bluuebunny/crossref_metadata_2025 huggingface dataset:
Oscillating and static dietary crude protein supply. I. Impacts on intake, digestibility, performance, and nitrogen balance in young Nellore bulls1
Authors: Menezes Ana Clara B , Valadares Filho Sebastião C , Pacheco Marcos V C , Pucetti Pauliane , Silva Breno C , Zanetti Diego , Paulino Mário F , Silva Fabyano F , Neville Tammi L , Caton Joel S
Published: August 2019

Effects of dietary crude protein (CP) supply on intake, digestibility, performance, and N balance were evaluated in young Nellore bulls consuming static or oscillating CP concentrations. Forty-two young bulls (initial BW of 260 ± 8.1 kg; age of 7 ± 1.0 mo) were fed ad libitum and were randomly assigned to receive one of six diets with different CP concentrations for 140 d: 105 (LO), 125 (MD), or 145 g CP /kg DM (HI), and LO to HI (LH), LO to MD (LM), or MD to HI (MH) oscillating CP at a 48-h interval for each feed. At the end of the experiment, bulls were slaughtered to evaluate carcass characteristics. Linear and quadratic effects were used to compare LO, MD, and HI, and specific contrasts were applied to compare oscillating dietary CP treatments vs. MD (125 g CP/kg DM) static treatment. Dry matter intake (DMI) was not affected (P > 0.26) by increasing or oscillating dietary CP. As dietary N concentration increased, there was a subsequent increase in apparent N compounds digestibility (P = 0.02), and no significant difference (P = 0.38) was observed between oscillating LH and MD. Daily total urinary and fecal N increased (P < 0.01) in response to increasing dietary CP. Significant differences were observed between oscillating LM and MH vs. MD, where bulls receiving the LM diet excreted less (P < 0.01; 71.21 g/d) and bulls fed MH excreted more (P < 0.01) urinary N (90.70 g/d) than those fed MD (85.52 g/d). A quadratic effect was observed (P < 0.01) for retained N as a percentage of N intake, where the bulls fed LO had greater N retention than those fed HI, 16.20% and 13.78%, respectively. Both LH and LM had greater (P < 0.01) daily retained N when compared with MD. Performance and carcass characteristics were not affected (P > 0.05) by increasing or oscillating dietary CP. Therefore, these data indicate that although there is no alteration in the performance of growing Nellore bulls fed with oscillating CP diets vs. a static level of 125 g CP/kg DM, nor static low (105 g CP/kg DM) and high (145 g CP/kg DM) levels; there may be undesirable increases in environmental N excretion when the average dietary CP content is increased. The results suggest that dietary CP concentrations of 105, 125 g/kg DM, or within this range can be indicated for finishing young Nellore bulls, since it reaches the requirements, reduces the environmental footprint related to N excretion, and may save on costs of high-priced protein feeds.
Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis
Authors: Kaftanovskaya Elena M. , Ng Hooi Hooi , Soula Mariluz , Rivas Bryan , Myhr Courtney , Ho Brian A. , Cervantes Briana A. , Shupe Thomas D. , Devarasetty Mahesh , Hu Xin , Xu Xin , Patnaik Samarjit , Wilson Kenneth J. , Barnaeva Elena , Ferrer Marc , Southall Noel T. , Marugan Juan J. , Bishop Colin E. , Agoulnik Irina U. , Agoulnik Alexander I.
Published: August 2019

Fibrosis is an underlying cause of cirrhosis and hepatic failure resulting in end stage liver disease with limited pharmacological options. The beneficial effects of relaxin peptide treatment were demonstrated in clinically relevant animal models of liver fibrosis. However, the use of relaxin is problematic because of a short half‐life. The aim of this study was to test the therapeutic effects of recently identified small molecule agonists of the human relaxin receptor, relaxin family peptide receptor 1 (RXFP1). The lead compound of this series, ML290, was selected based on its effects on the expression of fibrosis‐related genes in primary human stellate cells. RNA sequencing analysis of TGF‐β1–activated LX‐2 cells showed that ML290 treatment primarily affected extracellular matrix remodeling and cytokine signaling, with expression profiles indicating an antifibrotic effect of ML290. ML290 treatment in human liver organoids with LPS‐induced fibrotic phenotype resulted in a significant reduction of type I collagen. The pharmacokinetics of ML290 in mice demonstrated its high stability in vivo, as evidenced by the sustained concentrations of compound in the liver. In mice expressing human RXFP1 gene treated with carbon tetrachloride, ML290 significantly reduced collagen content, α‐smooth muscle actin expression, and cell proliferation around portal ducts. In conclusion, ML290 demonstrated antifibrotic effects in liver fibrosis.—Kaftanovskaya, E. M., Ng, H. H., Soula, M., Rivas, B., Myhr, C., Ho, B. A., Cervantes, B. A., Shupe, T. D., Devarasetty, M., Hu, X., Xu, X., Patnaik, S., Wilson, K. J., Barnaeva, E., Ferrer, M., Southall, N. T., Marugan, J. J., Bishop, C. E., Agoulnik, I. U., Agoulnik, A. I. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis. FASEB J. 33, 12435–12446 (2019). www.fasebj.org
ICTV Virus Taxonomy Profile: Megabirnaviridae
Authors: Sato Yukiyo , Miyazaki Naoyuki , Kanematsu Satoko , Xie Jiatao , Ghabrial Said A. , Hillman Bradley I. , Suzuki Nobuhiro ,   ICTV Report Consortium
Published: August 2019

Megabirnaviridae is a family of non-enveloped spherical viruses with dsRNA genomes of two linear segments, each of 7.2–8.9 kbp, comprising 16.1 kbp in total. The genus Megabirnavirus includes the species Rosellinia necatrix megabirnavirus 1, the exemplar isolate of which infects the white root rot fungus (Rosellinia necatrix) to which it confers hypovirulence. Megabirnaviruses are characterized by their bisegmented genome with large 5′-untranslated regions (1.6 kb) upstream of both 5′-proximal coding strand ORFs, and large protrusions on the particle surface. This is a summary of the ICTV Report on the family Megabirnaviridae, which is available at ictv.global/report/megabirnaviridae.

This Profile is dedicated to the memory of our valued colleague Professor Said A. Ghabrial.
Detection and characterization of a novel bat-borne coronavirus in Singapore using multiple molecular approaches
Authors: Lim Xiao Fang , Lee Chengfa Benjamin , Pascoe Sarah Marie , How Choon Beng , Chan Sharon , Tan Jun Hao , Yang Xinglou , Zhou Peng , Shi Zhengli , Sessions October M. , Wang Lin-Fa , Ng Lee Ching , Anderson Danielle E. , Yap Grace
Published: August 2019

Bats are important reservoirs and vectors in the transmission of emerging infectious diseases. Many highly pathogenic viruses such as SARS-CoV and rabies-related lyssaviruses have crossed species barriers to infect humans and other animals. In this study we monitored the major roost sites of bats in Singapore, and performed surveillance for zoonotic pathogens in these bats. Screening of guano samples collected during the survey uncovered a bat coronavirus (Betacoronavirus) inCynopterus brachyotis, commonly known as the lesser dog-faced fruit bat. Using a capture-enrichment sequencing platform, the full-length genome of the bat CoV was sequenced and found to be closely related to the bat coronavirus HKU9 species found in Leschenault’s rousette discovered in the Guangdong and Yunnan provinces.
Integrin α6β4 is downregulated in mutant IDH1 oligodendrogliomas, promotes glioma growth, and associates with a worse outcome in glioma patients
Authors: Stewart Rachel L. , Chen Min , Mulkearns-Hubert Erin E. , Lathia Justin , O’Connor Kathleen L. , Horbinski Craig
Published: August 2019

The integrin α6β4 is a laminin receptor that associates with aggressive behavior in many cancers, though its significance in gliomas has not been established. Mutations inisocitrate dehydrogenase 1and2(IDHmut) are common in gliomas, especially 1p/19q co-deleted oligodendrogliomas, and correlate with improved patient survival. We sought to determine whether there is a link between integrin β4 and malignant behavior in gliomas. An inverse relationship was identified between IDHmutand integrin β4 expression in a glioma TMA (P< 0.0001) and in TCGA grade II-IV gliomas (P< 0.0001). Methylation of CpG sites in theITGB4promoter is significantly higher in IDHmutgliomas when compared to wild-type tumors, and bothITGB4methylation and reducedITGB4mRNA are not only most prominent in the 1p/19q co-deleted subset of IDHmuttumors, but fully account for the lowerITGB4expression observed in IDHmutgliomas. In fact,ITGB4is one of the most downregulated genes in IDHmut1p/19q co-deleted gliomas compared to IDHmut1p/19q intact gliomas (P= 3.2×10-39). In patient-derived glioma cells, we found that integrin β4 is enriched in the stem-like population, and that knockdown of integrin β4 slows glioma growthin vitro(P< 0.001) andin vivo (P= 0.01). LowerITGB4mRNA levels were also associated with longer overall survival in multiple patient cohorts (P= 0.0005;P< 0.0001). These data suggest that integrin β4 increases glioma malignancy, and that its relative paucity may contribute to the better prognosis inIDH1/2mutant, 1p/19q co-deleted oligodendrogliomas.
Contextualising UK moorland burning studies: geographical versus potential sponsorship-bias effects on research conclusions
Authors: Brown Lee E. , Holden Joseph
Published: August 2019

It has recently been claimed that geographical variability resulted in false conclusions from some studies examining the impacts of prescribed moorland burning, including the Effects of Moorland Burning on the Ecohydrology of River basins (EMBER) project. We provide multiple lines of evidence to contradict these claims and show that the EMBER results are reliable.

A systematic review of the literature also confirms that EMBER conclusions were not out of line with the majority of other published UK studies on responses to prescribed burning ofSphagnumgrowth/abundance, soil properties, hydrological change, or peat exposure and erosion.

We suggest that sponsorship-bias is associated with some recent research conclusions related to moorland burning. Thus, it is of grave concern when sponsorship or other potential conflicts of interest are not declared on publications related to moorland burning.

We show that sponsorship and other conflicts of interest were not declared on a recent publication that criticised the EMBER project, thereby entirely undermining that critical assessment.

Policy implications:The EMBER findings are robust. Our study suggests that publications on moorland burning that have been funded by pro-burning groups should be treated with extreme caution by the policy community. Publications that have been shown to have failed to declare conflicts of interest from the outset, when first submitted to a journal, should be disregarded by the policy community because peer reviewers and editors may have been unable to evaluate those pieces of work properly.
Effects of forest management on the phenology of early-flowering understory herbs
Authors: Willems Franziska M. , Scheepens J.F. , Ammer Christian , Block Svenja , Bucharova Anna , Schall Peter , Sehrt Melissa , Bossdorf Oliver
Published: August 2019

Many organisms respond to anthropogenic environmental change through shifts in their phenology. In plants, flowering is largely driven by temperature, and therefore affected by climate change. However, on smaller scales climatic conditions are also influenced by other factors, including habitat structure. A group of plants with a particularly distinct phenology are the understorey herbs in temperate forests. In these forests, management alters tree species composition and stand structure and, as a consequence, light conditions and microclimate. Forest management should thus also affect the phenology of understorey herbs. To test this, we recorded the flowering phenology of 20 early-flowering herbs on 100 forest plots varying in management intensity, from near-natural to intensely managed forests, in Central and Southern Germany. We found that in forest stands with a high management intensity the plants flowered on average about two weeks later than in unmanaged forests. This was largely because management also affected microclimate (e.g. spring temperatures of 5.9 °C in managed coniferous, 6.7 in managed deciduous and 7.0 °C in unmanaged deciduous plots), which in turn affected phenology, with plants flowering later on colder and moister forest stands (+4.5 days per −1°C and 2.7 days per 10 % humidity increase). Among forest characteristics, the main tree species as well as the age, overall crown projection area, structural complexity and spatial distribution of trees had the greatest influence on microclimate. Our study demonstrates that forest management alters plant phenology, with potential far-reaching consequences for the ecology and evolution of understorey communities. More generally, our study suggests that besides climate change other drivers of environmental change, too, can influence the phenology of organisms.
THE COSTS AND BENEFITS OF BASAL INFECTION RESISTANCE VS DIVERSE IMMUNE PRIMING RESPONSES IN AN INSECT
Authors: Prakash Arun , Agashe Deepa , Khan Imroze
Published: August 2019

In insects, basal pathogen resistance and immune priming can evolve as mutually exclusive strategies, with distinct infection outcomes. However, the evolutionary drivers of such diverse immune functions remain poorly understood. Here, we addressed this key issue by systematically analyzing the differential fitness costs and benefits of priming vs. resistance evolution in Tribolium beetle populations infected with Bacillus thuringiensis. Surprisingly, resistant beetles had increased post-infection reproduction and a longer lifespan under both starving as well as fed conditions, with no other measurable costs. In contrast, priming reduced offspring early survival, development rate and reproduction. Priming did improve post-infection survival of offspring, but this added trans-generational benefit of immune priming might not compensate for its pervasive costs. Resistance was thus consistently more beneficial. Our work represents the first report of experimentally evolved trans-generational priming, and a detailed comparison of the complex fitness consequences of evolved priming vs resistance.

HIGHLIGHTS

Divergent costs and benefits of experimentally evolved immune priming vs resistance

Increased reproduction and lifespan in resistant populations

No other hidden costs of resistance

In contrast, reduced juvenile fitness and reproduction in primed populations

First evidence for experimentally evolved trans-generational immune priming
Group Similarity Constraint Functional Brain Network Estimation for Mild Congititive Impairment Classification
Authors: Gao Xin , Xu Xiaowen , Li Weikai , Li Rui
Published: August 2019

Functional brain network (FBN) provides an effective biomarker for understanding brain activation patterns, which also improve the diagnostic criteria for neurodegenerative diseases or the information transmission of brain. Unfortunately, despite its efficiency, FBN still suffers several challenges for accurately estimate the biological meaningful or discriminative FBNs, under the poor quality of functional magnetic resonance imaging (fMRI) data as well as the limited understanding of human brain. Hence, there still a motivation to alleviate those issues above, it is currently still an open field to discover. In this paper, a novel FBN estimation model based on group similarity constraints is proposed. In particular, we extend the FBN estimation model to the tensor form and incorporate the trace-norm regularizer for formulating the group similarity constraint. In order to verify the proposed method, we conduct experiments on identifying Mild Cognitive Impairments (MCIs) from normal controls (NCs) based on the estimated FBNs. The experimental results illustrated that the proposed method can construct a more discriminative brain network. Consequently, we achieved an 91.97% classification accuracy which outperforms the baseline methods. Thepost hocanalysis further shown more biologically meaningful functional brain connections obtained by our proposed method.
Mutational signatures in upper tract urothelial carcinoma define etiologically distinct subtypes with prognostic relevance
Authors: Li Xuesong , Lu Huan , Guan Bao , Xu Zhengzheng , Shi Yue , Li Juan , Kong Wenwen , Liu Jin , Fang Dong , Liu Libo , Shen Qi , Gong Yanqing , He Shiming , He Qun , Zhou Liqun , Ci Weimin
Published: August 2019

Parts of East Asia have a very high upper tract urothelial carcinoma (UTUC) prevalence, and an etiological link between the medicinal use of herbs containing aristolochic acid (AA) and UTUC has been established. The mutational signature of AA, which is characterized by a particular pattern of A:T to T:A transversions, can be detected by genome sequencing. Thus, integrating mutational signatures analysis with clinicopathological data may be a crucial step toward personalized treatment strategies for the disease. Therefore, we performed whole-genome sequencing (WGS) of 90 UTUC patients from China. Mutational signature analysis via nonnegative matrix factorization method defined three etiologically distinct subtypes with prognostic relevance: (i) AA, the typical AA mutational signature characterized by signature 22, had the highest tumor mutation burden, the best clinical outcomes; (ii) Age, an age-related group featured by signatures 1 and 5, had the lowest weighted genome instability index score, the worst clinical outcomes; and (iii) DSB, signature with deficiencies in DNA double strand break-repair featured by signatures 3, the intermediate clinical outcomes. Additionally, the distinct AA subtype was associated with AA exposure, the highest number of predicted neoantigens and heavier lymphocytes infiltrating. Thus, it may be good candidate for immune checkpoint blockade therapy. Notably, we showed AA-mutational signature was also identified in histologically “normal” urothelial cells. Thus, non-invasive urine test based on the AA-mutational signature could take advantage of this “field effect” to screen individuals at increased risk of recurrence due to exposure to herbal remedies containing the carcinogen AA. Collectively, the findings here may accelerate the development of novel prognostic markers and personalized therapeutic approaches for UTUC patients in China.
Analyzing combined eye-tracking/EEG experiments with (non)linear deconvolution models
Authors: Dimigen Olaf , Ehinger Benedikt V.
Published: August 2019

Fixation-related potentials (FRPs), neural responses aligned to saccade offsets, are a promising tool to study the dynamics of attention and cognition under natural viewing conditions. In the past, four methodological problems have complicated the analysis of such combined eye-tracking/EEG experiments: (i) the synchronization of data streams, (ii) the removal of ocular artifacts, (iii) the condition-specific temporal overlap between the brain responses evoked by consecutive fixations, (iv) and the fact that numerous low-level stimulus and saccade properties also influence the post-saccadic neural responses. While effective solutions exist for the first two problems, the latter ones are only beginning to be addressed. In the current paper, we present and review a unified framework for FRP analysis that allows us to deconvolve overlapping potentials and control for linear and nonlinear confounds on the FRPs. An open software implementation is provided for all procedures. We then demonstrate the advantages of this approach for data from three commonly studied paradigms: face perception, scene viewing, and natural sentence reading. First, for a traditional ERP face recognition experiment, we show how deconvolution can separate stimulus-ERPs from overlapping muscle and brain potentials produced by small (micro)saccades on the face. Second, in scene viewing, we isolate multiple non-linear influences of saccade parameters on the FRP. Finally, for a natural sentence reading experiment using the boundary paradigm, we show how it is possible to study the neural correlates of parafoveal preview after removing spurious overlap effects caused by the associated difference in average fixation time. Our results suggest a principal way of measuring reliable fixation-related brain potentials during natural vision.
Regulatory kinase genetic interaction profiles differ between environmental conditions and cellular states
Authors: Sun Siyu , Baryshnikova Anastasia , Brandt Nathan , Gresham David
Published: August 2019

Cell growth and quiescence in eukaryotic cells is controlled by an evolutionarily conserved network of signaling pathways. Signal transduction networks operate to modulate a wide range of cellular processes and physiological properties when cells exit proliferative growth and initiate a quiescent state. How signaling networks function to respond to diverse signals that result in cell cycle exit and establishment of a quiescent state is poorly understood. Here, we studied the function of signaling pathways in quiescent cells using global genetic interaction mapping in the model eukaryotic cell,Saccharomyces cerevisiae(budding yeast). We performed pooled analysis of genotypes using molecular barcode sequencing to test the role of ∼3,900 gene deletion mutants and ∼11,700 pairwise interactions between all non-essential genes and the protein kinasesTOR1, RIM15, PHO85in three different nutrient-restricted conditions in both proliferative and quiescent cells. We detect nearly five-fold more genetic interactions in quiescent cells compared to proliferative cells. We find that both individual gene effects and genetic interaction profiles vary depending on the specific pro-quiescence signal. The master regulator of quiescence,RIM15shows distinct genetic interaction profiles in response to different starvation signals. However, vacuole-related functions show consistent genetic interactions withRIM15in response to different starvation signals suggesting thatRIM15integrates diverse signals to maintain protein homeostasis in quiescent cells. Our study expands genome-wide genetic interaction profiling to additional conditions, and phenotypes, highlighting the conditional dependence of epistasis.
Cargo and Cell Specific Differences in Extracellular Vesicle Populations Identified by Multiplexed Immunofluorescent Analysis
Authors: Burbidge Kevin , Zwikelmaier Virginia , Cook Benjamin , Ispas Grace , Rademacher David J. , Campbell Edward M.
Published: August 2019

Extracellular vesicles (EVs) are implicated in a wide variety of biological activities, have been implicated in the pathogenesis of numerous diseases, and have been proposed to serve as potential biomarkers of disease in human patients and animal models. However, characterization of EV populations is often performed using methods that do not account for heterogeneity of EV populations and require comparatively large sample sizes to facilitate analysis. Here, we describe an imaging-based method that allows for the multiplexed characterization of EV populations at the single EV level following centrifugation of EV populations directly onto cover slips, allowing comprehensive analysis of EV populations with relatively small samples. We observe that canonical EV markers are present on subsets of EVs which differ substantially in a producer cell and cargo specific fashion, including differences in EVs containing different HIV-1 proteins previously reported to be incorporated into pathogenic EVs. We also describe a lectin binding assay to interrogate EVs based on their glycan content, which we observe to change in response to pharmacological modulation of secretory autophagy pathways. These studies collectively reveal that multiplexed analysis of EV populations using fluorescent microscopy can reveal differences in specific EV populations that may be used to understand the biogenesis of specific EV populations or to interrogate small subsets of EVs of interest within larger EV populations.
Monosynaptic tracing success depends critically on helper virus concentrations
Authors: Lavin Thomas K. , Jin Lei , Lea Nicholas E. , Wickersham Ian R.
Published: August 2019

Monosynaptically-restricted transsynaptic tracing using deletion-mutant rabies virus has become a widely used technique in neuroscience, allowing identification, imaging, and manipulation of neurons directly presynaptic to a starting neuronal population. Its most common implementation is to use Cre mouse lines in combination with Cre-dependent “helper” adeno-associated viral vectors (AAVs) to supply the required genes to the targeted population before subsequent injection of a first-generation (ΔG) rabies viral vector. Here we show that the efficiency of transsynaptic spread and the degree of nonspecific labeling in wild-type control animals depend strongly on the concentrations of these helper AAVs. Our results suggest practical guidelines for achieving good results.
The impact of Hurricane Michael on longleaf pine habitats in Florida
Authors: Zampieri Nicole E. , Pau Stephanie , Okamoto Daniel K.
Published: August 2019

The longleaf pine (Pinus palustris) ecosystem of the North American Coastal Plain (NACP) is a global biodiversity hotspot. Disturbances such as tropical storms play an integral role in ecosystem maintenance in these systems. However, altered disturbance regimes as a result of climate change may be outside the historical threshold of tolerance. Hurricane Michael impacted the Florida panhandle as a Category 5 storm on October 10th, 2018. In this study, we estimate the extent of Florida longleaf habitat that was directly impacted by Hurricane Michael. We then quantify the impact of Hurricane Michael on tree density and size structure using a Before-After study design at four sites (two wet flatwood and two upland pine communities). Finally, we identify the most common type of tree damage at each site and community type. We found that 39% of the total remaining extent of longleaf pine habitat was affected by the storm in Florida alone. Tree mortality ranged from 1.3% at the site furthest from the storm center to 88.7% at the site closest. Most of this mortality was in mature sized trees (92% mortality), upon which much of the biodiversity in this habitat depends. As the frequency and intensity of extreme events increases, management plans that mitigate for climate change impacts need to account for large-scale stochastic mortality events in order to effectively preserve critical habitats.
Molecular assays to detect the presence and viability ofPhytophthora ramorumandGrosmannia clavigera
Authors: Wong Barbara , Leal Isabel , Feau Nicolas , Dale Angela , Uzunovic Adnan , Hamelin Richard C.
Published: August 2019

Abstract/Keywords

To determine if living microorganisms of phytosanitary concern are present in wood after eradication treatment and to evaluate the efficacy of such treatments, the method of choice is to grow microbes in petri dishes for subsequent identification. However, some plant pathogens are difficult or impossible to grow in axenic cultures. A molecular methodology capable of detecting living fungi and fungus-like organismsin situcan provide a solution. RNA represents the transcription of genes and can therefore only be produced by living organisms, providing a proxy for viability. We designed and used RNA-based molecular diagnostic assays targeting genes essential to vital processes and assessed their presence in wood colonized by fungi and oomycetes through reverse transcription and real-time polymerase chain reaction (PCR). A stability analysis was conducted by comparing the ratio of mRNA to gDNA over time following heat treatment of wood infected with the OomycetePhytophthora ramorumand the fungusGrosmannia clavigera. The real-time PCR results indicated that the DNA remained stable over a period of 10 days post treatment in heat-treated wood samples, whereas mRNA could not be detected after 24 hours forP. ramorumor 96 hours forG. clavigera. Therefore, this method provides a reliable way to evaluate the viability of these pathogens and test the effectiveness of existing and emerging wood treatments. This can have important phytosanitary impacts on assessing both timber and non-timber forest products of commercial value in international wood trade.
A simple CPG-based model to generate human hip moment pattern in walking by generating stiffness and equilibrium point trajectories
Authors: Bahramian Alireza , Towhidkhah Farzad , Jafari Sajad
Published: August 2019

Equilibrium point hypothesis (its developed version named as referent control theory) presents a theory about how the central nerves system (CNS) generates human movements. On the other hand, it has been shown that nerves circuits known as central pattern generators (CPG) likely produce motor commands to the muscles in rhythmic motions. In the present study, we designed a bio-inspired walking model, by coupling double pendulum to CPGs that produces equilibrium and stiffness trajectories as reciprocal and co-activation commands. As a basic model, it is has been shown that this model can regenerate pattern of a hip moment in the swing phase by high correlation (ρ= 0.970) with experimental data. Moreover, it has been reported that a global electromyography (EMG) minima occurs in the mid-swing phase when the hip is more flexed in comparison with the other leg. Our model showed that equilibrium and actual hip angle trajectories match each other in mid-swing, similar to the mentioned posture, that is consistent with previous findings. Such a model can be used in active exoskeletons and prosthesis to make proper active stiffness and torque.
Using indication embeddings to represent patient health for drug safety studies
Authors: Melamed Rachel D.
Published: August 2019

Objective

The electronic health record is a rising resource for quantifying medical practice, discovering adverse effects of drugs, and studying comparative effectiveness. One of the challenges of applying these methods to health care data is the high dimensionality of the health record. Methods to discover effects of drugs in health data must account for tens of thousands of potentially relevant confounders. Our goal in this work is to reduce the dimensionality of the health data with the aim of accelerating the application of retrospective cohort studies to this data.

Materials and Methods

Here, we develop indication embeddings, a way to reduce the dimensionality of health data while capturing information relevant to treatment decisions. We evaluate these embeddings using external data on drug indications. Then, we use the embeddings as a substitute for medical history to match patients, and develop evaluation metrics for these matches.

Results

We demonstrate that these embeddings recover therapeutic uses of drugs. We use embeddings as an informative representation of relationships between drugs, between health history events and drug prescriptions, and between patients at a particular time in their health history. We show that using embeddings to match cohorts improves the balance of the cohorts, even in terms of poorly measured risk factors like smoking.

Discussion and Conclusion

Unlike other embeddings inspired by word2vec, indication embeddings are specifically designed to capture the medical history leading to prescription of a new drug. For retrospective cohort studies, our low-dimensional representation helps in finding comparator drugs and constructing comparator cohorts.
Models of heterogeneous dopamine signaling in an insect learning and memory center
Authors: Jiang Linnie , Litwin-Kumar Ashok
Published: August 2019

TheDrosophilamushroom body exhibits dopamine dependent synaptic plasticity that underlies the acquisition of associative memories. Recordings of dopamine neurons in this system have identified signals related to external reinforcement such as reward and punishment. However, other factors including locomotion, novelty, reward expectation, and internal state have also recently been shown to modulate dopamine neurons. This heterogeneity is at odds with typical modeling approaches in which these neurons are assumed to encode a global, scalar error signal. How is dopamine dependent plasticity coordinated in the presence of such heterogeneity? We develop a modeling approach that infers a pattern of dopamine activity sufficient to solve defined behavioral tasks, given architectural constraints informed by knowledge of mushroom body circuitry. Model dopamine neurons exhibit diverse tuning to task parameters while nonetheless producing coherent learned behaviors. Our results provide a mechanistic framework that accounts for the heterogeneity of dopamine activity during learning and behavior.
Haplotype genetic score analysis in 10,734 mother/infant pairs reveals complex maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes and adult phenotypes
Authors: Chen Jing , Bacelis Jonas , Navais Pol Sole , Srivastava Amit , Juodakis Julius , Rouse Amy , Hallman Mikko , Teramo Kari , Melbye Mads , Feenstra Bjarke , Freathy Rachel M. , Davey-Smith George , Lawlor Deborah A. , Murray Jeffrey C. , Williams Scott M. , Jacobsson Bo , Muglia Louis J. , Zhang Ge
Published: August 2019

Many maternal traits are associated with a neonate’s gestational duration, birth weight and birth length. These birth outcomes are subsequently associated with late onset health conditions. Based on 10,734 mother/infant duos of European ancestry, we constructed haplotype genetic scores to dissect the maternal and fetal genetic effects underlying these observed associations. We showed that maternal height and fetal growth jointly affect the duration of gestation – maternal height positively influences the gestational duration, while faster fetal growth reduces gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: tall maternal stature and higher blood glucose causally increase birth size; in the fetus, the height and metabolic risk increasing alleles can lead to increased and decreased birth size respectively; birth weight-raising alleles in fetus may reduce gestational duration and increase maternal blood pressure. These maternal and fetal genetic effects can largely explain the observed associations between the studied maternal phenotypes and birth outcomes as well as the life-course associations between these birth outcomes and adult phenotypes.
IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis
Authors: Arnaoutov Alexei , Lee Hangnoh , Haase Karen Plevock , Aksenova Vasilisa , Jarnik Michal , Oliver Brian , Serpe Mihaela , Dasso Mary
Published: August 2019

The maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells is essential for their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a rapid, premature loss of intestinal tissue integrity as flies age. This age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate an unexpected and novel role of the IRBIT-RNR pathway in gut homeostasis.
A DNA G-quadruplex/i-motif hybrid
Authors: Chu Betty , Zhang Daoning , Paukstelis Paul J.
Published: August 2019

DNA can form many structures beyond the canonical Watson-Crick double helix. It is now clear that noncanonical structures are present in genomic DNA and have biological functions. G-rich G-quadruplexes and C-rich i-motifs are the most well-characterized noncanonical DNA motifs that have been detectedin vivowith either proscribed or postulated biological roles. Because of their independent sequence requirements, these structures have largely been considered distinct types of quadruplexes. Here, we describe the crystal structure of the DNA oligonucleotide, d(CCAGGCTGCAA), that self-associates to form a quadruplex structure containing two central antiparallel G-tetrads and six i-motif C-C+base pairs. Solution studies suggest a robust structural motif capable of assembling as a tetramer of individual strands or as a dimer when composed of tandem repeats. This hybrid structure highlights the growing structural diversity of DNA and suggests that biological systems may harbor many functionally important non-duplex structures.
Single unit activity in marmoset posterior parietal cortex in a gap saccade task
Authors: Ma Liya , Selvanayagam Janahan , Ghahremani Maryam , Hayrynen Lauren K. , Johnston Kevin D. , Everling Stefan
Published: August 2019

Abnormal saccadic eye movements can serve as biomarkers for patients with several neuropsychiatric disorders. To investigate cortical control mechanisms of saccadic responses, the common marmoset (Callithrix jacchus) is a promising non-human primate model. Their lissencephalic brain allows for accurate targeting of homologues of sulcal areas in the macaque brain. Here we recorded single unit activity in the posterior parietal cortex of two marmosets using chronic microelectrode arrays, while the monkeys performed a saccadic task with Gap trials (stimulus onset lagged fixation point offset by 200ms) interleaved with Step trials (fixation point disappeared when the peripheral stimulus appeared). Both marmosets showed a gap effect—shorter saccadic reaction times (SRTs) in Gap vs. Step trials. On average, stronger gap-period response across the entire neuronal population preceded shorter SRTs on trials with contralateral targets, although this correlation was stronger among the 15% ‘gap neurons’, which responded significantly during the gap. We also found 39% ‘target neurons’ with significant visual target-related responses, which were stronger in Gap trials and correlated with the SRTs better than the remaining cells. Compared with slow saccades, fast saccades were preceded by both stronger gap-related and target-related response in all PPC neurons, regardless of whether such response reached significance. Our findings suggest that the PPC in the marmoset contains an area that is involved in the modulation of saccadic preparation and plays roles comparable to those of area LIP in macaque monkeys in eye movements.

SIGNIFICANCE STATEMENT

Abnormal saccadic eye movements can serve as biomarkers for different neuropsychiatric disorders. So far, processes of cerebral cortical control of saccades are not fully understood. Non-human primates are ideal models for studying such processes, and the marmoset is especially advantageous since their smooth cortex permits laminar analyses of cortical microcircuits. Using electrode arrays implanted in the posterior parietal cortex of marmosets, we found neurons responsive to key periods of a saccadic task in a manner that contribute to cortical modulation of saccadic preparation. Notably, this signal was correlated with subsequent saccadic reaction times and was present in the entire neuronal population. We suggest that the marmoset model will shed new light on the cortical mechanisms of saccadic control.
Rhapsody: Pathogenicity prediction of human missense variants based on protein sequence, structure and dynamics
Authors: Ponzoni Luca , Oltvai Zoltán N. , Bahar Ivet
Published: August 2019

The biological effects of human missense variants have been studied experimentally for decades but predicting their effects in clinical molecular diagnostics remains challenging. Available computational tools are usually based on the analysis of sequence conservation and structural properties of the mutant protein. We recently introduced a new machine learning method that demonstrated for the first time the significance of protein dynamics in determining the pathogenicity of missense variants. Here we present a significant extension that integrates coevolutionary data from Pfam database and we also introduce a new interface (Rhapsody) that enables fully automated assessment of pathogenicity. Benchmarked against a dataset of about 20,000 annotated variants, the methodology is shown to outperform well-established and/or advanced prediction tools. We illustrate the utility of our approach by in silico saturation mutagenesis study of human H-Ras. The tool is made available both as a webtool (rhapsody.csb.pitt.edu) and an open source Python package (pip install prody-rhapsody).
Developmental dynamics are a proxy for selective pressures on alternatively polyadenylated isoforms
Authors: Levin Michal , Zalts Harel , Mostov Natalia , Hashimshony Tamar , Yanai Itai
Published: August 2019

Alternative polyadenylation (APA) leads to multiple transcripts from the same gene, yet their distinct functional attributes remain largely unknown. Here, we introduce APA-seq to detect the expression levels of APA isoforms from 3’-end RNA-Seq data by exploiting both paired-end reads for gene isoform identification and quantification. Applying APA-seq, we detected the expression levels of APA isoforms from RNA-Seq data of single C. elegans embryos, and studied the patterns of 3’ UTR isoform expression throughout embryogenesis. We found that global changes in APA usage demarcate developmental stages, suggesting a requirement for distinct 3’ UTR isoforms throughout embryogenesis. We distinguished two classes of genes, depending upon the correlation between the temporal profiles of their isoforms: those with highly correlated isoforms (HCI) and those with lowly correlated isoforms (LCI) across time. This led us to hypothesize that variants produced with similar expression profiles may be the product of biological noise, while the LCI variants may be under tighter selection and consequently their distinct 3’ UTR isoforms are more likely to have functional consequences. Supporting this notion, we found that LCI genes have significantly more miRNA binding sites, more correlated expression profiles with those of their targeting miRNAs and a relative lack of correspondence between their transcription and protein abundances. Collectively, our results suggest that a lack of coherence among the regulation of 3’ UTR isoforms is a proxy for selective pressures acting upon APA usage and consequently for their functional relevance.
Retinal Vessels Detection Using Convolutional Neural Networks in Fundus Images
Authors: Islam Md. Mohaimenul , Poly Tahmina Nasrin , Li Yu-Chuan (Jack)
Published: August 2019

Computer-aided detection (CAD) system is a realistic option for physicians to screen fundus images. Automated segmentation of retinal vessel is in fundus important step to identify the retinal disease region. However, identification of the retinal disease region accurately is still challenging due to the varied distribution of blood vessel on noisy and low contrast fundus images. Healthcare system has been changing significantly with the emergence of machine learning (ML), deep learning (DL) and artificial intelligence (AI) in recent year. Retinal vessel detection is one such area of application of deep learning, for improving the accuracy of detection and segmentation and the quality of patient care. Recently, the convolutional neural networks (CNN) have been applied to the detection of the retinal vessel from fundus images and have demonstrated promising results. The range of accuracy of the CNN model was 0.91-0.95 and the area under the receiver operating curve was 0.09-0.98. Therefore, CNN may play a crucial role in determining the therapeutic methods and detecting the retinal vessel accurately in an individual manner. In this survey, we described the use of CNN in fundus imaging, especially focused on CNN technique, clinical application for retinal vessel detection and future prospective.
Gamma-irradiation-induced micro-structural variations in flame-retardant polyurethane foam using synchrotron X-ray micro-tomography
Authors: Agrawal A. K. , Singh B. , Kashyap Y. S. , Shukla M. , Manjunath B. S. , Gadkari S. C.
Published: August 2019

Flame-retardant polyurethane foams are potential packing materials for the transport casks of highly active nuclear materials for shock absorption and insulation purposes. Exposure of high doses of gamma radiation causes cross-linking and chain sectioning of macromolecules in this polymer foam, which leads to reorganization of their cellular microstructure and thereby variations in physico-mechanical properties. In this study, in-house-developed flame-retardant rigid polyurethane foam samples were exposed to gamma irradiation doses in the 0–20 kGy range and synchrotron radiation X-ray micro-computed tomography (SR-µCT) imaging was employed for the analysis of radiation-induced morphological variations in their cellular microstructure. Qualitative and quantitative analysis of SR-µCT images has revealed significant variations in the average cell size, shape, wall thickness, orientations and spatial anisotropy of the cellular microstructure in polyurethane foam.
A highly efficient antioxidant based on boron and a Schiff base bridged phenolic diphenylamine: synthesis, crystal structure and thermal and antioxidant properties
Authors: Wang Shengpei , Yu Shasha , Feng Jianxiang , Liu Shenggao
Published: August 2019

Antioxidants can effectively protect vegetable-oil-based lubricants against oxidative degradation and prolong their service life. A novel compound, (E)-4-({3,5-di-tert-butyl-2-[(diphenylboranyl)oxy]benzylidene}amino)-N-phenylaniline (BSPD) or {2-[(4-anilinophenyl)iminomethyl-κN]-4,6-di-tert-butylphenolato-κO}diphenylboron, C39H41BN2O, was synthesized by a one-pot reaction of the Schiff base bridged phenolic diphenylamine 2,4-di-tert-butyl-6-{N-[4-(phenylamino)phenyl]carboximidoyl}phenol (SPD) with phenylboronic acid. The corresponding single-crystal X-ray study revealed that the B atom in BSPD has a typical tetrahedral geometry, and the N,O-chelated six-membered ring adopts a chair conformation. According to thermogravimetric analysis, the 5% weight-loss temperature of BSPD increases to 328 °C and the 95% weight-loss temperature is up to 414 °C. More importantly, the antioxidant capability of BSPD in vegetable oil is much better than that of commercial antioxidants [diphenylamine (DPA) and 2,6-di-tert-butyl-4-methylphenol (BHT)] and unmodified SPD.
Corrosive wear and electrochemical corrosion behaviors of laser thermal sprayed CoCrAlYTaSi coatings in 3.5 Wt.% NaCl solution
Authors: Weitong Zhou , Dejun Kong
Published: August 2019

Purpose

This paper aims to enhance the corrosive wear and electrochemical corrosion of Ti–6Al–4V alloy.

Design/methodology/approach

A CoCrAlYTaSi alloy coating was fabricated on Ti–6Al–4V alloy using a laser thermal spraying (LTS). The surface and cross-section morphologies, chemical elements, phases and bonding strength of the obtained coating were analyzed using a scanning electron microscope, energy dispersive spectroscope, X-ray diffraction and scratch test, respectively, The corrosive wear and electrochemical corrosion of CoCrAlYTaSi coating in 3.5 Wt.% NaCl solution were investigated using a wear tester and electrochemical workstation, respectively.

Findings

The average coefficient of frictions (COFs) of CoCrAlYTaSi coating under the wear loads of 2, 4 and 6 N are 1.31, 1.02 and 0.88, respectively; and the corresponding wear rates are 0.66 × 10−4, 1.10 × 10−4 and 1.30 × 10−4 mm3·N–1·m–1, respectively. The wear mechanism under the wear load of 2 N is abrasive wear, while those under the wear loads of 4 and 6 N are adhesive wear and abrasive wear. The charge transfer resistance of CoCrAlYTaSi coating is 5.368 × 105 Ω·cm2, higher than 2.193 × 105 of the substrate.

Originality/value

In this study, a CoCrAlYTaSi coating was firstly fabricated on Ti–6Al–4V alloy using a LTS. Its corrosive wear and electrochemical corrosion in 3.5 Wt.% NaCl solution were investigated, which played a protective role of corrosive wear on Ti–6Al–4V alloy.