, whole-cell, spatially-resolved kinetic models require cellular architecture, including spatial distributions of ribosomes and the circular chromosome’s configuration. We reconstruct cellular architectures of Syn3A cells at the single-cell level directly from cryo-electron tomograms, including the ribosome distributions. We present a method of generating self-avoiding circular chromosome configurations in a lattice model with a resolution of 11.8 bp per monomer on a 4 nm cubic lattice. Realizations of the chromosome configurations are constrained by the ribosomes and geometry reconstructed from the tomograms and include DNA loops suggested by experimental chromosome conformation capture (3C) maps. Using ensembles of simulated chromosome configurations we predict chromosome contact maps for Syn3A cells at resolutions of 250 bp and greater and compare them to the experimental maps. Additionally, the spatial distributions of ribosomes and the DNA-crowding resulting from the individual chromosome configurations can be used to identify macromolecular structures formed from ribosomes and DNA, such as polysomes and expressomes.
Development and Validation of the Prognostic Index Based on Inflammation-Related Gene Analysis in Idiopathic Pulmonary Fibrosis
Authors: Lu Yanjiao , Chen Jinkun , Tang Kun , Wang Shanshan , Tian Zhen , Wang Meijia , Zhao Jianping , Xie Jungang
Published: July 2021

Background:Historically, idiopathic pulmonary fibrosis (IPF) was considered a chronic inflammation disorder, but this conception was reassessed in the past decades. Our understanding of the role of inflammation in IPF and its association with clinical significance remained incomplete.

Methods:We downloaded mRNA expression data of peripheral blood mononuclear cells (PBMCs) from the Gene Expression Omnibus (GEO) repository. Inflammation-related genes (IRGs) expressed differently between IPF and control (CTRL) were determined. In this study, we systemically analyzed the expression of differently expressed IRGs by comprehensive bioinformatic analysis, and then investigated their potential prognostic values. The related prognostic gene expressions were verified in our cohort.

Results:110 differently expressed IRGs were identified in this study, including 64 upregulated and 46 downregulated IRGs. Three IRGs (S100A12,CCR7, andTNFSF4) were identified as potential hub genes for prognosis. Those genes were subsequently subjected to the construction of the prognostic models. In the results, IPF patients categorized as high risk demonstrated a poor overall survival rate compared to patients categorized as low risk. Based on this prognostic model, the area under the curve (AUC) of the survival-dependent receiver operator characteristic (ROC) for 1-year, 2-year, and 3-year survival rates was 0.611, 0.695, and 0.681, respectively, in the GSE28042 cohort. These observations were validated in the GSE27957 cohort, confirming the good prognostic effect of this model. The expression of the three genes was validated in our cohort. We also conducted a nomogram based on the three IRGs’ mRNA for quantitative IPF prognosis.

Conclusion:Three IRGs (S100A12,CCR7, andTNFSF4) were identified as potential markers for the prognosis of IPF.
Can Control Infections Slow Down the Progression of Alzheimer’s Disease? Talking About the Role of Infections in Alzheimer’s Disease
Authors: Shi Mingchao , Li Chunrong , Tian Xiaoping , Chu Fengna , Zhu Jie
Published: July 2021

Alzheimer’s disease as the most common age-related dementia affects more than 40 million people in the world, representing a global public health priority. However, the pathogenesis of Alzheimer’s disease (AD) is complex, and it remains unclear. Over the past decades, all efforts made in the treatments of AD, with targeting the pathogenic amyloid β (Aβ), neurofibrillary tangles, and misfolded tau protein, were failed. Recently, many studies have hinted that infection, and chronic inflammation that caused by infection are crucial risk factors for AD development and progress. In the review, we analyzed the role of infections caused by bacteria, viruses, and other pathogens in the pathogenesis of AD and its animal models, and explored the therapeutic possibility with anti-infections for AD. However, based on the published data, it is still difficult to determine their causal relationship between infection and AD due to contradictory results. We think that the role of infection in the pathogenesis of AD should not be ignored, even though infection does not necessarily cause AD, it may act as an accelerator in AD at least. It is essential to conduct the longitudinal studies and randomized controlled trials in humans, which can determine the role of infection in AD and clarify the links between infection and the pathological features of AD. Finding targeting infection drugs and identifying the time window for applying antibacterial or antiviral intervention may be more promising for future clinical therapeutic strategies in AD.
Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders
Authors: Amalric Marianne , Pattij Tommy , Sotiropoulos Ioannis , Silva Joana M. , Sousa Nuno , Ztaou Samira , Chiamulera Cristiano , Wahlberg Lars U. , Emerich Dwaine F. , Paolone Giovanna
Published: July 2021

Historically, many investigations into neurodegenerative diseases have focused on alterations in specific neuronal populations such as, for example, the loss of midbrain dopaminergic neurons in Parkinson’s disease (PD) and loss of cholinergic transmission in Alzheimer’s disease (AD). However, it has become increasingly clear that mammalian brain activities, from executive and motor functioning to memory and emotional responses, are strictly regulated by the integrity of multiple interdependent neuronal circuits. Among subcortical structures, the dopaminergic nigrostriatal and mesolimbic pathways as well as cholinergic innervation from basal forebrain and brainstem, play pivotal roles in orchestrating cognitive and non-cognitive symptoms in PD and AD. Understanding the functional interactions of these circuits and the consequent neurological changes that occur during degeneration provides new opportunities to understand the fundamental inter-workings of the human brain as well as develop new potential treatments for patients with dysfunctional neuronal circuits. Here, excerpted from a session of the European Behavioral Pharmacology Society meeting (Braga, Portugal, August 2019), we provide an update on our recent work in behavioral and cellular neuroscience that primarily focuses on interactions between cholinergic and dopaminergic systems in PD models, as well as stress in AD. These brief discussions include descriptions of (1) striatal cholinergic interneurons (CINs) and PD, (2) dopaminergic and cholinergic modulation of impulse control, and (3) the use of an implantable cell-based system for drug delivery directly the into brain and (4) the mechanisms through which day life stress, a risk factor for AD, damage protein and RNA homeostasis leading to AD neuronal malfunction.
The Role of the Medial Septum—Associated Networks in Controlling Locomotion and Motivation to Move
Authors: Mocellin Petra , Mikulovic Sanja
Published: July 2021

The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing function in theta rhythm generation. Early studies relied on electrical stimulation, lesions and pharmacological manipulation, and reported an inconclusive picture regarding the role of the MSDB circuits. Recent studies using more specific methodologies have started to elucidate the differential role of the MSDB’s specific cell populations in controlling both theta rhythm and behaviour. In particular, a novel theory is emerging showing that different MSDB’s cell populations project to different brain regions and control distinct aspects of behaviour. While the majority of these behaviours involve movement, increasing evidence suggests that MSDB-related networks govern the motivational aspect of actions, rather than locomotion per se. Here, we review the literature that links MSDB, theta activity, and locomotion and propose open questions, future directions, and methods that could be employed to elucidate the diverse roles of the MSDB-associated networks.
Gated Recurrent Units Viewed Through the Lens of Continuous Time Dynamical Systems
Authors: Jordan Ian D. , Sokół Piotr Aleksander , Park Il Memming
Published: July 2021

Gated recurrent units (GRUs) are specialized memory elements for building recurrent neural networks. Despite their incredible success on various tasks, including extracting dynamics underlying neural data, little is understood about the specific dynamics representable in a GRU network. As a result, it is both difficult to know a priori how successful a GRU network will perform on a given task, and also their capacity to mimic the underlying behavior of their biological counterparts. Using a continuous time analysis, we gain intuition on the inner workings of GRU networks. We restrict our presentation to low dimensions, allowing for a comprehensive visualization. We found a surprisingly rich repertoire of dynamical features that includes stable limit cycles (nonlinear oscillations), multi-stable dynamics with various topologies, and homoclinic bifurcations. At the same time we were unable to train GRU networks to produce continuous attractors, which are hypothesized to exist in biological neural networks. We contextualize the usefulness of different kinds of observed dynamics and support our claims experimentally.
Effectiveness, Healthcare Resource Utilization and Adherence to Subcutaneous Interferon Beta-1a According to Age in Patients With Multiple Sclerosis: A Cohort Study Using a US Claims Database
Authors: Allignol Arthur , Boutmy Emmanuelle , Sabidó Espin Meritxell , Marhardt Kurt , Vermersch Patrick
Published: July 2021

Background: It is thought that older patients with multiple sclerosis (MS) may present with a different clinical disease phenotype, and therefore respond to subcutaneous interferon beta-1a (sc IFN β-1a) differently to younger patients. However, few real-world data are available concerning the effectiveness of sc IFN β-1a according to age. Using data from US claims databases, this cohort analysis aimed to determine the differences in relapse rates, healthcare utilization, treatment adherence, and discontinuation according to pre-defined age groups.

Methods: Patient data were pooled from the IBM® MarketScan® Commercial Claims Database and Medicare Supplemental Database. Patients with a confirmed MS diagnosis who initiated treatment with sc IFN β-1a between July 01, 2010 and December 31, 2015, along with at least 6 months continuous enrolment in a healthcare plan, were followed from first prescription (index date) until date of discontinuation, treatment switch, or end of observation period (1 year after index date).

Results: Of the 5,340 patients included in the analysis, there was a high proportion of patients free from relapse across all age groups (range: 94.1–95.4%), with a numerical decrease in the number of MRI performed by age (mean: 0.25, 18–30 years; 0.20, 31–40 years; 0.16, 41–50 years; 0.14, ≥51 years). Adherence (≥80%) was seen to increase with age (77.6%, 18–30 years; 79.6%, 31–40 years; 81.3%, 41–50 years; 84.0%, ≥51 years), at the same time as a non-significant decrease in discontinuation (incidence rate: 79.91, 73.01, 71.75, 68.71%).

Conclusion: The effectiveness of sc IFN β-1a does not appear reduced as a consequence of age in this real-world setting. Older patients had lower discontinuation rates and reduced disease activity, reflected in lower relapse rates and fewer MRI scans compared with younger patients.
Air Pollution: A Neglected Risk Factor for Dementia in Latin America and the Caribbean
Authors: Santos Nathália Villa dos , Yariwake Victor Yuji , Marques Karina do Valle , Veras Mariana Matera , Fajersztajn Laís
Published: July 2021

The risk of dementia and Alzheimer's disease in Latin America and the Caribbean (LAC) rises with increasing age and polluted air. Currently, at least 172 million people breathe unhealthy levels of air pollution in LAC countries. Several cohort studies have indicated that air pollution increases the risk of developing dementia and neurodegenerative diseases, but the mechanisms underlying the association are still not clear. Air pollution causes and aggravates five established risk factors for dementia (obesity, hypertension, stroke, diabetes mellitus, and heart diseases) and is linked to three other risk factors (physical inactivity, cognitive inactivity, and depression). Some of these risk factors could be mediating the association between air pollution and dementia. Reducing the risks for dementia is crucial and urgently needed in LAC countries. There is room for improving air quality in many urban areas in the LAC region and other low- and middle-income countries (LMICs), a routealready explored by many urban areas in developing regions. Moreover, reducing air pollution has proved to improve health outcomes before. In this article, we propose that despite the ongoing and valid scientific discussion, if air pollution can or cannot directly affect the brain and cause or aggravate dementia, we are ready to consider air pollution as a potentially modifiable risk factor for dementia in LAC and possibly in other LMICs. We suggest that controlling and reducing current air pollution levels in LAC and other LMIC regions now could strongly contribute.
Sex Differences in Neurophysiological Changes Following Voluntary Exercise in Adolescent Rats
Authors: Ferguson Lindsay , Giza Christopher C. , Serpa Rebecka O. , Greco Tiffany , Robert Hannah , Folkerts Michael , Prins Mayumi L.
Published: July 2021

Background: Adolescence is a period of time characterized by the onset of puberty and is marked by cognitive and social developments and gross physical changes that can play a role in athletic performance. Sex differences are present with differences in body size, height, physiology and behavior which contribute to differences in athletic performance as well. Pre-clinical studies representing this active group are lacking.

Methods: Acute and chronic effects of exercise were evaluated. Male and female adolescent rats were given voluntary access to a running wheel for 10 consecutive days. Running behavior (males and females) and estrous cycling (females only) were analyzed daily. A second group was given 10 days of voluntary access to a running wheel, then rested for 10 days to determine the long-term effects of exercise on the adolescent brain. Brain and muscle tissue were harvested at 10 and 20 day time points to understand exercise-dependent changes in mitochondrial activity and neuroplasticity. Animal cohorts were carried out at two different sites: University of California Los Angeles and Pepperdine University.

Results: On average, running distance, intensity of run, and length of running bout increased for both male and female rats across the 10 days measured. Females ran significantly further and for longer intervals compared to males. Cortical and muscle expression of PGC1α showed similar levels at 10 days regardless of sex and exercise. There was a significant increase in expression at 20 days in all groups correlating with body size (p's < 0.05). Cortical and hippocampal levels of BDNF were similar across all groups, however, BDNF was significantly higher in exercised females at the acute compared to long-term time point.

Discussion: Adolescent rats allowed 10 days of exercise show changes in physiologic function. There are sex differences in running behavior not impacted by sex hormones. These results are important to further our understanding of how exercise impacts the adolescent brain.
The Pathological Features of Common Hereditary Mitochondrial Dynamics Neuropathy
Authors: Wu Rui , Lv He , Wang Hui , Wang Zhaoxia , Yuan Yun
Published: July 2021

Objectives

Mitofusin 2 and ganglioside-induced differentiation-associated protein 1 are two main mitochondrial dynamics-related proteins. Dysfunction of these two proteins leads to different subtypes of Charcot–Marie–Tooth disease type 2A (CMT2A) and CMT2K. This study aims to report the pathological difference between CMT2A and CMT2K in a large cohort.

Methods

Thirty patients with molecularly confirmed CMT2A and nine with CMT2K were identified by next-generation sequencing. Sural nerve biopsies were performed in 29 patients.

Results

The patients with both diseases showed length-dependent neuropathy with distal weakness, sensory loss, and no deep tendon reflex. Optic neuropathy appeared in 3/30 (10%) patients with CMT2A. Tendon contracture appeared in 4/9 (50.0%) patients with CMT2K. Sural biopsy revealed the loss of both myelinated and unmyelinated nerve fibers. Closely packed, irregularly oriented neurofilaments were observed in axons of unmyelinated nerve fibers in both diseases. Another important finding was the ubiquitous presence of smaller, rounded, and fragmented mitochondria in CMT2A and elongated mitochondria in CMT2K in the myelinated and unmyelinated axons.

Conclusion

This study confirmed large diversity in phenotypes between CMT2A and CMT2K. Mitochondrial dynamics-related variations can induce different mitochondrial morphological changes and neurofilament accumulation in axons.
“Thermal Peroxidation” of Dietary Pentapeptides Yields N-Terminal 1,2-Dicarbonyls
Authors: Bikaki Maria , Kuhnert Nikolai
Published: July 2021

In this contribution we investigate the thermal degradation of dietary-relevant pentapeptides. Most unsaturated lipids degrade by the well-known peroxidation mechanism. Here we show a degradation mechanism of peptides analogous to lipid peroxidation, forming a series of novel degradation products with possible toxicological relevance. At elevated temperatures above 180°C, pentapeptides with an N-terminal phenylalanine moiety react via a debenzylation to form 1,2-dicabonyl compounds, replacing the N-terminal primary amine. We propose a radical-based reaction mechanism that leads via a common peroxoaminal intermediate to two distinct types of reaction products with a terminal α-1,2 diamide or an α-amide-aldehyde functionality.
Recent Advances in Bioactive Compounds, Health Functions, and Safety Concerns of Onion (Allium cepa L.)
Authors: Zhao Xin-Xin , Lin Fang-Jun , Li Hang , Li Hua-Bin , Wu Ding-Tao , Geng Fang , Ma Wei , Wang Yu , Miao Bao-He , Gan Ren-You
Published: July 2021

Onion (Allium cepa L.) is a common vegetable, widely consumed all over the world. Onion contains diverse phytochemicals, including organosulfur compounds, phenolic compounds, polysaccharides, and saponins. The phenolic and sulfur-containing compounds, including onionin A, cysteine sulfoxides, quercetin, and quercetin glucosides, are the major bioactive constituents of onion. Accumulated studies have revealed that onion and its bioactive compounds possess various health functions, such as antioxidant, antimicrobial, anti-inflammatory, anti-obesity, anti-diabetic, anticancer, cardiovascular protective, neuroprotective, hepatorenal protective, respiratory protective, digestive system protective, reproductive protective, and immunomodulatory properties. Herein, the main bioactive compounds in onion are summarized, followed by intensively discussing its major health functions as well as relevant molecular mechanisms. Moreover, the potential safety concerns about onion contamination and the ways to mitigate these issues are also discussed. We hope that this paper can attract broader attention to onion and its bioactive compounds, which are promising ingredients in the development of functional foods and nutraceuticals for preventing and managing certain chronic diseases.
Artificial Intelligence in Medical Imaging of the Breast
Authors: Lei Yu-Meng , Yin Miao , Yu Mei-Hui , Yu Jing , Zeng Shu-E , Lv Wen-Zhi , Li Jun , Ye Hua-Rong , Cui Xin-Wu , Dietrich Christoph F.
Published: July 2021

Artificial intelligence (AI) has invaded our daily lives, and in the last decade, there have been very promising applications of AI in the field of medicine, including medical imaging, in vitro diagnosis, intelligent rehabilitation, and prognosis. Breast cancer is one of the common malignant tumors in women and seriously threatens women’s physical and mental health. Early screening for breast cancer via mammography, ultrasound and magnetic resonance imaging (MRI) can significantly improve the prognosis of patients. AI has shown excellent performance in image recognition tasks and has been widely studied in breast cancer screening. This paper introduces the background of AI and its application in breast medical imaging (mammography, ultrasound and MRI), such as in the identification, segmentation and classification of lesions; breast density assessment; and breast cancer risk assessment. In addition, we also discuss the challenges and future perspectives of the application of AI in medical imaging of the breast.
c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma
Authors: Min Weili , He Chenyang , Zhang Shuqun , Zhao Yang
Published: July 2021

c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with “PDEP” motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs.
A Novel Nomogram Based on Log Odds of Metastatic Lymph Nodes to Predict Overall Survival in Patients With Perihilar Cholangiocarcinoma After Surgery
Authors: Zou Wenbo , Zhu Chunyu , Wang Zizheng , Tan Xianglong , Li Chenggang , Zhao Zhiming , Hu Minggen , Liu Rong
Published: July 2021

Background

Various lymph node staging strategies were reported to be significantly correlated with perihilar cholangiocarcinoma(pCCA) prognosis. This study aimed to evaluate their predictive abilities and construct an optimal model predicting overall survival (OS).

Methods

Patients with pCCA were collected as the training cohort from the Surveillance, Epidemiology, and End Results (SEER) database. Four models were constructed, involving four LNs staging strategies. The optimal model for predicting OS was evaluated by calculation of the concordance index (C-index) and Akaike information criterion (AIC), and validated by using the area under curve (AUC) and calibration curves. The clinical benefits of nomogram were evaluated by decision curve analysis (DCA). A Chinese cohort was collected to be an external validation cohort.

Results

There were 319 patients and 109 patients in the SEER database and Chinese cohort respectively. We developed an optimal model involving age, T stage, tumor size, LODDS, which showed better predictive accuracy than others. The C-index of the nomogram was 0.695, the time-dependent AUC exceeded 0.7 within 36 months which was significantly higher than that of the American Joint Committee on Cancer (AJCC) stage. The calibration curves for survival probability showed the nomogram prediction had good uniformity of the practical survival. The DCA curves exhibited our nomogram with higher clinical utility compared with the AJCC stage and single LOODS.

Conclusions

LODDS is a strong independent prognostic factor, and the nomogram has a great ability to predict OS, which helps assist clinicians to conduct personalized clinical practice.