bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of climatic conditions on malaria epidemics in Swat Valley
Authors: Khan Sohail
Published: April 2017

The vector for the transmission of malaria is a mosquito and like all diseases which are transmitted through mosquitoes are affected by climatic conditions. In the present study, such type of investigation was done to find the influence of different climatic changes such as temperature and humidity on the incidence of malarial cases in Swat, Khyber Pakhtunkhwa, Pakistan from 2000 to 2016. The data relating to malarial cases and climate conditions were collected from District Health Officer (Saidu Sharif) and Meteorological Center respectively. Statistical analysis of the data was done by using MS Office software, i.e., MS Excel. It was found that with the increase in temperature and humidity, an increase in the incidence of Malaria occurred and vice versa. The effect of global warming and the increasing temperature could become an alarming factor in deciding the fate of malarial epidemics.
Brainwide mapping of endogenous serotonergic transmission via chemogenetic-fMRI
Authors: Giorgi Andrea , Migliarini Sara , Gritti Marta , Galbusera Alberto , Maddaloni Giacomo , De Luca Maria Antonietta , Tonini Raffaella , Gozzi Alessandro , Pasqualetti Massimo
Published: April 2017

Serotonergic transmission affects behaviours and neuro-physiological functions via the orchestrated recruitment of distributed neural systems. It is however unclear whether serotonin’s modulatory effect entails a global regulation of brainwide neural activity, or is relayed and encoded by a set of primary functional substrates. Here we combine DREADD-based chemogenetics and mouse fMRI, an approach we term “chemo-fMRI”, to causally probe the brainwide substrates modulated by phasic serotonergic activity. We describe the generation of a conditional knock-in mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that chemogenetic stimulation of the serotonin system does not affect global brain activity, but results in region-specific activation of a set of primary target regions encompassing parieto-cortical, hippocampal, and midbrain structures, as well as ventro-striatal components of the mesolimbic reward systems. Many of the activated regions also exhibit increased c-Fos immunostaining upon chemogenetic stimulation in freely-behaving mice, corroborating a neural origin for the observed functional signals. These results identify a set of regional substrates that act as primary functional targets of endogenous serotonergic stimulation, and establish causation between phasic activation of serotonergic neurons and regional fMRI signals. They further highlight a functional cross-talk between serotonin and mesolimbic dopamine systems hence providing a novel framework for understanding serotonin dependent functions and interpreting data obtained from human fMRI studies of serotonin modulating agents.
Inflated false negative rates undermine reproducibility in task-based fMRI
Authors: Lohmann G. , Stelzer J. , Müller K. , Lacosse E. , Buschmann T. , Kumar V.J. , Grodd W. , Scheffler K.
Published: April 2017

Reproducibility is generally regarded as a hallmark of scientific validity. It can be undermined by two very different factors, namely inflated false positive rates or inflated false negative rates. Here we investigate the role of the second factor, i.e. the degree to which true effects are not detected reliably. The availability of large public databases and also supercomputing allows us to tackle this problem quantitatively. Specifically, we estimated the reproducibility in task-based fMRI data over different samples randomly drawn from a large cohort of subjects obtained from the Human Connectome Project. We use the full cohort as a standard of reference to approximate true positive effects, and compute the fraction of those effects that was detected reliably using standard software packages at various smaller sample sizes. We found that with standard sample sizes this fraction was less than 25 percent. We conclude that inflated false negative rates are a major factor that undermine reproducibility. We introduce a new statistical inference algorithm based on a novel test statistic and show that it improves reproducibility without inflating false positive rates.
Concurrent tACS-fMRI reveals causal influence of power synchronized neural activity on resting state fMRI connectivity
Authors: Bächinger Marc , Zerbi Valerio , Moisa Marius , Polania Rafael , Liu Quanying , Mantini Dante , Ruff Christian , Wenderoth Nicole
Published: April 2017

Resting state fMRI (rs-fMRI) is commonly used to study the brain’s intrinsic neural coupling, which reveals specific spatiotemporal patterns in the form of resting state networks (RSN). It has been hypothesized that slow rs-fMRI oscillations (<0.1 Hz) are driven by underlying electrophysiological rhythms that typically occur at much faster timescales (>5 Hz); however, causal evidence for this relationship is currently lacking. Here we measured rs-fMRI in humans while applying transcranial alternating current stimulation (tACS) to entrain brain rhythms in left and right sensorimotor cortices.

The two driving tACS signals were tailored to the individual’s alpha rhythm (8-12 Hz) and fluctuated in amplitude according to a 1 Hz power envelope. We entrained the left versus right hemisphere in accordance to two different coupling modes where either alpha oscillations were synchronized between hemispheres (phase-synchronized tACS) or the slower oscillating power envelopes (power-synchronized tACS).

Power-synchronized tACS significantly increased rs-fMRI connectivity within the stimulated RSN compared to phase-synchronized or no tACS. This effect outlasted the stimulation period and tended to be more effective in individuals who exhibited a naturally weak interhemispheric coupling. Using this novel approach, our data provide causal evidence that synchronized power fluctuations contribute to the formation of fMRI-based RSNs. Moreover, our findings demonstrate that the brain’s intrinsic coupling at rest can be selectively modulated by choosing appropriate tACS signals, which could lead to new interventions for patients with altered rs-fMRI connectivity.

Significance Statement

Resting state fMRI has become an important tool to estimate brain connectivity. However, relatively little is known about how slow hemodynamic oscillations measured with fMRI relate to electrophysiological processes.

It was suggested that slowly fluctuating power envelopes of electrophysiological signals synchronize across brain areas and that the topography of this activity is spatially correlated to resting state networks derived from rs-fMRI. Here we take a novel approach to address this problem and establish a causal link between the power fluctuations of electrophysiological signals and rs-fMRI via a new neuromodulation paradigm, which exploits these power-synchronization mechanisms.

These novel mechanistic insights bridge different scientific domains and are of broad interest to researchers in the fields of Medical Imaging, Neuroscience, Physiology and Psychology.
karyoploteR: an R/Bioconductor package to plot customizable linear genomes displaying arbitrary data
Authors: Gel Bernat , Serra Eduard
Published: April 2017

Motivation

Data visualization is a crucial tool for data exploration, analysis and interpretation. For the visualization of genomic data there lacks a tool to create customizable non-circular plots of whole genomes from any species.

Results

We have developed karyoploteR, an R/Bioconductor package to create linear chromosomal representations of any genome with genomic annotations and experimental data plotted along them. Plot creation process is inspired in R base graphics, with a main function creating karyoplots with no data and multiple additional functions, including custom functions written by the end-user, adding data and other graphical elements. This approach allows the creation of highly customizable plots from arbitrary data with complete freedom on data positioning and representation.

Availability

karyoploteR is released under Artistic-2.0 License. Source code and documentation are freely available through Bioconductor (http://www.bioconductor.org/packages/karyoploteR)

Contact

bgel@igtp.cat
The date palm (Phoenix dactyliferaL.) in Siwa oasis (Egypt): How ethnographic, morphometric, and genetic analyses together explain the local agrobiodiversity
Authors: Battesti Vincent , Gros-Balthazard Muriel , Ogéron Clémence , Ivorra Sarah , Terral Jean-Frédéric , Newton Claire
Published: April 2017

The agrobiodiversity of the Siwa oasis (in Egypt), located at the crossroads of ancient Trans-Saharan routes, is evaluated in this article focusing on the date palm (Phoenix dactyliferaL.), the oasis “ecosystem engineer”. This assessment confronts different ontologies: diversity as expressed and maintained by the folk categorization system of the Siwa inhabitants (through the results of an ethnographical analysis) and diversity described by genetic sciences and a morphometric tool based on the size and geometry of the seeds. This work is also an opportunity to evaluate this tool intended for archaeobotany. Beyond a simple instrumentalization of one discipline by another, this study offers a space of mutual enrichment: on the relative importance of the feral and cultivated date palms, the local relevance of the concept of “cultivar” and the confirmation of the existence of “ethnovarieties”.
Loss and gain of function experiments implicate TMEM18 as a mediator of the strong association between genetic variants at human Chromosome 2p25.3 and obesity
Authors: Larder Rachel , Michelle Sim M. F. , Gulati Pawan , Antrobus Robin , Loraine Tung Y.C. , Rimmington Debra , Ayuso Eduard , Polex-Wolf Joseph , Lam Brian Y.H. , Dias Cristina , Logan Darren W. , Virtue Sam , Bosch Fatima , Yeo Giles S.H. , Saudek Vladimir , O’Rahilly Stephen , Coll Anthony P.
Published: April 2017

An intergenic region of human Chromosome 2 (2p25.3) harbours genetic variants which are among those most strongly and reproducibly associated with obesity. The molecular mechanisms mediating these effects remain entirely unknown. The gene closest to these variants isTMEM18, encoding a transmembrane protein localised to the nuclear membrane. The expression ofTmem18within the murine hypothalamic paraventricular nucleus was altered by changes in nutritional state, with no significant change seen in three other closest genes. Germline loss ofTmem18in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression ofTmem18in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We confirmed the nuclear membrane localisation of TMEM18 but provide new evidence that it is has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis thatTMEM18itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.
A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data
Authors: Bertl Johanna , Guo Qianyun , Juul Malene , Besenbacher Søren , Muhlig Nielsen Morten , Hornshøj Henrik , Skou Pedersen Jakob , Hobolth Asger
Published: April 2017

Background

Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration.

Results

To take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures.

Conclusion

We find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model for the mutational process; regions that deviate from the null model are candidates for elements that drive cancer development.
Replication Fork Slowing and Stalling are Distinct, Checkpoint-Independent Consequences of Replicating Damaged DNA
Authors: Iyer Divya Ramalingam , Rhind Nicholas
Published: April 2017

In response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions, we have analyzed the checkpoint in the fission yeastSchizosaccharomyces pombeusing a single-molecule DNA combing assay, which allows us to unambiguously separate the contribution of origin and fork regulation towards replication slowing, and allows us to investigate the behavior of individual forks. Moreover, we have interrogated the role of forks interacting with individual sites of damage by using three damaging agents—MMS, 4NQO and bleomycin—that cause similar levels of replication slowing with very different frequency of DNA lesions. We find that the checkpoint slows replication by inhibiting origin firing, but not by decreasing fork rates. However, the checkpoint appears to facilitate replication of damaged templates, allowing forks to more quickly pass lesions. Finally, using a novel analytic approach, we rigorously identify fork stalling events in our combing data and show that they play a previously unappreciated role in shaping replication kinetics in response to DNA damage.

Author Summary

Faithful duplication of the genome is essential for genetic stability of organisms and species. To ensure faithful duplication, cells must be able to replicate damaged DNA. To do so, they employ checkpoints that regulate replication in response to DNA damage. However, the mechanisms by which checkpoints regulate DNA replication forks, the macromolecular machines that contain the helicases and polymerases required to unwind and copy the parental DNA, is unknown. We have used DNA combing, a single-molecule technique that allows us to monitor the progression of individual replication forks, to characterize the response of fission yeast replication forks to DNA damage that blocks the replicative polymerases. We find that forks pass most lesions with only a brief pause and that this lesion bypass is checkpoint independent. However, at a low frequency, forks stall at lesions, and that the checkpoint is required to prevent these stalls from accumulating single-stranded DNA. Our results suggest that the major role of the checkpoint is not to regulate the interaction of replication forks with DNA damage,per se, but to mitigate the consequences of fork stalling when forks are unable to successfully navigate DNA damage on their own.
Hypocretin underlies the evolution of sleep loss in the Mexican cavefish
Authors: Jaggard James B. , Stahl Bethany A. , Lloyd Evan , Prober David A. , Duboue Erik R. , Keene Alex C.
Published: April 2017

The duration of sleep varies dramatically between species, yet little is known about genetic bases or evolutionary factors driving this variation in behavior. The Mexican cavefish,Astyanax mexicanus, exists as surface populations that inhabit rivers, and multiple independently derived cave populations with convergent evolution on sleep loss. The number of Hypocretin/Orexin (HCRT)-positive hypothalamic neurons is increased significantly in cavefish, and HCRT is upregulated at both the transcript and protein levels. Pharmacological or genetic inhibition of HCRT signaling increases sleep duration in cavefish without affecting sleep in surface fish, suggesting enhanced HCRT signaling underlies sleep loss in cavefish. Ablation of the lateral line or starvation, manipulations that selectively promote sleep in cavefish, inhibithcrtexpression in cavefish while having little effect in surface fish. These findings provide the first evidence of genetic and neuronal changes that contribute to the evolution of sleep loss, and support a conserved role for HCRT in sleep regulation.
Exhaustive capture of biological variation in RNA-seq data through k-mer decomposition
Authors: Audoux Jérôme , Philippe Nicolas , Chikhi Rayan , Salson Mikaël , Gallopin Mélina , Gabriel Marc , Le Coz Jérémy , Commes Thérèse , Gautheret Daniel
Published: April 2017

Each individual cell produces its own set of transcripts, which is the combined result of genetic variation, transcription regulation and post-transcriptional processing. Due to this combinatorial nature, obtaining the exhaustive set of full-length transcripts for a given species is a never-ending endeavor. Yet, each RNA deep sequencing experiment produces a variety of transcripts that depart from the reference transcriptome and should be properly identified. To address this challenge, we introduce a k-mer-based software protocol for capturing local RNA variation from a set of standard RNA-seq libraries, independently of a reference genome or transcriptome. Our software, called DE-kupl, analyzes k-mer contents and detects k-mers with differential abundance directly from the raw data files, prior to assembly or mapping. This enables to retrieve the virtually complete set of unannotated variation lying in an RNA-seq dataset. This variation is subsequently assigned to biological events such as differential lincRNAs, antisense RNAs, splice and polyadenylation variants, introns, expressed repeats, and SNV-harboring or exogenous RNA. We applied DE-kupl to public RNA-seq datasets, including an Epythelial-Mensenchymal Transition model and different human tissues. DE-kupl identified abundant novel events and showed excellent reproducibility when applied to independent deep sequencing experiments. DE-kupl is a new paradigm for analyzing differential RNA-seq data with no preconception on target events, which can also provide fresh insights into existing RNA-seq repositories.
Local Connectome Phenotypes Predict Social, Health, and Cognitive Factors
Authors: Powell Michael A. , Garcia Javier O. , Yeh Fang-Cheng , Vettel Jean M. , Verstynen Timothy
Published: April 2017

The unique architecture of the human connectome is defined initially by genetics and subsequently sculpted over time with experience. Thus, similarities in predisposition and experience that lead to similarities in social, biological, and cognitive attributes should also be reflected in the local architecture of white matter fascicles. Here we employ a method known as local connectome fingerprinting that uses diffusion MRI to measure the fiber-wise characteristics of macroscopic white matter pathways throughout the brain. This fingerprinting approach was applied to a large sample (N=841) of subjects from the Human Connectome Project, revealing a reliable degree of between-subject correlation in the local connectome fingerprints, with a relatively complex, low-dimensional substructure. Using a cross-validated, high-dimensional regression analysis approach, we derived local connectome phenotype (LCP) maps that could reliably predict a subset of subject attributes measured, including demographic, health and cognitive measures. These LCP maps were highly specific to the attribute being predicted but also sensitive to correlations between attributes. Collectively, these results indicate that the local architecture of white matter fascicles reflects a meaningful portion of the variability shared between subjects along several dimensions.

Author Summary

The local connectome is the pattern of fiber systems (i.e., number of fibers, orientation, and size) within a voxel and reflects the proximal characteristics of white matter fascicles distributed throughout the brain. Here we show how variability in the local connectome is correlated in a principled way across individuals. This inter-subject correlation is reliable enough that unique phenotype maps can be learned to predict between-subject variability in a range of social, health, and cognitive attributes. This work shows, for the first time, how shared variability across individuals is reflected in the local connectome.
Intra-protein binding peptide fragments have specific and intrinsic sequence patterns
Authors: Wang Yuhong , Huang Junzhou , Li Wei , Wang Sheng , Ding Chuanfan
Published: April 2017

The key finding in the DNA double helix model is the specific pairing or binding between nucleotides A-T and C-G, and the pairing rules are the molecule basis of genetic code. Unfortunately, no such rules have been discovered for proteins. Here we show that similar rules and intrinsic sequence patterns between intra-protein binding peptide fragments do exist, and they can be extracted using a deep learning algorithm. Multi-millions of binding and non-binding peptide fragments from currently available protein X-ray structures are classified with an accuracy of up to 93%. This discovery has the potential in helping solve protein folding and protein-protein interaction problems, two open and fundamental problems in molecular biology.

One Sentence Summary

Classification of binding and non-binding intra-protein peptide fragments using feed-forward neural network
Ultrasensitivity and Fluctuations in the Barkai-Leibler Model of Chemotaxis Receptors inEscherichia coli
Authors: Roy Ushasi , Gopalakrishnan Manoj
Published: April 2017

A stochastic version of the Barkai-Leibler model of chemotaxis receptors inEscherichia coliis studied here with the goal of elucidating the effects of intrinsic network noise in their conformational dynamics. The model was originally proposed to explain the robust and near-perfect adaptation ofE. coliobserved across a wide range of spatially uniform attractant/repellent (ligand) concentrations. In the model, a receptor is either active or inactive and can stochastically switch between the two states. The enzyme CheR methylates inactive receptors while CheB demethylates active receptors and the probability for a receptor to be active depends on its level of methylation and ligand occupation. In a simple version of the model with two methylation sites per receptor (M= 2), we show rigorously, under a quasi-steady state approximation, that the mean active fraction of receptors is an ultrasensitive function of [CheR]/[CheB] in the limit of saturating receptor concentration. Hence the model shows zero-order ultrasensitivity (ZOU), similar to the classical two-state model of covalent modification studied by Goldbeter and Koshland (GK). We also find that in the limits of extremely small and extremely large ligand concentrations, the system reduces to two different two-state GK modules. A quantitative measure of the spontaneous fluctuations in activity is provided by the variancein the active fraction, which is estimated mathematically under linear noise approximation (LNA). It is found thatpeaks near the ZOU transition. The variance is a non-monotonic, but weak function of ligand concentration and a decreasing function of receptor concentration. Gillespie simulations are also performed in models withM= 2, 3 and 4. ForM= 2, simulations show excellent agreement with analytical results obtained under LNA. Numerical results forM= 3 andM= 4 are qualitatively similar to our mathematical results inM= 2; while all the models show ZOU in mean activity, the variance is found to be smaller for largerM. The magnitude of receptor noise deduced from available experimental data is consistent with our predictions. A simple analysis of the downstream signaling pathway shows that this noise is large enough to affect the motility of the organism, and may have a beneficial effect on it. The response of mean receptor activity to small time-dependent changes in the external ligand concentration is computed within linear response theory, and found to have a bilobe form, in agreement with earlier experimental observations.
The development of scientific consensus: analyzing conflict and concordance among Avian phylogenies
Authors: Brown Joseph W. , Wang Ning , Smith Stephen A.
Published: April 2017

Recent developments in phylogenetic methods and data acquisition have allowed for the construction of large and comprehensive phylogenetic relationships. Published phylogenies represent an enormous resource that not only facilitate the resolution of questions related to comparative biology, but also provide a resource on which to gauge the development of consensus across the tree of life. From the Open Tree of Life, we gathered 290 avian phylogenies representing all major groups that have been published over the last few decades and analyzed how concordance and conflict develop among these trees through time. Nine large scale backbone trees (including a new synthetic tree from this study) were used for the consensus assessment. We found that conflicts were over-represented both along the backbone (higher-level neoavian relationships) and within the oscine Passeriformes. Importantly, although we have made major strides in our knowledge of major clades, recent published comprehensive trees, as well as trees of individual clades, continue to contribute significantly to the resolution of clades in the avian phylogeny. These findings are somewhat unexpected, given that birds constitute a relatively well-studied and small clade of the tree of life (i.e., Aves). Therefore, our analysis highlights that much work is still needed before we can confidently resolve the less well studied areas of the tree of life.
Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specificHypocretin/Orexin receptor 1-KO mice
Authors: Li Sha , Franken Paul , Vassalli Anne
Published: April 2017

Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities. Salient stimuli activate spiking of locus coeruleus noradrenergic (NALC) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response. Hypothalamic HCRT neurons provide one of the densest input to NALCcells. To functionally address the HCRT-to-NA connection, we selectively disrupted theHcrtr1gene in NA neurons, and analyzed resulting (Hcrtr1Dbh-CKO) mice’, and their control littermates’ electrocortical response in several contexts of enhanced arousal. Under enforced wakefulness (EW), or after cage change (CC),Hcrtr1Dbh-CKOmice exhibited a weakened ability to lower infra-θ frequencies (1-7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz). A fast-γ (55-80 Hz) response, whose dynamics closely parallelled θ, also diminished, while β/slow-γ activity (15-45 Hz) increased. Furthermore, EW-associated locomotion was lower. Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced θ and fast-γ activities. Thus HCRT-to-NA signalling may fine-tune arousal, up in alarming conditions, and down during self-motivated, goal-driven behaviors. Lastly, slow-wave-sleep following EW and CC, but not nestbuilding, was severely deficient in slow-δ waves (0.75-2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-δ rebound characterizing sleep after stress-associated arousal.
Unbiased definition of a shared T-cell receptor motif enables population-based studies of tuberculosis
Authors: DeWitt W. S. , Quan K. K. , Wilburn D. , Sherwood A. , Vignali M. , De Rosa S. C. , Day C. L. , Scriba T. J. , Robins H. S. , Swanson W. , Emerson R. O. , Seshadri C.
Published: April 2017

Peptide-specific T cells that are restricted by highly polymorphic major histocompatibility complex (MHC) proteins express diverse T-cell receptors (TCRs) that are rarely shared among unrelated individuals. T-cells can also recognize bacterial lipid antigens that bind the relatively non-polymorphic CD1 family of proteins. However, genetic variation in human CD1 genes and TCR diversity expressed by CD1-restricted T-cells have not been quantitatively determined. Here, we show that CD1B is nearly nucleotide-identical across all five continental ancestry groups, providing evidence for purifying selection during human evolution. We used CD1B tetramers loaded with a mycobacterial glycolipid antigen to isolate T-cells from four genetically unrelated South African adults and cataloged thousands of TCRs fromin-vitroexpanded T-cells using immunosequencing. We identified highly conserved motifs that were co-expressed as a functional heterodimer and significantly enriched among tetramer-positive T-cells sorted directly from peripheral blood. Finally, we show that frequencies of these TCR motifs are increased in the blood of patients with active tuberculosis compared to uninfected controls, a finding that is confirmed by ex-vivo frequencies of tetramer-positive T-cells determined by flow cytometry. These data provide a framework for unbiased definition of TCRs targeting lipid antigens, which can be tested for clinical associations independently of host genetic background.

Brief Summary

We used human genetics and immunosequencing to define a shared T-cell receptor motif that is specific for a mycobacterial lipid antigen and associated with tuberculosis independently of host genetic background.
The Virtual Mouse Brain: a computational neuroinformatics platform to study whole mouse brain dynamics
Authors: Melozzi Francesca , Woodman Marmaduke M. , Jirsa Viktor K. , Bernard Christophe
Published: April 2017

Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain’s structure-function relationship, necessitating the close integration of diverse neuroinformatics fields.

Here we extend the open-source simulation software The Virtual Brain to whole mouse brain network modeling based on individual diffusion Magnetic Resonance Imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease.

The Virtual Mouse Brain enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.
Progressive Multiple Sequence Alignment with the Poisson Indel Process
Authors: Maiolo Massimo , Zhang Xiaolei , Gil Manuel , Anisimova Maria
Published: April 2017

Sequence alignment lies at the heart of many evolutionary and comparative genomics studies. However, the optimal alignment of multiple sequences is NP-hard, so that exact algorithms become impractical for more than a few sequences. Thus, state of the art alignment methods employ progressive heuristics, breaking the problem into a series of pairwise alignments guided by a phylogenetic tree. Changes between homologous characters are typically modelled by a continuous-time Markov substitution model. In contrast, the dynamics of insertions and deletions (indels) are not modelled explicitly, because the computation of the marginal likelihood under such models has exponential time complexity in the number of taxa. Recently, Bouchard-Côté and Jordan [PNAS (2012) 110(4):1160–1166] have introduced a modification to a classical indel model, describing indel evolution on a phylogenetic tree as a Poisson process. The model termed PIP allows to compute the joint marginal probability of a multiple sequence alignment and a tree in linear time. Here, we present an new dynamic programming algorithm to align two multiple sequence alignments by maximum likelihood in polynomial time under PIP, and apply it a in progressive algorithm. To our knowledge, this is the first progressive alignment method using a rigorous mathematical formulation of an evolutionary indel process and with polynomial time complexity.
Giantin knockout models reveal a feedback loop between Golgi function and glycosyltransferase expression
Authors: Stevenson Nicola L. , Bergen Dylan J. M. , Skinner Roderick E.H. , Kague Erika , Martin-Silverstone Elizabeth , Robson Brown Kate A. , Hammond Chrissy L. , Stephens David J.
Published: April 2017

The Golgi is the cellular hub for complex glycosylation, controlling accurate processing of complex proteoglycans, receptors, ligands, and glycolipids. Its structure and organisation is dependent on golgins, which tether cisternal membranes and incoming transport vesicles. Here we show that knockout of the largest golgin, giantin, leads to substantial changes in gene expression despite only limited effects on Golgi structure. Notably, 22 Golgi-resident glycosyltransferases, but not glycan processing enzymes or the ER glycosylation machinery, are differentially expressed following giantin ablation. This includes near-complete loss-of-function of GALNT3 in both mammalian cell and zebrafish models. Giantin knockout zebrafish exhibit hyperostosis and ectopic calcium deposits, recapitulating phenotypes of hyperphosphatemic familial tumoral calcinosis, a disease caused by mutations in GALNT3. These data reveal a new feature of Golgi homeostasis, the ability to regulate glycosyltransferase expression to generate a functional proteoglycome.

Summary statement

Knockout of giantin in a genome-engineered cell line and zebrafish models reveals the capacity of the Golgi to control its own biochemistry through changes in gene expression.
Single-Cell Genome Dynamics in Early Embryo Development: A Statistical Thermodynamics Approach
Authors: Giuliani Alessandro , Tsuchiya Masa , Yoshikawa Kenichi
Published: April 2017

A statistical thermodynamics approach to the temporal development of biological regulation provides a phenomenological description of the dynamical behavior of genome expression in terms of autonomous self-organization with a critical transition (Self-Organized Criticality: SOC). In early mouse embryo development, the dynamical change in the self-organization of overall expression determineshow and whenreprogramming of the genome-expression state occurs. Reprogramming occurs via a transition state (climbing over an epigenetic landscape), where the critical-regulation pattern of the zygote state disappears. A critical transition is well captured in terms of the bimodality of expression ensembles, which reflects distinct thermodynamic states (critical states). These critical states exhibit a genome avalanche pattern: competition between order (scaling) and disorder (divergence) around a critical point. The genome avalanche in mouse embryo development, which is committed to erase a previous ordered state, reveals that the direction of early embryo single-cell development traverses the same steps as in differentiation, but in the opposite order of self-organization.
Scc2-mediated loading of cohesin onto chromosomes in G1 yeast cells is insufficient to build cohesion during S phase
Authors: Nasmyth Kim A
Published: April 2017

Sister chromatids are held together from their replication until mitosis. Sister chromatid cohesion is mediated by the ring-shaped cohesin complex and it is thought that cohesin holds sister chromatids together by entrapping sister DNAs within the cohesin ring (Haering et al., 2008). However, how this occurs is not well understood. Because cohesin binds to DNA prior to replication it is possible that the replication fork passes through the lumen of the ring thereby placing replicated sisters inside cohesin rings. If this is the case, loading of cohesin in the G1 phase may be sufficient to build cohesion.

We show here that Scc2, a cohesin subunit required for loading cohesin onto chromosomesde novo, is necessary for establishment of cohesion even after Scc2-mediated loading has already taken place during late G1 or early S phase. Our results challenge a previous conclusion based on related experiments whereby Scc2 was found not to be required for cohesion establishment during S phase (Lengronne et al., 2006).
Scallop enables accurate assembly of transcripts through phasing-preserving graph decomposition
Authors: Shao Mingfu , Kingsford Carl
Published: April 2017

We introduce Scallop, an accurate, reference-based transcript assembler for RNA-seq data. Scallop significantly improves reconstruction of multi-exon and lowly expressed transcripts. On 10 human samples aligned with STAR, Scallop produces (on average) 35.7% and 37.5% more correct multi-exon transcripts than two leading transcript assemblers, StringTie [1] and TransComb [2], respectively. For transcripts expressed at low levels in the same samples, Scallop assembles 65.2% and 50.2% more correct multi-exon transcripts than StringTie and TransComb, respectively. Scallop obtains this improvement through a novel algorithm that we prove preserves all phasing paths from reads (including paired-end reads), while also producing a parsimonious set of transcripts and minimizing coverage deviation.
Spatial structure of synchronized inhibition in the olfactory bulb
Authors: Arnson Hannah A. , Strowbridge Ben W.
Published: April 2017

Olfactory sensory input is detected by receptor neurons in the nose which then send information to the olfactory bulb, the first brain region for processing olfactory information. Within the olfactory bulb, many local circuit interneurons, including axonless granule cells, function to facilitate fine odor discrimination. How interneurons interact with principal cells to affect bulbar processing is not known though the mechanism is likely to be different than in sensory cortical regions since the olfactory bulb lacks an obvious topographical organization; neighboring glomerular columns, representing inputs from different receptor neuron subtypes, typically have different odor tuning. Determining the spatial scale over which interneurons such as granule cells can affect principal cells is a critical step towards understanding how the olfactory bulb operates. We addressed this question by assaying inhibitory synchrony using intracellular recordings from pairs of principal cells with different inter-somatic spacing. We find that in acute rat olfactory bulb slices, inhibitory synchrony is evident in the spontaneous synaptic input in mitral cells separated up to 300μm. At all inter-somatic spacing assayed, inhibitory synchrony was dependent on fast Na+channels, suggesting that action potentials in granule cells function to coordinate GABA release at relatively distant dendrodendritic synapses formed throughout the the dendritic arbor. Our results suggest that individual granule cells are able to influence relatively large groups of mitral and tufted cells belonging to clusters of at least 15 glomerular modules, providing a potential mechanism to integrate signals reflecting a wide variety of odorants.
Optogenetic perturbation and bioluminescence imaging to analyze cell-to-cell transfer of oscillatory information
Authors: Isomura Akihiro , Ogushi Fumiko , Kori Hiroshi , Kageyama Ryoichiro
Published: April 2017

Cells communicate with each other to coordinate their gene activities at the population level through signaling pathways. It has been shown that many gene activities are oscillatory and that the frequency and phase of oscillatory gene expression encode various types of information. However, whether or how such oscillatory information is transmitted from cell to cell remains unknown. Here, we developed an integrated approach that combines optogenetic perturbations and single-cell bioluminescence imaging to visualize and reconstitute synchronized oscillatory gene expression in signal-sending and signal-receiving processes. We found that intracellular and intercellular periodic inputs of Notch signaling entrain intrinsic oscillations by frequency tuning and phase shifting at the single-cell level. In this way, the oscillation dynamics are transmitted through Notch signaling, thereby synchronizing the population of oscillators. Thus, this approach enabled us to control and monitor dynamic cell-to-cell transfer of oscillatory information to coordinate gene expression patterns at the population level.
Non-contact luminescence lifetime cryothermometry for macromolecular crystallography
Authors: Mykhaylyk V. B. , Wagner A. , Kraus H.
Published: April 2017

Temperature is a very important parameter when aiming to minimize radiation damage to biological samples during experiments that utilize intense ionizing radiation. A novel technique for remote, non-contact,in situmonitoring of the protein crystal temperature has been developed for the new I23 beamline at the Diamond Light Source, a facility dedicated to macromolecular crystallography (MX) with long-wavelength X-rays. The temperature is derived from the temperature-dependent decay time constant of luminescence from a minuscule scintillation sensor (<0.05 mm3) located in very close proximity to the sample under test. In this work the underlying principle of cryogenic luminescence lifetime thermometry is presented, the features of the detection method and the choice of temperature sensor are discussed, and it is demonstrated how the temperature monitoring system was integrated within the viewing system of the endstation used for the visualization of protein crystals. The thermometry system was characterized using a Bi4Ge3O12crystal scintillator that exhibits good responsivity of the decay time constant as a function of temperature over a wide range (8–270 K). The scintillation sensor was calibrated and the uncertainty of the temperature measurements over the primary operation temperature range of the beamline (30–150 K) was assessed to be ±1.6 K. It has been shown that the temperature of the sample holder, measured using the luminescence sensor, agrees well with the expected value. The technique was applied to characterize the thermal performance of different sample mounts that have been used in MX experiments at the I23 beamline. The thickness of the mount is shown to have the greatest impact upon the temperature distribution across the sample mount. Altogether, these tests and findings demonstrate the usefulness of the thermometry system in highlighting the challenges that remain to be addressed for the in-vacuum MX experiment to become a reliable and indispensable tool for structural biology.
Monitoring of thermal stresses in pressure components using inverse heat conduction methods
Authors: Taler Jan , Weglowski Bohdan , Pilarczyk Marcin
Published: April 2017

Purpose

The purpose of this paper is to present a method for monitoring transient thermal stresses. This paper also presents the analysis of thermal stresses of boiler pressure element heating during the start-up in real conditions. The inverse methods are used to determine the wall temperature, whereas the commercial software ANSYS is used to determine the thermal stresses in the pressure component.

Design/methodology/approach

The method is based on the solution of the inverse heat conduction problem. Thermal stresses are determined indirectly taking into account the measured temperature values at selected points on the outer wall of a pressure component. First, the transient temperature distribution in the entire pressure element is calculated, and then, thermal stresses are determined by the finite element method. Measured pressure changes are used to determine the stresses resultant from the internal pressure.

Findings

The obtained stresses and temperature in the thick-walled pipe are illustrated and compared with experimental data. Satisfactory agreement was found between computational and experimental results.

Originality/value

The method can be used in the monitoring of thermal and mechanical stresses during the boiler’s start-up and shut-down. Because the temperature distribution at each time level is determined, it can be applied as a thermal load during the structural analysis.
Identification of the cancer ablation parameters during RF hyperthermia using gradient, evolutionary and hybrid algorithms
Authors: Paruch Marek
Published: April 2017

Purpose

The purpose of this study is to show that the methods of the numerical simulation can be a very effective tool for a proper choice of control parameters of artificial hyperthermia. An electromagnetic field induced by two external electrodes and a temperature field resulting from electrodes action in a 3D domain of biological tissue is considered. An important problem is the appropriate directing of heat in the region of tumor, so as to avoid damaging healthy cells surrounding the tumor. Recently, to concentrate the heat on the tumor, magnetic nanoparticles, which are introduced into the tumor, were used. The nanoparticles should be made of material that ensures appropriate magnetic properties and has a high biocompatibility with the biological tissue. External electric field causes the heat generation in the tissue domain.

Design/methodology/approach

The distribution of electric potential in the domain considered is described by the Laplace system of equations, while the temperature field is described by the Pennes’ system of equations. These problems are coupled by source function being the additional component in the Pennes’ equation and resulting from the electric field action. The boundary element method is applied to solve the coupled problem connected with the heating of biological tissues.

Findings

The aim of investigations is to determine an electric potential of external electrodes and the number of nanoparticles introduced to a tumor region to obtain the artificial hyperthermia state. The tests performed showed that the proposed tool to solve the inverse problem provides correct results.

Research limitations/implications

In the paper the steady state bioheat transfer problem is considered, so the thermal damage is a function of the temperature only. Therefore, the solution can be considered as the maximum ablation zone of cancer. Additionally, the choice of appropriate parameters will be affected on the position and shape of the tumor and the electrodes.

Originality/value

In the paper the inverse problem has been solved using the evolutionary algorithm, gradient method and hybrid algorithm which is a combination of the two previous.