bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycocalyx breakdown is increased in African children with cerebral and uncomplicated falciparum malaria
Authors: Yeo Tsin W. , Bush Peggy A. , Chen Youwei , Young Sarah P. , Zhang Haoyue , Millington David S. , Granger Donald L. , Mwaikambo Esther D. , Anstey Nicholas M. , Weinberg J. Brice
Published: October 2019

Cerebral malaria (CM) from Plasmodium falciparum infection is associated with endothelial dysfunction and parasite sequestration. The glycocalyx (GCX), a carbohydrate‐rich layer lining the endothelium, is crucial in vascular homeostasis. To evaluate the role of its loss in the pathogenesis of pediatric CM, we measured GCX degradation in Tanzanian children with World Health Organization‐defined CM (n = 55), uncomplicated malaria (UM; n = 20), and healthy controls (HCs; n = 25). Urine GCX breakdown products [glycosaminoglycans (GAGs)] were quantified using dimethylmethylene blue (DMMB) and liquid chromatography‐tandem mass spectrometry assays. DMMB‐GAG and mass spectrometry (MS)‐GAG (g/mol creatinine) were increased in CM and UM compared with HCs (P < 0.001), with no differences in DMMB‐GAG and MS‐GAG between CM and UM children or between those with and without a fatal outcome. In CM survivors, urinary GCX DMMB‐GAG normalized by d 3. After adjusting for disease severity, DMMB‐GAG was significantly associated with parasitemia [partial correlation coefficient (Pcorr) = 0.34; P = 0.01] and plasma TNF (Pcorr = 0.26; P = 0.04) and inversely with plasma and urine NO oxidation products [Pcorr = ‐0.31 (P = 0.01) and Pcorr = ‐0.26 (P = 0.03), respectively]. GCX breakdown is increased in children with falciparum malaria, with similar elevations in CM and UM. Endothelial GCX degradation may impair endothelial NO production, exacerbate adhesion‐molecule expression, exposure, and parasite sequestration, and contribute to malaria pathogenesis.—Yeo, T. W., Bush, P. A., Chen, Y., Young S. P., Zhang H., Millington, D. S., Granger, D. L., Mwaikambo, E. D., Anstey, N. M., Weinberg J. B. Glycocalyx breakdown is increased in African children with cerebral and uncomplicated falciparum malaria. FASEB J. 33, 14185‐14193 (2019). www.fasebj.org
Cytosolic phospholipase A2 is a key regulator of blood‐brain barrier function in epilepsy
Authors: Hartz Anika M. S. , Rempe Ralf G. , Soldner Emma L. B. , Pekcec Anton , Schlichtiger Juli , Kryscio Richard , Bauer Bjoern
Published: October 2019

Blood‐brain barrier dysfunction in epilepsy contributes to seizures and resistance to antiseizure drugs. Reports show that seizures increase brain glutamate levels, leading to barrier dysfunction. One component of barrier dysfunction is overexpression of the drug efflux transporters P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP). Based on our previous studies, we hypothesized that glutamate released during seizures activates cytosolic phospholipase A2 (cPLA2), resulting in P‐gp and BCRP overexpression. We exposed isolated rat brain capillaries to glutamate ex vivo and used an in vivo‐ex vivo approach of isolating brain capillaries from rats after status epilepticus (SE) and in chronic epileptic (CE) rats. Glutamate increased cPLA2, P‐gp, and BCRP protein and activity levels in isolated brain capillaries. We confirmed the role of cPLA2 in the signaling pathway in brain capillaries from male and female mice lacking cPLA2. We also demonstrated, in vivo, that cPLA2 inhibition prevents overexpression of P‐gp and BCRP at the blood‐brain barrier in rats after status epilepticus and in CE rats. Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood‐brain barrier P‐gp and BCRP.—Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood‐brain barrier function in epilepsy. FASEB J. 33, 14281‐14295 (2019). www.fasebj.org
HMGB2 is a negative regulator of telomerase activity in human embryonic stem and progenitor cells
Authors: Kučírek Martin , Bagherpoor Alireza J. , Jaroš Josef , Hampl Aleš , Štros Michal
Published: October 2019

High‐mobility group box (HMGB)1 and HMGB2 proteins are the subject of intensive research because of their involvement in DNA replication, repair, transcription, differentiation, proliferation, cell signaling, inflammation, and tumor migration. Using inducible, stably transfected human embryonic stem cells (hESCs) capable of the short hairpin RNA‐mediated knockdown (KD) of HMGB1 and HMGB2, we provide evidence that deregulation of HMGB1 or HMGB2 expression in hESCs and their differentiated derivatives (neuroectodermal cells) results in distinct modulation of telomere homeostasis. Whereas HMGB1 enhances telomerase activity, HMGB2 acts as a negative regulator of telomerase activity in the cell. Stimulation of telomerase activity in the HMGB2‐deficient cells may be related to activation of the PI3K/protein kinase B/glycogen synthase kinase‐3β/ β‐catenin signaling pathways by HMGB1, augmented TERT/telomerase RNA subunit transcription, and possibly also because of changes in telomeric repeat‐containing RNA (TERRA) and TERRA‐polyA+ transcription. The impact of HMGB1/2 KD on telomerase transcriptional regulation observed in neuroectodermal cells is partially masked in hESCs by their pluripotent state. Our findings on differential roles of HMGB1 and HMGB2 proteins in regulation of telomerase activity may suggest another possible outcome of HMGB1 targeting in cells, which is currently a promising approach aiming at increasing the anticancer activity of cytotoxic agents.—Kučírek, M., Bagherpoor, A. J., Jaroš, J., Hampl, A., Štros, M. HMGB2 is a negative regulator of telomerase activity in human embryonic stem and progenitor cells. FASEB J. 33, 14307‐14324 (2019). www.fasebj.org
Fluorofenidone protects against acute kidney injury
Authors: Jiang YuPeng , Quan Jiao , Chen Yang , Liao Xiaohua , Dai Qin , Lu Rong , Yu Yue , Hu Gaoyun , Li Qianbin , Meng Jie , Xie Yanyun , Peng Zhangzhe , Tao Lijian
Published: October 2019

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP‐induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)‐induced AKI and LPS‐induced AKI are the major models representative of renal transplantation‐correlated AKI and sepsis‐related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP‐, IRI‐, and LPS‐caused AKI and elucidate the underlying mechanism.—Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury. FASEB J. 33, 14325‐14336 (2019). www.fasebj.org
High-quality draft genome sequences of Pseudomonas monteilii DSM 14164T, Pseudomonas mosselii DSM 17497T, Pseudomonas plecoglossicida DSM 15088T, Pseudomonas taiwanensis DSM 21245T and Pseudomonas vranovensis DSM 16006T: taxonomic considerations
Authors: Peña Arantxa , Busquets Antonio , Gomila Margarita , Mulet Magdalena , Gomila Rosa M. , Garcia-Valdes Elena , Reddy T. B. K. , Huntemann Marcel , Varghese Neha , Ivanova Natalia , Chen I-Min , Göker Markus , Woyke Tanja , Klenk Hans-Peter , Kyrpides Nikos , Lalucat Jorge
Published: October 2019

Pseudomonas

is the bacterial genus of Gram-negative bacteria with the highest number of recognized species. It is divided phylogenetically into three lineages and at least 11 groups of species. The

Pseudomonas putida

group of species is one of the most versatile and best studied. It comprises 15 species with validly published names. As a part of the Genomic Encyclopedia of Bacteria and Archaea (GEBA) project, we present the genome sequences of the type strains of five species included in this group:

Pseudomonas monteilii

(DSM 14164T),

Pseudomonas mosselii

(DSM 17497T),

Pseudomonas plecoglossicida

(DSM 15088T), Pseudomonas taiwanensis (DSM 21245T) and

Pseudomonas vranovensis

(DSM 16006T). These strains represent species of environmental and also of clinical interest due to their pathogenic properties against humans and animals. Some strains of these species promote plant growth or act as plant pathogens. Their genome sizes are among the largest in the group, ranging from 5.3 to 6.3 Mbp. In addition, the genome sequences of the type strains in the

Pseudomonas

taxonomy were analysed via genome-wide taxonomic comparisons of ANIb, gANI and GGDC values among 130

Pseudomonas

strains classified within the group. The results demonstrate that at least 36 genomic species can be delineated within the

P. putida

phylogenetic group of species.
To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system
Authors: Hage Adam , Rajsbaum Ricardo
Published: October 2019

The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target’s function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host–virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.
Mild Traumatic Brain Injury Disrupts Functional Dynamic Attractors of Healthy Mental States
Authors: Vergara Victor M. , van der Horn Harm J. , Mayer Andrew R. , Espinoza Flor A. , van der Naalt Joukje , Calhoun Vince D
Published: October 2019

The human brain has the ability of changing its wiring configuration by increasing or decreasing functional connectivity strength between specific areas. Variable but recurring configuration patterns in dynamic functional connectivity have been observed during resting fMRI experiments, patterns which are defined as dynamic brain states. The question arises whether in a regular healthy brain these states evolve in a random fashion or in a specific sequential order. The current work reveals both the specific state sequence in healthy brains, as well as the set of disruptions in this sequence produced by traumatic brain injury. The healthy sequence consists of oscillatory dynamic connectivity patterns that orbit an attractor state in a high dimensional space. Using discovery (96 subjects) and replication (74 subjects) cohorts, this study demonstrated that mild traumatic brain injury results in immediate orbital disruptions that recover over time. Brain dynamics enter a status of disrupted orbits right after injury, with partial recovery at 4 weeks, and full recovery at 3 months post-injury. In summary, our results describe an aspect of neuronal dysfunction in mild traumatic brain injury that is fully based on brain state dynamics, and different from traditional brain connectivity strength measures.
Operationalizing Occupational Fatigue in Pharmacists: An Exploratory Factor Analysis
Authors: Watterson Taylor , Look Kevin , Steege Linsey , Chui Michelle
Published: October 2019

Introduction

The Quadruple Aim recognizes that caring for the healthcare employee is necessary to optimize patient outcomes and health system performance. Although previous research has assessed pharmacists’ workload, this study is the first to describe pharmacist occupational fatigue – a characteristic of excessive workload that inhibits workers’ abilities to function at normal capacity. The purpose of this study was to describe occupational fatigue in pharmacists using exploratory factor analysis (EFA) – assessing whether dimensional structures used to describe occupational fatigue in other health professions fit pharmacist perceptions.

Methods

A model was created to conceptualize ‘fatigue’ domains found in the literature. A priori, the two domains identified were physical fatigue (ex. physical discomfort), and mental fatigue (ex. trouble thinking clearly). These domains were operationalized and used to create a paper survey that was distributed to licensed pharmacists at a pharmacy conference. An EFA was conducted to identify the key domains underlying pharmacist perceptions of fatigue.

Results

A total of 283 surveys were distributed and 115 were returned and usable. Respondents were primarily white, female, worked 9.52 hours-per-day on average, and mean age of 39-years-old. The EFA suggested a statistically significant two-factor model (χ2 9.73, p=0.28; TLI 0.998, RMSEA 0.048), which included physical fatigue (α = 0.87) and mental fatigue (α = 0.82).

Discussion

The EFA yielded a structure similar to what was anticipated from the literature with physical and mental fatigue dimensions. This is just the first step in promoting systematic interventions to prevent or cope with fatigue and prevent the downstream patient, pharmacist, and institutional outcomes. By addressing fatigue and caring for employees, health care systems can take steps to work toward the Quadruple Aim.
Exploring the effects of a lack of pocketmoney onthe learning activities of undergraduate health sciences students in their clinical year
Authors: Kumsa Marema Jebessa , Lemu Bizuayehu Nigatu , Ketema Taklehaimanot Mezgebe
Published: October 2019

Background

In Ethiopia, there is little understanding of students’ university expenses and how the lack of pocket money affects undergraduate learning. This is particularly evident for undergraduate health sciences students that need additional money when they start their clinical placement.

Objectives

We aimed to explore the economic challenges that clinical year undergraduate health sciences students face with limited pocket money, as well as how students perceive these limited funds as affecting their learning activities and their ability to meet challenges.

Methods

This descriptive qualitative study was conducted at the Department of Medical Radiology Technology (MRT), College of Health Sciences (CHS) at Addis Ababa University (AAU). Ten participants were recruited through purposive and snowball methods, and semi-structured interviews were conducted between January 28, 2019 and February 1, 2019. The semi-structured questions explored participants’ experiences and perceptions regarding the challenges of a lack of pocket money and its impacts on their learning activities. Their reaction to financial challenges was also assessed.

Results

Four themes that are related to impact of lack of money on learning activities emerged from the interviews and they revolved around the students’ challenges in obtaining pocket money, their difficulty in affording daily needs, their self-management and their ability to have an adequate social life.

Conclusion

Based on our data, the underlying causes that lead students to face financial hardships can be solved by increasing public awareness of university expenses, clarifying the cost sharing system to the public, redesigning the cost sharing policy, and improving university services In addition, training students self-management and pocket money management, as well giving providing adequate transportation services, cash-money, and consultations for students during clinical placement.
VALIDATION OF PHLEBOTOMY PERFORMANCE METRICS DEVELOPED AS PART OF A PROFICIENCY BASED PROGRESSION INITIATIVE TO MITIGATE WRONG BLOOD IN TUBE
Authors: O’ Herlihy N. , Griffin S , Henn P , Gaffney R. , Cahill M.R. , Gallagher A.G.
Published: October 2019

Aims

The purpose of this study was to 1) characterise the procedure of phlebotomy, deconstruct it into its constituent parts and develop a performance metric for the purpose of training healthcare professionals in a large teaching hospital, 2) evaluate the construct validity of the phlebotomy metric and establish a proficiency benchmark.

Method

Using video recordings of the procedure, we defined a performance metric. This was brought to a modified Delphi meeting, where consensus was reached by an expert panel. To demonstrate construct validity, we used the metric to objectively assess the performance of novices and expert practitioners.

Results

A phlebotomy metric consisting of 11 phases and 77 steps was developed. The mean inter-rater reliability was 0.91 (min 0.83, max 0.95). The Expert group completed more steps of the procedure (72 Vs 69), made 69% fewer errors (19 vs 13, p = 0.014) and 300% fewer critical errors (1 Vs 4, p = 0.002) than the Novice Group.

Conclusions

The metrics demonstrated construct validity and the proficiency benchmark was established with a minimum observation of 69 steps, with no critical errors and no more than 13 errors in total.
Prediction of Colorectal Cancer Risk Based on Profiling with Common Genetic Variants
Authors: Li Xue , Timofeeva Maria , Spiliopoulou Athina , McKeigue Paul , He Yazhou , Zhang Xiaomeng , Svinti Victoria , Campbell Harry , Houlston Richard S , Tomlinson Ian PM , Farrington Susan M , Dunlop Malcolm G , Theodoratou Evropi
Published: October 2019

Background

Stratifying the risk of colorectal cancer (CRC) based on polygenic risk scores (PRSs) within populations has the potential to optimize screening and develop targeted prevention strategies.

Methods

A meta-analysis of eleven genome-wide association studies (GWAS), comprising 16 871 cases and 26 328 controls, was performed to capture CRC susceptibility variants. Genetic models with several candidate PRSs were generated from Scottish CRC case–control studies (6478 cases and 11 043 controls) for prediction of overall and site-specific CRC. Model performance was validated in UK Biobank (4800 cases and 20 287 controls). The 10-year absolute risk of CRC was estimated by modelling PRS with age and sex using the CRC incidence and mortality rates in the UK population.

Findings

A weighted PRS including 116 CRC SNPs (wPRS116) showed the strongest performance. Deconstructing the PRS into multiple genetic risk regional scores or inclusion of additional SNPs that did not reach genome-wide significance did not provide any further improvement on predictive performance. The odds ratio (OR) for CRC risk per SD of wPRS116 in Scottish dataset was 1·46 (95%CI: 1·41-1·50, c-statistics: 0·603). Consistent estimates were observed in UK Biobank (OR=1·49, 95%CI: 1·44-1·54, c-statistics: 0·610) and showed no substantial heterogeneity among tumor sites. Compared to the middle quintile, those in the highest 1% of PRSs had 3·25-fold higher risk and those in the lowest 1% had 0·32-fold lower risk of developing CRC. Modelling PRS with age and sex in the general UK population allows the identification of a high-risk group with 10-year absolute risk ≥5%.

Interpretation

By optimizing wPRS116, we show that genetic factors increase predictive performance but this increment is equivalent to the extraction of only one-tenth of the genetic susceptibility. When employing genetic risk profiling in population settings it provides a degree of risk discrimination that could, in principle, be integrated into population-based screening programs.
Whole genome sequencing detects minimal clustering amongEscherichia coliSequence Type 131H30isolates collected from U.S. children’s hospitals
Authors: Miles-Jay Arianna , Weissmann Scott J. , Adler Amanda L. , Baseman Janet G. , Zerr Danielle M.
Published: October 2019

Escherichia colisequence type 131H30has garnered global attention as a dominant antimicrobial-resistant lineage of extraintestinal pathogenicE. coli, but its transmission dynamics remain undefined. We applied whole genome sequencing to identify putative transmission clusters among clinical isolates ofH30from children across the U.S. Of 126 isolates, 17 were involved in 8 putative transmission clusters; 4 clusters involved isolates with some evidence of healthcare-associated epidemiologic linkages. Geographic clustering analyses showed weak geographic clustering. These findings are consistent with a framework where within-hospital transmission is not a main contributor to the propagation ofH30in a pediatric setting.
Potential Predictive Factors for Breast Cancer Subtypes from a North Cyprus Cohort Analysis
Authors: Ulgen Ayse , Gürkut Özlem , Li Wentian
Published: October 2019

Purpose

We present a first epidemiological survey from North Cyprus to determine predictive factors for breast cancer subtypes.

Methods

More than 300 breast cancer patients, 90% of them having subtype information, are surveyed from the State Hospital in Nicosia between 2006 – 2015 for their demographic, reproductive, genetic, epidemiological factors. The breast cancer subtypes, Estrogen receptor (ER) +/-, Progesterone receptor (PR) +/-, and human epidermal growth factor 2 (HER2) +/- status, are determined. Single and multiple variable, regularized regressions, with predictive factors as independent variables, breast cancer subtypes as dependent variables are conducted.

Results

Our cohort differs significantly from larger cohorts (e.g., Breast Cancer Family Registry), in age, menopause status, age of menarche, parity, education, oral contraceptive use, breastfeeding, but the distribution of breast subtypes is not significantly different. Subtype distribution in our cohort is also not different from another Turkish cohort. We show that the ER+ subtype is positively related to age/post-menopause; ER+/PR+ is positively associated with age, but negatively associated with cancer stage; HER2+, which is negatively correlated with ER+ and ER+/PR+, is positively related to cancer stage but negatively associated with age/post-menopause.

Conclusion

Assuming ER+ and ER+/PR+ to have better prognostic, HER+ to have worse prognostic, then older age and postmenopause seem to be beneficial, smoking and family history of cancer seem to be detrimental. Next steps include looking at potential biomarkers and using cure models to determine long-term survivors.
Gaze, Visual, Myoelectric, and Inertial Data of Grasps for Intelligent Prosthetics
Authors: Cognolato Matteo , Gijsberts Arjan , Gregori Valentina , Saetta Gianluca , Giacomino Katia , Hager Anne-Gabrielle Mittaz , Gigli Andrea , Faccio Diego , Tiengo Cesare , Bassetto Franco , Caputo Barbara , Brugger Peter , Atzori Manfredo , Müller Henning
Published: October 2019

Hand amputation is a highly disabling event, having severe physical and psychological repercussions on a person’s life. Despite extensive efforts devoted to restoring the missing functionality via dexterous myoelectric hand prostheses, natural and robust control usable in everyday life is still challenging. Novel techniques have been proposed to overcome the current limitations, among which the fusion of surface electromyography with other sources of contextual information. We present a dataset to investigate the inclusion of eye tracking and first person video to provide more stable intent recognition for prosthetic control. This multimodal dataset contains surface electromyography and accelerometry of the forearm, and gaze, first person video, and inertial measurements of the head recorded from 15 transradial amputees and 30 able-bodied subjects performing grasping tasks. Besides the intended application for upper-limb prosthetics, we also foresee uses for this dataset to study eye-hand coordination in the context of psychophysics, neuroscience, and assistive robotics.
DNA methylation biomarker selected by an ensemble machine learning approach predicts mortality risk in an HIV-positive veteran population
Authors: Shu Chang , Justice Amy C. , Zhang Xinyu , Marconi Vincent C. , Hancock Dana B. , Johnson Eric O. , Xu Ke
Published: October 2019

Background

With the improved life expectancy of people living with HIV (PLWH), identifying vulnerable subpopulations at high risk of mortality is important for clinical care. Evidences showed that DNA methylation (DNAm) is associated with aging and mortality in non-HIV populations. Here, we aimed to establish a panel of DNAm biomarkers that can predict mortality risk among PLWH.

Methods

1,081 HIV-positive participants from the Veterans Aging Cohort Study (VACS) were divided into training (N=460), validation (N=114), and testing (N=507) sets. VACS index was used as a measure of mortality risk among PLWH. Model training and fine-tuning were conducted using the ensemble method in the training and validation sets and prediction performance was assessed in the testing set. The survival analysis comparing the predicted high and low mortality risk groups was conducted. The Gene Ontology enrichment analysis of the predictive CpG sites was performed.

Results

We selected a panel of 393 CpGs for the ensemble prediction model. The prediction model showed excellent performance in predicting high mortality risk with an auROC of 0.809 (95%CI: 0.767-0.851) and a balanced accuracy of 0.653 (95%CI: 0.611, 0.693) in the testing set. The predicted high mortality risk group was significantly associated with 10-year mortality (hazard ratio=1.79, p=4E-05) compared with low mortality risk group. These 393 CpGs were located in 280 genes enriched in immune and inflammation responses pathways.

Conclusions

We identified a panel of DNAm features associated with mortality risk in PLWH. These DNAm features may serve as predictive biomarkers for mortality risk among PLWH.
Prediction of Suicidal Ideation in the Canadian Community Health Survey - Mental Health Component Using Deep Learning
Authors: Desai Sneha , Tanguay-Sela Myriam , Benrimoh David , Fratila Robert , Brown Eleanor , Perlman Kelly , John Ann , DelPozo-Banos Marcos , Low Nancy , Israel Sonia , Palladini Lisa , Turecki Gustavo
Published: October 2019

Introduction

Suicidal ideation (SI) is prevalent in the general population, and is a prominent risk factor for suicide. However, predicting which patients are likely to have SI remains a challenge. Deep Learning (DL) may be a useful tool in this context, as it can be used to find patterns in complex, heterogeneous, and incomplete psychiatric datasets. An automated screening system for SI could help prompt clinicians to be more attentive to patients at risk for suicide.

Methods

Using the Canadian Community Health Survey - Mental Health Component, we trained a DL model based on 23,859 survey responses to predict lifetime SI on an individual patient basis. Models were created to predict both lifetime and last 12 month SI. We reduced 582 possible model parameters captured by the survey to 96 and 21 feature versions of the models. Models were trained using an undersampling procedure that balanced the training set between SI and non-SI respondents; validation was done on held-out data.

Results

AUC was used as the main model metric. For lifetime SI, the 96 feature model had an AUC of 0.79 and the 21 feature model had an AUC of 0.75. For SI in the last 12 months the 96 feature model had an AUC of 0.76 and the 21 feature model had an AUC of 0.69. DL outperformed random forest classifiers.

Discussion

Although requiring further study to ensure clinical relevance and sample generalizability, this study is a proof-of-concept for the use of DL to improve prediction of SI. This kind of model would help start conversations with patients which could lead to improved care and, it is hoped, a reduction in suicidal behavior.
Receptor tyrosine kinases regulate signal transduction through a liquid–liquid phase separated state
Authors: Lin Chi-Chuan , Suen Kin Man , Jeffrey Polly-Anne , Wieteska Lukasz , Stainthorp Amy , Seiler Caroline , Koss Hans , Molina-París Carmen , Miska Eric , Ahmed Zamal , Ladbury John E
Published: October 2019

Receptor tyrosine kinases (RTKs), the largest class of transmembrane cell surface receptors, initiate signalling pathways which regulate diverse cellular processes. On activation these receptors rapidly recruit multiple downstream effector proteins to moderate affinity tyrosyl phosphate (pY) binding sites. However, the mechanism for expedient downstream effector protein recruitment via random molecular diffusion through the cytoplasm is not fully understood. One way in which the probabilistic outcome associated with random diffusion could be alleviated is through localized accumulation of high effective concentrations of signalling proteins in discrete pools in the cell (1). The inclusion of interacting proteins into liquid-liquid phase-separated (LLPS), membraneless protein droplets maintains functionally relevant proteins at high concentrations in a liquid phase at the required point of action, enhancing equilibrium binding and enzyme activity (2–6). These LLPS states have been associated with a wide range of cellular functions including regulation of signalling through, for example, nephrin (7, 8), the T-cell receptor (9), mTOR (10), and Sos-Ras (11), however, whether LLPS extends to RTK-mediated signal transduction has not been investigated. Here, we show that an RTK, fibroblast growth factor receptor 2 (FGFR2), forms a signalling competent LLPS state with two downstream effectors, a tandem Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (Shp2), and 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma 1 (Plcγ1). We show that these proteins assemble into a ternary complex which exploits LLPS condensation to simultaneously modulate kinase, phosphatase and phospholipase activities. Therefore, LLPS formation ensures that the requirement for prolonged, high-fidelity signalling is achieved. Additional RTKs also form LLPS with their downstream effectors, suggesting that formation of biological condensates is a key organising principle of RTK-mediated signalling, with broad implications for further mechanistic studies as well as therapeutic intervention.
Barthelonids represent a deep-branching Metamonad clade with mitochondrion-related organelles generating no ATP
Authors: Yazaki Euki , Kume Keitaro , Shiratori Takashi , Eglit Yana , Tanifuji Goro , Harada Ryo , Simpson Alastair G.B. , Ishida Ken-ichiro , Hashimoto Tetsuo , Inagaki Yuji
Published: October 2019

We here report the phylogenetic position of barthelonids, small anaerobic flagellates previously examined using light microscopy alone.Barthelonaspp. were isolated from geographically distinct regions and we established five laboratory strains. Transcriptomic data generated from oneBarthelonastrain (PAP020) was used for large-scale, multi-gene phylogenetic (phylogenomic) analyses. Our analyses robustly placed strain PAP020 at the base of the Fornicata clade, indicating that barthelonids represent a deep-branching Metamonad clade. Considering the anaerobic/microaerophilic nature of barthelonids and preliminary electron microscopy observations on strain PAP020, we suspected that barthelonids possess functionally and structurally reduced mitochondria (i.e. mitochondrion-related organelles or MROs). The metabolic pathways localized in the MRO of strain PAP020 were predicted based on its transcriptomic data and compared with those in the MROs of fornicates. Strain PAP020 is most likely incapable of generating ATP in the MRO, as no mitochondrial/MRO enzymes involved in substrate-level phosphorylation were detected. Instead, we detected the putative cytosolic ATP-generating enzyme (acetyl-CoA synthetase), suggesting that strain PAP020 depends on ATP generated in the cytosol. We propose two separate losses of substrate-level phosphorylation from the MRO in the clade containing barthelonids and (other) fornicates.
Transcript isoform sequencing reveals widespread promoter-proximal transcriptional termination
Authors: Ard Ryan , Thomas Quentin , Li Bingnan , Wang Jingwen , Pelechano Vicent , Marquardt Sebastian
Published: October 2019

Higher organisms achieve optimal gene expression by tightly regulating the transcriptional activity of RNA Polymerase II (RNAPII) along DNA sequences of genes1. RNAPII density across genomes is typically highest where two key choices for transcription occur: near transcription start sites (TSSs) and polyadenylation sites (PASs) at the beginning and end of genes, respectively2,3. Alternative TSSs and PASs amplify the number of transcript isoforms from genes4, but how alternative TSSs connect to variable PASs is unresolved from common transcriptomics methods. Here, we define TSS/PAS pairs for individual transcripts in Arabidopsis thaliana using an improved Transcript Isoform sequencing (TIF-seq) protocol and find on average over four different isoforms corresponding to variable TSS/PAS pairs per expressed gene. While intragenic initiation represents a large source of regulated isoform diversity, we discover that ∼ 14% of expressed genes generate relatively unstable short promoter-proximal RNAs (sppRNAs) from nascent transcript cleavage and polyadenylation shortly after initiation. The location of sppRNAs coincides with increased RNAPII density, indicating these large pools of promoter-stalled RNAPII across genomes are often engaged in transcriptional termination. RNAPII elongation factors progress transcription beyond sites of sppRNA formation, demonstrating RNAPII density near promoters represents a checkpoint for early transcriptional termination that governs full-length gene isoform expression.
Aging and the encoding of event changes: The role of neural activity pattern reinstatement
Authors: Stawarczyk David , Wahlheim Christopher N. , Etzel Joset A. , Snyder Abraham Z. , Zacks Jeffrey M.
Published: October 2019

When encountering unexpected event changes, memories of relevant past experiences must be updated to form new representations. Current models of memory updating propose that people must first generate memory-based predictions to detect and register that features of the environment have changed, then encode the new event features and integrate them with relevant memories of past experiences to form configural memory representations. Each of these steps may be impaired in older adults. Using functional MRI, we investigated these mechanisms in healthy young and older adults. In the scanner, participants first watched a movie depicting everyday activities in a day of an actor’s life. They next watched a second nearly identical movie in which some scenes ended differently. Crucially, before watching the last part of each activity, the second movie stopped, and participants were asked to mentally replay how the activity previously ended. Three days later, participants were asked to recall the activities. Neural activity pattern reinstatement in medial temporal lobe (MTL) during the replay phase of the second movie was associated with detecting changes and with better memory for the original activity features. Reinstatements in posterior medial cortex (PMC) additionally predicted better memory for changed features. Compared to young adults, older adults showed a reduced ability to detect and remember changes, and weaker associations between reinstatement and memory performance. These findings suggest that PMC and MTL contribute to change processing by reinstating previous event features, and that older adults are less able to use reinstatement to update memory for changed features.
Map making: Constructing, combining, and inferring on abstract cognitive maps
Authors: Park Seongmin A. , Miller Douglas S. , Nili Hamed , Ranganath Charan , Boorman Erie D.
Published: October 2019

Cognitive maps are thought to enable model-based inferences from limited experience that can guide novel decisions–a hallmark of behavioral flexibility. We tested whether the hippocampus (HC), entorhinal cortex (EC), and ventromedial prefrontal cortex (vmPFC)/medial orbitofrontal cortex (mOFC) organize abstract and discrete relational information into a cognitive map to guide novel inferences. Subjects learned the status of people in two separate unseen 2-D social hierarchies defined by competence and popularity piecemeal from binary comparisons, with each dimension learned on a separate day. Although only one dimension was ever behaviorally relevant, multivariate activity patterns in HC, EC and vmPFC/mOFC were linearly related to the Euclidean distance between people in the mentally reconstructed 2-D space. Hubs created unique comparisons between the two hierarchies, enabling inferences between novel pairs of people. We found that both behavior and neural activity in EC and vmPFC/mOFC reflected the Euclidean distance to the retrieved hub, which was reinstated in HC. These findings reveal how abstract and discrete relational structures are represented, combined, and enable novel inferences in the human brain.
Unmasking the tissue microecology of ductal carcinoma in situ with deep learning
Authors: Narayanan Priya Lakshmi , Ahmed Raza Shan E , Hall Allison H. , Marks Jeffrey R. , King Lorraine , West Robert B. , Hernandez Lucia , Dowsett Mitch , Gusterson Barry , Maley Carlo , Hwang E. Shelley , Yuan Yinyin
Published: October 2019

Despite increasing evidence supporting the clinical relevance of tumour infiltrating lymphocytes (TILs) in invasive breast cancer, TIL spatial distribution pattern surrounding ductal carcinoma in situ (DCIS) and its association with progression is not well understood.

To characterize the tissue microecology of DCIS, we designed and tested a new deep learning pipeline, UNMaSk (UNet-IM-Net-SCCNN), for the automated detection and simultaneous segmentation of DCIS ducts. This new method achieved the highest sensitivity and recall over cutting-edge deep learning networks in three patient cohorts, as well as the highest concordance with DCIS identification based on CK5 staining.

Following automated DCIS detection, spatial tessellation centred at each DCIS duct created the boundary in which local ecology can be studied. Single cell identification and classification was performed with an existing deep learning method to map the distribution of TILs. In a dataset comprising grade 2-3 pure DCIS and DCIS adjacent to invasive cancer (adjacent DCIS), we found that pure DCIS cases had more TILs compared to adjacent DCIS. However, TILs co-localise significantly less with DCIS ducts in pure DCIS compared with adjacent DCIS, suggesting a more inflamed tissue ecology local to adjacent DCIS cases.

Our experiments demonstrate that technological developments in deep convolutional neural networks and digital pathology can enable us to automate the identification of DCIS as well as to quantify the spatial relationship with TILs, providing a new way to study immune response and identify new markers of progression, thereby improving clinical management.
Road and landscape-context impacts on bird pollination in a Mediterranean-type shrubland of the southeastern Cape Floristic Region
Authors: Grobler B. Adriaan , Campbell Eileen. E.
Published: October 2019

Road verges can provide important habitats for plants, especially in transformed landscapes. However, roads and their associated traffic have several adverse impacts on ecosystems that can disrupt vital ecological processes, including pollination. In transformed landscapes, road effects on pollination might be complemented by impacts of large-scale habitat modification. In these landscapes, road verge populations of plants that rely on pollinators for pollen transfer could thus be at risk of pollination failure. This study investigates the pollination of a reseeding, bird-pollinated shrub,Erica glandulosa, in road verges of a fragmented and transformed rural landscape in the southeastern Cape Floristic Region. We test for road impacts on pollination by comparing number of ruptured anther rings—a proxy for pollination—in fynbos vegetation fragments at different distances from the road (0–10, 20–30 and 40–50 m). We also test whether different land-cover types (intact fynbos, alien thickets and rangelands/pastures) next to road verges influence the number of ruptured anther rings. After controlling for robbing rate and plant density, fewer flowers were pollinated near the road than farther away, and fewer flowers were pollinated where road verges occurred next to alien thickets or pastures/rangelands compared to intact fynbos. However, bird pollination was not excluded in road verges: on average, ca. 20–30% of flowers were still visited by birds near the road. These findings potentially call into question the suitability of road verges as refugia for seed-dependent, bird-pollinated plant species in transformed landscapes.
Blood-brain barrier transport using a high-affinity, brain-selective VNAR (Variable Domain of New Antigen Receptor) antibody targeting transferrin receptor 1
Authors: Stocki Pawel , Szary Jaroslaw , Rasmussen Charlotte LM , Demydchuk Mykhaylo , Northall Leandra , Logan Diana Bahu , Gauhar Aziz , Thei Laura , Moos Torben , Walsh Frank S , Rutkowski J Lynn
Published: October 2019

Transfer across the blood-brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. We established a functional selection method to identify high-affinity single domain antibodies to the transferrin receptor 1 (TfR1) with efficient biotherapeutic delivery across the BBB.

Methods

A synthetic phage display library based on the variable domain of new antigen receptor (VNAR) was used forin vitroselection against recombinant human TfR1 ectodomain (rh-TfR1-ECD) followed byin vivoselection in mouse for brain parenchyma penetrating antibodies. Phage formatted VNARs cross-reactive to recombinant human and mouse TfR1-ECD were fused to Fc domain of human IgG1 (hFc) and tested for TfR1-ECD binding by ELISA and surface plasmon resonance. The pharmacokinetics and biodistribution of VNAR-hFcs were studied in mice by ELISA and immunolabeling following intravenous (IV) injection and cardiac perfusion. Functional activity was measured by body temperature reduction following the IV injection of neurotensin fused to a TXB2-hFc (TXB2-hFc-NT).

Results

TXB2 was identified as a high-affinity, species cross-reactive VNAR antibody against TfR1-ECD, that does not to compete with transferrin or ferritin for receptor binding. IV dosing of TXB2-hFc at 25 nmol/kg (1.875 mg/kg) in mice resulted in rapid binding to brain capillaries with subsequent transport into the brain parenchyma and specific uptake into TfR1-positive neurons. Likewise, IV dosing of TXB2-hFc-NT at 25 nmol/kg resulted in a rapid and reversible pharmacological response as measured by body temperature reduction. TXB2-hFc did not elicit any acute adverse reactions, bind or deplete circulating reticulocytes or reduce BBB-expressed endogenous TfR1 in mice. There was no evidence of target-mediated clearance or accumulation in peripheral organs except lung.

Conclusions

A species cross-reactive and brain-selective VNAR antibody to TfR1 was identified by a combination ofin vitroandin vivophage selection. As a high-affinity, bivalent Fc fusion protein, TXB2 rapidly crossed the BBB and exhibited a favorable pharmacokinetic and safety profile and can be readily adapted to carry a wide variety of biotherapeutics from blood to brain.
The effects of sex on extinction dynamics and evolutionary rescue ofChlamydomonas reinhardtiidepend on the rate of environmental change
Authors: Petkovic Nikola , Colegrave Nick
Published: October 2019

The continued existence of sex despite many costs it entails still lacks an adequate explanation. Previous experimental studies demonstrated that sex enhances the rate of adaptation in changing environments. To the best of our knowledge, no experimental study that investigated the effects of sex on adaptation has manipulated the rate of environmental change, which is negatively correlated with the probability of population survival. Since the patterns of adaptation (adaptive walk) depend on the rate of environmental change, the overall effects of sex may also be altered by this factor.

To investigate the interplay of sex and the rate of environmental deterioration, we carried out a long-term selection experiment with a unicellular alga (Chlamydomonas reinhardtii), by manipulating mode of reproduction (asexual or sexual populations) and the rate of environmental deterioration (an increase of salt concentration). We monitored both the population size and extinction dynamics and estimated the probability of evolutionary rescue.

We detected a faster decline of population size in the asexual group relative to both the obligate sexual and facultative sexual group, irrespective of the rate of environmental deterioration. The results revealed significant interaction between mode of reproduction and the rate of environmental deterioration on extinction rate of experimental populations. Obligate sexual reproduction was advantageous under the intermediate rate of environmental deterioration, while facultative sexuality was favoured under the high rate of environmental deterioration. The populations within the obligate sexual group were most likely to adapt to grow in conditions lethal for the ancestral populations, irrespective of the rate of environmental deterioration.

To the best of our knowledge, this is the first study which indicates that different modes of sexual reproduction will be beneficial (slower extinction rate) at different rates of environmental deterioration and that obligate sexuality maximizes the probability of adaptation irrespective of the rate of environmental deterioration.