bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy
Authors: Sayed Faten A. , Telpoukhovskaia Maria , Kodama Lay , Li Yaqiao , Zhou Yungui , Le David , Hauduc Axel , Ludwig Connor , Gao Fuying , Clelland Claire , Zhan Lihong , Cooper Yonatan A. , Davalos Dimitrios , Akassoglou Katerina , Coppola Giovanni , Gan Li
Published: September 2018

Alzheimer’s disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (
TREM2
) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.
Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming
Authors: Green Jack P. , Yu Shi , Martín-Sánchez Fátima , Pelegrin Pablo , Lopez-Castejon Gloria , Lawrence Catherine B. , Brough David
Published: September 2018

Significance

The NLRP3 inflammasome is a multimolecular protein complex which is responsible for regulating the processing and secretion of the proinflammatory cytokine interleukin-1β. Understanding the mechanisms regulating the assembly of the inflammasome is of outstanding biological interest and importance, not least because of the contributions of the NLRP3 inflammasome to disease processes. Here we report insights into the dynamic nature of inflammasome oligomerization and its dependence on chloride ions. These studies reveal an additional layer of regulation and priming that can further enhance and drive inflammatory responses.
PPP1R35 ensures centriole homeostasis by promoting centriole-to-centrosome conversion
Authors: Fong Chii Shyang , Ozaki Kanako , Tsou Meng-Fu Bryan
Published: September 2018

Centriole-to-centrosome conversion (CCC) safeguards centriole homeostasis by coupling centriole duplication with segregation, and is essential for stabilization of mature vertebrate centrioles naturally devoid of the geometric scaffold or the cartwheel. Here we identified PPP1R35, a putative regulator of the protein phosphatase PP1, as a novel centriolar protein required for CCC. We found that PPP1R35 is enriched at newborn daughter centrioles in S or G2 phase. In the absence of PPP1R35, centriole assembly initiates normally in S phase, but none of the nascent centrioles can form active centrosomes or recruit CEP295, an essential factor for CCC. Instead, all PPP1R35-null centrioles, although stable during their birth in interphase, become disintegrated after mitosis upon cartwheel removal. Surprisingly, we found that neither the centriolar localization nor the function of PPP1R35 in CCC requires the putative PP1-interacting motif. PPP1R35 is thus acting upstream of CEP295 to induce CCC for proper centriole maintenance.
High precision protein functional site detection using 3D convolutional neural networks
Authors: Torng Wen , Altman Russ B
Published: September 2018

Motivation

Accurate annotation of protein functions is fundamental for understanding molecular and cellular physiology. Data-driven methods hold promise for systematically deriving rules underlying the relationship between protein structure and function. However, the choice of protein structural representation is critical. Pre-defined biochemical features emphasize certain aspects of protein properties while ignoring others, and therefore may fail to capture critical information in complex protein sites.

Results

In this paper, we present a general framework that applies 3D convolutional neural networks (3DCNNs) to structure-based protein functional site detection. The framework can extract task-dependent features automatically from the raw atom distributions. We benchmarked our method against other methods and demonstrate better or comparable performance for site detection. Our deep 3DCNNs achieved an average recall of 0.955 at a precision threshold of 0.99 on PROSITE families, detected 98.89 and 92.88% of nitric oxide synthase and TRYPSIN-like enzyme sites in Catalytic Site Atlas, and showed good performance on challenging cases where sequence motifs are absent but a function is known to exist. Finally, we inspected the individual contributions of each atom to the classification decisions and show that our models successfully recapitulate known 3D features within protein functional sites.

Availability and implementation

The 3DCNN models described in this paper are available at https://simtk.org/projects/fscnn.

Supplementary information

Supplementary data are available at Bioinformatics online.
Sequence Alterations of Cortical Genes Linked to Individual Connectivity of the Human Brain
Authors: Xin Qilong , Ortiz-Terán Laura , Diez Ibai , Perez David L , Ginsburg Julia , El Fakhri Georges , Sepulcre Jorge
Published: September 2018

Individual differences in humans are driven by unique brain structural and functional profiles, presumably mediated in part through differential cortical gene expression. However, the relationships between cortical gene expression profiles and individual differences in large-scale neural network organization remain poorly understood. In this study, we aimed to investigate whether the magnitude of sequence alterations in regional cortical genes mapped onto brain areas with high degree of functional connectivity variability across individuals. First, human genetic expression data from the Allen Brain Atlas was used to identify protein-coding genes associated with cortical areas, which delineated the regional genetic signature of specific cortical areas based on sequence alteration profiles. Thereafter, we identified brain regions that manifested high degrees of individual variability by using test-retest functional connectivity magnetic resonance imaging and graph-theory analyses in healthy subjects. We found that rates of genetic sequence alterations shared a distinct spatial topography with cortical regions exhibiting individualized (highly-variable) connectivity profiles. Interestingly, gene expression profiles of brain regions with highly individualized connectivity patterns and elevated number of sequence alterations are devoted to neuropeptide-signaling-pathways and chemical-synaptic-transmission. Our findings support that genetic sequence alterations may underlie important aspects of brain connectome individualities in humans.

Significance Statement: The neurobiological underpinnings of our individuality as humans are still an unsolved question. Although the notion that genetic variation drives an individual’s brain organization has been previously postulated, specific links between neural connectivity and gene expression profiles have remained elusive. In this study, we identified the magnitude of population-based sequence alterations in discrete cortical regions and compared them to the brain topological distribution of functional connectivity variability across an independent human sample. We discovered that brain regions with high degree of connectional individuality are defined by increased rates of genetic sequence alterations; these findings specifically implicated genes involved in neuropeptide-signaling pathways and chemical-synaptic transmission. These observations support that genetic sequence alterations may underlie important aspects of the emergence of the brain individuality across humans.
Community-based interventions for prevention of Type 2 diabetes in low- and middle-income countries: a systematic review
Authors: Gyawali Bishal , Bloch Joakim , Vaidya Abhinav , Kallestrup Per
Published: September 2018

Type 2 diabetes is an increasing burden in low- and middle-income countries (LMICs). Knowledge of effective prevention programs in LMICs is thus important. The aim of this review was to establish an overview of studies evaluating the effectiveness of community-based interventions for prevention of Type 2 diabetes in LMICs. A literature review with searches in the databases using MEDLINE in Ovid (Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Version (R); Embase; PsycINFO; Global Health; and Google Scholar) between 1 January 2000 and 31 December 2015 was conducted. Only 10 studies that met our selection criteria were included; 3 were randomized controlled trials, 2 non-randomized controlled trials and 5 were pre-and post-intervention studies. About 9 of 10 studies reported significant reduction in both the glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels as a result of the intervention. A majority of the studies included multicomponent interventions such as education and behavioral encompassing both individual and group work, and included health education, nutrition education, nutrition counseling, exercise and promoting physical activity, psychosocial approaches and lifestyle modification. The interventions were delivered by community health workers, volunteers, social workers, community nutritionists and community nurses. Comparisons between studies, however, was not possible due to substantial heterogeneity in study design. This review contributes to the current literature on community-based interventions for prevention of Type 2 diabetes in LMICs, acknowledging the community-based approach can be effective in prevention and control of Type 2 diabetes. Due to the heterogeneity across study designs, outcomes and in terms of variation and duration of interventions, only limited conclusions can be drawn about the effectiveness of interventions. More evidence from randomized controlled trials on culturally tailored, community-based interventions is needed to compare findings and test implementation in practice.
Adherence to components of Health Promoting Schools in schools of Bengaluru, India
Authors: Periyasamy Sugavanesh , Krishnappa Pushpanjali , Renuka Piddennavar
Published: September 2018

Schools provide a crucial platform for health promotion as the school years are a vital stage in one’s life, where lifelong general and oral health-related behaviours are developed and established. The components of Health Promoting Schools (HPSs) suggested by World Health Organization provide guidance for facilitating health promotion within this setting. This study aimed to assess the adherence to the components of HPSs amongst schools in Bengaluru, India utilizing a comprehensive tool developed for the purpose. A cross-sectional survey was conducted among randomly selected 61 schools. Data were collected through structured interviews with the head of the schools, direct observation of school premises and verification of records. The significant findings of the study were that 80.3% of the schools had proper ventilation and separate washrooms for boys and girls, 83.6 and 88.5% of the schools had natural light and adequate water supply correspondingly. Only 39.3% of the schools had washrooms that were cleaned daily, and 55.7% of the schools were in proximity to business that sold tobacco products. Oral health education was not integrated into the curriculum in 39.3% of the schools, and 29.5% of the schools had no playgrounds. The study tool appeared to be sensitive in identifying the finer components of HPSs, indicating the lack of strict adherence to the components of HPSs in Bengaluru. This information can be utilized to design appropriate interventions at micro, meso and macro level to strengthen the capacity of schools for the attainment of health promotion.
Individual-level determinants of waterpipe smoking demand in four Eastern-Mediterranean countries
Authors: Salloum Ramzi G , Nakkash Rima , Abu-Rmeileh Niveen M E , Hamadeh Randah R , Darawad Muhammad W , Kheirallah Khalid A , Al-Farsi Yahya , Yusufali Afzalhussein , Thomas Justin , Mostafa Aya , Salama Mohamed , El Kadi Lama , Alzyoud Sukaina , Al-Sheyab Nihaya , Thrasher James F
Published: September 2018

The prevalence of waterpipe tobacco smoking in the Eastern Mediterranean Region is at alarmingly high levels, especially among young people. The objective of this research was to evaluate the preferences of young adult waterpipe smokers with respect to potential individual-level determinants of waterpipe smoking using discrete choice experiment methodology. Participants were young adult university students (18–29 years) who were ever waterpipe smokers, recruited from universities across four Eastern Mediterranean countries: Jordan, Oman, Palestine and the United Arab Emirates. The Internet-based discrete choice experiment, with 6 × 3 × 2 block design, evaluated preferences for choices of waterpipe smoking sessions, presented on hypothetical waterpipe café menus. Participants evaluated nine choice sets, each with five fruit-flavored options, a tobacco flavored option (non-flavored), and an opt-out option. Choices also varied based on nicotine content (0.0% vs. 0.05% vs. 0.5%) and price (low vs. high). Participants were randomized to receive menus with either a pictorial + text health-warning message or no message (between-subjects attribute). Multinomial logit regression models evaluated the influence of these attributes on waterpipe smoking choices.

Across all four samples (n = 1859), participants preferred fruit-flavored varieties to tobacco flavor, lower nicotine content and lower prices. Exposure to the health warning did not significantly predict likelihood to opt-out. Flavor accounted for 81.4% of waterpipe smoking decisions.

Limiting the use of fruit flavors in waterpipe tobacco, in addition to accurate nicotine content labeling and higher pricing may be effective at curbing the demand for waterpipe smoking among young adults.
Inclusion of ecosystem information in US fish stock assessments suggests progress toward ecosystem-based fisheries management
Authors: Marshall Kristin N , Koehn Laura E , Levin Phillip S , Essington Timothy E , Jensen Olaf P
Published: September 2018

The appetite for ecosystem-based fisheries management (EBFM) approaches has grown, but the perception persists that implementation is slow. Here, we synthesize progress toward implementing EBFM in the United States through one potential avenue: expanding fish stock assessments to include ecosystem considerations and interactions between species, fleets, and sectors. We reviewed over 200 stock assessments and assessed how the stock assessment reports included information about system influences on the assessed stock. Our goals were to quantify whether and how assessments incorporated broader system-level considerations, and to explore factors that might contribute to the use of system-level information. Interactions among fishing fleets (technical interactions) were more commonly included than biophysical interactions (species, habitat, climate). Interactions within the physical environment (habitat, climate) were included twice as often as interactions among species (predation). Many assessment reports included ecological interactions only as background or qualitative considerations, rather than incorporating them in the assessment model. Our analyses suggested that ecosystem characteristics are more likely to be included when the species was overfished (stock status), the assessment is conducted at a science centre with a longstanding stomach contents analysis program, and/or the species life history characteristics suggest it is likely to be influenced by the physical environment, habitat, or predation mortality (short-lived species, sessile benthic species, or low trophic-level species). Regional differences in stomach contents analysis programs may limit the inclusion of predation mortality in stock assessments, and more guidance is needed on best practices for the prioritization of when and how biophysical information should be considered. However, our results demonstrate that significant progress has been made to use best available science and data to expand single-species stock assessments, particularly when a broad definition of EBFM is applied.
Mathematical modelling of trastuzumab-induced immune response in an in vivo murine model of HER2+ breast cancer
Authors: Jarrett Angela M , Bloom Meghan J , Godfrey Wesley , Syed Anum K , Ekrut David A , Ehrlich Lauren I , Yankeelov Thomas E , Sorace Anna G
Published: September 2018

The goal of this study is to develop an integrated, mathematical–experimental approach for understanding the interactions between the immune system and the effects of trastuzumab on breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2+). A system of coupled, ordinary differential equations was constructed to describe the temporal changes in tumour growth, along with intratumoural changes in the immune response, vascularity, necrosis and hypoxia. The mathematical model is calibrated with serially acquired experimental data of tumour volume, vascularity, necrosis and hypoxia obtained from either imaging or histology from a murine model of HER2+ breast cancer. Sensitivity analysis shows that model components are sensitive for 12 of 13 parameters, but accounting for uncertainty in the parameter values, model simulations still agree with the experimental data. Given theinitial conditions, the mathematical model predicts an increase in the immune infiltrates over time in the treated animals. Immunofluorescent staining results are presented that validate this prediction by showing an increased co-staining of CD11c and F4/80 (proteins expressed by dendritic cells and/or macrophages) in the total tissue for the treated tumours compared to the controls ($p < 0.03$). We posit that the proposed mathematical–experimental approach can be used to elucidate driving interactions between the trastuzumab-induced responses in the tumour and the immune system that drive the stabilization of vasculature while simultaneously decreasing tumour growth—conclusions revealed by the mathematical model that were not deducible from the experimental data alone.
Integrity of clinical information in computerized order requisitions for diagnostic imaging
Authors: Lacson Ronilda , Laroya Romeo , Wang Aijia , Kapoor Neena , Glazer Daniel I , Shinagare Atul , Ip Ivan K , Malhotra Sameer , Hentel Keith , Khorasani Ramin
Published: September 2018

Objective

Assess information integrity (concordance and completeness of documented exam indications from the electronic health record [EHR] imaging order requisition, compared to EHR provider notes), and assess potential impact of indication inaccuracies on exam planning and interpretation.

Methods

This retrospective study, approved by the Institutional Review Board, was conducted at a tertiary academic medical center. There were 139 MRI lumbar spine (LS-MRI) and 176 CT abdomen/pelvis orders performed 4/1/2016-5/31/2016 randomly selected and reviewed by 4 radiologists for concordance and completeness of relevant exam indications in order requisitions compared to provider notes, and potential impact of indication inaccuracies on exam planning and interpretation. Forty each LS-MRI and CT abdomen/pelvis were re-reviewed to assess kappa agreement.

Results

Requisition indications were more likely to be incomplete (256/315, 81%) than discordant (133/315, 42%) compared to provider notes (p < 0.0001). Potential impact of discrepancy between clinical information in requisitions and provider notes was higher for radiologist’s interpretation than for exam planning (135/315, 43%, vs 25/315, 8%, p < 0.0001). Agreement among radiologists for concordance, completeness, and potential impact was moderate to strong (Kappa 0.66-0.89). Indications in EHR order requisitions are frequently incomplete or discordant compared to physician notes, potentially impacting imaging exam planning, interpretation and accurate diagnosis. Such inaccuracies could also diminish the relevance of clinical decision support alerts if based on information in order requisitions.

Conclusions

Improved availability of relevant documented clinical information within EHR imaging requisition is necessary for optimal exam planning and interpretation.
Too Expensive to Treat? Non-Treatment Decisions at the Margins of Viability
Authors: Flessas Tatiana , Jackson Emily
Published: September 2018

This article seeks to challenge the assumption that it is legitimate to consider the costs of premature babies’ future social and educational needs when deciding what treatment, if any, to provide in the neonatal intensive care unit (NICU) . It questions the elision that is made between the claim that a particular treatment is insufficiently cost-effective and the claim that a person will be a burden on the state in the future. It discusses a series of common misunderstandings about how treatment decisions are taken in the NICU and concludes by suggesting that the claim that premature babies are too expensive to treat may depend upon regarding a premature infant as if she were not yet a person, with rights and interests of her own.
Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice
Authors: Chemouny Jonathan M , Gleeson Patrick J , Abbad Lilia , Lauriero Gabriella , Boedec Erwan , Le Roux Karine , Monot Céline , Bredel Maxime , Bex-Coudrat Julie , Sannier Aurélie , Daugas Eric , Vrtovsnik Francois , Gesualdo Loreto , Leclerc Marion , Berthelot Laureline , Ben Mkaddem Sanae , Lepage Patricia , Monteiro Renato C
Published: September 2018

Background

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice.

Methods

Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies.

Results

Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1–mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1–mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease.

Conclusions

These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.
Withholding Perioperative Steroids in Patients Undergoing Transsphenoidal Resection for Pituitary Disease: Randomized Prospective Clinical Trial to Assess Safety
Authors: Sterl Karin , Thompson Bithika , Goss Charles W , Dacey Ralph G , Rich Keith M , Zipfel Gregory J , Chicoine Michael R , Kim Albert H , Silverstein Julie M
Published: September 2018

BACKGROUND

Perioperative steroid protocols for patients undergoing transsphenoidal surgery (TSS) for pituitary pathology vary by institution.

OBJECTIVE

To assess the safety of withholding glucocorticoids in patients undergoing TSS.

METHODS

Patients with an intact hypothalamic-pituitary-adrenal (HPA) axis undergoing TSS for a pituitary tumor at the same academic institution between 2012 and 2015 were randomized to either receive 100 mg of intravenous hydrocortisone followed by 0.5 mg of intravenous dexamethasone every 6 h for 4 doses (STER, n = 23) or to undergo surgery without steroids (NOSTER, n = 20). Postoperative cortisol levels were then used to determine the need for glucocorticoids after surgery. Data regarding postoperative cortisol levels, hospital stay length, and complications were collected.

RESULTS

Mean postoperative 8 am cortisol levels were higher in the NOSTER group compared to the STER group (745 ± 359 nmol/L and 386 ± 193 nmol/L, respectively, P = .001) and more patients were discharged on glucocorticoids in the STER group (42% vs 12%, P = .07). There was no difference in the incidence of postoperative complications, including hyperglycemia, diabetes insipidus, or permanent adrenal insufficiency. Permanent adrenal insufficiency occurred in 8% of patients.

CONCLUSION

Perioperative steroids can be safely withheld in patients with an intact HPA axis undergoing TSS. Although administration of perioperative glucocorticoids does not appear to increase the risk of complications, it may interfere with assessment of the HPA axis after surgery.
Low-cost detection of norovirus using paper-based cell-free systems and synbody-based viral enrichment
Authors: Ma Duo , Shen Luhui , Wu Kaiyue , Diehnelt Chris W , Green Alexander A
Published: September 2018

Noroviruses are a primary cause of gastroenteritis and foodborne illness with cases that affect millions of people worldwide each year. Inexpensive tests for norovirus that do not require sophisticated laboratory equipment are important tools for ensuring that patients receive timely treatment and for containing outbreaks. Herein, we demonstrate a low-cost colorimetric assay that detects norovirus from clinical samples by combining paper-based cell-free transcription–translation systems, isothermal amplification and virus enrichment by synbodies. Using isothermal amplification and cell-free RNA sensing with toehold switches, we demonstrate that the assay enables detection of norovirus GII.4 Sydney from stool down to concentrations of 270 aM in reactions that can be directly read by eye. Furthermore, norovirus-binding synbodies and magnetic beads are used to concentrate the virus and provide a 1000-fold increase in assay sensitivity extending its detection limit to 270 zM. These results demonstrate the utility of paper-based cell-free diagnostic systems for identification of foodborne pathogens and provide a versatile diagnostic assay that can be applied to the concentration, amplification and detection of a broad range of infectious agents.
Quantifying the phosphorylation timescales of receptor–ligand complexes: a Markovian matrix-analytic approach
Authors: López-García M. , Nowicka M. , Bendtsen C. , Lythe G. , Ponnambalam S. , Molina-París C.
Published: September 2018

Cells interact with the extracellular environment by means of receptor molecules on their surface. Receptors can bind different ligands, leading to the formation of receptor–ligand complexes. For a subset of receptors, called receptor tyrosine kinases, binding to ligand enables sequential phosphorylation of intra-cellular residues, which initiates a signalling cascade that regulates cellular function and fate. Most mathematical modelling approaches employed to analyse receptor signalling are deterministic, especially when studying scenarios of high ligand concentration or large receptor numbers. There exist, however, biological scenarios where low copy numbers of ligands and/or receptors need to be considered, or where signalling by a few bound receptor–ligand complexes is enough to initiate a cellular response. Under these conditions stochastic approaches are appropriate, and in fact, different attempts have been made in the literature to measure the timescales of receptor signalling initiation in receptor–ligand systems. However, these approaches have made use of numerical simulations or approximations, such as moment-closure techniques. In this paper, we study, from an analytical perspective, the stochastic times to reach a given signalling threshold for two receptor–ligand models. We identify this time as an extinction time for a conveniently defined auxiliary absorbing continuous time Markov process, since receptor–ligand association/dissociation events can be analysed in terms of quasi-birth-and-death processes. We implement algorithmic techniques to compute the different order moments of this time, as well as the steady-state probability distribution of the system. A novel feature of the approach introduced here is that it allows one to quantify the role played by each kinetic rate in the timescales of signal initiation, and in the steady-state probability distribution of the system. Finally, we illustrate our approach by carrying out numerical studies for the vascular endothelial growth factor and one of its receptors, the vascular endothelial growth factor receptor of human endothelial cells.
Anastasis: recovery from the brink of cell death
Authors: Tang Ho Man , Tang Ho Lam
Published: September 2018

Anastasis is a natural cell recovery phenomenon that rescues cells from the brink of death. Programmed cell death such as apoptosis has been traditionally assumed to be an intrinsically irreversible cascade that commits cells to a rapid and massive demolition. Interestingly, recent studies have demonstrated recovery of dying cells even at the late stages generally considered immutable. Here, we examine the evidence for anastasis in cultured cells and in animals, review findings illuminating the potential mechanisms of action, discuss the challenges of studying anastasis and explore new strategies to uncover the function and regulation of anastasis, the identification of which has wide-ranging physiological, pathological and therapeutic implications.
A coexistence theory in microbial communities
Authors: Dohi Marina , Mougi Akihiko
Published: September 2018

Microbes are widespread in natural ecosystems where they create complex communities. Understanding the functions and dynamics of such microbial communities is a very important theme not only for ecology but also for humankind because microbes can play major roles in our health. Yet, it remains unclear how such complex ecosystems are maintained. Here, we present a simple theory on the dynamics of a microbial community. Bacteria preferring a particular pH in their environment indirectly inhibit the growth of the other types of bacteria by changing the pH to their optimum value. This pH-driven interaction always causes a state of bistability involving different types of bacteria that can be more or less abundant. Furthermore, a moderate abundance ratio of different types of bacteria can confer enhanced resilience to a specific equilibrium state, particularly when a trade-off relationship exists between growth and the ability of bacteria to change the pH of their environment. These results suggest that the balance of the composition of microbiota plays a critical role in maintaining microbial communities.
Taking advantage of hybrid bioinspired intelligent algorithm with decoupled extended Kalman filter for optimizing growing and pruning radial basis function network
Authors: Chai Zhilei , Song Wei , Bao Qinxin , Ding Feng , Liu Fei
Published: September 2018

The growing and pruning radial basis function (GAP-RBF) network is a promising sequential learning algorithm for prediction analysis, but the parameter selection of such a network is usually a non-convex problem and makes it difficult to handle. In this paper, a hybrid bioinspired intelligent algorithm is proposed to optimize GAP-RBF. Specifically, the excellent local convergence of particle swarm optimization (PSO) and the extensive search ability of genetic algorithm (GA) are both considered to optimize the weights and bias term of GAP-RBF. Meanwhile, a competitive mechanism is proposed to make the hybrid algorithm choose the appropriate individuals for effective search and further improve its optimization ability. Moreover, a decoupled extended Kalman filter (DEKF) method is introduced in this study to reduce the size of error covariance matrix and decrease the computational complexity for performing real-time predictions. In the experiments, three classic forecasting issues including abalone age, Boston house price and auto MPG are adopted for extensive test, and the experimental results show that our method performs better than PSO and GA these two single bioinspired optimization algorithms. What is more, our method via DEKF achieves the better results in comparison with the state-of-art sequential learning algorithms, such as GAP-RBF, minimal resource allocation network, resource allocation network using an extended Kalman filter and resource allocation network.
Risk factors for respiratory illness in a community of wild chimpanzees (
Pan troglodytes schweinfurthii
)
Authors: Emery Thompson Melissa , Machanda Zarin P. , Scully Erik J. , Enigk Drew K. , Otali Emily , Muller Martin N. , Goldberg Tony L. , Chapman Colin A. , Wrangham Richard W.
Published: September 2018

Respiratory illnesses have caused significant mortality in African great ape populations. While much effort has been given to identifying the responsible pathogens, little is known about the factors that influence disease transmission or individual susceptibility. In the Kanyawara community of wild chimpanzees, respiratory illness has been the leading cause of mortality over 31 years, contributing to 27% of deaths. Deaths were common in all age groups except juveniles. Over 22 years of health observations, respiratory signs were rare among infants and most common among older adults of both sexes. Respiratory signs were also common among males during the transition to adulthood (ages 10–20 years), particularly among those of low rank. Respiratory signs peaked conspicuously in March, a pattern that we could not explain after modelling climatic factors, group sizes, diet or exposure to humans. Furthermore, rates of respiratory illness in the chimpanzees did not track seasonal rates of illness in the nearby village. Our data indicate that the epidemiology of chimpanzee respiratory illness warrants more investigation but clearly differs in important ways from humans. Findings on individual susceptibility patterns suggest that respiratory signs are a robust indicator for investigating immunocompetence in wild chimpanzees.
Untargeted metabolomics profiles delineate metabolic alterations in mouse plasma during lung carcinoma development using UPLC-QTOF/MS in MS
E
mode
Authors: Wu Huan , Chen Yang , Li Zegeng , Liu Xianhua
Published: September 2018

In this work, an untargeted metabolomic method based on ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) in MS
E
(E represents collision energy) mode was exploited to determine the dynamic metabolic alterations in the plasma of male C57BL/6 mice during the onset and development of lung carcinoma. Plasma samples were collected from control and model mice (male C57BL/6 mice experimentally inoculated with the
Lewis
lung carcinoma cells) at 7 and 14 days post-inoculation (DPI). As a result, 15 dysregulated metabolites, including cholesterol sulphate, tiglylcarnitine, 1-palmitoylglycerophosphoinositol, 2-stearoylglycerophosphoinositol, stearoylcarnitine, PC(20:2(11Z,14Z)/16:0), PC(22:4(7Z,10Z,13Z,16Z)/14:0), PC(22:5(7Z,10Z,13Z,16Z,19Z)/14:0), PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:0), 12,20-Dioxo-leukotriene B4, sphingosine 1-phosphate(d19:1-P), sphingomyelin(d18:0/16:1(9Z)), lysoPC(16:0), lysoPC(18:0) and lysoPC(20:4(5Z,8Z,11Z,14Z)), were identified in the plasma of model mice with xenografts at both 7 and 14 DPI. All the altered metabolites associated with the onset and development of lung carcinoma were involved in the metabolism of glycerophospholipid, fatty acid, sphingolipid and arachidonic acid. The feasible utility of these endogenous biomarkers as potential diagnostic indicators was validated through receiver operating characteristic curve analysis. Collectively, these findings provide a systematic view of metabolic changes linked to the onset and development of lung carcinoma.
Hyperons: the strange ingredients of the nuclear equation of state
Authors: Vidaña Isaac
Published: September 2018

We review the role and properties of hyperons in finite and infinite nuclear systems. In particular, we present different production mechanisms of hypernuclei, as well as several aspects of hypernuclearγ-ray spectroscopy, and the weak decay modes of hypernuclei. Then we discuss the construction of hyperon–nucleon and hyperon–hyperon interactions on the basis of the meson-exchange and chiral effective field theories. Recent developments based on the so-calledVlow kapproach and lattice quantum chromodynamics will also be addressed. Finally, we go over some of the effects of hyperons on the properties of neutron and proto-neutron stars with an emphasis on the so-called ‘hyperon puzzle’, i.e. the problem of the strong softening of the equation of state, and the consequent reduction of the maximum mass, induced by the presence of hyperons, a problem which has become more intriguing and difficult to solve due the recent measurements of approximately 2M⊙millisecond pulsars. We discuss some of the solutions proposed to tackle this problem. We also re-examine the role of hyperons on the cooling properties of newly born neutron stars and on the development of the so-called r-mode instability.
The origin of compression influences geometric instabilities in bilayers
Authors: Andres Sebastian , Steinmann Paul , Budday Silvia
Published: September 2018

Geometric instabilities in bilayered structures control the surface morphology in a wide range of biological and technical systems. Depending on the application, different mechanisms induce compressive stresses in the bilayer. However, the impact of the chosen origin of compression on the critical conditions, post-buckling evolution and higher-order pattern selection remains insufficiently understood. Here, we conduct a numerical study on a finite-element set-up and systematically vary well-known factors contributing to pattern selection under the four main origins of compression: film growth, substrate shrinkage and whole-domain compression with and without pre-stretch. We find that the origin of compression determines the substrate stretch state at the primary instability point and thus significantly affects the critical buckling conditions. Similarly, it leads to different post-buckling evolutions and secondary instability patterns when the load further increases. Our results emphasize that future phase diagrams of geometric instabilities should incorporate not only the film thickness but also the origin of compression. Thoroughly understanding the influence of the origin of compression on geometric instabilities is crucial to solving real-life problems such as the engineering of smart surfaces or the diagnosis of neuronal disorders, which typically involve temporally or spatially combined origins of compression.
Bottlenose dolphins can understand their partner's role in a cooperative task
Authors: Jaakkola Kelly , Guarino Emily , Donegan Katy , King Stephanie L.
Published: September 2018

In recent decades, a number of studies have examined whether various non-human animals understand their partner's role in cooperative situations. Yet the relatively tolerant timing requirements of these tasks make it theoretically possible for animals to succeed by using simple behavioural strategies rather than by jointly intended coordination. Here we investigated whether bottlenose dolphins could understand a cooperative partner's role by testing whether they could learn a button-pressing task requiring precise behavioural synchronization. Specifically, members of cooperative dyads were required to swim across a lagoon and each press their own underwater button simultaneously (within a 1 s time window), whether sent together or with a delay between partners of 1–20 s. We found that dolphins were able to work together with extreme precision even when they had to wait for their partner, and that their coordination improved over the course of the study, with the time between button presses in the latter trials averaging 370 ms. These findings show that bottlenose dolphins can learn to understand their partner's role in a cooperative situation, and suggest that the behavioural synchronization evident in wild dolphins' synchronous movement and coordinated alliance displays may be a generalized cognitive ability that can also be used to solve novel cooperative tasks.
Advances in Gene Ontology Utilization Improve Statistical Power of Annotation Enrichment
Authors: Hinderer Eugene W. , Flight Robert M. , Dubey Rashmi , MacLeod James N. , Moseley Hunter N.B.
Published: September 2018

Gene-annotation enrichment is a common method for utilizing ontology-based annotations in these gene and gene-product centric knowledgebases. Effective utilization of these annotations requires inferring semantic linkages by tracing paths through the ontology through edges in the ontological graph, referred to as relations. However, some relations are semantically problematic with respect to scope, necessitating their omission lest erroneous term mappings occur. To address these issues, we present GOcats, a novel tool that organizes the Gene Ontology (GO) into subgraphs representing user-defined concepts, while ensuring that all appropriate relations are congruent with respect to scoping semantics. Here, we demonstrate the improvements in annotation enrichment by re-interpreting edges that would otherwise be omitted by traditional ancestor path-tracing methods.

We demonstrate that GOcats’ unique handling of relations improves enrichment over conventional methods in the analysis of two different gene-expression datasets: a breast cancer microarray dataset and several horse cartilage development RNAseq datasets. With the breast cancer microarray dataset, we observed significant improvement (one-sided binomial test p-value=1.86E-25) in 182 of 217 significantly enriched GO terms identified from the conventional path traversal method when GOcats’ path traversal was used. We also found new significantly enriched terms using GOcats, whose biological relevancy has been experimentally demonstrated elsewhere. Likewise, on the horse RNAseq datasets, we observed a significant improvement in GO term enrichment when using GOcat’s path traversal: one-sided binomial test p-values range from 1.32E-03 to 2.58E-44.
Structural variants exhibit allelic heterogeneity and shape variation in complex traits
Authors: Chakraborty Mahul , Emerson J.J. , Macdonald Stuart J. , Long Anthony D.
Published: September 2018

Despite extensive effort to reveal the genetic basis of complex phenotypic variation, studies typically explain only a fraction of trait heritability. It has been hypothesized that individually rare hidden structural variants (SVs) could account for a significant fraction of variation in complex traits. To investigate this hypothesis, we assembled 14Drosophila melanogastergenomes and systematically identified more than 20,000 euchromatic SVs, of which ∼40% are invisible to high specificity short read genotyping approaches. SVs are common inDrosophilagenes, with almost one third of diploid individuals harboring an SV in genes larger than 5kb, and nearly a quarter harboring multiple SVs in genes larger than 10kb. We show that SV alleles are rarer than amino acid polymorphisms, implying that they are more strongly deleterious. A number of functionally important genes harbor previously hidden structural variants that likely affect complex phenotypes (e.g.,Cyp6g1, Drsl5, Cyp28d1&2, InR, andGss1&2).Furthermore, SVs are overrepresented in quantitative trait locus candidate genes from eight Drosophila Synthetic Population Resource (DSPR) mapping experiments. We conclude that SVs are pervasive in genomes, are frequently present as heterogeneous allelic series, and can act as rare alleles of large effect.
Persistent alterations in plasma lipid profiles prior to introduction of gluten in the diet associate with progression to celiac disease
Authors: Sen Partho , Carlsson Cecilia , Virtanen Suvi M. , Simell Satu , Hyöty Heikki , Ilonen Jorma , Toppari Jorma , Veijola Riitta , Hyötyläinen Tuulia , Knip Mikael , Orešič Matej
Published: September 2018

Background and Aims

Celiac disease (CD) is a chronic enteropathy characterized by an autoimmune reaction in the small intestine in genetically-susceptible individuals. Gluten is the required environmental trigger of clinical CD, but the underlying causes of the autoimmune reaction remain unknown. Herein, we apply lipidomics to elucidate the early events preceding clinical CD in a prospective study of children observed from birth until diagnosis of CD and subsequent introduction of a gluten-free diet.

Methods

Mass spectrometry–based lipidomics profiling was applied to a longitudinal series of 233 plasma samples from the Type 1 Diabetes Prediction and Prevention (DIPP) study, spanning the period between birth and the introduction of a gluten–free diet following CD diagnosis (n=23 CD progressors, n=23 controls matched for gender, HLA risk, period of birth, and age).

Results

23 children progressed to CD at a mean age of 4.8 years. They showed increased amounts of triacylglycerols (TGs) of low carbon number and double bond count and a decreased level of phosphatidylcholines by 3 months of age as compared to controls. These differences were exacerbated with age but were not observed at birth. No significant differences were observed in essential (dietary) TGs such as those containing polyunsaturated fatty acids.

Conclusion

Our findings suggest that abnormal lipid metabolism associated with development of clinical CD may occur prior to the introduction of gluten to the diet. Moreover, our data suggest that the specific TGs found elevated in CD progressors may be due to a host response to compromised intake of essential lipids in the small intestine, requiring de novo lipogenesis.