bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sonic Hedgehog is a member of the Hh/DD-peptidase family that spans the eukaryotic and bacterial domains of life
Authors: Roelink Henk 
Published: March 2018

AbstractSonic Hedgehog (Shh) coordinates Zn2+ in a manner that resembles that of peptidases. The ability of Shh to undergo autoproteolytic processing is impaired in mutants that affect the Zn2+ coordination, while mutating residues essential for catalytic activity results in more stable forms of Shh. The residues involved in Zn2+ coordination in Shh are found mutated in some individuals with the congenital birth defect holoprosencephaly, demonstrating their importance in development. Highly conserved Shh domains are found a parts of some bacterial proteins that are members of the larger family of DD-peptidases, supporting the notion that Shh acts as a peptidase. Whereas this Hh/DD-peptidase motif is present in Hedgehog (Hh) proteins of nearly all animals, it is not present in Drosophila Hh, indicating that Hh signaling in fruit flies is derived, and perhaps not a good model for vertebrate Shh signaling. Sequence analysis of Hh proteins and their possible evolutionary precursors suggest that the evolution of modern Hh might have involved horizontal transfer of a bacterial gene coding of a Hh/DD-peptidase into a Cnidarian ancestor, recombining to give rise to modern Hh.
Cost of resistance: an unreasonably expensive concept
Authors: Lenormand Thomas , Harmand Noémie , Gallet Romain 
Published: March 2018

AbstractThis preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (https://doi.org/10.24072/pci.evolbiol.100052). The cost of resistance, or the fitness effect of resistance mutation in absence of the drug, is a very widepsread concept in evolutionary genetics and beyond. It has represented an important addition to the simplistic view that resistance mutations should solely be considered as beneficial mutations. Yet, this concept also entails a series of serious difficulties in its definition, interpretation and current usage. In many cases, it may be simpler, clearer, and more insightful to study, measure and analyze the fitness effects of mutations across environments and to better distinguish those effects from ‘pleiotropic effects’ of those mutations.
A streamlined method for transposon mutagenesis ofRickettsia parkeriyields numerous mutations that impact infection
Authors: Lamason Rebecca L. , Kafai Natasha M. , Welch Matthew D. 
Published: March 2018

AbstractThe rickettsiae are obligate intracellular alphaproteobacteria that exhibit a complex infectious life cycle in both arthropod and mammalian hosts. As obligate intracellular bacteria,Rickettsiaare highly adapted to living inside a variety of host cells, including vascular endothelial cells during mammalian infection. Although it is assumed that the rickettsiae produce numerous virulence factors that usurp or disrupt various host cell pathways, they have been challenging to genetically manipulate to identify the key bacterial factors that contribute to infection. Motivated to overcome this challenge, we sought to expand the repertoire of available rickettsial loss-of-function mutants, using an improvedmariner-based transposon mutagenesis scheme. Here, we present the isolation of over 100 transposon mutants in the spotted fever group speciesRickettsia parkeri. These mutants targeted genes implicated in a variety of pathways, including bacterial replication and metabolism, hypothetical proteins, the type IV secretion system, as well as factors with previously established roles in host cell interactions and pathogenesis. Given the need to identify critical virulence factors, forward genetic screens such as this will provide an excellent platform to more directly investigate rickettsial biology and pathogenesis.
Differentiation of Alzheimer’s disease based on local and global parameters in personalized Virtual Brain models
Authors: Zimmermann J , Perry A , Breakspear M , Schirner M , Sachdev P , Wen W , Kochan N.A. , Mapstone M. , Ritter P. , McIntosh A.R. , Solodkin A 
Published: March 2018

AbstractAlzheimer’s disease (AD) is marked by cognitive dysfunction emerging from neuropathological processes impacting brain function. AD affects brain dynamics at the local level, such as changes in the balance of inhibitory and excitatory neuronal populations, as well as long-range changes to the global network. Individual differences in these changes as they relate to behaviour are poorly understood. Here, we use a multi-scale neurophysiological model, “The Virtual Brain (TVB)”, based on empirical multi-modal neuroimaging data, to study how local and global dynamics correlate with individual differences in cognition. In particular, we modeled individual resting-state functional activity of 124 individuals across the behavioral spectrum from healthy aging, to amnesic Mild Cognitive Impairment (MCI), to AD. The model parameters required to accurately simulate empirical functional brain imaging data correlated significantly with cognition, and exceeded the predictive capacity of empirical connectomes.
Magnesium increases homoeologous crossover frequency inZIP4(Ph1) mutant wheat-wild relative hybrids
Authors: Rey María-Dolores , Martín Azahara C. , Smedley Mark , Hayta Sadiye , Harwood Wendy , Shaw Peter , Moore Graham 
Published: March 2018

AbstractWild relatives provide an important source of useful traits in wheat breeding. Wheat and wild relative hybrids have been widely used in breeding programs to introduce such traits into wheat. However, successful introgression is limited by the low frequency of homoeologous crossover (CO) between wheat and wild relative chromosomes. Hybrids between wheat carrying a 70Mb deletion on chromosome 5B (ph1b) and wild relatives, have been exploited to increase the level of homoeologous CO, allowing chromosome exchange between their chromosomes. Inph1b-rye hybrids, CO number increases from a mean of 1 CO to 7 COs per cell. CO number can be further increased up to a mean of 12 COs per cell in theseph1bhybrids by treating the plants with Hoagland solution. More recently, it was shown that the major meiotic crossover geneZIP4on chromosome 5B (TaZIP4-B2) within the 70Mb deletion, was responsible for the restriction of homoeologous COs in wheat-wild relative hybrids, confirming theph1bphenotype as a completeTazip4-B2deletion mutant (Tazip4-B2 ph1b). In this study, we have identified the particular Hoagland solution constituent responsible for the increased chiasma frequency inTazip4-B2 ph1bmutant-rye hybrids and extended the analysis toTazip4-B2TILLING and CRISPR mutant-Ae variabilishybrids. Chiasma frequency at meiotic metaphase I, in the absence of each Hoagland solution macronutrient (NH4H2PO4, KNO3, Ca (NO3)2·4H2O or Mg SO4·7H2O) was analysed. A significant decrease in homoeologous CO frequency was observed when the Mg2+ion was absent. A significant increase of homoeologous CO frequency was observed in all analysed hybrids, when plants were irrigated with a 1mM Mg2+solution. These observations suggest a role for magnesium supplementation in improving the success of genetic material introgression from wild relatives into wheat.
Slow peak alpha frequency and corticomotor depression linked to high pain susceptibility in transition to sustained pain
Authors: Seminowicz DA , Thapa T , Furman AJ , Summers SJ , Cavaleri R , Fogarty JS , Steiner GZ , Schabrun SM 
Published: March 2018

AbstractMechanisms that predict an individual’s susceptibility to pain, before pain is present or in the first few days following pain onset, are unknown. We utilised a clinically-relevant human transitional pain model (intramuscular injections of nerve growth factor) to examine brain mechanisms that predict pain susceptibility. Resting state EEG and corticomotor excitability measured by TMS were evaluated longitudinally in healthy individuals as pain developed and resolved over 21 days. Whereas pre-pain central peak alpha frequency (PAF) correlated with peak pain occurring 4-6 days later, altered corticomotor excitability developed several days after pain onset and showed two distinct patterns (facilitation, depression). Individuals with combined slow PAF and corticomotor depression developed more severe pain. These data provide the first evidence of the temporal profile of key brain mechanisms as pain progressively develops. PAF and corticomotor excitability could represent biomarkers for susceptibility to high pain severity and subsequently, the development of chronic pain.
A systematic study of repetitive transcranial magnetic stimulation to enhance working memory manipulation abilities
Authors: Beynel L. , Davis S.W. , Crowell C.A. , Hilbig S.A. , Lim W. , Nguyen D. , Peterchev A.V. , Luber B. , Lisanby S.H. , Cabeza R. , Appelbaum L.G. 
Published: March 2018

AbstractA core element of human working memory (WM) is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. Given the profound importance of such WM manipulation (WM-M) abilities, there is a concerted effort aimed at developing approaches to improve them. Past research has identified neural substrates of WM-M centered in the dorsolateral prefrontal cortex (DLPFC), thereby providing a plausible and accessible target for noninvasive neuromodulatory stimulation that can be used to alter cortical excitability and potentially lead to facilitation of WM-M. In the current study, 5Hz online repetitive transcranial magnetic stimulation (rTMS), applied over the left DLPFC, was used to test the hypothesis that active rTMS would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in the WM-M conditions with the highest cognitive demand (registered Clinical Trial: #NCT02767323). Participants performed a delayed response alphabetization task with three individually-titrated levels of difficulty during active and sham rTMS. Analyses revealed that active rTMS led to numerically greater accuracy relative to sham stimulation for the hardest condition; however, this effect did not survive Bonferroni correction over all task conditions. Despite the lack of robust, study-wise significant effects, when considered in isolation, the magnitude of behavioral improvement in the hardest condition was negatively correlated with parametric difficulty-related fMRI activity in the targeted brain region, suggesting that individuals with less activation benefit more from rTMS. The present findings therefore suggest evidence towards the hypothesis that active rTMS can enhance performance during difficult memory manipulation conditions; however, firm conclusions cannot be drawn given the lack of overall significant effects. These findings are discussed in the context of individualized targeting and other factors that might moderate rTMS effects.
Non-Random Mis-Segregation of Human Chromosomes
Authors: Worrall J. T. , Tamura N. , Shaikh N. , Mazzagatti A. , van Lingen T. , Bakker B. , Spierings D. C. J. , Vladimirou E. , Foijer F. , McClelland S. E. 
Published: March 2018

SummaryRecurrent patterns of chromosomal changes (aneuploidy) are widespread in cancer. These patterns are mainly attributed to selection processes due to an assumption that human chromosomes carry equal chance of being mis-segregated into daughter cells when fidelity of cell division is compromised. Human chromosomes vary widely in size, gene density and other parameters that might generate bias in mis-segregation rates, however technological limitations have precluded a systematic and high throughput analysis of chromosome-specific aneuploidy. Here, using fluorescenceIn-Situhybridization (FISH) imaging of specific centromeres coupled with high-throughput single cell analysis, as well as single-cell sequencing we show that human chromosome mis-segregation is non-random. Merotelic kinetochore attachment induced by nocodazole washout leads to elevated aneuploidy of a subset of chromosomes, and high rates of anaphase lagging of chromosomes 1 and 2. Mechanistically, we show that these chromosomes are prone to cohesion fatigue that results in anaphase lagging upon release from nocodazole or Eg5 inhibition. Our findings suggest that inherent properties of specific chromosomes can influence chromosome mis-segregation and aneuploidy, with implications for studies on aneuploidy in human disease.
The RNA polymerase clamp interconverts dynamically among three states and is stabilized in a partly closed state by ppGpp
Authors: Duchi Diego , Mazumder Abhishek , Malinen Anssi M. , Ebright Richard H. , Kapanidis Achillefs N. 
Published: March 2018

ABSTRACTRNA polymerase (RNAP) contains a mobile structural module, the “clamp,” that forms one wall of the RNAP active-center cleft and that has been linked to crucial aspects of the transcription cycle, including loading of promoter DNA into the RNAP active-center cleft, unwinding of promoter DNA, transcription elongation complex stability, transcription pausing, and transcription termination. Crystal structures and single-molecule FRET studies establish that the clamp can adopt open and closed conformational states; however, the occurrence, pathway, and kinetics of transitions between clamp states have been unclear. Using single-molecule FRET (smFRET) on surface-immobilized RNAP molecules, we show that the clamp in RNAP holoenzyme exists in three distinct conformational states: the previously defined open state, the previously defined closed state, and a previously undefined partly closed state. smFRET time-traces show dynamic transitions between open, partly closed, and closed states on the 0.1-1 second time-scale. Similar analyses of transcription initiation complexes confirm that the RNAP clamp is closed in the catalytically competent transcription initiation complex and in initial transcribing complexes (RPITC), including paused initial transcribing complexes, and show that, in these complexes, in contrast to in RNAP holoenzyme, the clamp does not interconvert between the closed state and other states. The stringent-response alarmone ppGpp selectively stabilizes the partly-closed-clamp state, inhibiting interconversion between the partly closed state and the open state. The methods of this report should allow elucidation of clamp conformation and dynamics during all phases of transcription.SIGNIFICANCE STATEMENTThe clamp forms a pincer of the RNA polymerase “crab-claw” structure, and adopts many conformations with poorly understood function and dynamics. By measuring distances within single surface-attached molecules, we observe directly the motions of the clamp and show that it adopts an open, a closed, and a partly closed state; the last state is stabilized by a sensor of bacterial starvation, linking the clamp conformation to the mechanisms used by bacteria to counteract stress. We also show that the clamp remains closed in many transcription steps, as well as in the presence of a specific antibiotic. Our approach can monitor clamp motions throughout transcription and offers insight on how antibiotics can stop pathogens by blocking their RNA polymerase movements.
The TRPC6-AMPK pathway is involved in cytoskeleton reorganization and glucose uptake in podocytes
Authors: Rachubik Patrycja , Szrejder Maria , Rogacka Dorota , Audzeyenka Irena , Rychłowski Michał , Angielski Stefan , Piwkowska Agnieszka 
Published: March 2018

AbstractPodocytes are dynamic polarized cells on the surface of glomerular capillaries that are an essential part of the glomerular filtration barrier. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes and are involved in regulating glomerular filtration barrier. Here we investigated whether the AMPK-TRPC6 pathway is involved in insulin-dependent cytoskeleton reorganization and glucose uptake in cultured rat podocytes. Insulin regulates the interaction of TRPC6 with AMPKα2 in cultured rat podocytes The results suggested a key role for the TRPC6 channel in the mediation of insulin-dependent activation of AMPKα2, actin cytoskeleton reorganization and glucose uptake in podocyte. Moreover, AMPK and TRPC6 activation were required to stimulate the Rac1 signaling pathway. These results suggest a potentially important new mechanism that regulates glucose transport in podocytes and that could be injurious during diabetes.
Expansion stimulated emission depletion microscopy (ExSTED)
Authors: Gao Mengfei , Maraspini Riccardo , Beutel Oliver , Zehtabian Amin , Eickholt Britta , Honigmann Alf , Ewers Helge 
Published: March 2018

AbstractStimulated emission depletion (STED) microscopy is routinely used to resolve the ultra-structure of cells with a ∼10-fold higher resolution compared to diffraction limited imaging. While STED microscopy is based on preparing the excited state of fluorescent probes with light, the recently developed expansion microscopy (ExM) provides sub-diffraction resolution by physically enlarging the sample before microscopy. Expansion of fixed cells by crosslinking and swelling of hydrogels easily enlarges the sample ∼4-fold and hence increases the effective optical resolution by this factor. To overcome the current limits of these complimentary approaches, we here combined ExM with STED (ExSTED) and demonstrate an increase in resolution of up to 30-fold compared to conventional microscopy (<10 nm lateral and ∼50 nm isotropic). While the increase in resolution is straight forward, we found that high fidelity labelling via multi-epitopes is required to obtain emitter densities that allow to resolve ultra-structural details with ExSTED. Our work provides a robust template for super resolution microscopy of entire cells in the ten nanometer range.
Volvox barberi flocks, forming near-optimal, two-dimensional, polydisperse lattice packings
Authors: Balasubramanian Ravi Nicholas 
Published: March 2018

AbstractVolvox barberi is a multicellular green alga forming spherical colonies of 10000-50000 differentiated somatic and germ cells. Here, I show that these colonies actively self-organize over minutes into “flocks” that can contain more than 100 colonies moving and rotating collectively for hours. The colonies in flocks form two-dimensional, irregular, “active crystals”, with lattice angles and colony diameters both following log-normal distributions. Comparison with a dynamical simulation of soft spheres with diameters matched to the Volvox samples, and a weak long-range attractive force, show that the Volvox flocks achieve optimal random close-packing. A dye tracer in the Volvox medium revealed large hydrodynamic vortices generated by colony and flock rotations, providing a likely source of the forces leading to flocking and optimal packing.
Quantifying the impact of a periodic presence of antimicrobial on resistance evolution in a homogeneous microbial population of fixed size
Authors: Marrec Loïc , Bitbol Anne-Florence 
Published: March 2018

AbstractThe evolution of antimicrobial resistance often occurs in a variable environment, as antimicrobial is given periodically to a patient or added and removed from a medium. This environmental variability has a huge impact on the microorganisms’ fitness landscape, and thus on the evolution of resistance. Indeed, mutations conferring resistance often carry a fitness cost in the absence of antimicrobial, which may be compensated by subsequent mutations. As antimicrobial is added or removed, the relevant fitness landscape thus switches from a fitness valley to an ascending landscape or vice-versa.Here, we investigate the effect of these time-varying patterns of selection within a stochastic model. We focus on a homogeneous microbial population of fixed size subjected to a periodic alternation of phases of absence and presence of an antimicrobial that stops growth. Combining analytical approaches and stochastic simulations, we quantify how the time necessary for fit resistant bacteria to take over the microbial population depends on the period of the alternations. We demonstrate that fast alternations strongly accelerate the evolution of resistance, and that a plateau is reached once the period gets sufficiently small. Besides, the acceleration of resistance evolution is stronger for larger populations. For asymmetric alternations, featuring a different duration of the phases with and without antimicrobial, we shed light on the existence of a broad minimum of the time taken by the population to fully evolve resistance. At this minimum, if the alternations are sufficiently fast, the very first resistant mutant that appears ultimately leads to full resistance evolution within the population. This dramatic acceleration of the evolution of antimicrobial resistance likely occurs in realistic situations, and can have an important impact both in clinical and experimental situations.
OMCD: OncoMir Cancer Database
Authors: Sarver Aaron , Sarver Anne , Yuan Ce , Subramanian Subbaya 
Published: March 2018

AbstractMicroRNAs (miRNAs) are crucially important in the development of cancer. Their dysregulation, commonly observed in various types of cancer, is largely cancer-dependent. Thus, to understand the tumor biology and to develop accurate and sensitive biomarkers, we need to understand pan-cancer miRNA expression. At the University of Minnesota, we developed the OncoMir Cancer Database (OMCD), hosted on a web server, which allows easy and systematic comparative genomic analyses of miRNA sequencing data derived from more than 9,500 cancer patients tissue samples available in the Cancer Genome Atlas (TCGA). OMCD includes associated clinical information and is searchable by organ-specific terms common to the TCGA. Freely available to all users (www.oncomir.umn.edu/omcd/), OMCD enables (1) simple visualization of TCGA miRNA sequencing data, (2) statistical analysis of differentially expressed miRNAs for each cancer type, and (3) exploration of miRNA clusters across cancer types.Database URLwww.oncomir.umn.edu/omcd
Organ-specific translation elongation rates measured by in vivo ribosome profiling
Authors: Gerashchenko Maxim V. , Peterfi Zalan , Gladyshev Vadim N. 
Published: March 2018

Protein synthesis and degradation are intricate biological processes involving more than a hundred proteins operating in a highly orches-trated fashion. Despite the progress, few options are available to access translation in live animals as the increase in animal’s complexity limits the repertoire of experimental tools that could be applied to observe and manipulate processes within animal’s body, organs, and individual cells. It this study, we developed a labeling-free method for measuring organ- and cell-type specific translation elongation rates. It is based on a time-resolved delivery of translation initiation and elongation inhibitors in live animals followed by ribosome profiling. It also reports translation initiation sites in an organ-specific manner. Using this method, we found that the elongation rates differ among mouse organs and determined them to be 6.8, 5.2, and 4.4 amino acids per sec for liver, kidney, and skeletal muscle, respectively.SignificanceProtein synthesis is a vital biological process. Modern methods of genome editing enable generation of sophisticated animal models to study the regulation of protein synthesis in health end disease. However, the methods that could track various steps of translation at a gene level resolutionin vivoare lacking, particularly in complex vertebrates, such as mice and rats. Here, we measured the translation elongation rate in several organs by delivering inhibitors specific to certain phases of translation directly through the mouse bloodstream. This study lays out a path for interrogating translation in animals in response to various genetic and dietary interventions.