bluuebunny/crossref_metadata_2025 huggingface dataset:
Coal mining and lung disease in the 21st century
Authors: Leonard Rachel , Zulfikar Rafia , Stansbury Robert
Published: December 2019

Purpose of review

To review the impact of coal mining and resurgence of coal workers’ pneumoconiosis (CWP) in 21st century and effect of ambient air pollution on lung function.

Recent findings

At the beginning of 21st century, statistics by National Institute for Occupational Safety and Health showed a steep rise in pneumoconiosis. This was followed by numerous epidemiologic and pathologic studies that confirmed increasing CWP prevalence as well as disease in younger miners and those with a shorter mining tenure. Recent studies have demonstrated that poor dust control in mines, a relative shift in composition of the coal mine dust, small sized mines and increase in surface mining are all possible contributors to this resurgence. There is also growing literature evaluating the effects of worsening air pollution on health, including decreasing lung function and development of emphysema, worsening quality of life measures and lung cancer.

This irreversible but preventable disease currently haunts approximately 60 000 miners across United States and millions across the world. Its resurgence despite the strict dust regulations is a setback from the public health standpoint. The continued reliance on coal for energy will continue to place coal miners at danger of developing disease as well as the world.
Safety of withholding intubation in gamma-hydroxybutyrate- and gamma-butyrolactone-intoxicated coma patients in the emergency department
Authors: van Helmond Lidwien P.F.M. , Gresnigt Femke M.J.
Published: December 2019

Objective

The objective of this study was to determine if supportive care without endotracheal intubation in the emergency department (ED) was safe in the absence of complications in gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL) intoxicated patients with a decreased Glasgow Coma Scale (GCS) score.

Methods

This was a retrospective chart review of patients presenting to a Dutch tertiary urban ED with a reduced level of consciousness related to alleged GHB/GBL intoxication between April 2011–December 2014. Primary endpoint was major adverse events, defined by: upper airway obstruction not resolved with mayo tube or nasopharyngeal airway, hypoxia not resolved with 15 l of oxygen delivered via non-rebreathing mask, bradypnea not resolved after stimulation, intubation, bradycardia not resolved after intravenous atropine bolus, hypotension for which inotropes were started.

Results

Data of 209 patients were retrieved. Major adverse events were reported in five patients (2.4%; 95% CI: 0.8–5.5). Intubation with subsequent ICU admission was required for 1.4% of patients (95% CI: 0.3–4.1). The most frequently seen minor adverse events (N = 209) were: airway obstruction (22%), hypothermia (14.8%), hypoxia (12.9%), bradycardia (8.1%), hypotension (6.7%), bradypnea (5.7%), vomiting (5.3%). There were no deaths. None of the patients had signs of aspiration pneumonia or returned to our ED due to complications.

Conclusion

Our study suggests that conservative airway management for patients with a decreased GCS due to suspected GHB intoxication may be safe. Major adverse events were present in 2.4% of patients, only 1.4% of patients required intubation. All minor adverse events were managed effectively with conservative treatment.
Protocol Biopsies in Patients With Subclinical De Novo Donor-specific Antibodies After Kidney Transplantation: A Multicentric Study
Authors: Bertrand Dominique , Gatault Philippe , Jauréguy Maïté , Garrouste Cyril , Sayegh Johnny , Bouvier Nicolas , Caillard Sophie , Lanfranco Luca , Galinier Aliénor , Laurent Charlotte , Etienne Isabelle , Farce Fabienne , François Arnaud , Guerrot Dominique
Published: December 2019

Background.

De novo donor-specific antibodies (DSAs) are associated with antibody-mediated rejection (AMR) and allograft loss. Whether monitoring of de novo DSA (dnDSA) paired with systematic kidney biopsy should become routine remains to be established.

Methods.

A retrospective multicentric study (9 French kidney transplant units of the Spiesser group) included patients without graft dysfunction biopsied because of the presence of dnDSA (One Lambda, mean fluorescence intensity [MFI], >1000).

Results.

One hundred twenty-three patients (85 male/38 female; mean age, 49.5 ± 13.1 y old) were biopsied after the detection of a dnDSA, 65.3 months (median) after kidney transplantation. Graft function was stable within 3 months before biopsy (estimated glomerular filtration rate, 55.3 ± 18.9 mL/min/1.73 m2). Fifty-one subclinical AMRs (sAMRs) (41.4%) were diagnosed, of which 32 (26%) active and 19 (15.5%) chronic active sAMR. Seventy-two biopsies revealed no AMR (58.5%). Predictive factors associated with the diagnosis of active sAMR were MFI of immunodominant DSA >4000, MFI of the sum of DSA >6300, age of the recipient <45 years old, and the absence of steroids at biopsy. The presence of proteinuria >200 mg/g was predictive of chronic active sAMR. The decrease of estimated glomerular filtration rate at 5 years post-biopsy was significantly higher in patients with acute sAMR (−25.2 ± 28.3 mL/min/1.73 m2) and graft survival significantly lower.

Conclusions.

Performing a kidney graft biopsy for the occurrence of dnDSA without renal dysfunction leads to the diagnosis of a sAMR in over 40% of cases. Nevertheless, we did not observe any effect of standard treatment in acute sAMR.
How Ramanujan may have discovered the mock theta functions
Authors: Andrews George E.
Published: December 2019

Mock theta functions appeared out of the blue in Ramanujan's last letter to Hardy. What would lead Ramanujan to consider the possibility of such functions in the first place? This paper seeks to provide a plausible answer to this question.

This article is part of a discussion meeting issue ‘Srinivasa Ramanujan: in celebration of the centenary of his election as FRS’.
Ramanujan's legacy: the work of the SASTRA prize winners
Authors: Alladi Krishnaswami
Published: December 2019

The SASTRA Ramanujan Prize is an annual $10 000 prize given to mathematicians not exceeding the age of 32 for revolutionary contributions to areas influenced by Srinivasa Ramanujan. The prize has been unusually successful in recognizing highly gifted mathematicians at an early stage of their careers who have gone on to shape the development of mathematics. We describe the fundamental contributions of the winners and the impact they have had on current research. Several aspects of the work of the awardees either stem from or have been strongly influenced by Ramanujan's ideas.

This article is part of a discussion meeting issue ‘Srinivasa Ramanujan: in celebration of the centenary of his election as FRS’.
Assessment of Prognostic Value of Cystic Features in Glioblastoma Relative to Sex and Treatment with Standard-of-Care
Authors: Curtin Lee , Whitmire Paula , Rickertsen Cassandra R. , Mazza Gina L. , Canoll Peter , Johnston Sandra K. , Mrugala Maciej M. , Swanson Kristin R. , Hu Leland S.
Published: December 2019

Glioblastoma (GBM) is the most aggressive primary brain tumor and can have cystic components, identifiable through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7-23% of GBMs and report mixed results regarding their prognostic impact. Using our retrospective cohort of 493 patients with first-diagnosis GBM, we carried out an exploratory analysis on this potential link between cystic GBM and survival. Using pretreatment MRIs, we manually identified 88 patients with GBM that had a significant cystic component at presentation and 405 patients that did not. Patients with cystic GBM had significantly longer overall survival and were significantly younger at presentation. Within patients who received the current standard of care (SOC) (N=184, 40 cystic), we did not observe a survival benefit of cystic GBM. Unexpectedly, we did not observe a significant survival benefit between this SOC cystic cohort and patients with cystic GBM diagnosed before the standard was established (N=40 with SOC, N=19 without SOC); this significant SOC benefit was clearly observed in patients with noncystic GBM (N=144 with SOC, N=111 without SOC). When stratified by sex, this significant survival benefit was only preserved in male patients (N=303, 47 cystic). We report differences in the absolute and relative sizes of imaging abnormalities on MRI and the prognostic implication of cysts based on sex. We discuss hypotheses for these differences, including the possibility that the presence of a cyst could indicate a less aggressive tumor.
Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration
Authors: Revez Joana A , Lin Tian , Qiao Zhen , Xue Angli , Holtz Yan , Zhu Zhihong , Zeng Jian , Wang Huanwei , Sidorenko Julia , Kemper Kathryn E , Vinkhuyzen Anna AE , Frater Julanne , Eyles Darryl , Burne Thomas HJ , Mitchell Brittany , Martin Nicholas G , Zhu Gu , Visscher Peter M , Yang Jian , Wray Naomi R , McGrath John J
Published: December 2019

Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identified 143 independent loci in 112 1-Mb regions providing new insights into the physiology of vitamin D and implicating genes involved in (a) lipid and lipoprotein metabolism, (b) dermal tissue properties, and (c) the sulphonation and glucuronidation of 25OHD. Mendelian randomization models found no robust evidence that 25OHD concentration had causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes had (direct or indirect) causal effects on 25OHD concentration, clarifying the relationship between 25OHD status and health.
How much doesNevary among species?
Authors: Galtier Nicolas , Rousselle Marjolaine
Published: December 2019

Abstract

Genetic drift is an important evolutionary force of strength inversely proportional toNe, the effective population size. The impact of drift on genome diversity and evolution is known to vary among species, but quantifying this effect is a difficult task. Here we assess the magnitude of variation in drift power among species of animals via its effect on the mutation load – which implies also inferring the distribution of fitness effects of deleterious mutations (DFE). To this aim, we analyze the non-synonymous (amino-acid changing) and synonymous (amino-acid conservative) allele frequency spectra in a large sample of metazoan species, with a focus on the primates vs. fruit flies contrast. We show that a Gamma model of the DFE is not suitable due to strong differences in estimated shape parameters among taxa, while adding a class of lethal mutations essentially solves the problem. Using the Gamma + lethal model and assuming that the mean deleterious effects of non-synonymous mutations is shared among species, we estimate that the power of drift varies by a factor of at least 500 between large-Neand small-Nespecies of animals,i.e., an order of magnitude more than the among-species variation in genetic diversity. Our results are relevant to Lewontin’s paradox while further questioning the meaning of theNeparameter in population genomics.
Unsupervised Clustering Reveals Spatially Varying Single Neuronal Firing Patterns in the Subthalamic Nucleus of Patients with Parkinson’s Disease
Authors: Kaku Heet , Ozturk Musa , Viswanathan Ashwin , Shahed Joohi , Sheth Sameer Anil , Kumar Suneel , Ince Nuri F.
Published: December 2019

Introduction

Subthalamic nucleus (STN) is an effective target for deep brain stimulation (DBS) to reduce the motor symptoms of Parkinson’s disease (PD). It is important to identify firing patterns within the structure for a better understanding of the electro-pathophysiology of the disease. Using recently established metrics, our study aims to autonomously identify the discharge patterns of individual cells and examine their spatial distribution within the STN.

Methods

We recorded single unit activity (SUA) from 12 awake PD patients undergoing a standard clinical DBS surgery. Three extracted features from raw SUA (local variation, bursting index and prominence of peak) were used with k-means clustering to achieve the aforementioned unsupervised grouping of firing patterns.

Results

279 neurons were isolated and four distinct firing patterns were identified across patients: tonic (11%), irregular (55%), periodic (9%) and non-periodic bursts (25%). The mean firing rates for irregular discharges were significantly lower (p<0.05) than the rest. Tonic firings were significantly ventral (p<0.05) while periodic (p<0.05) and non-periodic (p<0.01) bursts were dorsal. The percentage of periodically bursting neurons in dorsal region and entire STN were significantly correlated with off state UPDRS tremor scores (r=0.51, p=0.04) and improvement in bradykinesia and rigidity (r=0.57, p=0.02) respectively.

Conclusion

Strengthening the application of unsupervised clustering for firing patterns of individual cells, this study shows a unique spatial affinity of tonic activity towards the ventral and bursting activity towards the dorsal region of STN in PD patients. This spatial preference, together with the correlation of clinical scores, can provide a clue towards understanding Parkinsonian symptom generation.
Contacting domains that segregate lipid from solute transporters in malaria parasites
Authors: Garten Matthias , Beck Josh R. , Roth Robyn , Tenkova-Heuser Tatyana , Heuser John , Bleck Christopher K. E. , Goldberg Daniel E. , Zimmerberg Joshua
Published: December 2019

While membrane contact sites (MCS) between intracellular organelles are abundant1, and cell-cell junctions are classically defined2, very little is known about the contacts between membranes that delimit extracellular junctions within cells, such as those of chloroplasts and intracellular parasites. The malaria parasite replicates within a unique organelle, the parasitophorous vacuole (PV) but the mechanism(s) are obscure by which the limiting membrane of the PV, the parasitophorous vacuolar membrane (PVM), collaborates with the parasite plasma membrane (PPM) to support the transport of proteins, lipids, nutrients, and metabolites between the cytoplasm of the parasite and the cytoplasm of the host erythrocyte (RBC). Here, we demonstrate the existence of multiple micrometer-sized regions of especially close apposition between the PVM and the PPM. To determine if these contact sites are involved in any sort of transport, we localized the PVM nutrient-permeable and protein export channel EXP2, as well as the PPM lipid transporter PfNCR1. We found that EXP2 is excluded from, but PfNCR1 is included within these regions of close apposition. Thus, these two different transport systems handling hydrophilic and hydrophobic substances, respectively, assume complementary and exclusive distributions. This new structural and molecular data assigns a functional significance to a macroscopic membrane domain.
Does breeding season variation affect evolution of a sexual signaling trait in a tropical lizard clade?
Authors: Gray Levi N. , Barley Anthony J. , Hillis David M. , Pavón-Vázquez Carlos J. , Poe Steven , White Brittney A.
Published: December 2019

Sexually selected traits can be expected to increase in importance when the period of sexual behavior is constrained, such as in seasonally restricted breeders.Anolislizard male dewlaps are classic examples of multifaceted signaling traits, with demonstrated reproductive function reflected in courtship behavior. Fitch and Hillis found a correlation between dewlap size and seasonality in mainlandAnolisusing traditional statistical methods. Here, we present two tests of the Fitch-Hillis Hypothesis using new phylogenetic and morphological data sets for 44 species of MexicanAnolis. A significant relationship between dewlap size and seasonality is evident in phylogenetically uncorrected analyses but erodes once phylogeny is accounted for. This loss of statistical support for a relationship between a key aspect of dewlap morphology and seasonality also occurs within a species complex (A. sericeusgroup) that inhabits seasonal and aseasonal environments. Our results fail to support seasonality as a strong driver of evolution ofAnolisdewlap size. We discuss the implications of our results and the difficulty of disentangling the strength of single mechanisms on trait evolution when multiple selection pressures are likely at play.
α1A-adrenoceptor inverse agonists and agonists modulate receptor signalling through a conformational selection mechanism
Authors: Wu Feng-Jie , Williams Lisa M. , Abdul-Ridha Alaa , Gunatilaka Avanka , Vaid Tasneem M. , Kocan Martina , Whitehead Alice R. , Griffin Michael D.W. , Bathgate Ross A.D. , Scott Daniel J. , Gooley Paul R.
Published: December 2019

G-Protein Coupled Receptors (GPCRs) transmit signals across the cell membrane via an allosteric network from the ligand-binding site to the G-protein binding site via a series of conserved microswitches. Crystal structures of GPCRs provide snapshots of inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here we analyse the correlation between ligand binding and receptor conformation of the α1A-adrenoceptor, known for stimulating smooth muscle contraction in response to binding noradrenaline. NMR of 13CεH3-methionine labelled α1A-adrenoreceptor mutants, each exhibiting differing signalling capacities, revealed how different classes of ligands modulate receptor conformational equilibria. 13CεH3-methionine residues near the microswitches revealed distinct states that correlated with ligand efficacies, supporting a conformational selection mechanism. We propose that allosteric coupling between the microswitches controls receptor conformation and underlies the mechanism of ligand modulation of GPCR signalling in cells.
Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes define survival threshold in erythroid progenitor cells
Authors: Adlung Lorenz , Stapor Paul , Tönsing Christian , Schmiester Leonard , Schwarzmüller Luisa E. , Wang Dantong , Timmer Jens , Klingmüller Ursula , Hasenauer Jan , Schilling Marcel
Published: December 2019

Survival or apoptosis is a binary decision in individual cells. Yet, at the cell population level, a graded increase in survival of CFU-E cells is observed upon stimulation with Erythropoietin (Epo). To identify components of JAK2/STAT5 signal transduction that contribute to the graded population response, a cell population-level model calibrated with experimental data was extended to study the behavior in single cells. The single-cell model showed that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of EpoR:JAK2 complexes and of SHP1 as well as the extent of nuclear import due to the large variance in the cytoplasmic volume of CFU-E cells. 24 to 118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes are responsible to convert a switch-like behavior at the single-cell level to a graded population level response.

Highlights

Mathematical modeling enables integration of heterogeneous data

Single-cell modeling captures binary decision process

Multiple sources of cell-to-cell variability in erythroid progenitor cells

Minimal amount of active STAT5 sufficient for survival of erythroid progenitor cells
One fly - one genome : Chromosome-scale genome assembly of a single outbred Drosophila melanogaster
Authors: Adams Matthew , McBroome Jakob , Maurer Nicholas , Pepper-Tunick Evan , Saremi Nedda , Green Richard E. , Vollmers Christopher , Corbett-Detig Russell B.
Published: December 2019

A high quality genome assembly is a vital first step for the study of an organism. Recent advances in technology have made the creation of high quality chromosome scale assemblies feasible and low cost. However, the amount of input DNA needed for an assembly project can be a limiting factor for small organisms or precious samples. Here we demonstrate the feasibility of creating a chromosome scale assembly using a hybrid method for a low input sample, a single outbred Drosophila melanogaster. Our approach combines an Illumina shotgun library, Oxford nanopore long reads, and chromosome conformation capture for long range scaffolding. This single fly genome assembly has a N50 of 26 Mb, a length that encompasses entire chromosome arms, contains 95% of expected single copy orthologs, and a nearly complete assembly of this individual’s Wolbachia endosymbiont. The methods described here enable the accurate and complete assembly of genomes from small, field collected organisms as well as precious clinical samples.
The socioeconomic burden of severe mental disorder in China, 2014-2017: a prevalence study
Authors: Xie Mengxue , Ju Ke , Ni Jie , Zhao Xiaoheng , Li Xiaorong , Pan Jay , Zhou Qian
Published: December 2019

Mental illness is a chronic disease with high morbidity and mortality rate, resulting in heavy economic burden for family and society, especially the severe ones. Chinese government has taken a series of action on the treatment and management of severe mental disorder (SMD), but the scale of economic burden caused by SMD was still unclear. In this paper, we applied prevalence-based bottom-up approach to estimate the direct and indirect economic burden of SMD in Southwest China from 2014 to 2017. We used the sampled inpatient medical record data of patient with SMD to calculate the total direct cost and estimated the indirect economic burden using human capital approach.The total ecomonic burden of SMD was USD9,733 million and direct burden was contiributed for 7.5% as USD734.5 million in four years total. The growth rate of direct medical cost was declined due to the health policy reform and total cost control policy. The indirect cost was rapidly increased in four years when estimated with DALYs reported in GBD2010 and resulting USD8,998.6 million. We next estimated the indirect burden using sample DALYs and occupation wage cost approach as sensitive analysis. We found that the indirect burden was sensitive to the key variable and the estimation approach, but the estimates share same increasing trend but with different velocity. Our study suggests that SMD in China have posed substantial economic burden at individual and social levels, with the appropriate estimation of total economic burden, our reaserch would attract more attention and be helpful for health resources distribution.
Differential tolerance of Zymoseptoria tritici to altered optimal moisture conditions during the early stages of wheat infection
Authors: Boixel Anne-Lise , Gélisse Sandrine , Marcel Thierry C. , Suffert Frédéric
Published: December 2019

Foliar plant pathogens require liquid or vapour water for at least part of their development, but their response and their adaptive tolerance to moisture conditions have been much less studied than other meteorological factors to date. We examined the impact on the wheat-Zymoseptoria tritici interaction of altering optimal moisture conditions conducive to infection. We assessed the responses in planta of 48 Z. tritici strains collected in two climatologically distinct locations (Ireland and Israel) to four high moisture regimes differing in the timing and the duration of uninterrupted exposure to saturated relative humidity (100% RH) during the first three days of infection. Individual- and population-level moisture reaction norms expressing how the sporulating area of a lesion change with the RH conditions were established based on visual assessments of lesion development at 14, 17 and 20 days post-inoculation (dpi). Our findings highlighted: (i) a critical time-dependent effect on lesion development of uninterrupted periods of exposure to 100% RH during these earliest infection stages; (ii) a marked interindividual variation in the sensitivity to RH conditions both in terms of strain average moisture response and plasticity; (iii) a higher tolerance – expressed at 14 dpi, not later – of the Israeli population to early interruption of optimal moisture conditions. By indicating that sensitivity to sub-optimal moisture conditions may vary greatly between Z. tritici individuals and populations, this study highlights the evidence of moisture adaptation signature in a plant pathogen. This suggests that understanding such variation will be critical to predict their response to changing climatic conditions.
The secreted acid phosphatase domain-containing GRA44 fromToxoplasma gondiiis required for C-myc induction in infected cells
Authors: Blakely William J , Holmes Michael J , Arrizabalaga Gustavo
Published: December 2019

During host cell invasion, the eukaryotic pathogenToxoplasma gondiiforms a parsitophorous vacuole to safely reside within, while partitioned from host cell defense mechanisms. From within this safe niche parasites sabotage multiple host cell systems including gene expression, apoptosis and intracellular immune recognition by secreting a large arsenal of effector proteins. Many parasite proteins studied for active host cell manipulative interactions have been kinases. Translocation of effectors from the parasitophorous vacuole into the host cell is mediated by a putative translocon complex, which includes proteins MYR1, MYR2, and MYR3. Whether other proteins are involved in the structure or regulation of this putative translocon is not known. We have discovered that the secreted protein GRA44, which contains a putative acid phosphatase domain, interacts with members of this complex and is required for host cell effects downstream of effector secretion. We have determined GRA44 is processed in a region with homology to sequences targeted by protozoan proteases of the secretory pathway and that both major cleavage fragments are secreted into the parasitophorous vacuole. Immunoprecipitation experiments showed that GRA44 interacts with a large number of secreted proteins included MYR1. Importantly, conditional knockdown of GRA44 resulted in a lack of host cell cMyc upregulation, which mimics the phenotype seen when members of the translocon complex are genetically disrupted. Thus, the putative acid phosphatase GRA44 is crucial for host cell alterations duringToxoplasmainfection and is associated with the translocon complex whichToxoplasmarelies upon for success as an intracellular pathogen.

IMPORTANCE

Approximately one third of humans are infected with the parasiteToxoplasma gondii.Toxoplasmainfections can lead to severe disease in those with a compromised or suppressed immune system. Additionally, infections during pregnancy present a significant health risk to the developing fetus. Drugs that target this parasite are limited, have significant side effects, and do not target all disease stages. Thus, a thorough understanding of how the parasite propagates within a host is critical in the discovery of novel therapeutic targets. To replicateToxoplasmarequires to enter the cells of the infected organism. In order to survive the environment inside a cell,Toxoplasmasecretes a large repertoire of proteins, which hijack a number of important cellular functions. How theseToxoplasmaproteins move from the parasite into the host cell is not well understood. Our work shows that the putative phosphatase GRA44 is part of a protein complex responsible for this process.
Mutations in disordered proteins as early indicators of nucleic acid changes triggering speciation
Authors: Forcelloni Sergio , Giansanti Andrea
Published: December 2019

Intrinsically disordered proteins are characterized by unusual sequence composition, structural flexibility, and functional spectra. These properties play an essential role in fostering protein evolution and in the formation of complex cellular pathways, especially in multicellular organisms. In this study, we analyze the role of different structural variants of proteins in speciation processes. Firstly, we separate human and mouse proteomes (taken as a reference) in three variants of disorder: ordered proteins (ORDPs), structured proteins with intrinsically disordered protein regions (IDPRs), and intrinsically disordered proteins (IDPs). Secondly, we compare the DNA divergence with the corresponding protein divergence, by confronting human and mouse coding sequences (separated in ORDPs, IDPRs, and IDPs) with their homologs from 26 eukaryotes. As a general rule, we find that IDPs phenotypically diverge earlier than ORDPs and IDPRs. ORDPs diverge later but are phenotypically more reactive to nucleotide mutations than IDPRs and IDPs. We suggest that IDPs may be involved in the early stages of the speciation process, likely connected to their functional spectra, mainly related to nucleic acid binding and transcription factors. In contrast, ORDPs may be essential in accelerating further phenotypic divergence.
Genomic evidence for global ocean plankton biogeography shaped by large-scale current systems
Authors: Richter Daniel J. , Watteaux Romain , Vannier Thomas , Leconte Jade , Frémont Paul , Reygondeau Gabriel , Maillet Nicolas , Henry Nicolas , Benoit Gaëtan , Silva Ophélie Da , Delmont Tom O. , Fernàndez-Guerra Antonio , Suweis Samir , Narci Romain , Berney Cédric , Eveillard Damien , Gavory Frederick , Guidi Lionel , Labadie Karine , Mahieu Eric , Poulain Julie , Romac Sarah , Roux Simon , Dimier Céline , Kandels Stefanie , Picheral Marc , Searson Sarah ,   Tara Oceans Coordinators, Pesant Stéphane , Aury Jean-Marc , Brum Jennifer R. , Lemaitre Claire , Pelletier Eric , Bork Peer , Sunagawa Shinichi , Lombard Fabien , Karp-Boss Lee , Bowler Chris , Sullivan Matthew B. , Karsenti Eric , Mariadassou Mahendra , Probert Ian , Peterlongo Pierre , Wincker Patrick , de Vargas Colomban , d’Alcalà Maurizio Ribera , Iudicone Daniele , Jaillon Olivier
Published: December 2019

Biogeographical studies have traditionally focused on readily visible organisms, but recent technological advances are enabling analyses of the large-scale distribution of microscopic organisms, whose biogeographical patterns have long been debated. Here we assessed the global structure of plankton geography and its relation to the biological, chemical and physical context of the ocean (the ‘seascape’) by analyzing metagenomes of plankton communities sampled across oceans during the Tara Oceans expedition, in light of environmental data and ocean current transport. Using a consistent approach across organismal sizes that provides unprecedented resolution to measure changes in genomic composition between communities, we report a pan-ocean, size-dependent plankton biogeography overlying regional heterogeneity. We found robust evidence for a basin-scale impact of transport by ocean currents on plankton biogeography, and on a characteristic timescale of community dynamics going beyond simple seasonality or life history transitions of plankton.
Population genetics of the coralAcropora millepora: Towards a genomic predictor of bleaching
Authors: Fuller Zachary L. , Mocellin Veronique J.L. , Morris Luke , Cantin Neal , Shepherd Jihanne , Sarre Luke , Peng Julie , Liao Yi , Pickrell Joseph , Andolfatto Peter , Matz Mikhail , Bay Line K. , Przeworski Molly
Published: December 2019

Although reef-building corals are rapidly declining worldwide, responses to bleaching vary both within and among species. Because these inter-individual differences are partly heritable, they should in principle be predictable from genomic data. Towards that goal, we generated a chromosome-scale genome assembly for the coralAcropora millepora. We then obtained whole genome sequences for 237 phenotyped samples collected at 12 reefs distributed along the Great Barrier Reef, among which we inferred very little population structure. Scanning the genome for evidence of local adaptation, we detected signatures of long-term balancing selection in the heat-shock co-chaperonesacsin. We further used 213 of the samples to conduct a genome-wide association study of visual bleaching score, incorporating the polygenic score derived from it into a predictive model for bleaching in the wild. These results set the stage for the use of genomics-based approaches in conservation strategies.
Proteomics identifies signal peptide features determining the substrate specificity in human Sec62/Sec63-dependent ER protein import
Authors: Schorr Stefan , Nguyen Duy , Haßdenteufel Sarah , Nagaraj Nagarjuna , Cavalié Adolfo , Greiner Markus , Weissgerber Petra , Loi Marisa , Paton Adrienne W. , Paton James C. , Molinari Maurizio , Förster Friedrich , Dudek Johanna , Lang Sven , Helms Volkhard , Zimmermann Richard
Published: December 2019

In mammalian cells one-third of all polypeptides are integrated into the membrane or translocated into the lumen of the endoplasmic reticulum (ER) via the Sec61-channel. While the Sec61-complex facilitates ER-import of most precursor polypeptides, the Sec61-associated Sec62/Sec63-complex supports ER-import in a substrate-specific manner. So far, mainly posttranslationally imported precursors and the two cotranslationally imported precursors of ERj3 and prion protein were found to depend on the Sec62/Sec63-complexin vitro. Therefore, we determined the rules for engagement of Sec62/Sec63 in ER-import in intact human cells using a recently established unbiased proteomics approach. In addition to confirming ERj3, we identified twenty-two novel Sec62/Sec63-substrates under thesein vivo-like conditions. As a common feature, those previously unknown substrates share signal peptides with comparatively longer but less hydrophobic H-region and lower C-region polarity. Further analyses with four substrates, and ERj3 in particular, revealed the combination of a slowly-gating signal peptide and a downstream translocation-disruptive positively charged cluster of amino acid residues as decisive for the Sec62-/Sec63-requirement. In the case of ERj3, these features were found to be responsible for an additional BiP-requirement and to correlate with sensitivity towards the Sec61-channel inhibitor CAM741. Thus, the human Sec62/Sec63-complex may support Sec61-channel opening for precursor polypeptides with slowly-gating signal peptides by direct interaction with the cytosolic amino-terminal peptide of Sec61α or via recruitment of BiP and its interaction with the ER-lumenal loop 7 of Sec61α. These novel insights into the mechanism of human ER protein import contribute to our understanding of the etiology ofSEC63-linked Polycystic Liver Disease.

Databases

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (http://www.ebi.ac.uk/pride/archive/projects/Identifiers) with the dataset identifiers: PXD008178, PXD011993, and PXD012078. Supplementary information was deposited at Mendeley Data under the DOI:10.17632/6s5hn73jcv.1 (http://dx.doi.or/10.17632/6s5hn73jcv.1).
Co-immunoprecipitation with MYR1 identifies three additional proteins within theToxoplasmaparasitophorous vacuole required for translocation of dense granule effectors into host cells
Authors: Cygan Alicja M. , Theisen Terence C. , Mendoza Alma G. , Marino Nicole D. , Panas Michael W. , Boothroyd John C.
Published: December 2019

Toxoplasma gondiiis a ubiquitous, intracellular protozoan that extensively modifies infected host cells through secreted effector proteins. Many such effectors must be translocated across the parasitophorous vacuole (PV) in which the parasites replicate, ultimately ending up in the host cytosol or nucleus. This translocation has previously been shown to be dependent on five parasite proteins: MYR1, MYR2, MYR3, ROP17, and ASP5. We report here the identification of several MYR1-interacting and novel PV-localized proteins via affinity purification of MYR1, including TGGT1_211460 (dubbed MYR4), TGGT1_204340 (dubbed GRA54) and TGGT1_270320 (PPM3C). Further, we show that three of the MYR1-interacting proteins, GRA44, GRA45, and MYR4, are essential for the translocation of theToxoplasmaeffector protein GRA16, and for the upregulation of human c-Myc and cyclin E1 in infected cells. GRA44 and GRA45 contain ASP5-processing motifs, but like MYR1, processing at these sites appears to be nonessential for their role in protein translocation. These results expand our understanding of the mechanism of effector translocation inToxoplasmaand indicate that the process is highly complex and dependent on at least eight discrete proteins.

Importance

Toxoplasmais an extremely successful intracellular parasite and important human pathogen. Upon infection of a new cell,Toxoplasmaestablishes a replicative vacuole and translocates parasite effectors across this vacuole to function from the host cytosol and nucleus. These effectors play a key role in parasite virulence. The work reported here newly identifies three parasite proteins that are necessary for protein translocation into the host cell. These results significantly increase our knowledge of the molecular players involved in protein translocation inToxoplasma-infected cells, and provide additional potential drug targets.
How community adaptation affects biodiversity-ecosystem functioning relationships
Authors: Aubree Flora , David Patrice , Jarne Philippe , Loreau Michel , Mouquet Nicolas , Calcagno Vincent
Published: December 2019

Evidence is growing that evolutionary dynamics can impact biodiversity-ecosystem functioning (BEF) relationships. However the nature of such impacts remains poorly understood. Here we use a modelling approach to compare random communities, with no trait evolutionary fine-tuning, and co-adapted communities, where traits have co-evolved, in terms of emerging biodiversity-productivity, biodiversitystability, and biodiversity-invasion relationships. Community adaptation impacted most BEF relationships, sometimes inverting the slope of the relationship compared to random communities. Biodiversity-productivity relationships were generally less positive among co-adapted communities, with reduced contribution of sampling effects. The effect of community-adaptation, though modest regarding invasion resistance, was striking regarding invasion tolerance: co-adapted communities could remain very tolerant to invasions even at high diversity. BEF relationships are thus contingent on the history of ecosystems and their degree of community adaptation. Short-term experiments and observations following recent changes may not be safely extrapolated into the future, once eco-evolutionary feedbacks have taken place.
Mapping chromatin accessibility and active regulatory elements reveals new pathological mechanisms in human gliomas
Authors: Stępniak Karolina , Machnicka Magdalena A. , Mieczkowski Jakub , Macioszek Anna , Wojtaś Bartosz , Gielniewski Bartłomiej , Król Sylwia K. , Guzik Rafał , Dąbrowski Michał J. , Dramiński Michał , Jardanowska Marta , Grabowicz Ilona , Dziedzic Agata , Kranas Hanna , Sienkiewicz Karolina , Diamanti Klev , Kotulska Katarzyna , Grajkowska Wiesława , Roszkowski Marcin , Czernicki Tomasz , Marchel Andrzej , Komorowski Jan , Kaminska Bozena , Wilczyński Bartek
Published: December 2019

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We performed whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel novel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we created an atlas of active enhancers and promoters in benign and malignant gliomas. We explored these elements and intersected with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

Significance

Epigenetics-driven deregulation of gene expression accompanies cancer development, but its comprehensive characterization in cancer patients is fragmentary. We performed whole-genome profiling of gene expression, open chromatin, histone modifications and DNA-methylation profiles in the same samples from benign and malignant gliomas. Our study provides a first comprehensive atlas of active regulatory elements in gliomas, which allowed identification of the functional enhancers and promoters in patient samples. This comprehensive approach revealed epigenetic patterns influencing gene expression in benign gliomas and a new pathogenic mechanism involving FOXM1-driven network in glioblastomas. This atlas provides a common set of elements for cross-comparisons of existing and new datasets, prompting novel discoveries and better understanding of gliomagenesis.

Highlights

We provide an atlas of cis-regulatory elements active in human gliomas

Enhancer-promoter contacts operating in gliomas are revealed

Diverse enhancer activation is pronounced in malignant gliomas

Chromatin loop activates FOXM1-ANXA2R pathological network in glioblastomas.
Recovering individual haplotypes and a contiguous genome assembly from pooled long read sequencing of the diamondback moth (Lepidoptera: Plutellidae)
Authors: Whiteford Samuel , van’t Hof Arjen E. , Krishna Ritesh , Marubbi Thea , Widdison Stephanie , Saccheri Ilik J. , Guest Marcus , Morrison Neil I. , Darby Alistair C.
Published: December 2019

Background

Recent advances in genomics have addressed the challenge that divergent haplotypes pose to the reconstruction of haploid genomes. However for many organisms, the sequencing of either field-caught individuals or a pool of heterogeneous individuals is still the only practical option. Here we present methodological approaches to achieve three outcomes from pooled long read sequencing: the generation of a contiguous haploid reference sequence, the sequences of heterozygous haplotypes; and reconstructed genomic sequences of individuals related to the pooled material.

Results

PacBio long read sequencing, Dovetail Hi-C scaffolding and linkage map integration yielded a haploid chromosome-level assembly for the diamondback moth (Plutella xylostella), a global pest of Brassica crops, from a pool of related individuals. The final assembly consisted of 573 scaffolds, with a total assembly size of 343.6Mbp a scaffold N50 value of 11.3Mbp (limited by chromosome size) and a maximum scaffold size of 14.4Mbp. This assembly was then integrated with an existing RAD-seq linkage map, anchoring 95% of the assembled sequence to defined chromosomal positions.

Conclusions

We describe an approach to resolve divergent haplotype sequences and describe multiple validation approaches. We also reconstruct individual genomes from pooled long-reads, by applying a recently developed k-mer binning method.
Genomic differentiation and intercontinental population structure of mosquito vectorsCulex pipiens pipiensandCulex pipiens molestus
Authors: Yurchenko Andrey A. , Masri Reem A. , Khrabrova Natalia V. , Sibataev Anuarbek K. , Fritz Megan L. , Sharakhova Maria V.
Published: December 2019

Understanding the population structure and mechanisms of taxa diversification is important for organisms responsible for the transmission of human diseases. Two vectors of West Nile virus,Culex pipiens pipiensandCx. p. molestus, exhibit epidemiologically important behavioral and physiological differences, but the whole-genome divergence between them was unexplored. In this study, we re-sequenced and compared the whole genomes of 40 individual mosquitoes from four locations in Eurasia and North America: the Republic of Belarus, the Kyrgyz Republic, and the United States of America. Principal Component, ADMIXTURE, and neighbor joining analyses of the nuclear genomes identified two intercontinental, monophyletic clusters ofCx. p. pipiensandCx. p. molestus.The third cluster, having a polyphyletic origin, was formed byCx. p. pipiensandCx. quinquefasciatusfrom the USA. The level of genomic differentiation between the subspecies was uniform along chromosomes. The ADMIXTURE analysis determined signatures of admixture in allCx. p. pipenspopulations but not inCx. p. molestuspopulations. Comparison of mitochondrial genomes among the specimens showed a paraphyletic origin of the major haplogroups between the subspecies but a monophyletic structure between the continents. Thus, our study identified thatCx. p. molestusandCx. p. pipiensrepresent different evolutionary units with monophyletic origin that have undergone incipient ecological speciation.
Lgl cortical dynamics are independent of binding to the Scrib-Dlg complex but require Dlg-dependent restriction of aPKC
Authors: Ventura Guilherme , Moreira Sofia , Barros-Carvalho André , Osswald Mariana , Morais-de-Sá Eurico
Published: December 2019

Apical-basal polarity underpins the formation of specialized epithelial barriers that are critical for metazoan physiology. Although apical-basal polarity is long known to require the basolateral determinants Lethal Giant Larvae (Lgl), Discs Large (Dlg) and Scribble (Scrib), mechanistic understanding of their function is limited. Lgl plays a role as an aPKC inhibitor, but it remains unclear whether Lgl also forms a complex with Dlg or Scrib. Using fluorescence recovery after photobleaching, we show that Lgl does not form immobile complexes at the lateral domain ofDrosophilafollicle cells. Optogenetic depletion of plasma membrane phosphatidylinositol 4,5-biphosphate (PIP2) or Dlg removal accelerate Lgl cortical dynamics. However, whereas Lgl turnover relies on PIP2binding, Dlg and Scrib are only required for Lgl localization and dynamic behavior in the presence of aPKC function. Furthermore, light-induced oligomerization of basolateral proteins indicate that Lgl is not part of the Scrib-Dlg complexin vivo. Thus, Scrib-Dlg are necessary to repress aPKC activity in the lateral domain but do not provide cortical binding sites for Lgl. Our work therefore highlights that Lgl does not act in a complex but in parallel with Scrib-Dlg to antagonize apical determinants.
Proteome-wide structural probing of low-abundant protein interactions by crosslinking
Authors: Fürsch Julius , Kammer Kai-Michael , Kreft Stefan G. , Beck Martin , Stengel Florian
Published: December 2019

Proteome-wide crosslinking studies have spurred great interest as they facilitate structural probing of protein interactions in living cells and organisms. However, current studies have a bias for high-abundant proteins. In a paradigm shift, we demonstrate both experimentally and by a kinetic model that this bias is caused by the propensity of crosslinks to preferentially form on high abundant proteins and not by the inability to detect crosslinks due to limitations in current technology. We further show, by using both an in-vitro mimic of a crowded cellular environment and eukaryotic cell lysates, that parameters optimized towards a pseudo 1storder kinetics model result in a significant 3 to 10-fold overall increase in the detection of lower-abundant proteins on a proteome-wide scale. Our study therefore explains the cause of a major limitation in current proteome-wide crosslinking studies and demonstrates how to address a larger part of the proteome by crosslinking.