bluuebunny/crossref_metadata_2025 huggingface dataset:
Morbidity and mortality after transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis
Authors: Dissegna Denis , Sponza Massimo , Falleti Edmondo , Fabris Carlo , Vit Alessandro , Angeli Paolo , Piano Salvatore , Cussigh Annarosa , Cmet Sara , Toniutto Pierluigi
Published: December 2018

Objectives

Transjugular intrahepatic portosystemic shunt (TIPS) is adopted to treat refractory complications of portal hypertension, such as variceal bleeding and ascites. This study aimed to assess predictors of hepatic encephalopathy (HE) development and cumulative transplant-free survival after TIPS placement in patients with cirrhosis complicated by refractory ascites and major gastroesophageal bleeding.

Materials and methods

Sixty-three cirrhotic patients who underwent TIPS positioning as a secondary prophylaxis of major upper gastroesophageal bleeding (N=30) or to control refractory ascites (N=33) were enrolled.

Results

After a median follow-up of 26 months following TIPS insertion, only 1/30 (3.3%) patients developed reoccurrence of bleeding. Complete control of refractory ascites was recorded in 19/23 (82.6%) patients. Within the first month after TIPS placement, 34/63 (53.9%) patients developed clinically significant HE, which was associated with the baseline presence of type 2 hepatorenal syndrome (P=0.022). At the end of 90 months of follow-up, 35 (55.6%) patients were alive, 12 (19.0%) patients underwent liver transplantation, and 16 (25.4%) patients died. Independent predictors of transplant-free survival were a model for end-stage liver disease score up to 15 (P<0.001), the absence of a history of spontaneous bacterial peritonitis (P=0.010) pre-TIPS, and no HE within 1 month post-TIPS (P=0.040).

Conclusion

TIPS insertion can be considered a safe and effective treatment in patients with cirrhosis and severe complications of portal hypertension that are not manageable with standard treatments. Interestingly, if confirmed in future studies, the history of spontaneous bacterial peritonitis pre-TIPS could be added to the model for end-stage liver disease score as a strong baseline predictor of post-TIPS mortality.
Subtle Motor Signs in Children With Chronic Traumatic Brain Injury
Authors: Crasta Jewel E. , Sibel Jamie , Slomine Beth S. , Mahone E. Mark , Mostofsky Stewart H. , Suskauer Stacy J.
Published: December 2018

Objective

The aim of the study was to characterize subtle motor signs in children with moderate-severe traumatic brain injury in the chronic phase of injury.

Design

Fourteen children with moderate (n= 6) or severe (n= 8) traumatic brain injury, ages 11–18 yrs, who had sustained their injury at least 1-yr before study participation (range 1–14 yrs since injury), and 14 matched typically developing controls were examined using the Physical and Neurological Examination of Subtle Signs (PANESS). To examine the neural correlates of subtle motor signs, measures of total cerebral volume and motor/premotor volume were derived from magnetic resonance imaging.

Results

Children with traumatic brain injury had significantly poorer PANESS performance than controls on the total timed subscore, proximal overflow, and the PANESS total score. Participants with severe traumatic brain injury had greater proximal overflow than those with moderate injury, after controlling for age at injury. Across all participants, greater proximal overflow correlated with reduced total cerebral volume, whereas within the traumatic brain injury group, reduced motor/premotor volume correlated with lower PANESS total score.

Conclusions

The study highlights the importance of examining subtle motor signs including overflow during clinical evaluation of chronic pediatric traumatic brain injury and establishes the clinical utility of the PANESS as a measure sensitive to chronic subtle motor signs in this population.

To Claim CME Credits

Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME

CME Objectives

Upon completion of this article, the reader should be able to: (1) Define subtle motor signs including motor overflow; (2) Identify subtle motor signs such as motor overflow during clinical evaluation of children with brain injury; and (3) Explain the relevance of examining subtle motor signs in chronic pediatric brain injury during clinical evaluations.

Level

Advanced.

Accreditation

The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Single Suture Synostosis and Isolated Cleft Palate in Non-Apert Syndrome Patients
Authors: Pezas Theodore , Slator Rona , White Nicholas , Lloyd Mark
Published: December 2018

Introduction:

Single suture craniosynostosis (SSC) and isolated cleft palate (ICP) in non-Apert syndrome patients rarely occur together. Management includes airway optimization, timing surgery appropriately, and assessing both cranial vault aesthetics and speech outcomes. The aim of this study was to compare treatment pathways and outcomes in patients with both conditions to standard treatment for these conditions in isolation.

Methods:

Patient hospital medical records were retrospectively reviewed for demographic data, timing of surgery, aesthetic outcome (using the Whitaker grading system for head shape), and speech outcome (from speech therapy records of general development and speech assessment).

Results:

Six patients with SSC and ICP were identified over an 18-year period. Cranial surgery was performed between 4 and 16 months and cleft surgery between 6 and 34 months of age in all cases. Documentation of cleft surgery and genetic testing was not available for 1 patient. One patient with hemi-palatal absence had an obturator inserted at 34 months. Two patients were found to have Fragile X and Emanuel syndrome, respectively.

No increased perioperative airway risk was highlighted in any case. Four cases were designated Whitaker grade 1, 1 case was designated grade 2, and 1 case was not graded as no cranial surgery was performed. Half of the patients had general and speech developmental delay, while the other half demonstrated no signs of developmental delay.

Discussion/Conclusion:

Examination of 6 patients with SSC and ICP suggests the presence of both conditions does not adversely impact management or outcome for each condition, or increase perioperative risk.
Eye Tracking as a Proxy for Perceptual Evaluation of Repaired Cleft Lip
Authors: Warne Christopher N. , Hallac Rami R. , Kane Alex A. , Derderian Christopher A. , Seaward James R.
Published: December 2018

Human interactions begin with near-instantaneous visual evaluation of the face, modifying emotional responses and social behavior toward the person. Eye-tracking technology can provide a potential window into how humans undertake this evaluation, and the threshold of whether a face containing a craniofacial difference is perceived as “normal.” This study's main questions were whether gaze patterns differ from normal when evaluating children with craniofacial differences, and whether these gaze patterns vary with different levels of craniofacial deformity. Two experiments tested the feasibility of using eye tracking to study facial evaluation and whether there was a difference in the gaze pattern and characteristics, correlating with the Asher McDade Aesthetic Index. Fifty-three participants’ eye movements were recorded as they gazed at photographs of children either with hemifacial microsomia or repaired cleft lip, with repaired cleft lip digitally corrected to symmetry, or with no craniofacial disorder. Recruitment and participation for this study occurred in a pediatric plastic surgery clinic and in a medical school student center. Participants gazed longer on the lip in the cleft-lip photographs compared with control photographs in the first experiment (207 ms; SD 75 versus 145 ms; SD 61, respectively; P = 0.04). This gaze bias was confirmed in the second experiment and found to correlate with severity (r = 0.042). Gaze patterns differ when individuals look at photographs with or without craniofacial differences. The degree to which these eye movement patterns differ correlates with the severity of craniofacial deformity.
Brain-behaviour modes of covariation in healthy and clinically depressed young people
Authors: Mihalik Agoston , Ferreira Fabio S. , Rosa Maria J. , Moutoussis Michael , Ziegler Gabriel , Monteiro Joao M. , Portugal Liana , Adams Rick A. , Romero-Garcia Rafael , Vértes Petra E. , Kitzbichler Manfred G. , Váša František , Vaghi Matilde M. , Bullmore Edward T. , Fonagy Peter , Goodyer Ian M. , Jones Peter B. ,   NSPN Consortium, Dolan Raymond , Mourao-Miranda Janaina
Published: December 2018

Understanding how variations in dimensions of psychometrics, IQ and demographics relate to changes in brain connectivity during the critical developmental period of adolescence and early adulthood is a major challenge. This has particular relevance for mental health disorders where a failure to understand these links might hinder the development of better diagnostic approaches and therapeutics. Here, we investigated this question in 306 adolescents and young adults (14-24y, 25 clinically depressed) using a multivariate statistical framework, based on canonical correlation analysis (CCA). By linking individual functional brain connectivity profiles to self-report questionnaires, IQ and demographic data we identified two distinct modes of covariation. The first mode mapped onto an externalization/internalization axis and showed a strong association with sex. The second mode mapped onto a well-being/distress axis independent of sex. Interestingly, both modes showed an association with age. Crucially, the changes in functional brain connectivity associated with changes in these phenotypes showed marked developmental effects. The findings point to a role for the default mode, frontoparietal and limbic networks in psychopathology and depression.
MAGIC: A tool for predicting transcription factors and cofactors binding sites in gene sets using ENCODE data
Authors: Roopra A
Published: December 2018

Transcriptomic profiling is an immensly powerful hypothesis generating tool. Whether one is comparing an experimental versus control condition or collecting transcriptomes from cohorts of disease tissue, it is often necessary to determine which transcription factors (TFs) and cofactors drive programs of gene expression in the datasets. Most available tools rely on searching for TF binding motifs near promoters of genes in a gene set. This approach can work well for TFs with extended recognition elements but is less useful for shorter elements and does not work at all for cofactors. The Encyclopedia Of DNA Elements (ENCODE) archives ChIPseq tracks of 169 TFs and cofactors assayed in 91 cells lines. The algorithm presented herein, Multiple Aligned Genomic Integration of ChIP (MAGIC), uses ENCODE ChIPseq data to look for statistical enrichment of TFs and cofactors in gene bodies and flanking regions in gene sets. When compared to a commonly used web resource o-Possum, MAGIC was able to more accurately predict TFs and cofactors that drive gene changes in 3 settings: 1) A cell line expressing or lacking REST, 2) Breast tumors divided along PAM50 designations and 3) Whole brain samples from WT mice or mice lacking CTCF in a particular neuronal subtype. In summary, MAGIC is a standalone application that runs on OSX machines and has a simple interface that produces meaningful predictions of which TFs and cofactors are enriched in a gene set.
Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits
Authors: Massrali Aicha , Brunel Helena , Hannon Eilis , Wong Chloe ,   iPSYCH-MINERvA Epigenetics Group, Baron-Cohen Simon , Warrier Varun
Published: December 2018

Previous studies have identified differences in DNA methylation in autistic individuals compared to neurotypical individuals. Yet, it is unclear if this extends to autistic traits – subclinical manifestation of autism features in the general population. Here, we investigate the association between DNA methylation at birth (cord blood), and scores on the Social and Communication Disorders Checklist (SCDC), a measure of autistic traits, in 701 8-year olds, by conducting a methylome-wide association study (MWAS) using DNA methylation data from cord-blood. Whilst did not identify significant loci demonstrating differential methylation, we observe a degree of overlap between the SCDC MWAS and post-mortem brain methylation signature in autism. Validating this, we observe an enrichment for genes that are dysregulated in the post-mortem autism brain. Finally, integrating genome-wide data from more than 40,000 individuals and mQTL maps from cord-blood, we demonstrate that mQTLs of CpGs associated with SCDC scores at different P-value thresholds are significantly shifted towards lower P-values in a GWAS for autism. We validate this using a GWAS of SCDC, and demonstrate a lack of enrichment in a GWAS of Alzheimer’s disease. Our results highlight the shared cross-tissue epigenetic architecture of autism and autistic traits, and demonstrate that mQTLs associated with methylation changes in childhood autistic traits are enriched for common genetic variants associated with autism and autistic traits.
Clostridioides difficileLuxS mediates inter-bacterial interactions within biofilms
Authors: Slater Ross , Frost Lucy , Jossi Sian , Millard Andrew , Unnikrishnan Meera
Published: December 2018

The anaerobic gut pathogen,Clostridioides difficile, forms adherent biofilms that may play an important role in recurrentC. difficileinfections. The mechanisms underlyingC. difficilecommunity formation and inter-bacterial interactions are nevertheless poorly understood.C. difficileproduces AI-2, a quorum sensing molecule that modulates biofilm formation across many bacterial species. We found that a strain defective in LuxS, the enzyme that mediates AI-2 production, is defective in biofilm developmentin vitro. Transcriptomic analyses of biofilms formed by wild type (WT) andluxSmutant (luxS) strains revealed a downregulation of prophage loci in theluxSmutant biofilms compared to the WT. Detection of phages and eDNA within biofilms may suggest that DNA release by phage-mediated cell lysis contributes toC. difficilebiofilm formation. In order to understand if LuxS mediatesC. difficilecrosstalk with other gut species,C. difficileinteractions with a common gut bacterium,Bacteroides fragilis, were studied. We demonstrate thatC. difficilegrowth is significantly reduced when co-cultured withB. fragilisin mixed biofilms. Interestingly, the absence ofC. difficileLuxS alleviates theB. fragilismediated growth inhibition. Dual species RNA-sequencing analyses from single and mixed biofilms revealed differential modulation of distinct metabolic pathways forC. difficileWT,luxSandB. fragilisupon co-culture, indicating that AI-2 may be involved in induction of selective metabolic responses inB. fragilis. Overall, our data suggest thatC. difficileLuxS/AI-2 utilises different mechanisms to mediate formation of single and mixed species communities.
Genome sequence ofPseudomonas aeruginosaPAO1161, a PAO1 derivative with the ICEFP2 integrative and conjugative element
Authors: Kawalek Adam , Kotecka Karolina , Modrzejewska Magdalena , Jagura-Burdzy Grazyna , Bartosik Aneta Agnieszka
Published: December 2018

Pseudomonas aeruginosais a common cause of nosocomial infections, especially in patients with cystic fibrosis and burn wounds. An attenuated PAO1 strain and its derivatives are widely used to study the biology of this bacterium, however recent studies indicated an ongoing evolution of the laboratory strains, highlighted by changes in the genomes of PAO1 sublines and derivatives used in different laboratories worldwide.

Here we have sequenced the genome ofPseudomonas aeruginosaPAO1161 strain, aleu-, RifR, restriction-modification defective PAO1 derivative. This strain is described as the host of IncP-8 plasmid FP2, conferring the resistance to mercury and used in the past for preparation of genetic map of theP. aeruginosachromosome. Comparison of PAO1161 genome sequence with PAO1-UW reference genome revealed an inversion of the large genome segment betweenrrnAandrrnBrRNA operons and more than 100 nucleotide polymorphisms and short insertions-deletions, many of which were also found within the recently re-sequenced PAO1 sublines. The PAO1161 specific sequence variants include E108K mutation in PA3792 (leuA), which we showed is responsible for leucine auxotrophy, H531L in PA4270 (rpoB), likely conferring rifampicin resistance, as well as nonsense mutations in PA2735 encoding a DNA methyltransferase as well as a putative OLD family endonuclease PA1939. Additionally, PAO1161 genome poses a 12 kb RPG42 prophage and a 108 kbp insertion within tRNA-Lys, encompassing a putative mercury resistance and showing similarity to PAPI-1 like integrative conjugative elements (ICE). Our data indicate that the ICE can excise from the bacterial chromosome and can be transferred toPseudomonas putidacells where it integrates in the genome at three specific sites and confers the cells with mercury resistance. Overall this data provide insight into the genome variation betweenP. aeruginosalaboratory strains. Moreover, this data indicate that the FP2 element for years described as a IncP-8 plasmid is an integrative conjugative element.
Uncultured marine cyanophages encode for active NblA, phycobilisome proteolysis adaptor protein
Authors: Nadel Omer , Rozenberg Andrey , Flores-Uribe José , Larom Shirley , Schwarz Rakefet , Béjà Oded
Published: December 2018

Phycobilisomes (PBS) are large water-soluble membrane-associated complexes in cyanobacteria and some chloroplasts that serve as a light-harvesting antennas for the photosynthetic apparatus. When short of nitrogen or sulfur, cyanobacteria readily degrade their phycobilisomes allowing the cell to replenish the vanishing nutrients. The key regulator in the degradation process is NblA, a small protein (~6 kDa) which recruits proteases to the PBS. It was discovered previously that not only do cyanobacteria possessnblAgenes but also that they are encoded by genomes of some freshwater cyanophages. A recent study, using assemblies from oceanic metagenomes, revealed genomes of a novel uncultured marine cyanophage lineage which contain genes coding for the PBS degradation protein. Here, we examine the functionality ofnblA-like genes from these marine cyanophages by testing them in a freshwater model cyanobacterialnblAknockout. One of the viral NblA variants could complement the non-bleaching phenotype and restore PBS degradation. Our findings reveal a functional NblA from a novel marine cyanophage lineage. Furthermore, we shed new light on the distribution ofnblAgenes in cyanobacteria and cyanophages.

Originality-Significance Statement

This is the first study to examine the distribution and function ofnblAgenes of marine cyanophage origin. We describe as well the distribution ofnblA-like genes in marine cyanobacteria using bioinformatic methods.
Broken symmetry in the human BK channel
Authors: Tonggu Lige , Wang Liguo
Published: December 2018

Voltage-gated and ligand-modulated ion channels play critical roles in excitable cells. To understand the interplay among voltage-sensing, ligand-binding and channel opening, the structures of ion channels in various functional states need to be determined. Here, the “random spherically constrained” (RSC) single-particle cryo-EM method was employed to study the human large conductance voltage- and calcium-activated potassium (hBK or hSlo1) channels reconstituted into liposomes. The hBK structure has been determined at 3.5 Å resolution in the absence of Ca2+. Instead of the common four-fold symmetry observed in ligand-modulated ion channels, a two-fold symmetry was observed in hBK. Two opposing subunits in the Ca2+ sensing gating ring rotate around the center of each subunit, which results in the movement of the assembly and flexible interfaces and Ca2+ binding sites. Despite the significant movement, the local conformation of the assembly interfaces and Ca2+ binding sites remains the same among the four subunits.
Comparison of subtyping approaches and the underlying drivers of microbial signatures for chronic rhinosinusitis
Authors: Biswas Kristi , Cavubati Raewyn , Gunaratna Shan , Hoggard Michael , Waldvogel-Thurlow Sharon , Chang Kevin , Wagner Mackenzie Brett , Taylor Michael W , Douglas Richard G
Published: December 2018

Chronic rhinosinusitis (CRS) is a heterogeneous condition characterised by persistent sinus inflammation and microbial dysbiosis. This study aimed to identify clinically relevant sub-groups of CRS patients based on distinct microbial signatures, with a comparison to the commonly used phenotypic subgrouping approach. The underlying drivers of these distinct microbial clusters were also investigated, together with associations with epithelial barrier integrity. Sinus biopsies were collected from CRS patients (n=23), and disease controls (n=8). Expression of 42 tight junction genes was evaluated using quantitative PCR, together with microbiota analysis and immunohistochemistry for measuring mucosal integrity and inflammation. CRS patients clustered into two distinct microbial sub-groups using probabilistic modelling Dirichlet (DC) multinomial mixtures. DC1 exhibited significantly reduced bacterial diversity, increased dispersion, and was dominated by Pseudomonas, Haemophilus, and Achromobacter. DC2 had significantly elevated B-cells, incidence of nasal polyps, and higher numbers of Anaerococcus, Megasphaera, Prevotella, Atopobium, and Propionibacterium. In addition, each DC exhibited distinct tight junction gene and protein expression profiles compared with controls. Stratifying CRS patients based on clinical phenotypic subtypes (absence or presence of nasal polyps (CRSsNP or CRSwNP respectively) or with cystic fibrosis (CRSwCF)) did account for a larger proportion of the variation in the microbial dataset compared with DC groupings. However, no significant differences between CRSsNP and CRSwNP cohorts were observed for inflammatory markers, beta-dispersion and alpha diversity measures. In conclusion, both stratification approaches used had benefits and pitfalls, but DC clustering did provide greater resolution when studying tight junction impairment. Future studies in CRS should give careful consideration into the patient subtyping approach used.
To cure or not to cure: consequences of immunological interactions in CML treatment
Authors: César Fassoni Artur , Roeder Ingo , Glauche Ingmar
Published: December 2018

Recent clinical findings in Chronic Myeloid Leukemia (CML) patients suggest that the number and function of immune effector cells are modulated by Tyrosine Kinase Inhibitors (TKI) treatment. There is further evidence that the success or failure of treatment cessation at least partly depends on the patient’s immunological constitution. Here, we propose a general ODE model to functionally describe the interactions between immune effector cells with leukemic cells during the TKI treatment of CML. In total, we consider 20 different sub-models, which assume different functional interactions between immune effector and leukemic cells. We show that quantitative criteria, which are purely based on the quality of model fitting, are not able to identify optimal models. On the other hand, the application of qualitative criteria based on a dynamical system framework allowed us to identify nine of those models as more suitable than the others to describe clinically observed patterns and, thereby, to derive conclusion about the underlying mechanisms. Additionally, including aspects of early CML onset, we can demonstrate that certain critical parameters, such as the strength of immune response or leukemia proliferation rate, need to change during CML growth prior to diagnosis, leading to bifurcations that alter the attractor landscape. Finally, we show that the crucial parameters determining the outcome of treatment cessation are not identifiable with tumor load data only, thereby highlighting the need to measure immune cell number and function to properly derive mathematical models with predictive power.

MSC Classification: 92B05, 37N25, 34C60, 37G35
Intraspecific variation promotes species coexistence and trait clustering through higher order interactions
Authors: Baruah Gaurav , John Robert
Published: December 2018

Ecological and evolutionary effects of individual variation on species coexistence remains unclear. Competition models for coexistence have emphasized species-level differences in pairwise interactions, and invoked no role for intraspecific variation. These models show that stronger competitive interactions result in smaller numbers of coexisting species. However, the presence of higher-order interactions (HOIs) among species appears to have a stabilizing influence on communities. How species coexistence is affected in a community where both pairwise and higher-order interactions are pervasive is not known. Furthermore, the effect of individual variation on species coexistence in complex communities with pairwise and HOIs remains untested. Using a Lotka-Volterra model, we explore the effects of intraspecific variation on the patterns of species coexistence in a competitive community dictated by pairwise and HOIs. We found that HOIs greatly stabilize species coexistence across different levels of strength in competition. Notably, high intraspecific variation promoted species coexistence, particularly when competitive interactions were strong. However, species coexistence promoted by higher levels of variation was less robust to environmental perturbation. Additionally, species’ traits tend to cluster together when individual variation in the community increased. We argue that individual variation can promote species coexistence by reducing trait divergence and attenuating the inhibitory effects of dominant species through HOIs
Stratified computational meta-analysis of 2213 acute myeloid leukemia patients reveals age- and sex-dependent gene expression signatures
Authors: Roushangar Raeuf , Mias George I.
Published: December 2018

In 2018 alone, an estimated 20,000 new acute myeloid leukemia (AML) patients were diagnosed, in the United States, and over 10,000 of them are expected to die from the disease. AML is primarily diagnosed among the elderly (median 68 years old at diagnosis). Prognoses have significantly improved for younger patients, but in patients older than 60 years old as much as 70% of patients will die within a year of diagnosis. In this study, we conducted stratified computational meta-analysis of 2,213 acute myeloid leukemia patients compared to 548 healthy individuals, using curated publicly available data. We carried out analysis of variance of normalized batch corrected data, including considerations for disease, age, tissue and sex. We identified 974 differentially expressed probe sets and 4 significant pathways associated with AML. Additionally, we identified 70 sex- and 375 age-related probe set expression signatures relevant to AML. Finally, we used a machine learning model (KNN model) to classify AML patients compared to healthy individuals with 90+% achieved accuracy. Overall our findings provide a new reanalysis of public datasets, that enabled the identification of potential new gene sets relevant to AML that can potentially be used in future experiments and possible stratified disease diagnostics.
Schizophrenia risk conferred by protein-coding de novo mutations
Authors: Howrigan Daniel P. , Rose Samuel A. , Samocha Kaitlin E. , Fromer Menachem , Cerrato Felecia , Chen Wei J. , Churchhouse Claire , Chambert Kimberly , Chandler Sharon D. , Daly Mark J. , Dumont Ashley , Genovese Giulio , Hwu Hai-Gwo , Laird Nan , Kosmicki Jack A. , Moran Jennifer L. , Roe Cheryl , Singh Tarjinder , Wang Shi-Heng , Faraone Stephen V. , Glatt Stephen J. , McCarroll Steven A. , Tsuang Ming , Neale Benjamin M.
Published: December 2018

Protein-coding de novo mutations (DNMs) in the form of single nucleotide changes and short insertions/deletions are significant genetic risk factors for autism, intellectual disability, developmental delay, and epileptic encephalopathy. In contrast, the burden of DNMs has thus far only had a modest documented impact on schizophrenia (SCZ) risk. Here, we analyze whole-exome sequence from 1,695 SCZ affected parent-offspring trios from Taiwan along with DNMs from 1,077 published SCZ trios to better understand the contribution of coding DNMs to SCZ risk. Among 2,772 SCZ affected probands, the increased burden of DNMs is modest. Gene set analyses show that the modest increase in risk from DNMs in SCZ probands is concentrated in genes that are either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified as DNM risk factors in other neurodevelopmental disorders. No single gene meets the criteria for genome-wide significance, but we identify 16 genes that are recurrently hit by a protein-truncating DNM, which is a 3.15-fold higher rate than mutation model expectation of 5.1 genes (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and this risk is polygenic in nature suggesting that coding variation across many different genes will be a risk factor for SCZ in the population.
Human visual cortex is organized along two genetically opposed hierarchical gradients with unique developmental and evolutionary origins
Authors: Gomez Jesse , Zhen Zonglei , Weiner Kevin
Published: December 2018

Human visual cortex is organized with striking consistency across individuals. While recent findings demonstrate an unexpected coupling between functional and cytoarchitectonic regions relative to the folding of human visual cortex, a unifying principle linking these anatomical and functional features of cortex remains elusive. To fill this gap in knowledge, we combined independent and ground truth measurements of human cytoarchitectonic regions and genetic tissue characterization within the visual processing hierarchy. Using a data-driven approach, we examined if differential gene expression among cortical areas could explain the organization of the visual processing hierarchy into early, middle, and late processing stages. This approach revealed that the visual processing hierarchy is explained by two opposing gene expression gradients: one that contains a series of genes with expression magnitudes that ascend from the first processing stage (e.g. area hOc1, or V1) to the last processing stage (e.g. area FG4) and another that contains a separate series of genes that show a descending gradient. In the living human brain, each of these gradients correlates strongly with anatomical variations along the visual hierarchy such as the thickness or myelination of cortex. We further reveal that these genetic gradients emerge along unique trajectories in human development: the ascending gradient is present at 10- 12 gestational weeks, while the descendent gradient emerges later (19-24 gestational weeks). Interestingly, it is not until early childhood (before 5 years of age) that the two expression gradients achieve their adult-like mean expression values. Finally, additional analyses in non-human primates (NHP) reveal the surprising finding that only the ascending, but not the descending, expression gradient is evolutionarily conserved. These findings create one of the first models bridging macroscopic features of human cytoarchitectonic areas in visual cortex with microscopic features of cellular organization and genetic expression, revealing that the hierarchy of human visual cortex, its cortical folding, and the cytoarchitecture underlying its computations, can be described by a sparse subset (~200) of genes, roughly one-third of which are not shared with NHP. These findings help pinpoint the genes contributing to both healthy cortical development and the cortical biology distinguishing humans from other primates, establishing essential groundwork for understanding future work linking genetic mutations with the function and development of the human brain.
Novel strand exchange activity of the human PALB2 DNA Binding Domain and its critical role for DNA repair in cells
Authors: Deveryshetty Jaigeeth , Ryzhikov Mikhail , Brahati Nadine , Peterlini Thibaut , Dellaire Graham , Masson Jean-Yves , Korolev Sergey
Published: December 2018

Breast cancer associated proteins 1 and 2 (BRCA1, -2) and partner and localizer of BRCA2 (PALB2) protein are tumor suppressors linked to a spectrum of malignancies, including breast cancer and Fanconi anemia. They stimulate RAD51 recombinase during homology-directed repair (HDR). Along with being a hub for a protein interaction network, PALB2 interacts with DNA. The mechanism of PALB2 DNA binding and its function are poorly understood. We identified a major DNA-binding site in PALB2, mutation of which reduces the RAD51 foci formation and the overall HDR efficiency in cells by 50%. PALB2 N-terminal DNA-binding domain (N-DBD) stimulates the RAD51 strand exchange reaction. Surprisingly, it promotes the strand exchange without RAD51. Moreover, N-DBD stimulates the inverse strand exchange and can use both DNA and RNA substrates. Our data reveal a versatile DNA interaction property of PALB2 and demonstrate a critical role of PALB2 DNA binding for chromosome repair in cells.
Multi-tissue analysis reveals short tandem repeats as ubiquitous regulators of gene expression and complex traits
Authors: Fotsing Stephanie Feupe , Margoliash Jonathan , Wang Catherine , Saini Shubham , Yanicky Richard , Shleizer-Burko Sharona , Goren Alon , Gymrek Melissa
Published: December 2018

Short tandem repeats (STRs) have been implicated in a variety of complex traits in humans. However, genome-wide studies of the effects of STRs on gene expression thus far have had limited power to detect associations and provide insights into putative mechanisms. Here, we leverage whole genome sequencing and expression data for 17 tissues from the Genotype-Tissue Expression Project (GTEx) to identify STRs for which repeat number is associated with expression of nearby genes (eSTRs). Our analysis reveals more than 28,000 eSTRs. We employ fine-mapping to quantify the probability that each eSTR is causal and characterize a group of the top 1,400 fine-mapped eSTRs. We identify hundreds of eSTRs linked with published GWAS signals and implicate specific eSTRs in complex traits including height and schizophrenia, inflammatory bowel disease, and intelligence. Overall, our results support the hypothesis that eSTRs contribute to a range of human phenotypes and will serve as a valuable resource for future studies of complex traits.
The clarifying role of time series data in the population genetics of HIV
Authors: Feder Alison F , Pennings Pleuni S , Petrov Dmitri A
Published: December 2018

HIV can evolve remarkably quickly in response to anti-retroviral therapies and the immune system. This evolution stymies treatment effectiveness and prevents the development of an HIV vaccine. Consequently, there has been great interest in using population genetics to disentangle the forces that govern the HIV adaptive landscape (selection, drift, mutation, recombination). Traditional population genetics approaches look at the current state of genetic variation and infer the processes that can generate them. However, because HIV evolves rapidly, we can also sample populations repeatedly over time and watch evolution in action. In this paper, we demonstrate how time series data can bound evolutionary parameters in a way that complements and informs traditional population genetic approaches. Specifically, we focus on our recent paper (Feder et al. 2016), in which we show that, as improved HIV drugs have led to fewer patients failing therapy due to resistance evolution, less genetic diversity has been maintained following the fixation of drug resistance mutations. We interpret this as evidence that resistance to early HIV drugs that failed quickly and predictably was driven by soft sweeps while evolution of resistance to better drugs is both less frequent and when it takes place it is associated with harder sweeps due to an effectively lower HIV population mutation rate (θ). Recently, Harris et al. 2018 have proposed an alternative interpretation: the signal could be due to an increase in the selective benefit of mutations conferring resistance to better drugs. Therefore, better drugs lead to faster sweeps with less opportunity for recombination to rescue diversity. In this paper, we use time series data to show that drug resistance evolution during ineffective treatment is very fast, providing new evidence that soft sweeps drove early HIV treatment failure.
RACER: A data visualization strategy for exploring multiple genetic associations
Authors: Sabik Olivia L. , Farber Charles R.
Published: December 2018

Genome-wide association studies (GWASs) have identified thousands of loci associated with risk of various diseases; however, the genes responsible for the majority of loci have not been identified. One means of uncovering potential causal genes is the identification of expression quantitative trait loci (eQTL) that colocalize with disease loci. Statistical methods have been developed to assess the likelihood that two associations (e.g. disease locus and eQTL) share a common causal variant, however, visualization of the two loci is often a crucial step in determining if a locus is pleiotropic. While the current convention is to plot two associations side-by-side, it is difficult to compare across two x-axes, even if they are identical. Thus, we have developed the Regional Association ComparER (RACER) package, which creates “mirror plots”, in which the two associations are plotted on a shared x-axis. Mirror plots provide an effective tool for the visual exploration and presentation of the relationship between two genetic associations.

Availability and Implementation

RACER is provided under the GNU General Public License version 3 (GPL-3.0). Source code is available at https://github.com/oliviasabik/RACER.

Contact

ols5fg@virginia.edu

Supplementary information

Supplementary data are available online with the paper, see the Supplemental Data Manifest.
Metabolic proof-reading in Plasmodium berghei: essentiality of phosphoglycolate phosphatase
Authors: Nagappa Lakshmeesha Kempaiah , Satha Pardhasaradhi , Govindaraju Thimmaiah , Balaram Hemalatha
Published: December 2018

Plasmodium falciparum (Pf) 4-nitrophenylphosphatase was earlier shown to be involved in vitamin B1 metabolism by KnÖckel et al., (Mol. Biochem. Parasitol. 2008, 157, 241-243). An independent BLASTp search showed that the protein had significant homology with phosphoglycolate phosphatase from mouse, human and yeast, and prompted us to re-investigate the biochemical properties of the recombinant Plasmodium enzyme. Owing to the insoluble nature of the Pf enzyme, an extended substrate screen and biochemical characterization was performed on its P. berghei (Pb) homolog that led to the identification of 2-phosphoglycolate and 2-phospho L-lactate as the relevant physiological substrates. 2-phosphoglycolate is known to be generated during repair of damaged DNA ends whereas, 2-phospho L-lactate is a product of pyruvate kinase side reaction. These metabolites are potent inhibitors of the key glycolytic enzymes, triosephosphate isomerase and phosphofructokinase, and hence clearance of these toxic metabolites is vital for cell survival and functioning. Gene knockout studies conducted in P. berghei revealed the essential nature of this conserved 'metabolic proof-reading enzyme'.
Characterization of young and old adult brains: An EEG functional connectivity analysis
Authors: Moezzi Bahar , Pratti Latha Madhuri , Hordacre Brenton , Graetz Lynton , Berryman Carolyn , Lavrencic Louise M , Ridding Michael C , Keage Hannah AD , McDonnell Mark D , Goldsworthy Mitchell R
Published: December 2018

Brain connectivity studies have reported that functional networks change with older age. We aim to (1) investigate whether electroencephalography (EEG) data can be used to distinguish between individual functional networks of young and old adults; and (2) identify the functional connections that contribute to this classification. Two eyes-open resting-state EEG recording sessions with 64 electrodes for each of 22 younger adults (19-37 years) and 22 older adults (63-85 years) were conducted. For each session, imaginary coherence matrices in theta, alpha, beta and gamma bands were computed. A range of machine learning classification methods were utilized to distinguish younger and older adult brains. A support vector machine (SVM) classifier was 94% accurate in classifying the brains by age group. We report decreased functional connectivity with older age in theta, alpha and gamma bands, and increased connectivity with older age in beta band. Most connections involving frontal, temporal, and parietal electrodes, and approximately two-thirds of connections involving occipital electrodes, showed decreased connectivity with older age. Just over half of the connections involving central electrodes showed increased connectivity with older age. Functional connections showing decreased strength with older age had significantly longer electrode-to-electrode distance than those that increased with older age. Most of the connections used by the classifier to distinguish participants by age group belonged to the alpha band. Findings suggest a decrease in connectivity in key networks and frequency bands associated with attention and awareness, and an increase in connectivity of the sensorimotor functional networks with ageing during a resting state.
An integrated genome-wide multi-omics analysis of gene expression dynamics in the preimplantation mouse embryo
Authors: Israel Steffen , Ernst Mathias , Psathaki Olympia E. , Drexler Hannes C. A. , Casser Ellen , Suzuki Yutaka , Makalowski Wojciech , Boiani Michele , Fuellen Georg , Taher Leila
Published: December 2018

Early mouse embryos have an atypical translational machinery comprised of cytoplasmic lattices, poorly competent for translation. Thus, the impact of transcriptomic changes on the operational levels of proteins has likely been overestimated in the past. To find out, we used liquid chromatography–tandem mass spectrometry to detect and quantify 6,550 proteins in the oocyte and in six developmental stages (from zygote to blastocyst) collected in triplicates, and we also performed mRNA sequencing.

In contrast to the known split between the 2-cell and 4-cell stages at the transcript level, on the protein level the oocyte-to-embryo transition appeared to last until the morula stage. In general, protein abundance profiles were weakly correlated with those of their cognate mRNAs and we found little or no concordance between changes in protein and transcript expression relative to the oocyte at early stages. However, concordance increased towards morula and blastocyst, hinting at a more direct coupling of proteins with transcripts at these stages, in agreement with the increase in free ribosome abundance. Independent validation by immunofluorescence and qPCR confirmed the existence of genes featuring strongly positively and negatively correlated protein and transcript. Moreover, consistent coverage of most known protein complexes indicates that our dataset represents a large fraction of the expressed proteome. Finally, we identified 20 markers, including members of the endoplasmic reticulum pathway, for discriminating between early and late stages.

This resource contributes towards closing the gap between the ‘predicted’ phenotype, based on mRNA, and the ‘actual’ phenotype, based on protein, of the mouse embryo.
Selection for synchronized replication of genes encoding the same protein complex during tumorigenesis
Authors: Chen Ying , Li Ke , Chu Xiao , Carey Lucas B. , Qian Wenfeng
Published: December 2018

DNA replication alters the dosage balance among genes; at the mid-S phase, early-replicating genes have doubled their copies while late-replicating genes have not. Dosage imbalance among proteins, especially within members of a protein complex, is toxic to cells. Here, we propose the synchronized replication hypothesis: genes sensitive to stoichiometric relationships will be replicated simultaneously to maintain stoichiometry. In support of this hypothesis, we observe that genes encoding the same protein complex have similar replication timing, but surprisingly, only in fast-proliferating cells such as embryonic stem cells and cancer cells. The synchronized replication observed in cancer cells, but not in slow-proliferating differentiated cells, is due to convergent evolution during tumorigenesis that restores synchronized replication timing within protein complexes. Collectively, our study reveals that the selection for dosage balance during S phase plays an important role in the optimization of the replication-timing program; that this selection is relaxed during differentiation as the cell cycle is elongated, and restored as the cell cycle shortens during tumorigenesis.
Distinct ipRGC subpopulations mediate light's acute and circadian effects on body temperature and sleep
Authors: Rupp Alan C. , Ren Michelle , Altimus Cara , Fernandez Diego , Richardson Melissa , Turek Fred , Hattar Samer , Schmidt Tiffany M
Published: December 2018

The light environment greatly impacts human alertness, mood, and cognition by acute regulation of physiology and indirect alignment of circadian rhythms. Both processes require the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), but the relevant downstream brain areas remain elusive. ipRGCs project widely in the brain, including to the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Here we show that body temperature and sleep responses to light are absent after genetic ablation of all ipRGCs except a subpopulation that projects to the SCN. Furthermore, by chemogenetic activation of the ipRGCs that avoid the SCN, we show that these cells are sufficient for acute changes in body temperature. Our results challenge the idea that the SCN is a major relay for the acute effects of light on non-image forming behaviors and identify the sensory cells that initiate light's profound effects on body temperature and sleep.
Electron cryo-tomography of vestibular hair-cell stereocilia
Authors: Metlagel Zoltan , Krey Jocelyn F , Song Junha , Swift Mark F , Tivol William J , Dumont Rachel A , Thai Jasmine , Chang Alex , Seifikar Helia , Volkmann Niels , Hanein Dorit , Barr-Gillespie Peter G , Auer Manfred
Published: December 2018

High-resolution imaging of hair-cell stereocilia of the inner ear has contributed substantially to our understanding of auditory and vestibular function. To provide three-dimensional views of the structure of stereocilia cytoskeleton and membranes, we developed a method for rapidly freezing unfixed stereocilia on electron microscopy grids, which allowed subsequent 3D imaging by electron cryo-tomography. Structures of stereocilia tips, shafts, and tapers were revealed, demonstrating that the actin paracrystal was not perfectly ordered. This sample-preparation and imaging procedure will allow for examination of structural features of stereocilia in a near-native state.