bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conservation of theToxoplasmaconoid complex proteome reveals a cryptic conoid inPlasmodiumthat differentiates between blood- and vector-stage zoites
Authors: Koreny Ludek , Zeeshan Mohammad , Barylyuk Konstantin , Tromer Eelco C. , van Hooff Jolien J. E. , Brady Declan , Ke Huiling , Chelaghma Sara , Ferguson David J. P. , Eme Laura , Tewari Rita , Waller Ross F. 
Published: June 2020

AbstractThe apical complex is the instrument of invasion used by apicomplexan parasites, and the conoid is a conspicuous feature of this apparatus found throughout this phylum. The conoid, however, is believed to be heavily reduced or missing fromPlasmodiumspecies and other members of the class Aconoidasida. Relatively few conoid proteins have previously been identified, making it difficult to address how conserved this feature is throughout the phylum, and whether it is genuinely missing from some major groups. Moreover, parasites such asPlasmodiumspecies cycle through three invasive forms and there is the possibility of differential presence of the conoid between these stages. We have applied spatial proteomics and high-resolution microscopy to develop a more complete molecular inventory and understanding of the organisation of conoid-associated proteins in the model apicomplexanToxoplasma gondii. These data revealed molecular conservation of all conoid substructures throughout Apicomplexa, includingPlasmodium, and even in allied Myzozoa such asChromeraand dinoflagellates. We reporter-tagged and observed the expression and location of several conoid complex proteins in the malaria modelP. bergheiand revealed equivalent structures in all of its zoite forms, as well as evidence of molecular differentiation between blood-stage merozoites and the ookinetes and sporozoites of the mosquito vector. Collectively we show that the conoid is a conserved apicomplexan element at the heart of the invasion mechanisms of these highly successful and often devastating parasites.
The neural architecture of language: Integrative modeling converges on predictive processing
Authors: Schrimpf Martin , Blank Idan , Tuckute Greta , Kauf Carina , Hosseini Eghbal A. , Kanwisher Nancy , Tenenbaum Joshua , Fedorenko Evelina 
Published: June 2020

AbstractThe neuroscience of perception has recently been revolutionized with an integrative modeling approach in which computation, brain function, and behavior are linked across many datasets and many computational models. By revealing trends across models, this approach yields novel insights into cognitive and neural mechanisms in the target domain. We here present a first systematic study taking this approach to higher-level cognition: human language processing, our species’ signature cognitive skill. We find that the most powerful ‘transformer’ models predict nearly 100% of explainable variance in neural responses to sentences and generalize across different datasets and imaging modalities (fMRI, ECoG). Models’ neural fits (‘brain score’) and fits to behavioral responses are both strongly correlated with model accuracy on the next-word prediction task (but not other language tasks). Model architecture appears to substantially contribute to neural fit. These results provide computationally explicit evidence that predictive processing fundamentally shapes the language comprehension mechanisms in the human brain.SignificanceLanguage is a quintessentially human ability. Research has long probed the functional architecture of language processing in the mind and brain using diverse brain imaging, behavioral, and computational modeling approaches. However, adequate neurally mechanistic accounts of how meaning might be extracted from language are sorely lacking. Here, we report an important first step toward addressing this gap by connecting recent artificial neural networks from machine learning to human recordings during language processing. We find that the most powerful models predict neural and behavioral responses across different datasets up to noise levels. Models that perform better at predicting the next word in a sequence also better predict brain measurements – providing computationally explicit evidence that predictive processing fundamentally shapes the language comprehension mechanisms in the human brain.
Recruitment of MRE-11 to complex DNA damage is modulated by meiosis-specific chromosome organization
Authors: Harrell Kailey , Day Madison , Smolikove Sarit 
Published: June 2020

AbstractDNA double-strand breaks (DSBs) are one of the most dangerous assaults on the genome, and yet their natural and programmed production are inherent to life. When DSBs arise close together (clustered) they are particularly deleterious, and their repair may require an altered form of the DNA damage response. Our understanding of how clustered DSBs are repaired in the germline is unknown. Using UV laser microirradiation, we examine early events in the repair of clustered DSBs in germ cells within whole, live,Caenorhabditis elegans. We use precise temporal resolution to show how the recruitment of MRE-11 to complex damage is regulated, and that clustered DNA damage can recruit proteins from various repair pathways. Abrogation of non-homologous end joining or COM-1 attenuates the recruitment of MRE-11 through distinct mechanisms. The synaptonemal complex plays both positive and negative regulatory roles in these mutant contexts. These findings together indicate that MRE-11 is regulated by modifying its accessibility to chromosomes.
A conserved role for sleep in supporting spatial learning inDrosophila
Authors: Melnattur Krishna , Kirszenblat Leonie , Morgan Ellen , Militchin Valentin , Sakran Blake , English Denis , Patel Rushi , Chan Dorothy , van Swinderen Bruno , Shaw Paul J. 
Published: June 2020

ABSTRACTSleep loss and aging impair hippocampus-dependent spatial learning in mammalian systems. Here we use the flyDrosophila melanogasterto investigate the relationship between sleep and spatial learning in healthy and impaired flies. The spatial learning assay is modeled after the Morris Water Maze. The assay uses a ‘thermal maze’ consisting of a 5×5 grid of Peltier plates maintained at 36-37°C and a visual panorama. The first trial begins when a single tile that is associated with a specific visual cue is cooled to 25°C. For subsequent trials, the cold tile is heated, the visual panorama is rotated and the flies must find the new cold-tile by remembering its association with the visual cue. Significant learning was observed with two different wild-type strains –Csand 2U, validating our design. Sleep deprivation prior to training impaired spatial learning. Learning was also impaired in the classic learning mutantrutabaga(rut); enhancing sleep restored learning torutmutants. Further we found that flies exhibited dramatic age-dependent cognitive decline in spatial learning starting at 20-24 days of age. These impairments could be reversed by enhancing sleep. Finally, we find that spatial learning requires dopaminergic signaling and that enhancing dopaminergic signaling in aged flies restored learning. Our results are consistent with the impairments seen in rodents and humans. These results thus demonstrate a critical conserved role for sleep in supporting spatial learning, and suggest potential avenues for therapeutic intervention during aging.STATEMENT OF SIGNIFICANCEWe have studied the relationship between sleep and plasticity using a Drosophila learning assay modified after the Morris Water Maze. Using this assay, we find that sleep loss impairs spatial learning. As in mammals, flies exhibited age-dependent spatial learning impairments. Importantly, the age-dependent impairments were reversed by enhancing sleep. Interestingly, our results mirror studies on hippocampus dependent memories in rodents and humans. Thus, our data describe an evolutionarily conserved role for sleep in regulating spatial learning. They also support augmenting sleep as a therapeutic strategy to ameliorate learning impairments.
Intense expression of Neurokinin-1 Receptor is associated with Urothelial carcinoma
Authors: Mehboob Riffat , Hassan Amber , Perveen Shahida , Gilani Syed Amir , Waseem Humera , Ahmad Fridoon Jawad , Akram Javed 
Published: June 2020

ABSTRACTI+ntroductionSubstance P (SP)/ Neurokinin-1 Receptor (NK-1R), induces inflammatory reactions in peripheral tissues but its regulatory effects in target tissues are dependent on receptor signaling. SP has a high affinity for the NK-1 receptor, to which it binds preferentially. SP/NK-1R complex plays a key role in the interaction in the onset of pain and inflammation.ObjectiveThe aim of this study was to investigate the expression of NK-1R in Urotheilial carcinoma and its association with cancer progression.MethodThe study included ten biopsy samples of Urinary bladder, obtained retrospectively from a tertiary care hospital of Lahore. An Immunohistochemical study was performed using monoclonal antibodies against NK-1R. The presence or absence of staining and the intensity of the immunoreactivity were noted, as well as the number and type of cells. Evaluation of the Immunohistochemical expression was determined by the semi-quantitative method and scored.ResultNK-1 receptor was intensely expressed in patients with higher grade Urotheilial carcinoma. The cases clinically diagnosed as High Grade Urotheilial Carcinoma showed intense expression of NK-1R. However, the cases clinically diagnosed as low grade Urotheilial carcinoma showed very weak staining with NK-1R. However, the normal margins of the same tissue showed negative expression.ConclusionsElevated expression of NK-1R was associated with advanced stage of urothelial carcinoma. It is the first study to our knowledge to report this association. It may serve as a good diagnostic as well as prognostic marker and therapeutic strategy.
Tissue context determines the penetrance of regulatory DNA variation
Authors: Halow Jessica M. , Byron Rachel , Hogan Megan S. , Ordoñez Raquel , Groudine Mark , Bender M. A. , Stamatoyannopoulos John A. , Maurano Matthew T. 
Published: June 2020

AbstractAssessment of the functional consequences of disease-associated sequence variation at non-coding regulatory elements is complicated by their high degree of context sensitivity to both the local chromatin and nuclear environments. Allelic profiling of DNA accessibility across individuals has shown that only a select minority of sequence variation affects transcription factor (TF) occupancy, yet the low sequence diversity in human populations means that no experimental assessment is available for the majority of disease-associated variants. Here we describe high-resolutionin vivomaps of allelic DNA accessibility in liver, kidney, lung and B cells from 5 increasingly diverged strains of F1 hybrid mice. The high density of heterozygous sites in these hybrids enables precise quantification of the effect size and cell-type specificity of hundreds of thousands of variants throughout the mouse genome. We show that chromatin-altering variants delineate characteristic sensitivity profiles for hundreds of TF motifs. We develop a compendium of TF-specific sensitivity profiles accounting for genomic context effects. Finally, we link these maps of allelic accessibility to allelic transcript levels in the same samples. This work provides a foundation for quantitative prediction of cell-type specific effects of non-coding variation on TF activity, which will dramatically facilitate both fine-mapping and systems-level analyses of common disease-associated variation in human genomes.
Stiffening of the Extracellular Matrix is a Sufficient Condition for Airway Hyperreactivity
Authors: Jamieson Ryan R , Stasiak Suzanne E , Polio Samuel R , Ruberti Jeffrey W , Parameswaran Harikrishnan 
Published: June 2020

AbstractThe current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force in an effort to prevent the recurrence of symptoms. However, the treatment is not a cure and has little beneficial effect on the progression of asthma. This suggests that there are mechanisms at play that are likelytriggeredby inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that the stiffening of the airway extracellular matrix is a core pathological changesufficientto support excessive bronchoconstriction in asthmatics even when in the absence of inflammation. To test this hypothesis, we increased the stiffness of airway ECM by photo-crosslinking collagen fibers within the airway wall using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a three-fold increase in stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, at a faster rate when exposed to a low dose of contractile agonist. Our results highlight the need for therapeutic approaches that target matrix remodeling to develop a lasting cure for this disease.
Prolonged deployed hospital care in the management of military eye injuries
Authors: Dhillon Amrit Singh , Ahmad Mohammad Salman Zia , Breeze John , Blanch Richard James 
Published: June 2020

ABSTRACTBackground/ObjectivesProlonged hospital care is described as deployed medical care, applied beyond doctrinal planning timelines and military medical planning envisages that in future conflicts, patients will have to be managed for up to five days without evacuation to their home country. We aimed to investigate the effect of prolonged hospital care on visual outcomes in the management of open and closed globe injures.MethodsWe conducted a retrospective cohort study in the setting of British military operations in Afghanistan. We included consecutive UK military patients with ocular trauma evacuated from Afghanistan between December 2005 and April 2013. We assessed outcome using best corrected visual acuity (VA) 6-12 months after injury.ResultsAll patients were male, with a mean age of 25. Outcomes adjusted for ocular trauma score (OTS) at presentation were similar to previous reports of military ocular trauma. The mean time to arrival at a centre with an ophthalmologist was 1.74 days. Both patients with penetrating open globe injuries and patients with hyphaema and an OTS of 3 or less displayed an association between worsening 6-12 month VA and time between injury and repair or assessment by an ophthalmologist.ConclusionTime to specialist ophthalmic care contributes to outcome after military open and closed globe injuries, supporting deployment of ophthalmologists on military operations.
An Effector Index to Predict Causal Genes at GWAS Loci
Authors: Forgetta Vincenzo , Jiang Lai , Vulpescu Nicholas A. , Hogan Megan S. , Chen Siyuan , Morris John A. , Grinek Stepan , Benner Christian , Jang Dong-Keun , Hoang Quy , Burtt Noel , Flannick Jason A. , McCarthy Mark I , Fauman Eric , Greenwood Celia MT , Maurano Matthew T. , Richards J. Brent 
Published: June 2020

AbstractDrug development and biological discovery require effective strategies to map existing genetic associations to causal genes. To approach this problem, we began by identifying a set of positive control genes for 12 common diseases and traits that cause a Mendelian form of the disease or are the target of a medicine used for disease treatment. We then identified a widely-available set of genomic features enriching GWAS-associated single nucleotide variants (SNVs) for these positive control genes. Using these features, we trained and validated the Effector Index (Ei), a causal gene mapping algorithm using the 12 common diseases and traits. The area underEi’sreceiver operator curve to identify positive control genes was 80% and area under the precision recall curve was 29%. Using an enlarged set of independently curated positive control genes for type 2 diabetes which included genes identified by large-scale exome sequencing, these areas increased to 85% and 61%, respectively. The best predictors were coding or transcript altering SNVs, distance to gene and open chromatin-based metrics. We provide theEialgorithm for its widespread use and have created a web-portal to facilitate understanding of results. This work outlines a simple, understandable approach to prioritize genes at GWAS loci for functional follow-up and drug development.Author summaryIn order to derive biological insight, or develop drugs based on genome-wide association studies (GWAS) data, causal genes at associated loci need to be identified. GWAS usually identify large genome regions containing many genes, but seldomly identifies specific causal genes. We have developed an algorithm to predict which genes in a region of disease association are likely causal and have named this algorithm the Effector Index. The Effector Index was optimized on diseases that have known causal or drug target genes, and further validated to predict these types of genes in independent datasets. The Effector Index formalizes these predictive features into a tool that can be used by researchers, and results from the traits and diseases studied here are available via the Accelerating Medicine Partnership web-portal athttp://hugeamp.org/effectorgenes.html.
Impact of high-fat diet on lifespan, metabolism, fecundity and behavioral senescence inDrosophila
Authors: Liao Sifang , Amcoff Mirjam , Nässel Dick R. 
Published: June 2020

AbstractExcess consumption of high-fat diet (HFD) is likely to result in obesity and increases the predisposition to associated health disorders.Drosophila melanogasterhas emerged as an important model to study the effects of HFD on metabolism, gut function, behavior, and ageing. In this study, we investigated the effects of HFD on physiology and behavior of female flies at different time-points over several weeks. We found that HFD decreases lifespan, and also with age leads to accelerated decline of climbing ability in both virgins and mated flies. In virgins HFD also increased sleep fragmentation with age. Furthermore, long-term exposure to HFD results in elevated adipokinetic hormone (AKH) transcript levels and an enlarged crop with increased lipid stores. We detected no long-term effects of HFD on body mass, or levels of triacylglycerides (TAG), glycogen or glucose, although fecundity was diminished. However, one week of HFD resulted in decreased body mass and elevated TAG levels in mated flies. Finally, we investigated the role of AKH in regulating effects of HFD during aging. Both with normal diet (ND) and HFD,Akhmutant flies displayed increased longevity compared to control flies. However, both mutants and controls showed shortened lifespan on HFD compared to ND. In flies exposed to ND, fecundity is decreased inAkhmutants compared to controls after one week, but increased after three weeks. However, HFD leads to a similar decrease in fecundity in both genotypes after both exposure times. Thus, long-term exposure to HFD increases AKH signaling, impairs lifespan and fecundity and augments age-related behavioral senescence.
A critical role for trkB signaling in the adult function of parvalbumin interneurons and prefrontal network dynamics
Authors: Guyon Nicolas , Zacharias Leonardo Rakauskas , van Lunteren Josina Anna , Immenschuh Jana , Fuzik Janos , Märtin Antje , Xuan Yang , Zilberter Misha , Kim Hoseok , Meletis Konstantinos , Lopes-Aguiar Cleiton , Carlén Marie 
Published: June 2020

AbstractInhibitory interneurons expressing parvalbumin (PV) in the prefrontal cortex (PFC) are central to excitatory/inhibitory (E/I) balance, generation of gamma oscillations, and cognition. Dysfunction of PV interneurons disrupts information processing and cognitive behavior. Tyrosine receptor kinase B (trkB) signaling is known to regulate the differentiation and maturation of cortical PV interneurons during development, but is also suggested to be involved in the activity and network functions of PV interneurons in the adult brain. Using a novel viral strategy for cell-type and region-specific expression of a dominant negative trkB in adult mice, we show that reduced trkB signaling in PV interneurons in the PFC leads to pronounced morphological, physiological, and behavioral changes. Our results provide evidence for a critical role of trkB signaling in the function of PV interneurons in the adult brain, local network activities central to prefrontal circuit dynamics, and cognitive behavior.
Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme
Authors: Fedoryshchak Roman O. , Přechová Magdalena , Butler Abbey , Lee Rebecca , O’Reilly Nicola , Flynn Helen , Snijders Ambrosius P. , Eder Noreen , Ultanir Sila , Mouilleron Stéphane , Treisman Richard 
Published: June 2020

ABSTRACTPPP-family phosphatases such as PP1 have little intrinsic specificity. Cofactors can target PP1 to substrates or subcellular locations, but it remains unclear how they might confer sequence-specificity on PP1. The cytoskeletal regulator Phactr1 is a neuronally-enriched PP1 cofactor that is controlled by G-actin. Structural analysis showed that Phactr1 binding remodels PP1’s hydrophobic groove, creating a new composite surface adjacent to the catalytic site. Using phosphoproteomics, we identified numerous fibroblast and neuronal Phactr1/PP1 substrates, which include cytoskeletal components and regulators. We determined high-resolution structures of Phactr1/PP1 bound to the dephosphorylated forms of its substrates IRSp53 and spectrin αII. Inversion of the phosphate in these holoenzyme-product complexes supports the proposed PPP-family catalytic mechanism. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with the composite Phactr1/PP1 surface, which are required for efficient dephosphorylation. Sequence specificity explains why Phactr1/PP1 exhibits orders-of-magnitude enhanced reactivity towards its substrates, compared to apo-PP1 or other PP1 holoenzymes.
Excess mortality and potential undercounting of COVID-19 deaths by demographic group in Ohio
Authors: Quast Troy , Andel Ross 
Published: June 2020

AbstractBackgroundThere are significant gaps in our understanding of the mortality effects of COVID-19 due to evolving diagnosis criteria, shortages of testing supplies, and challenges faced by physicians in treating patients in crisis environments. Accurate information on the number of deaths caused by COVID-19 is vital for policy makers and health care providers.MethodsWe performed a retrospective study of weekly data for Ohio. To estimate expected mortality in 2020 we employed data from 2010 through 2019, adjusted for secular trends and seasonality. We estimated excess mortality as the number of observed deaths less the number of expected deaths. We conducted the analysis for the entire population and by age, gender, and county.ResultsWe estimated 2,088 (95% CI 1,119-3,119) excess deaths due to natural causes in Ohio from March 15, 2020 through June 6, 2020. While the largest number excess of deaths was observed in the 80+ age group, our estimate of 366 (95% CI 110-655) excess deaths for those between 20 and 49 years of age substantially exceeds the reported number of COVID-19 deaths of 66.ConclusionsOur methodology addressed some of the challenges of estimating the number of deaths caused by COVID-19. Our finding of excess deaths being considerably greater than the reported number of COVID-19 deaths for those aged 20 to 49 years old suggests that current tracking methods may not capture a significant number of COVID-19 deaths for this group. Further, increases in the infection rates for this cohort may have a greater mortality impact than anticipated.