bluuebunny/crossref_metadata_2025 huggingface dataset:
The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors
Authors: Baker Michael E. , Lathe Richard
Published: December 2017

Many actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor-α (ERα) and ERβ. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and Δ5-androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen. In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain. Some of these ER actions in non-reproductive tissues appeared early in vertebrate evolution, long before mammals evolved.
Testing Equality of Curves after Covariate Adjustment
Authors: Pal Choudhury Parichoy , Kundu Prosenjit , Xue Qian-Li , Westbrook Reyhan , Crainiceanu Ciprian M.
Published: December 2017

Summary

This paper is concerned with providing simple methodological approaches for global and local tests of difference between the mean of treatment and control groups when the measured outcome is a function. The added complexity is that for every subject we have repeated samples for the same curve and additional covariates of interest. We propose a permutation based approach to test for a global difference between the averages of two functional processes after covariate adjustment. The within group averages are estimated by modeling the relationship of the functional outcome on the covariate using functional regression methods and then averaging with respect to the covariate distribution in each group. The test statistic is the L2 area under the squared difference curve. We also test for the localized differences between the two average curves using a nonparametric bootstrap of subjects to obtain the 95% pointwise and joint confidence intervals for the estimated covariate-adjusted difference curve. Extensive simulation studies illustrate that the proposed tests preserve the type one error and are highly sensitive to detecting departures from the null assumption. We illustrate our method by studying the differences in time varying oxygen consumption between the frail Interleukin 10tm1Cgn (IL10tm) mice and the wildtype mice after adjusting for body composition measures.
Unifying intra- and inter-specific variation in tropical tree mortality
Authors: Camac James S , Condit Richard , FitzJohn Richard G , McCalman Lachlan , Steinberg Daniel , Westoby Mark , Wright S Joseph , Falster Daniel S
Published: December 2017

Tree death is a fundamental process driving population dynamics, nutrient cycling, and evolution within plant communities. While past research has identified factors influencing tree mortality across a variety of scales, these distinct drivers are yet to be integrated within a unified predictive framework. In this study, we use a cross-validated Bayesian framework coupled with classic survival analysis techniques to derive instantaneous mortality functions for 203 tropical rainforest tree species at Barro Colorado Island (BCI) Panama. Specifically, we develop mortality functions that not only integrate individual, species, and temporal effects, but also partition the contributions of growth-dependent and growth-independent effects on the overall instantaneous mortality rate. We show that functions that separate mortality rates into growth-dependent and growth-independent hazards, use stem diameter growth rather than basal-area growth, and attribute the effect of wood density to growth-independent mortality outperform alternative formulations. Moreover, we show that the effect of wood density – a prominent trait known to influence tree mortality – explains only 22% of the total variability observed among species. Lastly, our analysis show that growth-dependent processes are the predominant contributor to rates of tree mortality at BCI. Combined, this study provides a framework for predicting individual-level mortality in highly diverse tropical forests. It also highlights how little we know about the causes of species-level and temporal plot-scale effects needed to effectively predict tree mortality.
CONFOLD2: Improved contact-driven ab initio protein structure modeling
Authors: Adhikari Badri , Cheng Jianlin
Published: December 2017

Background

Contact-guided protein structure prediction methods are becoming more and more successful because of the latest advances in residue-residue contact prediction. To support the contact-driven structure prediction, effective tools that can quickly build tertiary structural models of good quality from predicted contacts need to be developed.

Results

We develop an improved contact-driven protein modeling method, CONFOLD2, and study how it may be effectively used for ab initio protein structure prediction with predicted contacts as input. It builds models using various subsets of input contacts to explore the fold space under the guidance of a soft square energy function, and then clusters the models to obtain top five models. CONFOLD2 is benchmarked on various datasets including CASP11 and 12 datasets with publicly available predicted contacts and yields better performance than the popular CONFOLD method.

Conclusion

CONFOLD2 allows to quickly generate top five structural models for a protein sequence, when its secondary structures and contacts predictions at hand. CONFOLD2 is publicly available athttps://github.com/multicom-toolbox/CONFOLD2/.
Transcription activation domains of the yeast factors Met4 and Ino2: tandem activation domains with properties similar to the yeast Gcn4 activator
Authors: Pacheco Derek , warfield Linda , Brajcich Michelle , Robbins Hannah , Luo Jie , Ranish jeff , Hahn Steven
Published: December 2017

Eukaryotic transcription activation domains (ADs) are intrinsically disordered polypeptides that typically interact with coactivator complexes, leading to stimulation of transcription initiation, elongation and chromatin modifications. Here we examine the properties of two strong and conserved yeast ADs: Met4 and Ino2. Both factors have tandem ADs that were identified by conserved sequence and functional studies. While AD function from both factors depends on hydrophobic residues, Ino2 further requires key conserved acidic and polar residues for optimal function. Binding studies show that the ADs bind multiple Med15 activator binding domains (ABDs) with a similar order of micromolar affinity, and similar but distinct thermodynamic properties. Protein crosslinking shows that no unique complex is formed upon Met4-Med15 binding. Rather, we observed heterogeneous AD-ABD contacts with nearly every possible AD-ABD combination. Many of these properties are similar to those observed with the yeast activator Gcn4, which forms a large heterogeneous, dynamic, and fuzzy complex with Med15. We suggest that this molecular behavior is common among eukaryotic activators.
Non-blocking modulation as the major mechanism of sodium channel inhibition by riluzole
Authors: Szabo AK , Pesti K , Lukacs P , Földi MC , Gerevich Z , Sperlagh B , Mike A
Published: December 2017

Modulated- or guarded receptor hypothesis; Channel block or modulation; “Voltage-sensor block” or “lipophilic block” are some of the questions that arise when drug effects on sodium channels are investigated. Understanding the exact mechanism of action for individual drugs is essential, because it is one of the major factors that determine their therapeutic applicability.

In this study we created a kinetic model of sodium channels, which can help us understand the modes of action for individual drugs in the context of these hypotheses. The model was constructed so that it could integrate the above hypotheses.

In particular we aimed to understand the mode of action of riluzole, a neuroprotective drug with a peculiar state-dependent inhibition. In experiments the inhibition by 100μM riluzole was full within the first two milliseconds, but it was almost completely removed between 2 and 20 ms post-depolarization. This abrupt loss of inhibition could not be explained by dissociation, which was proceeding with a time constant of ~300 ms. We propose that for sodium channel inhibitors binding without blocking is possible, and riluzole predominantly inhibits by non-blocking modulation. We used lidocaine as a reference compound, and found that non-blocking modulation, although less prominent, also may play a role in its mechanism of inhibition. Non-blocking modulation may selectively inhibit cells with pathological activity patterns, therefore this property may be a good trait to investigate in the development of sodium channel inhibitor drugs.

Although never actually proven, presence of sodium channel inhibitors at their binding site is assumed to prevent ion conduction. Authors provide evidence from experiments and kinetic simulations that bound riluzole permits conduction and exerts its inhibitory effect almost entirely by modulation.
Competition and niche construction in a model of cancer metastasis
Authors: Qian Jimmy J. , Akçay Erol
Published: December 2017

Niche construction theory states that not only does the environment act on populations to generate Darwinian selection, but organisms reciprocally modify the environment and the sources of natural selection. Cancer cells participate in niche construction as they alter their microenvironments and create pre-metastatic niches; in fact, metastasis is a product of niche construction. Here, we present a mathematical model of niche construction and metastasis. Our model contains producers, which pay a cost to contribute to niche construction that benefits all tumor cells, and cheaters, which reap the benefits without paying the cost. We derive expressions for the conditions necessary for metastasis, showing that the establishment of a mutant lineage that promotes metastasis depends on niche construction specificity and strength of interclonal competition. We identify a tension between the arrival and invasion of metastasis-promoting mutants, where tumors composed only of cheaters remain small but are susceptible to invasion whereas larger tumors containing producers may be unable to facilitate metastasis depending on the level of niche construction specificity. Our results indicate that even if metastatic subclones arise through mutation, metastasis may be hindered by interclonal competition, providing a potential explanation for recent surprising findings that most metastases are derived from early mutants in primary tumors.
Neural Computations Underlying Causal Structure Learning
Authors: Tomov Momchil S. , Dorfman Hayley M. , Gershman Samuel J.
Published: December 2017

Behavioral evidence suggests that beliefs about causal structure constrain associative learning, determining which stimuli can enter into association, as well as the functional form of that association. Bayesian learning theory provides one mechanism by which structural beliefs can be acquired from experience, but the neural basis of this mechanism is unknown. A recent study (Gershman, 2017) proposed a unified account of the elusive role of “context” in animal learning based on Bayesian updating of beliefs about the structure of causal relationships between contexts and cues in the environment. The model predicts that the computations which arbitrate between these abstract causal structures are distinct from the computations which learn the associations between particular stimuli under a given structure. In this study, we used fMRI with male and female human subjects to interrogate the neural correlates of these two distinct forms of learning. We show that structure learning signals are encoded in rostrolateral prefrontal cortex and the angular gyrus, anatomically distinct from correlates of associative learning. Within-subject variability in the encoding of these learning signals predicted variability in behavioral performance. Moreover, representational similarity analysis suggests that some regions involved in both forms of learning, such as parts of the inferior frontal gyrus, may also encode the full probability distribution over causal structures. These results provide evidence for a neural architecture in which structure learning guides the formation of associations.

Significance Statement

Animals are able to infer the hidden structure behind causal relations between stimuli in the environment, allowing them to generalize this knowledge to stimuli they have never experienced before. A recently published computational model based on this idea provided a parsimonious account of a wide range of phenomena reported in the animal learning literature, suggesting that the neural mechanisms dedicated to learning this hidden structure are distinct from those dedicated to acquiring particular associations between stimuli. Here we validate this model by measuring brain activity during a task which dissociates structure learning from associative learning. We show that different brain networks underlie the two forms of learning and that the neural signal corresponding to structure learning predicts future behavioral performance.
Histone modifications and active gene expression are associated with enhanced CRISPR activity in de-silenced chromatin
Authors: Daer René , Barrett Cassandra M. , Haynes Karmella A
Published: December 2017

Recently we demonstrated that closed chromatin composed of Polycomb proteins and histone 3 lysine 27 trimethylation impedes CRISPR-mediated genome editing by blocking the accessibility of chromosomal DNA to spCas9/sgRNA. Editing efficiencies were higher in cells where the same reporter locus had not been repressed, thus we presume that silenced chromatin can be modified to generate a Cas9-accessible state. To test this idea, we exposed the locus to antagonists of Polycomb silencing: Gal4-p65, a targeted transcriptional activator, and UNC1999, a chemical inhibitor of the histone H3K27 methyltransferase EZH2. For both we observed loss of histone trimethylation. Only Gal4-p65 treatment increased target gene expression. Initial Gal4-p65 overexpression impedes Cas9 activity, while a 9-day recovery period leads to enhanced Cas9 efficiency up to 1000 bp from the Gal4 binding site. No enhancement was observed with UNC1999. These results demonstrate the strong influence of transcription-driven chromatin remodeling on CRISPR editing at closed chromatin.
Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
Authors: Lukács P , Földi M C , Valánszki L , Casanova E.H , Biri-Kovács B , Nyitray L , Málnási-Csizmadia A , Mike A
Published: December 2017

Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation"). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by confromation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.
A-to-I RNA editing uncovers hidden signals of adaptive genome evolution in animals
Authors: Popitsch Niko , Huber Christian D. , Buchumenski Ilana , Eisenberg Eli , Jantsch Michael , von Haeseler Arndt , Gallach Miguel
Published: December 2017

In animals, the most common type of RNA editing is the deamination of adenosines (A) into inosines (I). Because inosines base-pair with cytosines (C), they are interpreted as guanosines (G) by the cellular machinery and genomically encoded G alleles at edited sites mimic the function of edited RNAs. The contribution of this hardwiring effect on genome evolution remains obscure. We looked for population genomics signatures of adaptive evolution associated with A-to-I RNA edited sites in humans andDrosophila melanogaster. We found that single nucleotide polymorphisms at edited sites occur 3 (humans) to 15 times (Drosophila) more often than at unedited sites, the nucleotide G is virtually the unique alternative allele at edited sites and G alleles segregate at higher frequency at edited sites than at unedited sites. Our study reveals that coding synonymous and nonsynonymous as well as silent and intergenic A-to-I RNA editing sites are likely adaptive in the distantly related human andDrosophilalineages.
Targeted RNA knockdown by crRNA guided Csm in zebrafish
Authors: Fricke Thomas , Tamulaitis Gintautas , Smalakyte Dalia , Pastor Michal , Kolano Agnieszka , Siksnys Virginijus , Bochtler Matthias
Published: December 2017

RNA interference (RNAi) is a powerful experimental tool for RNA knockdown, but not all organisms are amenable. Here, we provide a “proof of principle” demonstration that CRISPR endoribonucleases can be used for programmable mRNA transcript degradation. Using zebrafish as the animal model and Csm(crRNA) complexes as the CRISPR endoribonucleases, we have targeted a transgenic EGFP transcript expressed from a variety of promoters. A drastic decrease of fluorescence was achieved in germ cells of the vasa:EGFP line. Weaker effects were also seen in fish lines that express EGFP zygotically. Knockdown was statistically significant in cmcl2:EGFP and fli1:EGFP zebrafish lines at 1 day post fertilization (dpf), but reduced to background levels at 2 dpf. The nkx2.5:EGFP fish line was least susceptible to Csm mediated EGFP knockdown. We conclude that at the present stage, Csm mediated knockdown is already efficient for maternal transcripts, and may compare favorably with morpholinos for such targets in zebrafish.
Hybrid peeling for fast and accurate calling, phasing, and imputation with sequence data of any coverage in pedigrees
Authors: Whalen Andrew , Ros-Freixedes Roger , Wilson David L , Gorjanc Gregor , Hickey John M
Published: December 2017

In this paper we extend multi-locus iterative peeling to be a computationally efficient method for calling, phasing, and imputing sequence data of any coverage in small or large pedigrees. Our method, called hybrid peeling, uses multi-locus iterative peeling to estimate shared chromosome segments between parents and their offspring, and then uses single-locus iterative peeling to aggregate genomic information across multiple generations. Using a synthetic dataset, we first analysed the performance of hybrid peeling for calling and phasing alleles in disconnected families, families which contained only a focal individual and its parents and grandparents. Second, we analysed the performance of hybrid peeling for calling and phasing alleles in the context of the full pedigree. Third, we analysed the performance of hybrid peeling for imputing whole genome sequence data to the remaining individuals in the population. We found that hybrid peeling substantially increase the number of genotypes that were called and phased by leveraging sequence information on related individuals. The calling rate and accuracy increased when the full pedigree was used compared to a reduced pedigree of just parents and grandparents. Finally, hybrid peeling accurately imputed whole genome sequence information to non-sequenced individuals. We believe that this algorithm will enable the generation of low cost and high accuracy whole genome sequence data in many pedigreed populations. We are making this algorithm available as a standalone program called AlphaPeel.
Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division
Authors: Chen Cuie , Cummings Ryan , Mordovanakis Aghapi , Hunt Alan J. , Mayer Michael , Sept David , Yamashita Yukiko M.
Published: December 2017

Asymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome’s role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.
Modifiable risk factors moderate the relationship between beta-amyloid and cognition in midlife
Authors: Clark Lindsay R. , Koscik Rebecca L. , Allison Samantha L. , Berman Sara E. , Carlsson Cynthia M. , Norton Derek , Bendlin Barbara B. , Asthana Sanjay , Betthauser Tobey , Christian Bradley T. , Johnson Sterling C.
Published: December 2017

Although evidence suggests a relationship between elevated beta-amyloid and cognitive decline, approximately 30% of older adults with positive markers of amyloid remain cognitively healthy. Our objective was to test if the presence of modifiable risk factors (i.e., central obesity, hypertension, and depressive symptoms) moderated the relationship between amyloid and longitudinal cognitive performance. Data were from 207 adults (140 females; age range=40-70) enriched for Alzheimer’s disease risk (73% parental history of Alzheimer’s disease) enrolled in the Wisconsin Registry for Alzheimer’s Prevention study. Participants completed at least three neuropsychological evaluations and one biomarker visit ([C11]Pittsburgh Compound B PET scan or lumbar puncture). Participants were characterized as high or low on beta-amyloid using cutoffs developed for [C11]Pittsburgh Compound B-PET distribution volume ratio or CSF amyloid beta 1-42 values. Participants were also coded as high or low risk on obesity (waist circumference > 102 cm for males or 88 cm for females), hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg), and depressive symptoms (Center for Epidemiologic Studies of Depression scale ≥ 16). Linear mixed effects regression models examined three-way interactions between modifiable risk factor status x beta-amyloid status x visit age on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. Results indicated that the relationship between beta-amyloid and Verbal Learning & Memory decline was moderated by the presence of hypertension at baseline (p = .02), presence of hypertension at all visits (p = .001), and presence of obesity at all visits (p = .049). Depressive symptoms did not moderate the association between beta-amyloid and longitudinal Verbal Learning & Memory (p = .62) or Speed & Flexibility (p = .15) performances. In this at-risk for Alzheimer’s disease cohort, modifiable risk factors of hypertension and obesity moderated the relationship between beta-amyloid and cognitive decline. Identification and modification of these risk factors in late middle age may slow the effect of amyloid on the progression of cognitive symptoms.
Personalized modeling of the human gut microbiome reveals distinct bile acid deconjugation and biotransformation potential in healthy and IBD individuals
Authors: Heinken Almut , Ravcheev Dmitry A. , Baldini Federico , Heirendt Laurent , Fleming Ronan M.T. , Thiele Ines
Published: December 2017

The human gut microbiome performs important functions human health and disease. Intestinal microbes are capable of deconjugation and biotransformation of human primary bile acids to secondary bile acids. Alterations of the bile acid pool as a result of microbial dysbiosis have been linked to multifactorial diseases, such as inflammatory bowel disease (IBD).

Constraint-based modeling is a powerful approach for the mechanistic, systems-level analysis of metabolic interactions in microbial communities. Recently, we constructed a resource of 773 curated genome-scale reconstructions of human gut microbes, AGORA. Here, we performed a comparative genomic analysis of bile acid deconjugation and biotransformation pathways in 693 human gut microbial genomes to expand these AGORA reconstructions accordingly (available athttp://vmh.life).

To elucidate the metabolic potential of individual microbiomes, publicly available metagenomic data from a cohort of healthy Western individuals, as well as two cohorts of IBD patients and healthy controls, were mapped onto the reference set of AGORA genomes. We constructed for each individual a large-scale personalized microbial community model that take strain-level abundances into account. Using flux balance analysis, we found that distinct potential to deconjugate and tranform primary bile acids between the gut microbiomes of healthy individuals. Moreover, the microbiomes of pediatric IBD patients were significantly depleted in their bile acid production potential compared with controls. The contributions of each strain to overall bile acid production potential across individuals were found to be distinct between IBD patients and controls. IBD microbiomes were depleted in contributions of Bacteroidetes strains but enriched in contributions of Proteobacteria. Finally, bottlenecks limiting secondary bile acid production potential were identified in each microbiome model. For ursodeoxycholate, the abundance of strains producing the precursor rather than of strains directly producing this secondary bile acid was synthesis-limiting in certain microbiomes.

In summary, we integrated for the first-time metagenomics data with large-scale personalized metabolic modeling of microbial communities. We provided mechanistic insight into the link between dysbiosis and metabolic potential in IBD microbiomes. This large-scale modeling approach provides a novel way of analyzing metagenomics data to accelerate our understanding of the metabolic interactions between human host and gut microbiomes in health and diseases states.
Evolution of vertical and oblique transmission under fluctuating selection
Authors: Ram Yoav , Liberman Uri , Feldman Marcus W.
Published: December 2017

Vertical and oblique cultural transmission of a dichotomous phenotype is studied under constant, periodic cycling, and randomly fluctuating selection. Conditions are derived for the existence of a stable polymorphism in a periodically cycling selection regime. Under such a selection regime, the fate of a genetic modifier of the rate of vertical transmission depends on the length of the cycle and the strength of selection. In general, the evolutionarily stable rate of vertical transmission differs markedly from the rate that maximizes the geometric mean fitness of the population. The evolution of rules of transmission has dramatically different dynamics from the more frequently studied modifiers of recombination, mutation, or migration.
Laws of concatenated perception: Vision goes for novelty, Decisions for perseverance
Authors: Pascucci D. , Mancuso G. , Santandrea E. , Della Libera C. , Plomp G. , Chelazzi L.
Published: December 2017

Every instant of perception depends on a cascade of brain processes calibrated to the history of sensory and decisional events. In the present work, we show that human visual perception is constantly shaped by two contrasting forces, exerted by sensory adaptation and past decisions. In a series of experiments, we used multilevel modelling and cross-validation approaches to investigate the impact of previous stimuli and responses on current errors in adjustment tasks. Our results revealed that each perceptual report is permeated by opposite biases from a hierarchy of serially dependent processes: low-level adaptation repels perceptionawayfrom previous stimuli; high-level, decisional traces attract perceptual reportstowardprevious responses. Contrary to recent claims, we demonstrated that positive serial dependence does not result fromcontinuity fieldsoperating at the level of early visual processing, but arises from the inertia of decisional templates. This finding is consistent with a Two-process model of serial dependence in which the persistence of read-out weights in a decision unit compensates for sensory adaptation, leading to attractive biases in sequential responses. We propose the first unified account of serial dependence in which functionally distinct mechanisms, operating at different stages, promote the differentiation and integration of visual information over time.
TIMELINE OF BRAIN ALTERATIONS IN ALZHEIMER’S DISEASE ACROSS THE ENTIRE LIFESPAN
Authors: Coupé Pierrick , Manjón José Vicente , Lanuza Enrique , Catheline Gwenaelle ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2017

Brain imaging studies have shown that progressive cerebral atrophy characterized the development of Alzheimer’s Disease (AD). The key question is how long before the diagnosis of AD the neurodegenerative process started leading to these structural alterations. To answer this question, we proposed an innovative way by inferring brain structure volume trajectories across the entire lifespan using massive number of MRI (N=4714). Our study provides evidences of early divergence of the AD model from the control model for the hippocampus before 40 years, followed by the lateral ventricles and the amygdala around 40 years for the AD model. Moreover, our lifespan investigation reveals the dynamic of the evolution of these biomarkers and suggest close abnormality trajectories for the hippocampus and the amygdala. Finally, our results highlight that the temporal lobe atrophy, a key biomarker in AD, is a very early pathophysiological event potentially associated to early life exposures to risk factors.
Regionalization of the nervous system requires axial allocation prior to neural lineage commitment
Authors: Metzis Vicki , Steinhauser Sebastian , Pakanavicius Edvinas , Gouti Mina , Stamataki Despina , Lovell-Badge Robin , Luscombe Nicholas M , Briscoe James
Published: December 2017

Neural induction in vertebrates generates a central nervous system that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity, with caudalising signals then converting a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility assays to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations this identified a developmental time window in which genome-wide chromatin remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This “primary regionalization” allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate central nervous system.
A Multi-Species Functional Embedding Integrating Sequence and Network Structure
Authors: Fan Jason , Cannistra Anthony , Fried Inbar , Lim Tim , Schaffner Thomas , Crovella Mark , Hescott Benjamin , Leiserson Mark D.M.
Published: December 2017

A key challenge to transferring knowledge between species is that different species have fundamentally different genetic architectures. Initial computational approaches to transfer knowledge across species have relied on measures of heredity such as genetic homology, but these approaches suffer from limitations. First, only a small subset of genes have homologs, limiting the amount of knowledge that can be transferred, and second, genes change or repurpose functions, complicating the transfer of knowledge. Many approaches address this problem by expanding the notion of homology by leveraging high-throughput genomic and proteomic measurements, such as through network alignment.

In this work, we take a new approach to transferring knowledge across species by expanding the notion of homology through explicit measures of functional similarity between proteins in different species. Specifically, our kernel-based method, Handl(Homology Assessment across Networks using Diffusion and Landmarks), integrates sequence and network structure to create a functional embedding in which proteins from different species are embedded in the same vector space. We show that inner products in this space capture functional similarity across species, and the vectors themselves are useful for a variety of cross species tasks. We perform the first whole-genome method for predicting phenologs, generating many that were previously identified, but also predicting new phenologs supported from the biological literature. We also demonstrate the Handl-embedding captures pairwise gene function, in that gene pairs with synthetic lethal interactions are co-located in Handl-space both within and across species. Software for the Handl algorithm is available at http://github.com/lrgr/HANDL.
Optogenetics reprogramming of planktonic cells for biofilm formation
Authors: Xia Aiguo , Yang Shuai , Huang Yajia , Jin Zhenyu , Ni Lei , Pu Lu , Yang Guang , Jin Fan
Published: December 2017

Single-cell behaviors play essential roles during early-stage biofilms formation. In this study, we evaluated whether biofilm formation could be guided by precisely manipulating single cells behaviors. Thus, we established an illumination method to precisely manipulate the type IV pili (TFP) mediated motility and microcolony formation of Pseudomonas aeruginosa by using a combination of a high-throughput bacterial tracking algorithm, optogenetic manipulation and adaptive microscopy. We termed this method as Adaptive Tracking Illumination (ATI). We reported that ATI enables the precise manipulation of TFP mediated motility and microcolony formation during biofilm formation by manipulating bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) levels in single cells. Moreover, we showed that the spatial organization of single cells in mature biofilms can be controlled using ATI. Thus, the established method (i.e., ATI) can markedly promote ongoing studies of biofilms.
Observation of DNA intertwining along authentic budding yeast chromosomes
Authors: Mariezcurrena Ainhoa , Uhlmann Frank
Published: December 2017

DNA replication of circular genomes generates physically interlinked or catenated sister DNAs. These are resolved through transient DNA fracture by type II topoisomerases to permit chromosome segregation during cell division. Topoisomerase II is similarly required for linear chromosome segregation, suggesting that linear chromosomes also remain intertwined following DNA replication. Indeed, chromosome resolution defects are a frequent cause of chromosome segregation failure and consequent aneuploidies. When and where intertwines arise and persist along linear chromosomes are not known, owing to the difficulty of demonstrating intertwining of linear DNAs. Here, we used excision of chromosomal regions as circular “loop outs” to convert sister chromatid intertwines into catenated circles. This revealed intertwining at replication termination and cohesin-binding sites, where intertwines are thought to arise and persist but not to a greater extent than elsewhere in the genome. Intertwining appears to spread evenly along chromosomes but is excluded from heterochromatin. We found that intertwines arise before replication termination, suggesting that replication forks rotate during replication elongation to dissipate torsion ahead of the forks. Our approach provides previously inaccessible insight into the topology of eukaryotic chromosomes and illuminates a process critical for successful chromosome segregation.
SIDR: simultaneous isolation and parallel sequencing of genomic DNA and total RNA from single cells
Authors: Han Kyung Yeon , Kim Kyu-Tae , Joung Je-Gun , Son Dae-Soon , Kim Yeon Jeong , Jo Areum , Jeon Hyo-Jeong , Moon Hui-Sung , Yoo Chang Eun , Chung Woosung , Eum Hye Hyeon , Kim Sangmin , Kim Hong Kwan , Lee Jeong Eon , Ahn Myung-Ju , Lee Hae-Ock , Park Donghyun , Park Woong-Yang
Published: December 2017

Simultaneous sequencing of the genome and transcriptome at the single-cell level is a powerful tool for characterizing genomic and transcriptomic variation and revealing correlative relationships. However, it remains technically challenging to analyze both the genome and transcriptome in the same cell. Here, we report a novel method for simultaneous isolation of genomic DNA and total RNA (SIDR) from single cells, achieving high recovery rates with minimal cross-contamination, as is crucial for accurate description and integration of the single-cell genome and transcriptome. For reliable and efficient separation of genomic DNA and total RNA from single cells, the method uses hypotonic lysis to preserve nuclear lamina integrity and subsequently captures the cell lysate using antibody-conjugated magnetic microbeads. Evaluating the performance of this method using real-time PCR demonstrated that it efficiently recovered genomic DNA and total RNA. Thorough data quality assessments showed that DNA and RNA simultaneously fractionated by the SIDR method were suitable for genome and transcriptome sequencing analysis at the single-cell level. The integration of single-cell genome and transcriptome sequencing by SIDR (SIDR-seq) showed that genetic alterations, such as copy-number and single-nucleotide variations, were more accurately captured by single-cell SIDR-seq compared with conventional single-cell RNA-seq, although copy-number variations positively correlated with the corresponding gene expression levels. These results suggest that SIDR-seq is potentially a powerful tool to reveal genetic heterogeneity and phenotypic information inferred from gene expression patterns at the single-cell level.
Impact of regulatory variation across human iPSCs and differentiated cells
Authors: Banovich Nicholas E. , Li Yang I. , Raj Anil , Ward Michelle C. , Greenside Peyton , Calderon Diego , Tung Po Yuan , Burnett Jonathan E. , Myrthil Marsha , Thomas Samantha M. , Burrows Courtney K. , Romero Irene Gallego , Pavlovic Bryan J. , Kundaje Anshul , Pritchard Jonathan K. , Gilad Yoav
Published: December 2017

Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type–specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type–specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type–specific chromatin accessibility.
(2E)-2-[4-(Dimethylamino)benzylidene]-5-methylcyclohexanone
Authors: Jebapriya J. Christina , Reuben Jonathan D. , Prasana Johanan Christian , Usha G.
Published: December 2017

In the title compound, C16H21NO, the cyclohexanone ring adopts a half-chair conformation; the dihedral angle between this ring (all atoms) and the benzene ring is 41.74 (16)°. No directional interactions could be identified in the crystal.
Naphthalene-1-carbaldehyde oxime
Authors: Green Alexander R. , Owczarzak Kendall K. , Thomas Mallory , Olrogg Garrett M. , Whitver Ethan , Crescente Joseph V. , Peters Joshua , Doud Cheyann M. , Storm Mitchell M. , Fink Kathryn D. , Bilotti Caroline , Cardenas Allan Jay
Published: December 2017

The title compound, C11H9NO, crystallizes with two molecules,AandB, with similar conformations (r.m.s. overlay fit = 0.030 Å) in the asymmetric unit: the C—C=N...O torsion angles are −177.8 (3) and −179.1 (3)°. In the crystal, molecules are linked by alternating O—H...N (A→B) and O—H...O (B→A) hydrogen bonds to generate [100] chains. A weak C—H...O interaction is also observed.
Researching the financial abuse of individuals lacking mental capacity
Authors: Dalley Gillian , Gilhooly Mary Lynn , Gilhooly Kenneth , Levi Michael , Harries Priscilla
Published: December 2017

Purpose

The purpose of this paper is to report on the aspects of an exploratory investigation into the scale and nature of the financial abuse of adults lacking mental capacity.

Design/methodology/approach

It uses mixed-methods study which comprises of: a review of safeguarding adults’ statistics; analysis of court case findings; classification of types of financial abuse, victims and perpetrators; qualitative exploration of professional views of the nature of financial abuse of those lacking mental capacity; and a consideration of policy implications.

Findings

It demonstrates the significance of financial abuse within the spectrum of abuse experienced by adults at risk; the wide range of both victims lacking capacity being abused and type of financial abuse; its often hidden nature embedded within the family; and the limitations of processes designed to protect.

Research limitations/implications

The investigation reveals the paucity of statistical data available on the nature of financial abuse and the outcomes of official investigations into reported cases, both of which limit analysis and understanding of the phenomenon.

Practical implications

It demonstrates the need for greater transparency and consistency in the reporting of safeguarding and legal processes to enable practitioners and policymakers to fully understand the nature and significance of this abuse for both victims and society.

Social implications

It questions the extent to which existing protective processes are sufficient in terms of safeguarding victims and deterring perpetrators.

Originality/value

It involves original research that brings together data from a range of sources involved in the protection of a particular hard-to-reach group of individuals (those lacking capacity) from a particular type of risk (financial abuse) of increasing social significance.
Distributed leadership and teacher job satisfaction in Singapore
Authors: García Torres Darlene
Published: December 2017

Purpose

Singapore is a country with low teacher attrition rates and high performance on international assessments (TIMSS 2011/2015 and PISA 2012/2015). Consequently, its education system is often considered as a model for other nations. The purpose of this paper is to extend research on teacher job satisfaction in Singapore and provide comparative information for other education systems.

Design/methodology/approach

This paper presents a secondary analysis of data from the Organization for Economic Cooperation and Development’s 2013 Teaching and Learning International Survey with a focus on relationships among teacher and principal perceptions of distributed leadership and teachers’ job satisfaction in Singapore. Hierarchical linear modeling is applied to investigate teacher job satisfaction with principal perceptions and aggregate teacher perceptions of distributed leadership as school-level (level 2) variables and individual teacher perceptions of distributed leadership as a level 1 variable.

Findings

Results indicated that distributed leadership significantly predicted teachers’ work and professional satisfaction; higher distributed leadership scores were associated with higher satisfaction scores.

Originality/value

The significant positive relationship between distributed leadership and both dimensions of job satisfaction after accounting for individual teacher characteristics is a new finding in the Singapore schooling context.
The financial services industry and society
Authors: Murray Noel , Manrai Ajay K. , Manrai Lalita Ajay
Published: December 2017

Purpose

This paper aims to present an analysis of the role of financial incentives, moral hazard and conflicts of interests leading up to the 2008 financial crisis.

Design/methodology/approach

The study’s analysis has identified common structural flaws throughout the securitization food chain. These structural flaws include inappropriate incentives, the absence of punishment, moral hazard and conflicts of interest. This research sees the full impact of these structural flaws when considering their co-occurrence throughout the financial system. The authors address systemic defects in the securitization food chain and examine the inter-relationships among homeowners, mortgage originators, investment banks and investors. The authors also address the role of exogenous factors, including the SEC, AIG, the credit rating agencies, Congress, business academia and the business media.

Findings

The study argues that the lack of criminal prosecutions of key financial executives has been a key factor in creating moral hazard. Eight years after the Great Recession ended in the USA, the financial services industry continues to suffer from a crisis of trust with society.

Practical implications

An overwhelming majority of Americans, 89 per cent, believe that the federal government does a poor job of regulating the financial services industry (Puzzanghera, 2014). A study argues that the current corporate lobbying framework undermines societal expectations of political equality and consent (Alzola, 2013). The authors believe the Singapore model may be a useful starting point to restructure regulatory agencies so that they are more responsive to societal concerns and less responsive to special interests. Finally, the widespread perception is that the financial services sector, in particular, is ethically challenged (Ferguson, 2012); perhaps there would be some benefit from the implementation of ethical climate monitoring in firms that have been subject to deferred prosecution agreements for serious ethical violations (Arnaud, 2010).

Originality/value

The authors believe the paper makes a truly original contribution. They provide new insights via their analysis of the role of financial incentives, moral hazard and conflicts of interests leading up to the 2008 financial crisis.