bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies on Biochemical Changes and Prolactin Level Evaluation in Patients with Chronic Kidney Disease
Authors: Rahman Foyzur , Kabir Faisal , Rezwan Sawgat
Published: June 2019

Background

Chronic kidney disease (CKD) is progressive loss in kidney function over a period of months or years. CKD is an internationally recognized public health problem affecting 5–10% of the world population and day-by-day the number of cases are increasing at an alarming rate. In CKD, raised levels of prolactin in blood may cause vascular derangements which might lead to worse cardiovascular consequences in CKD patients.

Objectives

To assess serum creatinine, hemoglobin (Hb), urea, red blood cell (RBC), protein creatinine ratio (PCR) and prolactin in CKD patients.

Material and Methods

This study included 110 patients, 61 were males and 49 were females and their age range 1 to more than 60 years. The control group also consisted of same number of participants as the patients; who were free from signs and symptoms of kidney disease and prolactin hormone disorders.

Results

The study shows that all the biochemical parameters in CKD patients were found to be significantly high compared with control group (P<0.001). Serum prolactin concentrations in CKD patients were also increased significantly compared with control group (P≤ 0.05). It was found that level of prolactin hormone secretion was higher in male CKD patients than male control.

Conclusion

Although males are more prone to chronic kidney disease, but the percentage of females is not negligible. All the biochemical parameters and prolactin level changed significantly in the CKD patients. It is interesting that in case of CKD, male’s prolactin secretion becomes higher.
SPsimSeq: semi-parametric simulation of bulk and single cell RNA sequencing data
Authors: Assefa Alemu Takele , Vandesompele Jo , Thas Olivier
Published: June 2019

SPsimSeq is a semi-parametric simulation method for bulk and single cell RNA sequencing data. It simulates data from a good estimate of the actual distribution of a given real RNA-seq dataset. In contrast to existing approaches that assume a particular data distribution, our method constructs an empirical distribution of gene expression data from a given source RNA-seq experiment to faithfully capture the data characteristics of real data. Importantly, our method can be used to simulate a wide range of scenarios, such as single or multiple biological groups, systematic variations (e.g. confounding batch effects), and different sample sizes. It can also be used to simulate different gene expression units resulting from different library preparation protocols, such as read counts or UMI counts.

Availability and implementation

The R package and associated documentation is available from https://github.com/CenterForStatistics-UGent/SPsimSeq.

Supplementary information

Supplementary data are available at bioRχiv online.
A temporal map of gene expression pattern during zebrafish liver regeneration
Authors: Jagtap Urmila , Sivadas Ambily , Basu Sandeep , Verma Ankit , Sivasubbu Sridhar , Scaria Vinod , Sachidanandan Chetana
Published: June 2019

Background & Aims

Zebrafish is increasingly being used to study liver injury and regeneration. However, very little is known about molecular players that respond to injury and participate in liver regeneration. Here we aim to generate a temporal map of gene expression changes at injury and during regeneration of the adult zebrafish liver.

Methods

We use a metronidazole-nitroreductase (MTZ-nfsb) based system to selectively ablate hepatocytes in adult zebrafish to create a model for liver injury and regeneration. Through RNA sequencing of liver samples at multiple time points we generate a comprehensive temporal map of gene expression changes during injury and regeneration.

Results

Gene expression reveals that soon after injury the immediate early transcription factor MYC induces a battery of genes that respond to the metronidazole-induced ROS by activating oxido-reductase pathways and apoptosis machinery. Upon injury, liver cells down regulate genes encoding complement proteins, bile acid and lipid biosynthesis pathway in a concerted manner. Midway through regeneration, we discover a spike of cholesterol biosynthesis and protein folding machinery genes suggesting an important role for these pathways in liver regeneration.

Conclusions

The temporal transcriptomic map of liver regeneration would serve as a framework for further studies in understanding, and for screening for compounds that augment liver regeneration.

General significance

Using a hepatocyte specific ablation of zebrafish liver, we create a model of adult liver regeneration. This model was used to generate a comprehensive transcriptomic map of gene expression trends during liver regeneration. This temporal map lays the groundwork to study important events in liver regeneration.

Highlights

Zebrafish is a valuable model for developing therapeutic strategies to augment liver regeneration

Liver regeneration in zebrafish is not well studied and pathways poorly understood

We develop a hepatocyte ablation model of liver injury and regeneration in adult zebrafish

We generate a comprehensive transcriptomic map of various stages of liver injury and regeneration

We discover a novel regulation of cholesterol biosynthesis pathways during liver regeneration

Graphical abstract
Biomechanical Analysis of Angular Motion in Association with Bilateral Semicircular Canal Function
Authors: Shen Shuang , Zhao Fei , Chen Zhaoyue , Zheng Qingyin , Yu Shen , Cao Tongtao , Ma Peng
Published: June 2019

The aim of this study was to develop a finite element (FE) model of bilateral human semicircular canals (SCCs) in order to simulate and analyze the complex fluid-structural interaction between the endolymph and cupulae by calculating the degree of cupular expansion and the cupular deflection. The results showed that cupular deflection responses were consistent with Ewald’s II law, whereas each pair of bilateral cupulae simultaneously expanded or compressed to the same degree. In addition, both the degree of cupular expansion and cupular deflection can be expressed as the solution of forced oscillation during head sinusoidal rotation, and the amplitude of cupular expansion was approximately two times greater than that of cupular deflection. Regarding the amplitude-frequency and phase-frequency characteristics, the amplitude ratios among the horizontal semicircular canal (HC) cupular expansion, the anterior semicircular canal (AC) cupular expansion, and the posterior semicircular canal (PC) cupular expansion was constant at 1:0.82:1.62, and the phase differences among them were constant at 0 or 180 degrees at the frequencies of 0.5 to 6 Hz. However, both the amplitude ratio and the phase differencies of the cupular deflection incresed nonlinearly with the increase of frequency and tended to be constant at the frequency band between 2 and 6 Hz. The results indicate that the responses of cupular expansion might only be related to the mass and rigidity of three cupulae and the endolymph, but the responses of cupular deflection are related to the mass, rigidity, or damping of them, and these physical properties would be affected by vestibular dysfunction. Therefore, both the degree of cupular expansion and cupular deflection should be considered important mechanical variables for induced neural signals. Such a numerical model can be further built to provide a useful theoretical approach for exploring the biomechanical nature underlying vestibular dysfunction.

Statement of significance

By taking the advantage of the torsional pendulum model and the FE model, a healthy human vestibular SCCs was developed to investigate the angular motion in association with SCC function. As a result, the responses of cupular expansion and deflection during head horizontal sinusoidal rotation were analyzed for the first time, showing quantitative correlation to the eye movement due to the vestibular ocular reflex (VOR) pathway. These responses play important roles in the cupular mechano-electrical transduction process. The significant outcome derived from this study provides a useful theoretical approach for further exploring the biomechanical nature underlying vestibular dysfunction.
Rho-kinase mediates the anorexigenic action of melanocortin by suppressing AMPK
Authors: Kim Sang Soo , Hwang Won Min , Yang Won-Mo , Lee Hyon , Park Kyong Soo , Dagon Yossi , Kim Young-Bum
Published: June 2019

Objective

Melanocortin action is essential for the maintenance of energy homeostasis. However, knowledge of the signaling mechanism(s) that mediates the effect of melanocortin remains incomplete.

Methods

ROCK1 is a key regulator of energy balance in the hypothalamus. To explore the role of ROCK1 in the anorexigenic action of melanocortin, we deleted ROCK1 in MC4R neurons in mice. Next, we studied the metabolic effects of MC4R neuron-specific ROCK1-deficiency and following treatment with α-melanocyte-stimulating hormone (MSH).

Results

Here we show that α-MSH increases Rho-kinase 1 (ROCK1) activity in the hypothalamus. Deficiency of ROCK1 in MC4R-expressing neurons results in increased body weight in mice fed normal chow diet. This is likely due to increased food intake and decreased energy expenditure. Importantly, we find that ROCK1 activation in MC4R expressing neurons is required for melanocortin action, as evidenced by the fact that α– MSH’s ability to suppress food intake is impaired in MC4R neuron-specific ROCK1-deficient mice. To elucidate the mechanism by which ROCK1 mediates melanocortin action, we performedin vitrostudies in hypothalamic cells expressing MC4R. We demonstrate that α–MSH promotes the physical interaction of ROCK1 and Gα12, and this results in suppression of AMPK activity.

Conclusions

Our study identifies ROCK1 as a novel mediator of melanocortin’s anorexigenic action and uncover a new MC4R→Gα12→ROCK1→AMPK signaling pathway. Targeting Rho-kinase in MC4R-expressing neurons could provide a new strategy to combat obesity and its related complications.
Temporal distribution of deleterious variations influences the estimation of FST
Authors: Subramanian Sankar
Published: June 2019

Estimating the extent of genetic differentiation between populations is an important measure in population genetics, ecology and evolutionary biology. Fixation index or FST is an important measure, which is routinely used to quantify this. Previous studies have shown that FST estimated for selectively constrained regions was significantly lower than that estimated for neutral regions. By deriving the theoretical relationship between FST at neutral and constrained sites we show that an excess in the fraction of deleterious variations segregating within populations compared to that segregates between populations is the cause for the reduction in FST estimated at constrained sites. Using whole genome data, our results revealed that the magnitude of reduction in FST estimates obtained for selectively constrained regions was much higher for distantly related populations compared to those estimated for closely related pairs. For example, the reduction was 49% for comparison between European-African populations, 31% for European-Asian comparison, 16% for the Northern-Southern European pair and only 4% for the comparison involving two Southern European (Italian and Spanish) populations. Since deleterious variants are purged over time due to purifying selection, their contribution to the among population diversity at constrained sites decreases with the increase in the divergence between populations. However, within population diversity remain the same for all pairs compared above and therefore FST estimated at constrained sites for distantly related populations are much smaller than those estimated for closely related populations. Our results suggest that the level of population divergence should be considered when comparing constrained site FST estimates obtained for different pairs of populations.
Genome-wide sequence information reveals recurrent hybridization among diploid wheat wild relatives
Authors: Bernhardt Nadine , Brassac Jonathan , Dong Xue , Willing Eva-Maria , Poskar C. Hart , Kilian Benjamin , Blattner Frank R.
Published: June 2019

Many conflicting hypotheses regarding the relationships among crops and wild species closely related to wheat (the generaAegilops,Amblyopyrum, andTriticum) have been postulated. The contribution of hybridization to the evolution of these taxa is intensely discussed. To determine possible causes for this, and provide a phylogeny of the diploid taxa based on genome-wide sequence information, independent data was obtained from genotyping-by-sequencing and a target-enrichment experiment that returned 244 low-copy nuclear loci. The data were analyzed with Bayesian, likelihood and coalescent-based methods.Dstatistics were used to test if incomplete lineage sorting alone or together with hybridization is the source for incongruent gene trees. Here we present the phylogeny of all diploid species of the wheat wild relatives. We hypothesize that most of the wheat-group species were shaped by a primordial homoploid hybrid speciation event involving the ancestralTriticumandAm. muticumlineages to form all other species butAe. speltoides. This hybridization event was followed by multiple introgressions affecting all taxa butTriticum. Mostly progenitors of the extant species were involved in these processes, while recent interspecific gene flow seems insignificant. The composite nature of many genomes of wheat group taxa results in complicated patterns of diploid contributions when these lineages are involved in polyploid formation, which is, for example, the case in the tetra-and hexaploid wheats. Our analysis provides phylogenetic relationships and a testable hypothesis for the genome compositions in the basic evolutionary units within the wheat group of Triticeae.
Predicting dysfunctional age-related task activations from resting-state network alterations
Authors: Mill Ravi D. , Gordon Brian A. , Balota David A. , Zacks Jeffrey M. , Cole Michael W.
Published: June 2019

Alzheimer’s disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the timecourse of illness. Study of these fMRI correlates of unhealthy aging has been conducted in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC network alterations associated with Alzheimer’s disease disrupt the ability for activations to flow between brain regions, leading to aberrant task activations. We apply this activity flow modeling framework in a large sample of clinically unimpaired older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) risk factors for AD. We identified healthy task activations in individuals at low risk for AD, and then by estimating activity flow using at-risk AD restFC data we were able to predict the altered at-risk AD task activations. Thus, modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy aged activations. These results provide evidence that activity flow over altered intrinsic functional connections may act as a mechanism underlying Alzheimer’s-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights linking restFC with cognitive task activations, this approach has potential clinical utility as it enables prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks.

Significance Statement

Developing analytic approaches that can reliably predict features of Alzheimer’s disease is a major goal for cognitive and clinical neuroscience, with particular emphasis on identifying such diagnostic features early in the timeline of disease. We demonstrate the utility of an activity flow modeling approach, which predicts fMRI cognitive task activations in subjects identified as at-risk for Alzheimer’s disease. The approach makes activation predictions by transforming a healthy aged activation template via the at-risk subjects’ individual pattern of fMRI resting-state functional connectivity (restFC). The observed prediction accuracy supports activity flow as a mechanism linking age-related alterations in restFC and task activations, thereby providing a theoretical basis for incorporating restFC into imaging biomarker and personalized medicine interventions.
Emergence of alternative stable states in microbial communities in a fluctuating environment
Authors: Andersen Woltz Vilhelm L. , Abreu Clare I. , Friedman Jonathan , Gore Jeff
Published: June 2019

The effect of environmental fluctuations is a major question in ecology. While it is widely accepted that fluctuations and other types of disturbances can increase biodiversity, we have only a limited understanding of the circumstances in which other types of outcomes can occur in a fluctuating environment. Here we explore this question with laboratory microcosms, using cocultures of two bacterial species, P. putida and P. veronii. At low dilution rates we observe competitive exclusion of P. veronii, whereas at high dilution rates we observe competitive exclusion of P. putida. When the dilution rate alternates between high and low, we do not observe coexistence between the species, but rather alternative stable states, in which only one species survives and initial species’ fractions determine the identity of the surviving species. The Lotka-Volterra model with a fluctuating mortality rate predicts that this outcome is independent of the timing of the fluctuations, and that the time-averaged mortality would also lead to alternative stable states, a prediction that we confirm experimentally. Other pairs of species can coexist in a fluctuating environment, and again consistent with the model we observe coexistence in the time-averaged dilution rate. We find a similar time-averaging result holds in a three-species community, highlighting that simple linear models can in some cases provide powerful insight into how communities will respond to environmental fluctuations.
Precise Coordination of 3-dimensional Rotational Kinematics by Ventral Tegmental Area GABAergic Neurons
Authors: Hughes Ryan N. , Watson Glenn D.R. , Petter Elijah , Kim Namsoo , Bakhurin Konstantin I. , Yin Henry H.
Published: June 2019

The Ventral Tegmental Area (VTA) is a midbrain region implicated in a variety of motivated behaviors. However, the function of VTA GABAergic (Vgat+) neurons remains poorly understood. Here, using 3D motion capture, in vivo electrophysiology and calcium imaging, and optogenetics, we demonstrate a novel function of VTAVgat+ neurons. We found three distinct populations of neurons, each representing head angle about a principal axis of rotation: pitch, roll, and yaw. For each axis, opponent cell groups were found that increase firing when the head moves in one direction, and decrease firing in the opposite direction. Selective excitation and inhibition of VTAVgat+ neurons generate opposite rotational movements. The relationship between these neurons and head angle is degraded only at the time of reward consumption, at which point all head-angle related neuronal subpopulations show indistinguishable reward-related responses. Thus, VTAVgat+ neurons serve a critical role in the control of rotational kinematics while pursuing a moving target. This general-purpose steering function can guide animals toward desired spatial targets in any motivated behavior.
Persister Cells Resuscitate via Ribosome Modification by 23S rRNA Pseudouridine Synthase RluD
Authors: Song Sooyeon , Wood Thomas K.
Published: June 2019

Upon a wide range of stress conditions (e.g., nutrient, antibiotic, oxidative), a subpopulation of bacterial cells known as persisters survive by halting metabolism. These cells resuscitate rapidly to reconstitute infections once the stress is removed and nutrients are provided. However, how these dormant cells resuscitate is not understood well but involves reactivating ribosomes. By screening 10,000 compounds directly for stimulatingEscherichia colipersister cell resuscitation, we identified that 2-{[2-(4-bromophenyl)-2-oxoethyl]thio}-3-ethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (BPOET) stimulates resuscitation. Critically, by screening 4,267E. coliproteins, we determined that BPOET activates hibernating ribosomes via 23S rRNA pseudouridine synthase RluD, which increases ribosome activity. Corroborating the increased waking with RluD, production of RluD increased the number of active ribosomes in persister cells. Also, inactivating the small RNA RybB which repressesrluDled to faster persister resuscitation. Hence, persister cells resuscitate via activation of RluD.
Single-cell entropy to quantify the cellular transcriptome from single-cell RNA-seq data
Authors: Liu Jingxin , Song You , Lei Jinzhi
Published: June 2019

We present the use of single-cell entropy (scEntropy) to measure the order of the cellular transcriptome profile from single-cell RNA-seq data, which leads to a method of unsupervised cell type classification through scEntropy followed by the Gaussian mixture model (scEGMM). scEntropy is straightforward in defining an intrinsic transcriptional state of a cell. scEGMM is a coherent method of cell type classification that includes no parameters and no clustering; however, it is comparable to existing machine learning-based methods in benchmarking studies and facilitates biological interpretation.
Conjugative delivery of CRISPR-Cas9 for the selective depletion of antibiotic-resistant enterococci
Authors: Rodrigues Marinelle , McBride Sara W. , Hullahalli Karthik , Palmer Kelli L. , Duerkop Breck A.
Published: June 2019

The innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiontEnterococcus faecalisis associated with HAIs and some strains are MDR. Therefore, novel strategies to controlE. faecalispopulations are needed. We previously characterized anE. faecalisType II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers toE. faecalisfor the selective removal of antibiotic resistance genes. Usingin vitrocompetition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistantE. faecalisby several orders of magnitude. Finally, we show thatE. faecalisdonor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinantsin vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.

Importance

CRISPR-Cas nucleic acid targeting systems hold promise for the amelioration of multidrug-resistant enterococci, yet the utility of such tools in the context of the intestinal environment where enterococci reside is understudied. We describe the development of a CRISPR-Cas antimicrobial, deployed on a conjugative plasmid, for the targeted removal of antibiotic resistance genes from intestinalEnterococcus faecalis. We demonstrate that CRISPR-Cas targeting reduces antibiotic resistance ofE. faecalisby several orders of magnitude in the intestine. Although barriers exist that influence the penetrance of the conjugative CRISPR-Cas antimicrobial among target recipientE. faecaliscells, the removal of antibiotic resistance genes inE. faecalisupon uptake of the CRISPR-Cas antimicrobial is absolute. In addition, cells that obtain the CRISPR-Cas antimicrobial are immunized against the acquisition of new antibiotic resistance genes. This study suggests a potential path toward plasmid based CRISPR-Cas therapies in the intestine.
Engineering an Enzyme for Direct Electrical Monitoring of Activity
Authors: Zhang Bintian , Deng Hanqing , Mukherjee Sohini , Song Weisi , Wang Xu , Lindsay Stuart
Published: June 2019

Proteins have been shown to be electrically-conductive if tethered to an electrode by means of a specific binding agent, allowing single molecules to be wired into an electrical sensing circuit. This development opens the possibility of exploiting the remarkable chemical versatility of enzymes as sensors, detectors and sequencing devices. We have engineered contact points into a Φ29 polymerase by introducing biotinylatable peptide sequences. The modified enzyme was bound to electrodes functionalized with streptavidin. Φ29 connected by one biotinylated contact and a second non-specific contact showed rapid small fluctuations in current when activated. Signals were greatly enhanced with two specific contacts. Features in the distributions of DC conductance increased by a factor 2 or more over the open-to closed conformational transition of the polymerase. Polymerase activity is manifested by rapid (millisecond) large (25% of background) current fluctuations imposed on the DC conductance.
Highly Multiplexed Spatial Mapping of Microbial Communities
Authors: Shi Hao , Zipfel Warren , Brito Ilana , De Vlaminck Iwijn
Published: June 2019

Mapping the complex biogeography of microbial communities in situ with high taxonomic and spatial resolution poses a major challenge because of the high density and rich diversity of species in environmental microbiomes and the limitations of optical imaging technology. Here, we introduce High Phylogenetic Resolution microbiome mapping by Fluorescence In-Situ Hybridization (HiPR-FISH), a versatile and cost-effective technology that uses binary encoding and spectral imaging and machine learning based decoding to create micron-scale maps of the locations and identities of hundreds of microbial species in complex communities. We demonstrate the ability of 10-bit HiPR-FISH to distinguish 1023 E. coli strains, each fluorescently labeled with a unique binary barcode. HiPR-FISH, in conjunction with custom algorithms for automated probe design and segmentation of single-cells in the native context of tissues, reveals the intricate spatial architectures formed by bacteria in the human oral plaque microbiome and disruption of spatial networks in the mouse gut microbiome in response to antibiotic treatment. HiPR-FISH provides a framework for analyzing the spatial organization of microbial communities in tissues and the environment at single cell resolution.
A likelihood approach for uncovering selective sweep signatures from haplotype data
Authors: Harris Alexandre M. , DeGiorgio Michael
Published: June 2019

Selective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverage the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statisticTto probe whole genome polymorphism datasets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that theTstatistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied theTstatistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, includingLCT, RSPH3, andZNF211in CEU,SYT1, RGS18, andNNTin YRI, andHLAgenes in both populations. We also searched for sweep signatures inDrosophila melanogaster, finding expected candidates at Ace,Uhg1, andPimet. Finally, we provide open-source software to compute theTstatistic and the inferred number of presently sweeping haplotypes from whole-genome data.
Compositional heterogeneity confers selective advantage to protocellular membranes during the origins of cellular life
Authors: Sarkar Susovan , Dagar Shikha , Verma Ajay , Rajamani Sudha
Published: June 2019

Protocells are primitive cellular entities that are thought to have emerged during the dawn of life on Earth. Their membranes are considered to be made up of mixtures of single chain amphiphiles, such as fatty acids and their derivatives, moieties that would have been part of the complex prebiotic chemical landscape. In addition to their composition, the physico-chemical properties of these prebiological membranes would have been significantly affected and regulated by the physical environment that they were present in. In this study, the physico-chemical properties of two different chain length membrane systems were systematically characterized, under pertinent early Earth conditions. The membrane systems were designed to comprise a fatty acid and its alcohol and/or glycerol monoester derivative, to make a range of binary and tertiary vesicle combinations. Their properties were then evaluated as a function of multiple factors including their composition, stability under varying pH, Mg2+ ion concentrations and dilution regimes, and their permeability to small molecules. Our results demonstrate how these environmental constraints would have acted as important prebiotic selection pressures to shape the evolution of prebiological membranes. This study also illustrates how different fatty acid derivatives confer varying degree of stability when combined with their respective fatty acid moiety. Interestingly, when the membrane systems were subjected to multiple selection pressures in a consecutive manner, only the heterogeneous membrane systems survived the ‘race’. Our results illustrate that compositionally diverse membrane systems are more stable and robust to multiple selection pressures, thereby making them more suitable for supporting protocellular life.

Significance statement

The physico-chemical environment would have played an important role in shaping the composition and evolution of primitive membrane systems. This study demonstrates the importance of compositional heterogeneity on the stability of protomembrane systems under pertinent prebiotic selection pressures. Two different fatty acid based systems were mixed with their respective alcohol and/or glycerol monoester derivatives, to generate combinations of binary and tertiary membrane systems. Increasing chain length effected the physical property of the membranes thus affecting their stability. Furthermore, we also demonstrate how the head groups of the derivatives employed in this study (e.g. glycerol monoester and alcohol) contribute differently towards stabilizing the mixed membranes under a given selection condition, by discerning the molecular mechanism underlying this process. Our results illustrate how multiple selection pressures would have preferentially supported the emergence of compositionally heterogeneous membrane systems.
Structure-based drug repositioning explains ibrutinib as VEGFR2 inhibitor
Authors: Adasme Melissa F. , Parisi Daniele , Van Belle Kristien , Salentin Sebastian , Haupt V. Joachim , Jennings Gary S. , Heinrich Jörg-Christian , Herman Jean , Sprangers Ben , Louat Thierry , Moreau Yves , Schroeder Michael
Published: June 2019

Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Bruton’s tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinib’s anti VEGFR2 action through a specific pattern of interactions shared between BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.
Evidence supporting a viral origin of the eukaryotic nucleus
Authors: Bell Philip JL
Published: June 2019

The defining feature of the eukaryotic cell is the possession of a nucleus that uncouples transcription from translation. This uncoupling of transcription from translation depends on a complex process employing hundreds of eukaryotic specific genes acting in concert and requires the 7-methylguanylate (m7G) cap to prime eukaryotic mRNA for splicing, nuclear export, and cytoplasmic translation. The origin of this complex system is currently a paradox since it is not found or needed in prokaryotic cells which lack nuclei, yet it was apparently present and fully functional in the Last Eukaryotic Common Ancestor (LECA). According to the Viral Eukaryogenesis (VE) hypothesis the abrupt appearance of the nucleus in the eukaryotic lineage occurred because the nucleus descends from the viral factory of a DNA phage that infected the archaeal ancestor of the eukaryotes. Consequently, the system for uncoupling of transcription from translation in eukaryotes is predicted by the VE hypothesis to be viral in origin. In support of this hypothesis it is shown here that m7G capping apparatus that primes the uncoupling of transcription from translation in eukaryotes is present in viruses of the Mimiviridae but absent from bona-fide archaeal relatives of the eukaryotes such as Lokiarchaeota. Furthermore, phylogenetic analysis of the m7G capping pathway indicates that eukaryotic nuclei and Mimiviridae obtained this pathway from a common ancestral source that predated the origin of LECA. These results support the VE hypothesis and suggest the eukaryotic nucleus and the Mimiviridae descend from a common First Eukaryotic Nuclear Ancestor (FENA).
Reconstructing neural representations of tactile space
Authors: Tamè Luigi , Tucciarelli Raffaele , Sadibolova Renata , Sereno Martin I. , Longo Matthew R.
Published: June 2019

Psychophysical experiments have demonstrated large and highly systematic perceptual distortions of tactile space. We investigated the neural basis of tactile space by analyzing activity patterns induced by tactile stimulation of nine points on a 3 × 3 square grid on the hand dorsum using functional magnetic resonance (fMRI). We used a searchlight approach within pre-defined regions of interests (ROIs) to compute the pairwise Euclidean distances between the activity patterns elicited by tactile stimulation. Then, we used multidimensional scaling (MDS) to reconstruct tactile space at the neural level and compare it with skin space at the perceptual level. Our reconstructions of the shape of skin space in contralateral primary somatosensory (SI) and motor (M1) cortices reveal that it is distorted in a way that matches the perceptual shape of skin space. This suggests that early sensorimotor areas are critical to processing tactile space perception.

Significant Statement

Here, we show that the primary somatosensory (SI) and motor (M1) cortices, rather than higher-level brain areas, are critical to estimating distances between tactile stimuli on the hand dorsum. By combining functional magnetic resonance (fMRI), Procrustes alignment, and multidimensional scaling, we reconstructed the shape of skin space in the brain. Strikingly, the shape of the skin that we reconstructed from neural data matches the distortions we found at the behavioral level, providing strong evidence that early sensorimotor areas are critical for the construction of tactile space. Our work therefore supports the view that tactile distance perception is computed at lower level in the somatosensory system than is usually supposed.
Inferring quantity and qualities of superimposed reaction rates in single molecule survival time distributions
Authors: Reisser Matthias , Hettich Johannes , Kuhn Timo , Gebhardt J. Christof M.
Published: June 2019

Actions of molecular species, for example binding of transcription factors to chromatin, are intrinsically stochastic and may comprise several mutually exclusive pathways. Inverse Laplace transformation in principle resolves the rate constants and frequencies of superimposed reaction processes, however current approaches are challenged by single molecule fluorescence time series prone to photobleaching. Here, we present a genuine rate identification method (GRID) that infers the quantity, rates and frequencies of dissociation processes from single molecule fluorescence survival time distributions using a dense grid of possible decay rates. In particular, GRID is able to resolve broad clusters of rate constants not accessible to common models of one to three exponential decay rates. We validate GRID by simulations and apply it to the problem of in-vivo TF-DNA dissociation, which recently gained interest due to novel single molecule imaging technologies. We consider dissociation of the transcription factor CDX2 from chromatin. GRID resolves distinct, decay rates and identifies residence time classes overlooked by other methods. We confirm that such sparsely distributed decay rates are compatible with common models of TF sliding on DNA.
High precision coding in visual cortex
Authors: Stringer Carsen , Michaelos Michalis , Pachitariu Marius
Published: June 2019

Single neurons in visual cortex provide unreliable measurements of visual features due to their high trial-to-trial variability. It is not known if this “noise” extends its effects over large neural populations to impair the global encoding of stimuli. We recorded simultaneously from ∼20,000 neurons in mouse primary visual cortex (V1) and found that the neural populations had discrimination thresholds of ∼0.34° in an orientation decoding task. These thresholds were nearly 100 times smaller than those reported behaviorally in mice. The discrepancy between neural and behavioral discrimination could not be explained by the types of stimuli we used, by behavioral states or by the sequential nature of perceptual learning tasks. Furthermore, higher-order visual areas lateral to V1 could be decoded equally well. These results imply that the limits of sensory perception in mice are not set by neural noise in sensory cortex, but by the limitations of downstream decoders.
HTT is a repressor of ABL activity required for APP induced axonal growth
Authors: Marquilly Claire , Busto Germain , Leger Brittany S. , Giniger Edward , Walker James A. , Fradkin Lee G. , Dura Jean-Maurice
Published: June 2019

ABL tyrosine kinase activity controls several aspects of development including axon patterning. Amyloid precursor protein (APP) is linked to Alzheimer’s disease and previous work established that ABL is a downstream effector in anAppl, theDrosophilaApp ortholog, signaling pathway which modulates axon outgrowth in the mushroom bodies (MBs), the fly memory center. Here we show thatAblis required for the MB neuron axonal growth. Importantly, bothAbloverexpression and lack of expression produce a similar phenotype in the MBs indicating the necessity of tightly regulating ABL activity. We find that the fly huntingtin protein (HTT), the homolog of the protein involved in Huntington’s disease, behaves genetically as a repressor of ABL activity. Supporting this, FRET-based measurements ofin vivoABL activity in the MBs reveal a clear increase in its activity when HTT levels are reduced. Thus, in addition to its many other reported roles, HTT acts as a negative regulator of ABL activity, at least in the MBs, to maintain its appropriate physiological levels necessary for axon growth.
Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors
Authors: Patel Akash J. , Wan Ying-Wooi , Al-Ouran Rami , Revelli Jean-Pierre , Cardenas Maria F. , Oneissi Mazen , Xi Liu , Jalali Ali , Magnotti John F. , Muzny Donna M. , Doddapaneni HarshaVardhan , Sebastian Sherly , Heck Kent A. , Goodman J. Clay , Gopinath Shankar P. , Liu Zhandong , Rao Ganesh , Plon Sharon E. , Yoshor Daniel , Wheeler David A. , Zoghbi Huda Y. , Klisch Tiemo J.
Published: June 2019

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

Significance Statement

Meningiomas are the most common primary brain tumors. Although most of these tumors are benign, one-fifth will recur despite apparently complete resection. Several studies have demonstrated that genomic approaches can yield important insights into the biology of these tumors. We performed RNA sequencing and whole-exome sequencing of 160 tumors from 140 patients, which identified three distinct groups of meningioma that correlate with recurrence better than the current WHO grading system. Our analysis also revealed that the most aggressive type was characterized by loss of the repressive DREAM complex. These findings should improve prognostication for patients and lead to viable therapeutic targets.
TRESK K+Channel Activity Regulates Trigeminal Nociception and Headache
Authors: Guo Zhaohua , Qiu Chang-Shen , Jiang Xinhua , Zhang Jintao , Li Fengxian , Liu Qin , Dhaka Ajay , Cao Yu-Qing
Published: June 2019

Although dominant-negative mutations of TRESK background K+channel have been reported in migraine patients, whether TRESK activity controls the generation of trigeminal pain, especially headache, is not established. We found that loss of TRESK in all trigeminal ganglia (TG) neurons preferentially increased the intrinsic excitability of small-diameter TG nociceptors that express neuropeptide CGRP or TRPM8 channels. Surprisingly, loss of TRESK increased the number of TG neurons expressing TRPV1 channels. In dorsal root ganglia neurons, neither the persistent outward current nor the intrinsic excitability was affected by the loss of TRESK. Compared with wild-type controls, TRESK knockout mice exhibited more robust trigeminal pain, especially headache-like behaviors; but displayed normal body and visceral pain responses. Our findings indicate that endogenous TRESK activity is required for trigeminal pain regulation. A substantial reduction of TRESK activity may selectively affect the functions of TG nociceptors, thereby increasing the susceptibility to migraine headache in humans.
Interactions with presynaptic photoreceptors mediated by the Dpr11 and DIP-γ cell surface proteins control selection and survival of Drosophila amacrine neurons
Authors: Menon Kaushiki P. , Kulkarni Vivek , Takemura Shin-ya , Anaya Michael , Zinn Kai
Published: June 2019

Drosophila R7 UV photoreceptors (PRs) are divided into yellow (y) and pale (p) subtypes with different wavelength sensitivities. yR7 PRs express the Dpr11 cell surface protein and are presynaptic to Dm8 amacrine neurons (yDm8) that express Dpr11’s binding partner DIP-γ, while pR7 PRs synapse onto DIP-γ-negative pDm8 neurons. Dpr11 and DIP-γ expression patterns define yellow and pale medulla color vision circuits that project to higher-order areas. DIP- γ and dpr11 mutations affect the morphology of yDm8 arbors in the yellow circuit. yDm8 neurons are generated in excess during development and compete for presynaptic yR7 partners. Transsynaptic interactions between Dpr11 and DIP-γ are required for generation of neurotrophic signals that allow yDm8 neurons to survive. yDm8 and pDm8 neurons do not normally compete for neurotrophic support, but can be forced to do so by manipulating R7 subtype fates. DIP-γ-Dpr11 interactions allow yDm8 neurons to select yR7 PRs as their home column partners.
The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi contact sites
Authors: Wakana Yuichi , Hayashi Kaito , Nemoto Takumi , Watanabe Chiaki , Taoka Masato , Campelo Felix , Kumata Hidetoshi , Umemura Tomonari , Inoue Hiroki , Arasaki Kohei , Tagaya Mitsuo
Published: June 2019

In response to cholesterol deprivation, SCAP escorts SREBP transcription factors from the endoplasmic reticulum (ER) to the Golgi complex for their proteolytic activation, leading to gene expression for cholesterol synthesis and uptake. Here we show that in cholesterol-fed cells ER-localized SCAP interacts through Sac1 phosphoinositide 4-phosphate (PI4P) phosphatase with a VAP/OSBP complex, which mediates counter-transport of ER cholesterol and Golgi PI4P at ER-Golgi contact sites. SCAP knockdown inhibited the turnover of PI4P perhaps due to a cholesterol transport defect and altered the subcellular distribution of the VAP/OSBP complex. As in the case of perturbation of lipid transfer complexes at ER-Golgi contact sites, SCAP knockdown inhibited the biogenesis of thetrans-Golgi network-derived transport carriers CARTS, which was reversed by expression of wild-type SCAP but not cholesterol sensing-defective mutants. Altogether, our findings reveal a new role of SCAP under cholesterol-fed conditions in the facilitation of CARTS biogenesis at ER-Golgi contact sites, depending on the ER cholesterol.

SCAP is the key regulatory protein in cholesterol metabolism. Wakana et al. describe a new role of SCAP in controlling Golgi PI4P turnover and the biogenesis of the Golgi-derived transport carries CARTS via cholesterol/PI4P exchange machinery at ER-Golgi contact sites.