bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Rescue Is Mediated by the History of Selection and Dispersal in Diversifying Metacommunities
Authors: O'Connor Louise M. J. , Fugère Vincent , Gonzalez Andrew
Published: December 2020

Rapid evolution can sometimes prevent population extirpation in stressful environments, but the conditions leading to “evolutionary rescue” in metacommunities are unclear. Here we studied the eco-evolutionary response of microbial metacommunities adapting to selection by the antibiotic streptomycin. Our experiment tested how the history of antibiotic selection and contrasting modes of dispersal influenced diversification and subsequent evolutionary rescue in microbial metacommunities undergoing adaptive radiation. We first tracked the change in diversity and density of Pseudomonas fluorescens morphotypes selected on a gradient of antibiotic stress. We then examined the recovery of these metacommunities following abrupt application of a high concentration of streptomycin lethal to the ancestral organisms. We show that dispersal increases diversity within the stressed metacommunities, that exposure to stress alters diversification dynamics, and that community composition, dispersal, and past exposure to stress mediate the speed at which evolutionary rescue occurs, but not the final outcome of recovery in abundance and diversity. These findings extend recent experiments on evolutionary rescue to the case of metacommunities undergoing adaptive diversification, and should motivate new theory on this question. Our findings are also relevant to evolutionary conservation biology and research on antimicrobial resistance.
The Dilemma of Wildfire Definition: What It Reveals and What It Implies
Authors: Tedim Fantina , Leone Vittorio
Published: December 2020

This paper presents the results of an explorative survey, based on a questionnaire sent by email, about how wildfire experts, operating in different countries, perceive wildfire and express their mindset by defining “wildfire” from a list of 14 terms and how they justify their preference for the term selected as the most important. Using a five-point Likert Scale, results from 221 valid replies indicate a general convergence toward a reduced number of terms. Six of them exhibit a mean >3.20 (Disturbance, Natural hazard, Climate-sensitive hazard, Socio-ecological hazard, Socio-ecological disturbance, andSocial-ecological hazard). The three most preferred terms (i.e.,Disturbance, Natural hazard, andClimate-sensitive hazard)reflect wildfire as a natural process or phenomenon (about 59% of the replies). The three terms characterized by both the social and ecological adjectives (i.e.,Socio-ecological hazard, Socio-ecological disturbance, Social-ecological hazard) occupy relatively less favorable positions in the ranking. For each term, a synthesis of the explanations given by the respondents is provided, together with a critical comment. Our findings show very different perceptions of wildfires inclusively within the same disciplinary field. In addition, for the same term selected, different definitions are often presented. This reflects sectorial, disciplinary, and personal perspectives of the wildfire phenomenon and the lack of a common understanding of wildfire “nature” (i.e., its own identity). The different perceptions on wildfire concept influence the knowledge that can be used by decision makers to improve wildfire management policies. This work puts into perspective one of the most widespread problems in science: the lack of appropriate and similar terminology across different scientific fields dealing with the same problem. A common conceptualization of the nature of wildfires and the creation of a common language across different scientific fields related to wildfires is of paramount importance to address the complexity of the existing problems, and enhance an interactive communication not only among scientific community but also with stakeholders and citizens.
The Usage of Human IGHJ Genes Follows a Particular Non-random Selection: The Recombination Signal Sequence May Affect the Usage of Human IGHJ Genes
Authors: Shi Bin , Dong Xiaoheng , Ma Qingqing , Sun Suhong , Ma Long , Yu Jiang , Wang Xiaomei , Pan Juan , He Xiaoyan , Su Danhua , Yao Xinsheng
Published: December 2020

The formation of the B cell receptor (BCR) heavy chain variable region is derived from the germline V(D)J gene rearrangement according to the “12/23” rule and the “beyond 12/23” rule. The usage frequency of each V(D)J gene in the peripheral BCR repertoires is related to the initial recombination, self-tolerance selection, and the clonal proliferative response. However, their specific differences and possible mechanisms are still unknown. We analyzed in-frame and out-of-frame BCR-H repertoires from human samples with normal physiological and various pathological conditions by high-throughput sequencing. Our results showed that IGHJ gene frequency follows a similar pattern which is previously known, where IGHJ4 is used at high frequency (>40%), IGHJ6/IGHJ3/IGHJ5 is used at medium frequencies (10∼20%), and IGH2/IGHJ1 is used at low frequency (<4%) under whether normal physiological or various pathological conditions. However, our analysis of the recombination signal sequences suggested that the conserved non-amer and heptamer and certain 23 bp spacer length may affect the initial IGHD-IGHJ recombination, which results in different frequencies of IGHJ genes among the initial BCR-H repertoire. Based on this “initial repertoire,” we recommend that re-evaluation and further investigation are needed when analyzing the significance and mechanism of IGHJ gene frequency in self-tolerance selection and the clonal proliferative response.
Identification of Hub Prognosis-Associated Oxidative Stress Genes in Pancreatic Cancer Using Integrated Bioinformatics Analysis
Authors: Qiu Xin , Hou Qin-Han , Shi Qiu-Yue , Jiang Hai-Xing , Qin Shan-Yu
Published: December 2020

Background

Intratumoral oxidative stress (OS) has been associated with the progression of various tumors. However, OS has not been considered a candidate therapeutic target for pancreatic cancer (PC) owing to the lack of validated biomarkers.

Methods

We compared gene expression profiles of PC samples and the transcriptome data of normal pancreas tissues from The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to identify differentially expressed OS genes in PC. PC patients’ gene profile from the Gene Expression Omnibus (GEO) database was used as a validation cohort.

Results

A total of 148 differentially expressed OS-related genes in PC were used to construct a protein-protein interaction network. Univariate Cox regression analysis, least absolute shrinkage, selection operator analysis revealed seven hub prognosis-associated OS genes that served to construct a prognostic risk model. Based on integrated bioinformatics analyses, our prognostic model, whose diagnostic accuracy was validated in both cohorts, reliably predicted the overall survival of patients with PC and cancer progression. Further analysis revealed significant associations between seven hub gene expression levels and patient outcomes, which were validated at the protein level using the Human Protein Atlas database. A nomogram based on the expression of these seven hub genes exhibited prognostic value in PC.

Conclusion

Our study provides novel insights into PC pathogenesis and provides new genetic markers for prognosis prediction and clinical treatment personalization for PC patients.
The Involvement of Metals in Alzheimer’s Disease Through Epigenetic Mechanisms
Authors: Cai Menghua , Zhang Xiangjin , He Wei , Zhang Jianmin
Published: December 2020

Alzheimer’s disease (AD) is the most frequent cause of dementia among neurodegenerative diseases. Two factors were hypothesized to be involved in the pathogenesis of AD, namely beta-amyloid cascade and tauopathy. At present, accumulating evidence suggest that epigenetics may be the missing linkage between genes and environment factors, providing possible clues to understand the etiology of the development of AD. In this article, we focus on DNA methylation and histone modification involved in AD and the environment factor of heavy metals’ contribution to AD, especially epigenetic mechanisms. If we can integrate information together, and that may find new potential targets for the treatment.
Case Report: Secondary Hemophagocytic Lymphohistiocytosis With Disseminated Infection in Chronic Granulomatous Disease—A Serious Cause of Mortality
Authors: Squire Jacqueline D. , Vazquez Stephanie N. , Chan Angela , Smith Michele E. , Chellapandian Deepak , Vose Laura , Teppa Beatriz , Hanson I. Celine , Chinn Ivan K. , Forbes-Satter Lisa , Seeborg Filiz O. , Nicholas Sarah K. , Martinez Caridad A. , Allen Carl E. , Connors Thomas J. , Satwani Prakash , Shtessel Maria , Ale Hanadys , Noroski Lenora M. , Rider Nicholas L. , Milner Joshua D. , Leiding Jennifer W.
Published: December 2020

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.
CD86 Is a Selective CD28 Ligand Supporting FoxP3+ Regulatory T Cell Homeostasis in the Presence of High Levels of CTLA-4
Authors: Halliday Neil , Williams Cayman , Kennedy Alan , Waters Erin , Pesenacker Anne M. , Soskic Blagoje , Hinze Claudia , Hou Tie Zheng , Rowshanravan Behzad , Janman Daniel , Walker Lucy S. K. , Sansom David M.
Published: December 2020

CD80 and CD86 are expressed on antigen presenting cells and are required to engage their shared receptor, CD28, for the costimulation of CD4 T cells. It is unclear why two stimulatory ligands with overlapping roles have evolved. CD80 and CD86 also bind the regulatory molecule CTLA-4. We explored the role of CD80 and CD86 in the homeostasis and proliferation of CD4+FoxP3+ regulatory T cells (Treg), which constitutively express high levels of CTLA-4 yet are critically dependent upon CD28 signals. We observed that CD86 was the dominant ligand for Treg proliferation, survival, and maintenance of a regulatory phenotype, with higher expression of CTLA-4, ICOS, and OX40. We also explored whether CD80-CD28 interactions were specifically compromised by CTLA-4 and found that antibody blockade, clinical deficiency of CTLA-4 and CRISPR-Cas9 deletion of CTLA-4 all improved Treg survival following CD80 stimulation. Taken together, our data suggest that CD86 is the dominant costimulatory ligand for Treg homeostasis, despite its lower affinity for CD28, because CD80-CD28 interactions are selectively impaired by the high levels of CTLA-4. These data suggest a cell intrinsic role for CTLA-4 in regulating CD28 costimulation by direct competition for CD80, and indicate that that CD80 and CD86 have discrete roles in CD28 costimulation of CD4 T cells in the presence of high levels of CTLA-4.
Honing the Double-Edged Sword: Improving Human iPSC-Microglia Models
Authors: Hedegaard Anne , Stodolak Szymon , James William S. , Cowley Sally A.
Published: December 2020

Human induced Pluripotent Stem Cell (hiPSC) models are a valuable new tool for research into neurodegenerative diseases. Neuroinflammation is now recognized as a key process in neurodegenerative disease and aging, and microglia are central players in this. A plethora of hiPSC-derived microglial models have been published recently to explore neuroinflammation, ranging from monoculture through to xenotransplantation. However, combining physiological relevance, reproducibility, and scalability into one model is still a challenge. We examine key features of thein vitromicroglial environment, especially media composition, extracellular matrix, and co-culture, to identify areas for improvement in current hiPSC-microglia models.
The Celtic Sea Through Time and Space: Ecosystem Modeling to Unravel Fishing and Climate Change Impacts on Food-Web Structure and Dynamics
Authors: Hernvann Pierre-Yves , Gascuel Didier , Grüss Arnaud , Druon Jean-Noël , Kopp Dorothée , Perez Ilan , Piroddi Chiara , Robert Marianne
Published: December 2020

Both trophic structure and biomass flow within marine food webs are influenced by the abiotic environment and anthropogenic stressors such as fishing. The abiotic environment has a large effect on species spatial distribution patterns and productivity and, consequently, spatial co-occurrence between predators and prey, while fishing alters species abundances and food-web structure. In order to disentangle the impacts of the abiotic environment and fishing in the Celtic Sea ecosystem, we developed a spatio-temporal trophic model, specifically an Ecopath with Ecosim with Ecospace model, for the period 1985–2016. In this model, particular attention was paid to the parameterization of the responses of all trophic levels to abiotic environmental changes. Satellite remote sensing data were employed to determine the spatial distribution and annual fluctuations of primary production (PP). Spatial and temporal changes in the habitat favorable for zooplankton were predicted with a novel ecological-niche approach using daily detection of productivity fronts from satellite ocean color. Finally, functional responses characterizing the effect of several abiotic environmental variables (including, among others, temperature, salinity and dissolved oxygen concentration, both at the surface and at the bottom) on fish species groups’ habitat suitability were produced from the predictions of statistical habitat models fitted to presence-absence data collected by multiple fisheries-independent surveys. The dynamic component of our model (Ecosim) was driven by time-series of fishing effort, PP, zooplankton habitat suitability and abiotic environmental variables, and was fitted to abundance and fisheries catch data. The spatial component of our model (Ecospace) was constructed, for specific years of the period 1985–2016 with contrasted abiotic environmental conditions, to predict the variable distribution of the biomass of all functional groups. We found that fishing was the main driver of observed ecosystem changes in the Celtic Sea over the period 1985–2016. However, the integration of the environmental variability into the model and the subsequent improvement of the fit of the dynamic Ecosim component highlighted (i) the control of the overall pelagic production by PP and (ii) the influence of temperature on the productivity of several trophic levels in the Celtic Sea, especially on trophic groups with warm and cold water affinities. In addition, Ecospace predictions indicated that the spatial distributions of commercial fish species may have substantially changed over the studied period. These spatial changes mainly appeared to be driven by temperature and may, therefore, largely impact future fisheries given the continuity of climatic changes.
Ballistic Performance of Natural Fiber Based Soft and Hard Body Armour- A Mini Review
Authors: Naveen J. , Jayakrishna K. , Hameed Sultan Mohamed Thariq Bin , Amir Siti Madiha Muhammad
Published: December 2020

Increase in awareness towards utilization of eco-friendly materials, encouraged the researchers to find a sustainable alternative to synthetic fibers for different engineering applications. High performance Kevlar fabrics are widely used in ballistic applications such as bullet proof helmets, vest, and other armour systems. Ballistic impact produces shock waves which may cause severe trauma injuries to the soldiers. Kevlar fabric based armour system provides acceptable range of protection to the soldiers. However, disposal of Kevlar affects the eco system and pollutes the environment. Replacing Kevlar fabric in the protective structures with an eco-friendly light weight material, together with an improved kinetic energy absorption and dissipation has become an interesting approach to enhance the ballistic performance of the composite panels. This mini review addresses the effect of adding different natural fibers on the ballistic performance of soft and multilayered hard body armour systems. Many researchers explored the possibility of utilizing eco-friendly natural fibers (Kenaf, Cocos nucifera sheath, Malva, rami, curaua, bagasse, jute, bamboo) as an alternate material to Kevlar fabric in the armour system and reported that natural fibers can act as a potential reinforcement in the ballistic structures.
Effects of Extended Postmortem Interval on Microbial Communities in Organs of the Human Cadaver
Authors: Lutz Holly , Vangelatos Alexandria , Gottel Neil , Osculati Antonio , Visona Silvia , Finley Sheree J. , Gilbert Jack A. , Javan Gulnaz T.
Published: December 2020

Human thanatomicrobiota studies have shown that microorganisms inhabit and proliferate externally and internally throughout the body and are the primary mediators of putrefaction after death. Yet little is known about the source and diversity of the thanatomicrobiome or the underlying factors leading to delayed decomposition exhibited by reproductive organs. The use of the V4 hypervariable region of bacterial 16S rRNA gene sequences for taxonomic classification (“barcoding”) and phylogenetic analyses of human postmortem microbiota has recently emerged as a possible tool in forensic microbiology. The goal of this study was to apply a 16S rRNA barcoding approach to investigate variation among different organs, as well as the extent to which microbial associations among different body organs in human cadavers can be used to predict forensically important determinations, such as cause and time of death. We assessed microbiota of organ tissues including brain, heart, liver, spleen, prostate, and uterus collected at autopsy from criminal casework of 40 Italian cadavers with times of death ranging from 24 to 432 h. Both the uterus and prostate had a significantly higher alpha diversity compared to other anatomical sites, and exhibited a significantly different microbial community composition from non-reproductive organs, which we found to be dominated by the bacterial orders MLE1-12, Saprospirales, and Burkholderiales. In contrast, reproductive organs were dominated by Clostridiales, Lactobacillales, and showed a marked decrease in relative abundance of MLE1-12. These results provide insight into the observation that the uterus and prostate are the last internal organs to decay during human decomposition. We conclude that distinct community profiles of reproductive versus non-reproductive organs may help guide the application of forensic microbiology tools to investigations of human cadavers.
Engineering the Erythromycin-Producing Strain Saccharopolyspora erythraea HOE107 for the Heterologous Production of Polyketide Antibiotics
Authors: Lü Jin , Long Qingshan , Zhao Zhilong , Chen Lu , He Weijun , Hong Jiali , Liu Kai , Wang Yemin , Pang Xiuhua , Deng Zixin , Tao Meifeng
Published: December 2020

Bacteria of the genus Saccharopolyspora produce important polyketide antibiotics, including erythromycin A (Sac. erythraea) and spinosad (Sac. spinosa). We herein report the development of an industrial erythromycin-producing strain, Sac. erythraea HOE107, into a host for the heterologous expression of polyketide biosynthetic gene clusters (BGCs) from other Saccharopolyspora species and related actinomycetes. To facilitate the integration of natural product BGCs and auxiliary genes beneficial for the production of natural products, the erythromycin polyketide synthase (ery) genes were replaced with two bacterial attB genomic integration sites associated with bacteriophages ϕC31 and ϕBT1. We also established a highly efficient conjugation protocol for the introduction of large bacterial artificial chromosome (BAC) clones into Sac. erythraea strains. Based on this optimized protocol, an arrayed BAC library was effectively transferred into Sac. erythraea. The large spinosad gene cluster from Sac. spinosa and the actinorhodin gene cluster from Streptomyces coelicolor were successfully expressed in the ery deletion mutant. Deletion of the endogenous giant polyketide synthase genes pkeA1-pkeA4, the product of which is not known, and the flaviolin gene cluster (rpp) from the bacterium increased the heterologous production of spinosad and actinorhodin. Furthermore, integration of pJTU6728 carrying additional beneficial genes dramatically improved the yield of actinorhodin in the engineered Sac. erythraea strains. Our study demonstrated that the engineered Sac. erythraea strains SLQ185, LJ161, and LJ162 are good hosts for the expression of heterologous antibiotics and should aid in expression-based genome-mining approaches for the discovery of new and cryptic antibiotics from Streptomyces and rare actinomycetes.
Membrane Vesicle Production as a Bacterial Defense Against Stress
Authors: Mozaheb Negar , Mingeot-Leclercq Marie-Paule
Published: December 2020

Membrane vesicles are the nano-sized vesicles originating from membranes. The production of membrane vesicles is a common feature among bacteria. Depending on the bacterial growth phase and environmental conditions, membrane vesicles show diverse characteristics. Various physiological and ecological roles have been attributed to membrane vesicles under both homeostatic and stressful conditions. Pathogens encounter several stressors during colonization in the hostile environment of host tissues. Nutrient deficiency, the presence of antibiotics as well as elements of the host’s immune system are examples of stressors threatening pathogens inside their host. To combat stressors and survive, pathogens have established various defensive mechanisms, one of them is production of membrane vesicles. Pathogens produce membrane vesicles to alleviate the destructive effects of antibiotics or other types of antibacterial treatments. Additionally, membrane vesicles can also provide benefits for the wider bacterial community during infections, through the transfer of resistance or virulence factors. Hence, given that membrane vesicle production may affect the activities of antibacterial agents, their production should be considered when administering antibacterial treatments. Besides, regarding that membrane vesicles play vital roles in bacteria, disrupting their production may suggest an alternative strategy for battling against pathogens. Here, we aim to review the stressors encountered by pathogens and shed light on the roles of membrane vesicles in increasing pathogen adaptabilities in the presence of stress-inducing factors.
Loop-Mediated Isothermal Amplification (LAMP) as a Rapid, Affordable and Effective Tool to Involve Students in Undergraduate Research
Authors: Nguyen Andrew V. , Orlofsky Amos , Pubill Kaylynn , Tawde Mangala , Li Gaozhen , Mata Diana , Bermudes Oscar , Fernandez Miguel , Santana Jonathan , Kim Woochul , Chimbay Enzon , Kim Yeeun , Nguyen Trieu , Fox Malcolm , Eralte Janelly , Metz Molly , Smyth Davida S. , Panzeca Caterina , Khan Mazhar I.
Published: December 2020

Undergraduate research (UR) is a high-impact practice (HIP) to engage undergraduate student in science, technology, engineering and mathematics (STEM), especially from underrepresented groups. UR experiences (UREs) can be integrated into the classroom, making authentic research experiences inclusive and available to all students. However, developing UR pedagogy can be challenging for faculty in resource-limited labs, such as community colleges and small liberal arts colleges. Often molecular biology research methods are expensive, time-consuming and need equipment not readily available or affordable in small schools. Polymerase chain reaction (PCR) is one of the most commonly used techniques in research labs and many UREs. We have investigated loop-mediated isothermal amplification (LAMP) as an inexpensive, accessible alternative to PCR for DNA amplification enabling the identification of microorganisms in the context of UREs. LAMP does not require expensive instrumentation or reagents and uses equipment commonly found in teaching labs. By performing the technique, students learn several key scientific skills that will be useful in their undergraduate or graduate STEM careers. We designed guided independent research experiences for several undergraduates that included the use of LAMP. Students successfully applied the technique to culture samples of common environmental bacteria, including Escherichia coli, Salmonella spp., Staphylococcus aureus, and Enterococcus, and were in addition, able to detect both Salmonella and Enterococcus in directly sampled environmental waters. To highlight the accessibility and affordability of this URE, a simple boiling method was used for DNA preparation from environmental samples. Student response data show positive attitudes toward UR when LAMP is utilized as a research tool to tackle relevant biological questions. The feasibility of using simplified LAMP in UREs points to a potential, more expanded application to public engagement with science and broader and more inclusive interactions with the research community.
Four Immune-Related Long Non-coding RNAs for Prognosis Prediction in Patients With Hepatocellular Carcinoma
Authors: Li Muqi , Liang Minni , Lan Tian , Wu Xiwen , Xie Wenxuan , Wang Tielong , Chen Zhitao , Shen Shunli , Peng Baogang
Published: December 2020

Background

Long non-coding RNA (LncRNA) plays an important role in the occurrence and development of hepatocellular carcinoma (HCC). This study aims to establish an immune-related LncRNA model for risk assessment and prognosis prediction in HCC patients.

Methods

Hepatocellular carcinoma patient samples with complete clinical data and corresponding whole transcriptome expression were obtained from the Cancer Genome Atlas (TCGA). Immune-related genes were acquired from the Gene Set Enrichment Analysis (GSEA) website and matched with LncRNA in the TCGA to get immune-related LncRNA. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for screening the candidate LncRNAs and calculating the risk coefficient to establish the prognosis model. Patients were divided into a high-risk group and a low-risk group depending on the median risk score. The reliability of the prediction was evaluated in the validation cohort and the whole cohort. GSEA and principal component analysis were used for function evaluation.

Results

A total of 319 samples met the screening criteria and were randomly distributed across the training cohort and the validation cohort. After comparison with the IMMUNE_RESPONSE gene set and the IMMUNE_SYSTEM_PROCESS gene set, a total of 3094 immune-related LncRNAs were screened. Ultimately, four immune-related LncRNAs were used to construct a formula using LASSO regression. According to the formula, the low-risk group showed a higher survival rate than the high-risk group in the validation cohort and the whole cohort. The receiver operating characteristic curves data demonstrated that the risk score was more specific than other traditional clinical characteristics in predicting the 5-year survival rate for HCC.

Conclusion

The four-immune-related-LncRNA model can be used for survival prediction in HCC and guide clinical therapy.
Have I Been Here? Sense of Location in People With Alzheimer's Disease
Authors: Pai Ming-Chyi , Jan Shau-Shiun
Published: December 2020

Background: When navigating in a particular space, a sense of being at a current location is of great help for the navigators in reaching their destination or getting back to the start. To accomplish this work, interwoven neural structures and neurons are called into play. This system is called the heading direction cell-place cell-grid cell circuit. Evidence from various neuroscience studies has revealed that the regions responsible for this circuit are damaged in the early stages of Alzheimer's disease (AD). This may explain why wayfinding difficulty is one of the most frequent symptoms in persons with AD. The aim of this study was to examine the sense of location (SoL) in persons with mild AD, persons with prodromal AD (prAD), and those who were cognitively unimpaired (CU).

Methods: We invited people with mild AD, prAD, and CU to participate in this study. The venue of the core experiment to assess SoL was a 660-m path located on the university campus. The participants were instructed to take a walk on the path and press a device to indicate their arrival at each of the five carefully chosen targets. The linear deviations from the target site were compared among the groups.

Results: A total of 20 AD, 28 prAD, and 29 CU persons completed the study. Their Mini-Mental State Examination scores were on average 20 (SD 3), 24 (SD 3), and 28 (SD 2). The groups were well differentiated regarding several measurements for cognitive ability and spatial navigation. As for the SoL, the hit rates of exact location with linear deviation of 16 m or less were 0.05, 0.54, and 0.86 for AD, prAD, and CU persons, respectively. The hit rates were well correlated with the presence of getting lost. Also, SoL differentiated well among CU, PrAD, and AD in terms of average linear deviation.

Conclusions: Our employing linear deviation by utilizing a grid-cell function device as an assessment for SoL showed distinct features among the three groups. This model can be used to develop more delicate devices or instruments to detect, monitor, and aid spatial navigation in persons with prAD and AD.
Metal Exposure and SNCA rs356219 Polymorphism Associated With Parkinson Disease and Parkinsonism
Authors: Lucchini Roberto G. , Guazzetti Stefano , Renzetti Stefano , Broberg Karin , Caci Margherita , Covolo Loredana , Crippa Patrizia , Gelatti Umberto , Hashim Dana , Oppini Manuela , Pepe Fulvio , Pilotto Andrea , Passeri Chiara , Placidi Donatella , Rizzetti Maira Cristina , Turla Marinella , Wahlberg Karin , Padovani Alessandro
Published: December 2020

Objective: In the province of Brescia, Italy, historical neurotoxic metal exposure has occurred for several decades. This study aimed to explore the role of metal exposure and genetics on Parkinson's Disease (PD) and Parkinsonism.

Methods: Cases were enrolled from four local clinics for movement disorders. Randomly selected controls non-affected by neurological or psychiatric conditions were enrolled from the same health centers keeping a similar gender ratio and age distribution as for cases. Data on sociodemographic variables, clinical onset and life habits were collected besides accurate occupational and residential history. Blood samples were collected from all participants for genotyping of target polymorphisms in genes linked to PD and/or metal transport.

Results: A total number of 432 cases and 444 controls were enrolled in the study, with average age of 71 years (72.2 for cases and 70 for controls). The average age at diagnosis was 65.9 years (SD 9.9). Among the potential risk factors, family history of PD or Parkinsonism showed the strongest association with the diseases (OR = 4.2, 95% CI 2.3, 7.6 on PD; OR = 4.3, 95% CI 1.9, 9.5 for Parkinsonism), followed by polymorphism rs356219 in the alpha-synuclein (SNCA) gene (OR = 2.03, 95% CI 1.3, 3.3 for CC vs. TT on PD; OR = 2.5, 95% CI 1.1, 5.3 for CC vs. TT on Parkinsonism), exposure to metals (OR = 2.4;, 95% CI 1.3, 4.2 on PD), being born in a farm (OR = 1.8; 95% CI 1.1, 2.8 on PD; OR = 2.6; 95% CI 1.4, 4.9 on Parkinsonism) and being born in the province of Brescia (OR = 1.7; 95% CI 1.0, 2.9 on PD). Conditional OR of having PD depending by SNCA polymorphism and metal exposure highlights higher risk of PD among CC SNCA carriers and being exposed to metals. However, the interaction term was not statistically significant.

Conclusions: Lifetime exposure to metals and genetic variation in SNCA gene are relevant determinants of PD and Parkinsonism in the highly industrialized area of Brescia, Italy. The lack of evidence of statistical interaction between environmental and genetic factors may be due to the low frequencies of subjects representing the exposure categories and the polymorphism variants and does not rule out the biological interaction.
Case Report: [18F]PI2620 as a Tau Imaging Agent in Posterior Cortical Atrophy
Authors: Kong Yu , Xie Kexin , Qiao Hongwen , Cui Yue , Jing Donglai , Wang Yuting , Li Xuying , Wu Liyong
Published: December 2020

Posterior cortical atrophy (PCA) is widely considered as an atypical variant of Alzheimer disease and is characterized by a progressive decline in visual function. PCA has been investigated from the standpoints of brain structure and metabolism, but tau deposition and its relationship to disease severity still remain unclear. Here, we used a novel tau ligand, [18F]PI2620, to visualize tau deposition in a PCA patient. The results showed that high [18F]PI2620 uptake in posterior cortical regions was associated with clinical manifestations, morphologic changes in the brain observed by magnetic resonance imaging (MRI), and hypometabolism detected by [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET). This is the first report demonstrating a clinical anatomical correspondence between [18F]PI2620 PET results, clinical manifestations, MRI, and [18F]FDG PET findings in a Chinese patient with PCA. The results also support the utility of [18F]PI2620 for visualizing tau aggregation in PCA.
Tissue-Type Plasminogen Activator and Tenecteplase-Mediated Increase in Blood Brain Barrier Permeability Involves Cell Intrinsic Complement
Authors: Keragala Charithani B. , Woodruff Trent M. , Liu Zikou , Niego Be'eri , Ho Heidi , McQuilten Zoe , Medcalf Robert L.
Published: December 2020

Background: Tissue-type plasminogen activator (t-PA) has been the mainstay of therapeutic thrombolysis for patients with acute ischaemic stroke (AIS). However, t-PA can cause devastating intracerebral hemorrhage. t-PA can also influence the CNS in part by modulation of BBB permeability. Complement activation also occurs after AIS and has also been reported to increase BBB permeability. The complement components, C3 and C5, can also be activated by t-PA via plasmin formation and cell intrinsic complement may be involved in this process. Tenecteplase (TNK-tPA) is a t-PA variant with a longer plasma half-life, yet the ability of TNK-tPA to modulate the BBB and complement is less clear.

Aim: To evaluate the effect of C5 and C5a-receptor 1 (C5aR1) inhibitors on t-PA- and TNK-tPA-mediated opening of the BBB.

Methods: We used an in vitro model of the BBB where human brain endothelial cells and human astrocytes were co-cultured on the opposite sides of a porous membrane assembled in transwell inserts. The luminal (endothelial) compartment was stimulated with t-PA or TNK-tPA together with plasminogen, in the presence of PMX205 (a non-competitive C5aR1 antagonist), Avacopan (a competitive C5aR1 antagonist) or Eculizumab (a humanized monoclonal inhibitor of human C5). BBB permeability was assessed 5 and 24 h later. Immunofluorescence was also used to detect changes in C5 and C5aR1 expression in endothelial cells and astrocytes.

Results: PMX205, but not Avacopan or Eculizumab, blocked t-PA-mediated increase in BBB permeability at both the 5 and 24 h time points. PMX205 also blocked TNK-tPA-mediated increase in BBB permeability. Immunofluorescence analysis revealed intracellular staining of C5 in both cell types. C5aR1 expression was also detected on the cell surfaces and also located intracellularly in both cell types.

Conclusion: t-PA and TNK-tPA-mediated increase in BBB permeability involves C5aR1 receptor activation from cell-derived C5a. Selective inhibitors of C5aR1 may have therapeutic potential in AIS.
Pathophysiology of Blood–Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery
Authors: Bernardo-Castro Sara , Sousa João André , Brás Ana , Cecília Carla , Rodrigues Bruno , Almendra Luciano , Machado Cristina , Santo Gustavo , Silva Fernando , Ferreira Lino , Santana Isabel , Sargento-Freitas João
Published: December 2020

The blood–brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1–3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.
Reconstruction of Immune Microenvironment and Signaling Pathways in Endometrioid Endometrial Adenocarcinoma During Formation of Lymphovascular Space Involvement and Lymph Node Metastasis
Authors: Cheng Yuan , Zhang Xiaobo , Wang Zhiqi , Wang Jianliu
Published: December 2020

Background

The amplification or mutation of oncogenes and escape from immune surveillance systems promote tumor metastasis. However, subtle changes in the immune microenvironment and signaling pathways are poorly understood during the formation of lymphovascular space involvement (LVSI) and lymph node (LN) metastasis of endometrioid endometrial adenocarcinoma (EEA).

Patients and methods

We detected tumor immunology-related signaling pathways and immunocyte subtypes according to the mRNA levels of 750 oncogenes and genes relating to the tumor microenvironment and immune response using the Nanostring PanCancer IO 360 Panel in 24 paraffin-embedded tissues of EEAs and benign gynecological diseases. Internal reference genes were used for data normalization.

Results

Angiogenesis and immune cell adhesion signaling pathways were activated during LVSI formation of EEA progression. However, during the development of LVSI to LN metastasis, immune system signaling pathways were significantly inhibited, including antigen presentation, cytotoxicity, lymphoid compartment, interferon signaling, and costimulatory signaling pathways. Immune-related genes (CD69, HLA-DOA, ATF3, GBP1, AP2, DTX3L, EGR1, GBP4, TAP1, EIF2AK2, MX1, ISG15, STAT1, and HLA-DRA) were significantly downregulated in EEA with LN metastasis compared to those in EEA with LVSI. Instead, hypoxia, metabolic stress, epigenetic regulation, matrix remodeling, and metastasis signaling pathways were continuously activated in LN metastasis. We also found that neutrophils, macrophages, and mast cells might be involved in LVSI formation and LN metastasis in EEA.

Conclusions

EEA with metastatic LNs showed significant immunosuppressive effects. Some oncogenes, matrix remodeling- and hypoxia-related genes, and neutrophil signatures showed higher expression, suggesting their potential as therapeutic targets and offering new immunotherapy strategies in EEA during LN metastasis.
Acquisition, Divergence, and Personalization of the Female Perineal Microbiomes Are Driven by Developmental Milestones and Disrupted by Urinary Tract Infection: A Pilot Study
Authors: Lucas Elizabeth J. , Ching Christina B. , Saraswat Shweta , Dabdoub Shareef M. , Kumar Purnima P. , Justice Sheryl S.
Published: December 2020

Introduction:The pediatric perineal microbiomes inhabit a dynamic environment with changes related to diet, toileting habits, and hormonal development. We hypothesized that next-generation sequencing would reveal different perineal bacterial signatures associated with developmental milestones in premenstrual females. Furthermore, we predicted that these microbial changes would be disrupted in premenstrual females with a history of urinary tract infection (UTI).

Study Design:Healthy females were recruited at well-child visits. Subjects were divided into 4 developmental groups: (1) 0–3 month old newborns; (2) 4–10 month old infants transitioning to solid foods; (3) 2–6 year old toddlers peri-toilet training; and (4) 7–12 year old premenstrual girls. A separate group of females with a history of culture proven UTI and off antibiotics >1 month was also recruited. DNA was isolated from swabs of the perineum and subjected to 16S rRNA sequencing. The diversity and species changes between developmental cohorts and age matched children with history of UTI was determined.

Results:A total of 75 subjects were recruited: 15 in each group. There was a clear evolution of the perineal microbiomes with development. There was a significant microbial disruption in girls with a history of UTI, irrespective of developmental milestone age group. The periurethral/perivaginal site displayed greater changes in microbiome structure than other sites in girls with a history of UTI.

Discussion:This pilot study evaluates the normal microbiome of the premenstrual girl at specific developmental milestones. Although the number of children per cohort was limited to 15, we observed statistical significance corresponding with developmental milestones. This study provides the first, culture independent delineation of the development of the perineal microbiome in girls. Furthermore, the sites closest to the site of infection appear to be more sensitive to antibiotic remodeling than those more distant. The factors that remodel the perineal microbiomes and predispose females, particularly girls, to UTIs (e.g., increase in uropathogen presence, absence of protective organisms) are unclear. Identification of specific signatures that increase susceptibility to UTI and their sequelae will improve patient care and promote personalized medicine.
Risk Factors Related to Operative Duration and Their Relationship With Clinical Outcomes in Pediatric Patients Undergoing Roux-en-Y Hepaticojejunostomy
Authors: Zhou Yongjun , Zhang Yunfei , Guo Hongjie , Zheng Chao , Guo Chunbao
Published: December 2020

Background: Operative duration might be important for perioperative morbidity, and its involvement has not been fully characterized in pediatric patients. We identified perioperative variables associated with operative duration and determined their influence on clinical outcomes in pediatric patients.

Methods: We retrospectively reviewed 701 patients who underwent elective removal of choledochal cysts followed by Roux-en-Y hepaticojejunostomy. The patients were separated into the long operative time group (>165 min) and short operative time group (<165 min) based on the median operative time (165 min). Propensity score matching was performed to adjust for any potential selection bias. The independent risk factors for operative time were determined using multivariable logistic regression analyses.

Results: The operative time was often increased by excision difficulty caused by a larger choledochal cyst size (OR = 1.56; 95% CI, 1.09–2.23; p < 0.001), a greater BMI (OR = 1.02; 95% CI, 1.00–1.15; p = 0.018), and older age (OR = 1.17; 95% CI, 1.02–1.39; p = 0.012) in the multivariate analysis. A long surgical duration was associated with delayed gastrointestinal functional recovery, as measured using the time to first defecation (p = 0.027) and first bowel movement (p = 0.019). Significantly lower levels of serum albumin were found in the long operative time group than in the short operative time group (p = 0.0035). The total length of postoperative hospital stay was longer in patients in the long operative time group (7.51 ± 2.03 days) than in those in the short operative time group (6.72 ± 1.54 days, p = 0.006).

Conclusions: Our data demonstrated that a short operative time was associated with favorable postoperative results. The influencing factors of operative time should be ameliorated to achieve better outcomes.
Appendicitis in Children in a Large Italian COVID-19 Pandemic Area
Authors: La Pergola Enrico , Sgrò Alberto , Rebosio Federico , Vavassori Daniele , Fava Giorgio , Codrich Daniela , Montanaro Beatrice , Leva Ernesto , Schleef Jurgen , Cheli M. , Pelizzo Gloria , Gamba Piergiorgio , Alberti Daniele , Betalli Pietro
Published: December 2020

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed the routine activities of pediatric surgical centers, and it determined the reduction of admissions in the pediatric emergency departments (PED). We reviewed the records of patients affected by acute appendicitis (AA) during the COVID-19 pandemic period in a large Italian COVID-19 pandemic area.

Methods: Data regarding demographics, age, macroscopic and microscopic findings, and time between symptom onset and PED admission of patients affected by confirmed AA in the period between March and April 2020 were considered. The data were compared with those obtained during the same period of 2019, 2018, and 2017 in the included centers. Data were quoted as median (range) or absolute number. Non-parametric statistical tests were used to compare groups. A p ≤ 0.05 was regarded as significant. Since only anonymous data have been used and the data storage meets current data protection regulations, ethical committee approval was not required for this study.

Results: Eighty-six patients underwent surgical appendectomy for AA between February 20th, 2020 and April 20th, 2020; 32.5% were complicated appendicitis and 67.5% were uncomplicated. Fifty-three patients were males and 33 were females. Patients' age ranged from 3 to 17 years and the median age was 10 years. The median time between the onset of symptoms and the admission in PED was 1.85 days. The average time between the symptom onset and PED admission was 1.8 days.

Conclusions: Although fear from the COVID-19 pandemic determined a delayed diagnosis of serious pediatric diseases, the increasing prevalence and severity of AA were not demonstrated in the most COVID-19-affected areas of Italy.