bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe traumatic brain injury is associated with a unique coagulopathy phenotype
Authors: Samuels Jason M. , Moore Ernest E. , Silliman Christopher C. , Banerjee Anirban , Cohen Mitchell J. , Ghasabyan Arsen , Chandler James , Coleman Julia R. , Sauaia Angela
Published: December 2018

BACKGROUND

Traumatic brain injury (TBI) patients present on a spectrum from hypocoagulability to hypercoagulability, depending on the injury complexity, severity, and time since injury. Prior studies have found a unique coagulopathy associated with TBI using conventional coagulation assays such as INR; however, few studies have assessed the association of TBI and coagulopathy using viscoelastic assays that comprehensively evaluate the coagulation in whole blood. This study aims to reevaluate the TBI-specific trauma-induced coagulopathy using arrival thrombelastography. Because brain tissue is high in key procoagulant molecules, we hypothesize that isolated TBI is associated with procoagulant and hypofibrinolytic profiles compared with injuries of the torso, extremities, and polytrauma, including TBI.

METHODS

Data are from the prospective Trauma Activation Protocol study. Activated clotting time (ACT), angle, maximum amplitude (MA), 30-minute percent lysis after MA (LY30), and functional fibrinogen levels (FFLEV) were recorded. Patients were categorized into isolated severe TBI (I-TBI), severe TBI with torso and extremity injuries (TBI + TORSO/EXTREMITIES), and isolated torso and extremity injuries (I-TORSO/EXTREMITIES). Poisson regression was used to adjust for multiple confounders.

RESULTS

Overall, 572 patients (48 I-TBI, 45 TBI + TORSO/EXTREMITIES, 479 I-TORSO/EXTREMITIES) were included in this analysis. The groups differed in INR, ACT, angle, MA, and FFLEV but not in 30-minute percent lysis. When compared with I-Torso/Extremities, after adjustment for confounders, severe I-TBI was independently associated with ACT less than 128 seconds (relative risk [RR], 1.5; 95% confidence interval [CI], 1.1–2.2), angle less than 65 degrees (RR, 2.2; 95% CI, 1.4–3.6), FFLEV less than 356 (RR, 1.7; 95% CI, 1.2–2.4) but not MA less than 55 mm, hyperfibrinolysis, fibrinolysis shutdown, or partial thromboplastin time (PTT) greater than 30.

CONCLUSION

Severe I-TBI was independently associated with a distinct coagulopathy with delayed clot formation but did not appear to be associated with fibrinolysis abnormalities. Low fibrinogen and longer ACT values associated with I-TBI suggest that early coagulation factor replacement may be indicated in I-TBI patients over empiric antifibrinolytic therapy. Mechanisms triggering coagulopathy in TBI are unique and warrant further investigation.

LEVEL OF EVIDENCE

Retrospective cohort study, prognostic, level III.
The EGS grading scale for skin and soft-tissue infections is predictive of poor outcomes: a multicenter validation study
Authors: Savage Stephanie A. , Li Shi Wen , Utter Garth H. , Cox Jessica A. , Wydo Salina M. , Cahill Kevin , Sarani Babak , Holzmacher Jeremy , Duane Therese M. , Gandhi Rajesh R. , Zielinski Martin D. , Ray-Zack Mohamed , Tierney Joshua , Chapin Trinette , Murphy Patrick B. , Vogt Kelly N. , Schroeppel Thomas J. , Callaghan Emma , Kobayashi Leslie , Coimbra Raul , Schuster Kevin M. , Gillaspie Devin , Timsina Lava , Louis Alvancin , Crandall Marie
Published: December 2018

INTRODUCTION

Over the last 5 years, the American Association for the Surgery of Trauma has developed grading scales for emergency general surgery (EGS) diseases. In a previous validation study using diverticulitis, the grading scales were predictive of complications and length of stay. As EGS encompasses diverse diseases, the purpose of this study was to validate the grading scale concept against a different disease process with a higher associated mortality. We hypothesized that the grading scale would be predictive of complications, length of stay, and mortality in skin and soft-tissue infections (STIs).

METHODS

This multi-institutional trial encompassed 12 centers. Data collected included demographic variables, disease characteristics, and outcomes such as mortality, overall complications, and hospital and ICU length of stay. The EGS scale for STI was used to grade each infection and two surgeons graded each case to evaluate inter-rater reliability.

RESULTS

1170 patients were included in this study. Inter-rater reliability was moderate (kappa coefficient 0.472–0.642, with 64–76% agreement). Higher grades (IV and V) corresponded to significantly higher Laboratory Risk Indicator for Necrotizing Fasciitis scores when compared with lower EGS grades. Patients with grade IV and V STI had significantly increased odds of all complications, as well as ICU and overall length of stay. These associations remained significant in logistic regression controlling for age, gender, comorbidities, mental status, and hospital-level volume. Grade V disease was significantly associated with mortality as well.

CONCLUSION

This validation effort demonstrates that grade IV and V STI are significantly predictive of complications, hospital length of stay, and mortality. Though predictive ability does not improve linearly with STI grade, this is consistent with the clinical disease process in which lower grades represent cellulitis and abscess and higher grades are invasive infections. This second validation study confirms the EGS grading scale as predictive, and easily used, in disparate disease processes.

LEVEL OF EVIDENCE

Prognostic/Epidemiologic retrospective multicenter trial, level III.
Indocyanine green dye angiography as an adjunct to assess indeterminate burn wounds: A prospective, multicentered, triple-blinded study
Authors: Wongkietkachorn Apinut , Surakunprapha Palakorn , Winaikosol Kengkart , Waraasawapati Sakda , Chaiwiriyakul Surachat , Eua-angkanakul Kant , Wongkietkachorn Nuttapone , Punyavong Pattama , Jenwitheesuk Kamonwan , Chowchuen Bowornsilp
Published: December 2018

BACKGROUND

Clinical assessment of indeterminate burn wounds has been reported to yield poor accuracy, even when performed by burn experts. Indocyanine green (ICG) dye angiography has been found to be highly accurate in assessing burn depth, but there is still limited evidence of its use in indeterminate burn wounds. This study aims to compare the accuracy of ICG angiography to that of clinical assessment in assessing indeterminate burn wounds.

METHODS

This is a prospective, multicentered, triple-blinded, experimental study. Participants were stable patients, admitted to the hospital with burn wounds of indeterminate depth. The burn wounds were clinically assessed by an attending plastic surgeon. ICG angiography was performed and evaluated by another surgeon. Tissue biopsies were obtained and sent for histological study to be assessed as the gold standard.

RESULTS

In the 30 burn sites that were assessed, the accuracy of ICG angiography was 100.0%, compared with 50.0% for clinical assessment (p < 0.001). Clinical assessment yielded a sensitivity of 33.3% and specificity of 66.7%, while ICG angiography yielded both a sensitivity and specificity of 100.0%. Therefore, the number needed to treat for using ICG angiography in indeterminate burn wounds was two.

CONCLUSION

Indocyanine green angiography yields a significantly higher accuracy than clinical assessment in indeterminate burn wounds. This intervention can, thus, be a useful tool to aid clinical judgment.

TRIAL REGISTRATION

Thai Clinical Trials Registry, number TCTR20170821001.

LEVEL OF EVIDENCE

Diagnostic test, level I.
Clearance of Indocyanine Green in Severe Pediatric Burns
Authors: Diaz Eva C. , Herndon David Newcomb , Cleves Mario Alberto , Mlcak Ronald P. , Aarsland Asle , Børsheim Elisabet
Published: December 2018

BACKGROUND

Clearance of indocyanine green dye (ICGc) reflects sinusoidal perfusion and hepatocyte cell membrane function. Thus, ICGc is a reflection of the functional reserve of intact hepatocytes. The purpose of this study was to identify predictors of ICGc in severely burned children during the acute hospitalization and at the time of discharge from the intensive care unit (ICU). A secondary aim was to determine the relationship between liver size and patient ICGc.

METHODS

Twenty-six children (0.8–17 years old) with 35% or greater total body surface area burned (%TBSA-B) were included. Assessment of ICGc (in milliliters per minute per meter squared) was done during the acute hospitalization (median: 6 days after admission, median: 14 days postburn) and at the time of discharge from the ICU (median: 19 days after admission, median: 27 days postburn). Age, TBSA-B, % third-degree burns, inhalation injury, preexisting chronic malnutrition, hematocrit, liver dysfunction, and time from burn injury were incorporated in multiple linear regressions as predictive variables of ICGc. Only variables with p < 0.05 were retained in the final models.

RESULTS

Time from injury and age were the strongest predictors of ICGc during the acute admission but not at the time of discharge from the ICU. Time from injury was negatively associated with ICGc, whereas age was positively associated. At the time of discharge from the ICU, ICGc was increased in proportion to the %TBSA-B, whereas inhalation injury and preexisting chronic malnutrition were associated with lower ICGc. There was no correlation between change-to-predicted liver length and ICGc.

CONCLUSIONS

The intrinsic ability of the liver to extract ICG from plasma was lower in younger burned patients during the acute admission and in those with preexisting chronic malnutrition and inhalation injury at the time of discharge from the ICU.

LEVEL OF EVIDENCE

Prognostic/Epidemiologic, level III.
Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications
Authors: Isles Anthony R. , Winstanley Catharine A. , Humby Trevor
Published: December 2018

Our willingness to take risks, our ability to wait or the speed with which to make decisions are central features of our personality. However, it is now recognized that impulsive and risk-taking behaviours are not a unitary construct, and different aspects can be both psychologically and neurally dissociated. The range of neurochemicals and brain systems that govern these behaviours is extensive, and this may be a contributing factor to the phenotypic range seen in the human population. However, this variety can also be pathological as extremes in risk-taking and impulsive behaviours are characteristics of many neuropsychiatric and indeed neurodegenerative disorders. This spans obsessive–compulsive disorder, where behaviour becomes ridged and non-spontaneous, to the nonsensical risk-taking seen in gambling and drug taking.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.
Relationships among impulsive, addictive and sexual tendencies and behaviours: a systematic review of experimental and prospective studies in humans
Authors: Leeman Robert F. , Rowland Bonnie H. P. , Gebru Nioud Mulugeta , Potenza Marc N.
Published: December 2018

Impulsivity's relationships to addictive and sexual behaviours raise questions regarding the extent impulsivity may constitute a vulnerability factor for subsequent addictive and sexual behaviours and/or results from each of these. Here, we systematically reviewed empirical support for impulsivity as a precipitating factor or a consequence of addictive or sexual behaviours. We restricted ourselves to recent, human studies with assessments over time, including at least one measure of impulsivity, addictive and sexual behaviours, yielding a review including 29 published reports from 28 studies. Findings point to generalized, self-reported impulsivity as a predictor of addictive and sexual behaviours at a wide range of severity, with elements of both impulsivity and compulsivity to these acts. Alcohol consumption often increases impulsive behaviour, including inclinations towards impulsive and potentially compulsive sexual acts. Research using the Sexual Delay Discounting Task has yielded findings linking impulsivity, addictive and sexual behaviour and as such is a valuable research tool that should be used more extensively. The present review identified gaps to be addressed in further research that concurrently examines facets of impulsivity, addictive and sexual behaviours, especially because criteria for compulsive sexual behaviour disorder have been included in the eleventh edition of the
International Classification of Diseases
.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Impulsivities and addictions: a multidimensional integrative framework informing assessment and interventions for substance use disorders
Authors: Vassileva Jasmin , Conrod Patricia J.
Published: December 2018

Impulse control is becoming a critical survival skill for the twenty-first century. Impulsivity is implicated in virtually all externalizing behaviours and disorders, and figures prominently in the aetiology and long-term sequelae of substance use disorders (SUDs). Despite its robust clinical and predictive validity, the study of impulsivity is complicated by its multidimensional nature, characterized by a variety of trait-like personality dimensions, as well as by more state-dependent neurocognitive dimensions, with variable convergence across measures. This review provides a hierarchical framework for linking self-report and neurocognitive measures to latent constructs of impulsivity and, in turn, to different psychopathology vulnerabilities, including substance-specific addictions and comorbidities. Impulsivity dimensions are presented as novel behavioural targets for prevention and intervention. Novel treatment approaches addressing domains of impulsivity are reviewed and recommendations for future directions in research and clinical interventions for SUDs are offered.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
SingleCellNet: a computational tool to classify single cell RNA-Seq data across platforms and across species
Authors: Tan Yuqi , Cahan Patrick
Published: December 2018

Single cell RNA-Seq has emerged as a powerful tool in diverse applications, ranging from determining the cell-type composition of tissues to uncovering the regulators of developmental programs. A near-universal step in the analysis of single cell RNA-Seq data is to hypothesize the identity of each cell. Often, this is achieved by finding cells that express combinations of marker genes that had previously been implicated as being cell-type specific, an approach that is not quantitative and does not explicitly take advantage of other single cell RNA-Seq studies. Here, we describe our tool, SingleCellNet, which addresses these issues and enables the classification of query single cell RNA-Seq data in comparison to reference single cell RNA-Seq data. SingleCellNet compares favorably to other methods, and it is notably able to make sensitive and accurate classifications across platforms and species. We demonstrate how SingleCellNet can be used to classify previously undetermined cells, and how it can be used to assess the outcome of cell fate engineering experiments.
Multiple mutations acquired into canine RecQ-like helicases encoded by the aneuploid genome of transmissible sarcoma
Authors: Kapulkin Wadim J.
Published: December 2018

Sticker sarcoma – a highly aneuploid, contagious neoplasm circulating in a domestic dog population - is broadly referred as a canine transmissible venereal tumour (CTVT). The karyotype of transmissible Sticker sarcoma appears as a collage of numerical and structural aberrations; the CTVT genome represents the generalized but stable neoplastic aneuploidy of monoclonal origins. Presented is an analysis of genetic events and variants underlying the aneuploid genomic structure of Sticker sarcoma described previously by Murchison et al. (2014) and Decker et al. (2015). Here we explored the above CTVT genomic compendia and mined the existing data - specifically looking for cases of convergence of multiple non-synonymous variants onto a single gene - the mutational patterns indicative for Knudsonian ‘two-hit’ kinetics. A Table I is given, providing theoretical estimates of retaining the intact wild-type copy, expected as a function of a cumulative mutational convergence observed in unphased sequence consensus. We demonstrate that the two canine RecQ-like helicases: Bloom syndrome helicase and RECQL4, encoded by the aneuploid transmissible tumour, have accumulated a multitude of different mutations. Among the sets of most intensely mutated transmissible sarcoma genes, we also identified a canine FANCD2 – yet another previously unnoticed multiple-hit candidate factor. We discuss a possible role of mutated RecQ-like helicases and other cooperating factors, perceivably involved in the maintenance of the neoplastic aneuploidy. We suggest the proposed cooperative actions of CTVT RecQ-like DNA helicases could be relevant interpreting whether variants contributing to RecQ-dependent karyotypic traits, respond to selective pressures that preserve the aneuploid genomic structure of transmissible Sticker sarcoma.
Live cell monitoring for factors affecting genome variation
Authors: Xia Yuntao , Zhu Kuangzheng , Irianto Jerome , Andrechak Jason C , Dooling Lawrence J , Pfeifer Charlotte R , Discher Dennis E
Published: December 2018

Cancer cells and pluripotent stem cells frequently exhibit gains or losses of entire chromosomes and chromosome segments, and the typical terminal analyses of genomes suggest this aneuploidy is ongoing and particularly variable in solid tumors. Here, we quantify aneuploidy-inducing perturbations by live cell fluorescence monitoring for changes in chromosome-5 in a lung cancer line and in normal diploid iPS cells. Inhibition of the spindle assembly checkpoint (SAC) and knockdown of DNA repair factors cause chromosome mis-segregation to increase several-fold above a low baseline level, and both perturbations also generate several-fold more rare fluorescent-null cells. Loss of chromosome-5 is confirmed by single cell karyotyping, SNP arrays on stable isolated clones, and downregulated expression of genes on chromosome-5 in single cell transcriptomics. The iPS cells also show loss of fluorescence in infrequent cells after SAC inhibition and upon growth as teratomas in mice. Viability, selection, and altered expression can thus be tracked to reveal molecular mechanisms in aneuploidy.
Transcriptome landscape of a thermal-tolerant coral endosymbiont reveals molecular signatures of symbiosis and dysbiosis
Authors: Bellantuono Anthony J. , Dougan Katherine E. , Granados-Cifuentes Camila , Rodriguez-Lanetty Mauricio
Published: December 2018

Warming oceans disrupt the critical endosymbiosis between corals and their photosynthetic dinoflagellate endosymbionts of the family Symbiodiniaceae.Durusdinium trenchiiis a heat-tolerant species of Symbiodiniaceae and enhances survival of its coral host, but the basis for tolerance is largely unknown. To identify the underpinnings of heat tolerance and symbiosis, we compared thein hospiteand free-living transcriptomes ofD. trenchiiunder stable temperature conditions and acute hyperthermal stress. We discovered that under stable conditions,in hospitecells exhibit lower transcriptional activity than free-living counterparts, suggesting the shutdown of genes uniquely required for a free-living lifestyle. However, under hyperthermal stress the transcriptional response was largerin hospite, indicating an exacerbated stress environment within the host cell. Significantly, we unraveled the molecular signatures of symbiont heat tolerance within the host, which is a critical step to enable the development of engineered endosymbionts as a tool for restoration of coral reefs.
Speech Fine Structure Contains Critical Temporal Cues to Support Speech Segmentation
Authors: Teng Xiangbin , Cogan Gregory , Poeppel David
Published: December 2018

Segmenting the continuous speech stream into units for further perceptual and linguistic analyses is fundamental to speech recognition. The speech amplitude envelope (SE) has long been considered a fundamental temporal cue for segmenting speech. Does the temporal fine structure (TFS), a significant part of speech signals often considered to contain primarily spectral information, contribute to speech segmentation? Using magnetoencephalography, we show that the TFS entrains cortical oscillatory responses between 3-6 Hz and demonstrate, using mutual information analysis, that (i) the temporal information in the TFS can be reconstructed from a measure of frame-to-frame spectral change and correlates with the SE and (ii) that spectral resolution is key to the extraction of such temporal information. Furthermore, we show behavioural evidence that, when the SE is temporally distorted, the TFS provides cues for speech segmentation and aids speech recognition significantly. Our findings show that it is insufficient to investigate solely the SE to understand temporal speech segmentation, as the SE and the TFS derived from a band-filtering method convey comparable, if not inseparable, temporal information. We argue for a more synthetic view of speech segmentation — the auditory system groups speech signals coherently in both temporal and spectral domains.
Duffy Antigen Expression in Erythroid Bone Marrow Precursor Cells of Genotypically Duffy Negative Individuals
Authors: Dechavanne Célia , Dechavanne Sebastien , Metral Sylvain , Roeper Brooke , Krishnan Sushma , Fong Rich , Bennett Seth , Carias Lenore , Chen Edwin , Salinas Nichole D. , Ghosh Anil , Tolia Niraj H. , Woost Philip G. , Jacobberger James W. , Colin Yves , Gamain Benoit , King Christopher L. , Zimmerman Peter A.
Published: December 2018

The gene encoding the Duffy blood group protein (Fy, CD234; additional designations Duffy Antigen Receptor of Chemokines [DARC] and Atypical Chemokine Receptor 1 [ACKR1]) is characterized by a SNP in a GATA-1 transcription factor binding site associated with the erythrocyte silent (ES) phenotype.FYEShomozygous people are viewed to be highly resistant to blood stage infection withPlasmodium vivax. Increasingly, however, studies are reportingP. vivaxinfections in Fy-negative individuals across malarious African countries whereFYESapproaches genetic fixation. This suggests thatP. vivaxhas evolved a Fy-independent RBC invasion pathway, or that the GATA-1 SNP does not abolish Fy expression. Here, we tested the second hypothesis through binding studies to erythroid lineage cells using recombinantP. vivaxDuffy binding protein, the parasite’s invasion ligand and Fy6-specific antibodies. We first observed variable Fy expression on circulating RBCs, irrespective ofFYgenotype;FYESRBCs were periodically Fy-positive. Furthermore, during thein vitroerythroid differentiation of CD34+ cells and onex vivobone marrow samples, we observed Fy expression on erythroid precursor cells fromFYESpeople. Finally, the Fy6-specific nanobody, CA111 was used to capture Fy from the surface ofFYESRBCs. Our findings reveal that the GATA-1 SNP does not fully abolish Fy expression and provide insight on potential susceptibility of Fy-negative people to vivax malaria.

Significance

Duffy blood group negativity results from a single nucleotide polymorphism (SNP) in the gene promoter, and reaches genetic fixation in many African ethnicities. Because the Duffy protein (Fy) is an important contact point duringPlasmodium vivaxhuman red blood cell invasion, Fy-negativity is considered to confer resistance toP. vivaxmalaria. With recent studies in African countries reportingP. vivaxinfection in Fy-negative people, we studied Fy expression across erythroid development. Here we report that theFYpromoter SNP does not abolish Fy protein expression in erythroid progenitors developing in the bone marrow. These results further emphasizes the importance of reticulocytes as targets forP. vivaxblood stage infection and propose a mechanism forP. vivaxinfections in Fy-negative people.
Eco-evolutionary significance of 'loners'
Authors: Rossine Fernando W , Martinez-Garcia Ricardo , Sgro Allyson E. , Gregor Thomas , Tarnita Corina E
Published: December 2018

Loners, individuals out-of-sync with a coordinated majority, occur frequently in nature. Are loners incidental byproducts of large-scale synchronization attempts or are they part of a mosaic of life-history strategies? Here, we provide the first empirical evidence of naturally occurring heritable variation in loner behavior, using the social amoeba Dictyostelium discoideum. Moreover, we show that Dictyostelium loners, cells that do not join the multicellular life-stage, result from a dynamic population-partitioning process. Underlying this partitioning, we find evidence that each cell makes a stochastic, signal-based decision resulting in an imperfectly synchronized multicellular development affected by both abiotic (environmental porosity) and biotic (strain-specific signaling) factors. Finally, we predict that when strains differing in their partitioning behavior co-occur, cross-signaling impacts slime-mold diversity across spatio-temporal scales. Loners are therefore critical to understanding collective and social behaviors, multicellular development, and ecological dynamics in D. discoideum. More broadly, across taxa, imperfect synchronization might be adaptive by enabling diversification of life-history strategies.
Mapping and characterization of structural variation in 17,795 deeply sequenced human genomes
Authors: Abel Haley J. , Larson David E. , Chiang Colby , Das Indraniel , Kanchi Krishna L. , Layer Ryan M. , Neale Benjamin M. , Salerno William J. , Reeves Catherine , Buyske Steven ,   NHGRI Centers for Common Disease Genomics, Matise Tara C. , Muzny Donna M. , Zody Michael C. , Lander Eric S. , Dutcher Susan K. , Stitziel Nathan O. , Hall Ira M.
Published: December 2018

A key goal of whole genome sequencing (WGS) for human genetics studies is to interrogate all forms of variation, including single nucleotide variants (SNV), small insertion/deletion (indel) variants and structural variants (SV). However, tools and resources for the study of SV have lagged behind those for smaller variants. Here, we used a cloud-based pipeline to map and characterize SV in 17,795 deeply sequenced human genomes from common disease trait mapping studies. We publicly release site-frequency information to create the largest WGS-based SV resource to date. On average, individuals carry 2.9 rare SVs that alter coding regions, which affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Based on a computational model, we estimate that SVs account for 17.2% of rare alleles genome-wide whose predicted deleterious effects are equivalent to loss-of-function (LoF) coding alleles; ~90% of such SVs are non-coding deletions (mean 19.1 per genome). We report 158,991 ultra-rare SVs and show that ~2% of individuals carry ultra-rare megabase-scale SVs, nearly half of which are balanced and/or complex rearrangements. Finally, we exploit this resource to infer the dosage sensitivity of genes and non-coding elements, revealing strong trends related to regulatory element class, conservation and cell-type specificity. This work will help guide SV analysis and interpretation in the era of WGS.
Cyclic Nucleotide-Gated Ion Channel 2 modulates auxin homeostasis and signaling
Authors: Chakraborty Sonhita , Toyota Masatsugu , Moeder Wolfgang , Chin Kimberley , Fortuna Alex , Champigny Marc , Vanneste Steffen , Gilroy Simon , Beeckman Tom , Nambara Eiji , Yoshioka Keiko
Published: December 2018

Cyclic Nucleotide Gated Ion Channels (CNGCs) have been firmly established as Ca2+-conducting ion channels that regulate a wide variety of physiological responses in plants. CNGC2 has been implicated in plant immunity and Ca2+signaling due to the autoimmune phenotypes exhibited by null mutants ofCNGC2. However,cngc2mutants display additional phenotypes that are unique among autoimmune mutants, suggesting that CNGC2 has functions beyond defense and generates distinct Ca2+signals in response to different triggers. In this study we found thatcngc2mutants showed reduced gravitropism, consistent with a defect in auxin signaling. This was mirrored in the diminished auxin response detected by the auxin reporters DR5::GUS and DII-VENUS and in a strongly impaired auxin-induced Ca2+response. Moreover, thecngc2mutant exhibits higher levels of the endogenous auxin indole-3-acetic acid (IAA), indicating that excess auxin incngc2causes its pleiotropic phenotypes. These auxin signaling defects and the autoimmunity syndrome ofcngc2could be suppressed by loss-of-function mutations in the auxin biosynthesis geneYUCCA6(YUC6), as determined by identification of thecngc2suppressor mutantrepressor of cngc2(rdd1) as an allele ofYUC6. A loss-of-function mutation in the upstream auxin biosynthesis geneTRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS(TAA1, WEAK ETHYLENE INSENSITIVE8) also suppressed thecngc2phenotypes, further supporting the tight relationship between CNGC2 and the TAA–YUC-dependent auxin biosynthesis pathway. Taking these results together, we propose that the Ca2+signal generated by CNGC2 is a part of the negative feedback regulation of auxin homeostasis in which CNGC2 balances cellular auxin perception by influencing auxin biosynthesis.
Stochastic transcriptional pulses orchestrate flagellum biosynthesis in E. coli
Authors: Kim J. Mark , Garcia-Alcala Mayra , Balleza Enrique , Cluzel Philippe
Published: December 2018

The classic picture of flagellum biosynthesis in E. coli, inferred from population measurements, describes a tightly controlled, deterministic transcriptional program. In individual E. coli cells, we discover that flagellar promoters are in fact stochastically activated in pulses. Such pulses comprise coordinated ‘on’ and ‘off’ states of promoter activity, each of which can span multiple generations. We demonstrate that this pulsing program obeys the regulatory logic of flagellar assembly, which dictates whether some promoters skip pulses. Remarkably, pulses in this transcriptional network appear to be actually governed by a post-translational circuit. Our results suggest that even topologically simple transcriptional networks can generate unexpectedly rich temporal dynamics and phenotypic heterogeneities.
Rab converter DMon1 constitutes a novel node in the brain-gonad axis essential for female germline maturation
Authors: Dhiman Neena , Deshpande Girish , Ratnaparkhi Girish S , Ratnaparkhi Anuradha
Published: December 2018

Monensin-sensitive 1 (Mon1) is an endocytic regulator that participates in the conversion of Rab5 positive early endosomes to Rab7 positive late endosomes. In Drosophila, loss of mon1 (Dmon1) leads to sterility. The Dmon1 mutant females have extremely small ovaries with complete absence of late stage egg chambers, a phenotype reminiscent of mutations in the insulin pathway genes. Consistently, we find that expression of many Drosophila insulin-like peptides (Dilps) is down regulated in Dmon1 mutants. Conversely, feeding an insulin-rich diet can rescue the ovarian defects induced by the loss of Dmon1. Surprisingly however, Dmon1 is required in the tyramine/octopaminergic neurons (OPNs) and not in the ovaries or the insulin producing cells (IPCs). Thus, knockdown of Dmon1 in just the OPNs is sufficient to mimic the ovarian phenotype while expression of Dmon1 in the OPNs alone, is sufficient to rescue the mutant defect. Lastly, we have identified dilp5 as a critical target of Dmon1. Both, protein and mRNA levels of Dilp5 are reduced in Dmon1 mutants and IPC-specific dilp5 over expression can ameliorate the Dmon1 dependent sterility defect. The study thus identifies Dmon1 as a novel molecular player in the brain-gonad axis and underscores the significance of inter-organ systemic communication during development.
Comparison of the structural organisation of reeler hippocampal CA1 region with wild type CA1.
Authors: Yousuf Malikmohamed , Zhao Shanting , Frotscher Michael
Published: December 2018

The dendritic pattern defines the input capacity of a neuron. Existing methods such as Golgi impregnation or intracellular staining only label a small number of neurons. By using high-resolution imaging and 3D reconstruction of green fluorescent protein-expressing neurons, the present study provides an approach to investigate the anatomical organization of dendritic structures in defined brain regions. We characterized the structural organization of dendrites in the CA1 region of the mouse hippocampus by analyzing Sholl intersections, dendritic branches, branching and orientation angles of dendrites, and the different types of spine on the dendritic branches. Utilizing this quantitative imaging approach, we show that there are differences in the number of Sholl intersections and in the orientation of apical and basal dendrites of CA1 pyramidal neurons. Performing 3D reconstructions of the CA1 region of the reeler hippocampus, we show that neurons of this mutant display an arbitrary orientation of apical dendrites at angles ranging from -180 to +180 degrees in contrast to wild-type mice that show a preferred orientation angle. This methodology provides a way of analyzing network organization in wild type and mutant brains using quantitative imaging techniques. Here, we have provided evidence that in reeler a sparse, weakly connected network results from the altered lamination of CA1 pyramidal neurons and the variable orientation of their dendrites.
Structural basis of recognition and destabilization of histone H2B ubiquitinated nucleosome by DOT1L histone H3 Lys79 methyltransferase
Authors: Jang Seongmin , Kang Chanshin , Yang Han-Sol , Jung Taeyang , Hebert Hans , Chung Ka Young , Kim Seung Joong , Hohng Sungchul , Song Ji-Joon
Published: December 2018

DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B-ubiquitination. Here, we present cryo-EM structures of DOT1L complex with unmodified and H2B-ubiquitinated nucleosomes, showing that DOT1L recognizes H2B-ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L respectively. Furthermore, the structures combined with single-molecule FRET experiment show that H2B-ubiquitination enhances a non-catalytic function of DOT1L destabilizing nucleosome. These results establish the molecular basis of the cross-talk between H2B ubiquitination and H3 Lys79 methylation as well as nucleosome destabilization by DOT1L.
Common fragile sites are characterised by faulty condensin loading after replication stress
Authors: Boteva Lora , Nozawa Ryu-Suke , Naughton Catherine , Samejima Kumiko , Earnshaw William C , Gilbert Nick
Published: December 2018

Cells coordinate interphase to mitosis transition but recurrent cytogenetic lesions appear at common fragile sites (CFSs) in a tissue-specific manner following replication stress, marking regions of instability in cancer. Despite such a distinct defect no model fully explains their molecular configuration. We show that CFSs are characterised by impaired chromatin folding manifested as disrupted mitotic structures visible using molecular FISH probes in the presence and absence of replication stress. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle and mitosis. Subsequently cytogenetic and molecular lesions arise due to faulty condensin loading at CFSs, through a defect in condensin I mediated compaction and are coincident with mitotic DNA synthesis (MIDAS). This model suggests that in conditions of exogenous replication stress, aberrant condensin loading leads to molecular defects and CFS formation, concomitantly providing an environment for MIDAS, which, if not resolved, result in chromosome instability.
Automated nuclear cartography reveals conserved sperm chromosome territory localization across 2 million years of mouse evolution
Authors: Skinner Benjamin Matthew , Bacon Joanne , Rathje Claudia Cattoni , Larson Erica Lee , Kopania Emily Emiko Konishi , Good Jeffrey Martin , Affara Nabeel Ahmed , Ellis Peter James Ivor
Published: December 2018

Measurements of nuclear organization in asymmetric nuclei in 2D images have traditionally been manual. This is exemplified by attempts to measure chromosome position in sperm samples, typically by dividing the nucleus into zones, and manually scoring which zone a FISH signal lies in. This is time consuming, limiting the number of nuclei that can be analyzed, and prone to subjectivity. We have developed a new approach for automated mapping of FISH signals in asymmetric nuclei, integrated into an existing image analysis tool for nuclear morphology. Automatic landmark detection defines equivalent structural regions in each nucleus, then dynamic warping of the FISH images to a common shape allows us to generate a composite of the signal within the entire cell population. Using this approach, we mapped the positions of the sex chromosomes and two autosomes in three mouse lineages (Musmusculus domesticus, Mus musculus musculusandMus spretus). We found that in all three, chromosomes 11 and 19 tend to interact with each other, but are shielded from interactions with the sex chromosomes. This organization is conserved across 2 million years of mouse evolution.
Leveraging protein dynamics to identify cancer mutational hotspots in 3D-structures
Authors: Kumar Sushant , Clarke Declan , Gerstein Mark B.
Published: December 2018

Large-scale exome sequencing of tumors has enabled the identification of cancer drivers using recurrence and clustering-based approaches. Some of these methods also employ three-dimensional protein structures to identify mutational hotspots in cancer-associated genes. In determining such mutational clusters in structures, existing approaches overlook protein dynamics, despite the essential role of dynamics in protein functionality. In this work, we present a framework to identify driver genes using a dynamics-based search of mutational hotspot communities. After partitioning 3D structures into distinct communities of residues using anisotropic network models, we map variants onto the partitioned structures. We then search for signals of positive selection among these residue communities to identify putative drivers. We applied our method using the TCGA pan-cancer atlas missense mutation catalog. Overall, our analyses predict one or more mutational hotspots within the resolved structures of 434 genes. Ontological and pathway enrichment analyses implicate genes with predicted hotspots to be enriched in biological processes associated with tumor progression. Additionally, a comparison between our approach and existing hotspot detection methods that use structural data suggests that the inclusion of dynamics significantly increases the sensitivity of driver detection.
Identifying Changepoints in Biomarkers During the Preclinical Phase of AD
Authors: Younes Laurent , Albert Marilyn , Moghekar Abhay , Soldan Anja , Pettigrew Corinne , Miller Michael
Published: December 2018

Objective: Several models have been proposed for the evolution of Alzheimer's disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD. Methods: We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset. Results: All nine measures had significant changepoints, all of which preceded symptom onset, however the timing of these changepoints varied considerably. A single measure, CSF-tau, had an early changepoint (40 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF-Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a five-year time difference between the right and left side (respectively nine and three years prior to symptom onset). Conclusions: These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance.
Molecular Crowding Tunes Material States of Ribonucleoprotein Condensates
Authors: Kaur Taranpreet , Alshareedah Ibraheem , Wang Wei , Ngo Jason , Moosa Mahdi Muhammad , Banerjee Priya R.
Published: December 2018

Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to changing cellular environment. RNP condensation is largely governed by the promiscuous attractive inter-chain interactions, mediated by low-complexity domains (LCDs). Using an archetypal disordered RNP, Fused in Sarcoma (FUS), here we study how molecular crowding impacts the RNP liquid condensation. We observe that the liquid-liquid coexistence boundary of FUS is lowered by polymer crowders, consistent with the excluded volume model. With increasing bulk crowder concentration, RNP partition increases and the diffusion rate decreases in the condensed phase. Furthermore, we show that RNP condensates undergo substantial hardening wherein protein-dense droplets transition from viscous fluid to a viscoelastic gel-like state in a crowder concentration-dependent manner. Utilizing two distinct LCDs that broadly represent the most commonly occurring sequence motifs driving RNP phase transition, we reveal that the impact of crowding is largely independent of LCD charge/sequence patterns. These results are consistent with a thermodynamic model of crowder-mediated depletion interaction where inter-RNP attraction is enhanced by molecular crowding. The depletion force is likely to play key roles in tuning the physical properties of RNP condensates within a crowded intracellular space.
The convoluted evolutionary history of the capped-golden langur lineage (Cercopithecidae: Colobinae) – concatenation versus coalescent analyses
Authors: Arekar Kunal , Parigi Abhijna , Karanth K. Praveen
Published: December 2018

Evolutionary studies have traditionally relied on concatenation based methods to reconstruct relationships from multiple markers. However, due to limitations of concatenation analyses, recent studies have proposed coalescent based methods to address evolutionary questions. Results from these methods tend to diverge from each other under situations where there is incomplete lineage sorting or hybridization. Here we used concatenation as well as multispecies coalescent (MSC) methods to understand the evolutionary origin of capped and golden langur (CG) lineage. Previous molecular studies have retrieved conflicting phylogenies, with mitochondrial tree grouping CG lineage with a largely Indian genus Semnopithecus, while nuclear markers support their affinities with a Southeast Asian genus, Trachypithecus. However, as pointed by others, the use of nuclear copies of mitochondrial DNA in the above studies might have generated the discordance. Because of this discordance, the phylogenetic position of CG lineage has been much debated in recent times. In this study, we have used nine nuclear and eight mitochondrial markers. Concatenated nuclear as well as the mitochondrial dataset recovered congruent relationships where CG lineage was sister to Trachypithecus. However nuclear species tree estimated using different MSC methods were incongruent with the above result, suggesting presence of incomplete lineage sorting (ILS)/hybridisation. Furthermore, CG lineage is morphologically intermediate between Semnopithecus and Trachypithecus. Based on this evidence, we argue that CG lineage evolved through hybridisation between Semnopithecus and Trachypithecus. Finally, we reason that both concatenation as well as coalescent methods should be used in conjunction for better understanding of various evolutionary hypotheses.
Fundamental bounds on learning performance in neural circuits
Authors: Raman Dhruva V. , O’Leary Timothy
Published: December 2018

How does the size of a neural circuit influence its learning performance? Intuitively, we expect the learning capacity of a neural circuit to grow with the number of neurons and synapses. Larger brains tend to be found in species with higher cognitive function and learning ability. Similarly, adding connections and units to artificial neural networks can allow them to solve more complex tasks. However, we show that in a biologically relevant setting where synapses introduce an unavoidable amount of noise, there is an optimal size of network for a given task. Beneath this optimal size, our analysis shows how adding apparently redundant neurons and connections can make tasks more learnable. Therefore large neural circuits can either devote connectivity to generating complex behaviors, or exploit this connectivity to achieve faster and more precise learning of simpler behaviors. Above the optimal network size, the addition of neurons and synaptic connections starts to impede learning performance. This suggests that overall brain size may be constrained by the need to learn efficiently with unreliable synapses, and may explain why some neurological learning deficits are associated with hyperconnectivity. Our analysis is independent of specific learning rules and uncovers fundamental relationships between learning rate, task performance, network size and intrinsic noise in neural circuits.
Configural properties underlie the perceived faceness of a stimulus
Authors: Gnolo Carmine , Senden Mario , Grillini Alessandro , Cornelissen Frans W. , Goebel Rainer
Published: December 2018

The global geometrical arrangement of face parts (eyes over nose over mouth), commonly referred to as first order configural (FOC) properties, is believed to constitute a fundamental aspect of face detection. Indeed, several brain regions in the face processing network have been shown to display increased activity in response to abstract stimuli for face-like as compared to random spatial arrangements. However, the absence of a mathematical formalization of FOC properties makes it difficult to systematically study their contribution to face perception. To fill this gap, we used analytical geometry to define a set of 19 FOC features. In two psychophysical studies, a 2-alternative forced choice task assessing difference in perceived faceness between two stimuli and a Likert test assessing measuring perceived faceness of individual stimuli, we evaluated the contribution of each feature to the perceived faceness of abstract stimuli consisting of four black rectangular shapes reflecting the two eyes, the nose and the mouth. From the two experiments two subsets of features relevant for face detection were selected, including 10 and 11 features, respectively. Interestingly, 7 features are shared between the two sets. The difference between the subsets reflects processing of individual FOC features in the first study and holistic processing in the second study. The partial superimposition, on the other hand, is reflective of a shared basic mechanism in the perception of first order configural properties.