bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uneven declines between corals and cryptobenthic fish symbionts from multiple disturbances
Authors: Froehlich Catheline Y.M. , Klanten O. Selma , Hing Martin L. , Dowton Mark , Wong Marian Y.L. 
Published: January 2021

ABSTRACTWith the onset and increasing frequency of multiple disturbances, the recovery potential of critical ecosystem-building species and their mutual symbionts is threatened. Similar effects to both hosts and their symbionts following disturbances have been assumed. However, we report unequal declines between hosts and symbionts throughout multiple climate-driven disturbances in reef-buildingAcroporacorals and cryptobenthic coral-dwellingGobiodongobies. Communities were surveyed before and after consecutive cyclones (2014, 2015) and heatwaves (2016, 2017). After cyclones, coral size and goby group size decreased similarly by 28-30%. After heatwave-induced bleaching, coral size decreased substantially (47%) and the few gobies recorded mostly inhabited corals singly. Despite several coral species still occurring after bleaching, all goby species declined, leaving 78% of corals uninhabited. These findings suggest that gobies, which are important mutual symbionts for corals, are unable to cope with consecutive disturbances. This disproportionate decline could lead to ecosystem-level disruptions through loss of key symbiotic services to corals.
Periplasm homeostatic regulation maintains spatial constraints essential for cell envelope processes and cell viability
Authors: Mandela Eric , Stubenrauch Christopher J. , Ryoo David , Hwang Hyea , Cohen Eli J. , Torres Von L. , Deo Pankaj , Webb Chaille T. , Huang Cheng , Schittenhelm Ralf B. , Beeby Morgan , Gumbart JC , Lithgow Trevor , Hay Iain D. 
Published: January 2021

ABSTRACTThe cell envelope of Gram-negative bacteria consists of two membranes surrounding a periplasm and peptidoglycan layer. Molecular machines spanning the cell envelope depend on spatial constraints and load-bearing forces across the cell envelope and surface. The mechanisms dictating spatial constraints across the cell envelope remain incompletely defined. InEscherichia coli, the coiled-coil lipoprotein Lpp contributes the only covalent linkage between the outer membrane and the underlying peptidoglycan layer. Using proteomics, molecular dynamics and a synthetic lethal screen we show that lengthening Lpp to the upper limit does not change the spatial constraint, but rather impacts the load-bearing capacity across the outer membrane. Our findings demonstrateE. coliexpressing elongated Lpp homeostatically counteracts periplasmic enlargement with a combination of tilting Lpp and reducing Lpp abundance. By genetic screening we identified all of the genes inE. colithat become essential in order to enact this homeostasis, and by quantitative proteomics discovered that very few proteins need to be up- or down-regulated in steady-state levels in order to enact this homeostasis. We observed increased levels of factors determining cell stiffness, decrease membrane integrity, increase membrane vesiculation and a dependance on otherwise non-essential tethers to maintain lipid transport and peptidoglycan biosynthesis. Further this has implications for understanding how spatial constraint across the envelope controls processes such as flagellum-driven motility, cellular signaling and protein translocation
FOXO1 and FOXO3 cooperatively regulate innate lymphoid cell development
Authors: Luu Thuy T. , Søndergaard Jonas Nørskov , Peña-Pérez Lucía , Kharazi Shabnam , Krstic Aleksandra , Meinke Stephan , Schmied Laurent , Frengen Nicolai , Heshmati Yaser , Kierczak Marcin , Bouderlique Thibault , Wagner Arnika Kathleen , Gustafsson Charlotte , Chambers Benedict J. , Achour Adnane , Kutter Claudia , Höglund Petter , Månsson Robert , Kadri Nadir 
Published: January 2021

SUMMARYThe natural killer (NK) and non-cytotoxic innate lymphoid cells (ILC) lineages play vital role in the regulation of the immune system. Yet understanding of mechanisms controlling NK/ILC development remains incomplete. The evolutionary conserved FOXO family of forkhead transcription factors are critical regulators of cellular processes. We found that the loss of FOXO1 and FOXO3 together caused impaired activation of the NK gene expression program and reduced ETS binding already at the common lymphoid progenitor (CLP) level and a block at the ILC progenitor (ILCP) to NK progenitor transition. FOXO controlled NK cell maturation in organ specific manner and their ability to respond to IL-15. At the ILCP level, disruption of the ILC lineage specific gene programs was associated with broad perturbation of the generation of the non-cytotoxic ILC subsets. We concluded that FOXO1 and FOXO3 cooperatively regulate ILC lineage specification at the progenitor level as well as the generation of mature ILCs.
Correcting statistical bias in correlation-based kinship estimators
Authors: Jiang Wei , Zhang Xiangyu , Li Siting , Song Shuang , Zhao Hongyu 
Published: January 2021

AbstractAccurate estimate of relatedness is important for genetic data analyses, such as association mapping and heritability estimation based on data collected from genome-wide association studies. Inaccurate relatedness estimates may lead to spurious associations and biased heritability estimations. Individual-level genotype data are often used to estimate kinship coefficient between individuals. The commonly used sample correlation-based genomic relationship matrix (scGRM) method estimates kinship coefficient by calculating the average sample correlation coefficient among all single nucleotide polymorphisms (SNPs), where the observed allele frequencies are used to calculate both the expectations and variances of genotypes. Although this method is widely used, a substantial proportion of estimated kinship coefficients are negative, which are difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists bias in the estimated kinship coefficient using the scGRM method when the observed allele frequencies are regarded as true frequencies. This leads to negative bias for the average estimate of kinship among all individuals, which explains the estimated negative kinship coefficients. Based on this observation, we propose an unbiased estimation method, UKin, which can reduce the bias. We justify our improved method with rigorous mathematical proof. We have conducted simulations as well as two real data analyses to demonstrate that both bias and root mean square error in kinship coefficient estimation can be reduced by using UKin. Further simulations indicate that the power in association mapping can also be improved by using our unbiased kinship estimates to adjust for cryptic relatedness.Author summaryInference of relatedness plays an important role in genetic data analysis. Many methods have been proposed to estimate kinship coefficients, including the commonly used genomic relationship matrix method. However, a substantial proportion of the kinship coefficients estimated by this method are negative, which is difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists a negative bias in this approach. To correct for this bias, we propose a new kinship coefficient estimation method, UKin, which is unbiased without requiring extra genetic information nor added computational complexity. The better performance of UKin in reducing bias and root mean squared error is demonstrated through theory, simulations and analysis of data from the young-onset breast cancer and familial intracranial aneurysm studies.
Development of loop-mediated isothermal amplification (LAMP) assay for detection of Pseudocercospora angolensis in sweet orange
Authors: Driciru Patricia , Claire Mugasa M , Acidri Robert , Adriko John 
Published: January 2021

AbstractPseudocercospora angolensisis the causative agent ofPseudocercosporaleaf and fruit spot disease in citrus which can result in up to 100% yield loss. Early diagnosis of this disease is vital for effective control. This study aimed at developing a loop-mediated amplification (LAMP) system for detectingP. angolensisin sweet oranges in comparison with Polymerase Chain Reaction (PCR) and using microscopy as a gold standard. Twelve non-target species were used to assess the analytical specificity of LAMP and PCR whereas the analytical sensitivity was determined using serial dilutions ofP. angolensisDNA. The diagnostic accuracies of the two assays were evaluated using DNA from 150 diseased and 50 non-diseased sweet orange leaf samples. The analytical sensitivity and detection time of LAMP were of 10−4ng/ μl and 40 minutes, respectively. The analytical sensitivity of PCR was 10ng/μl and it was specific toP. angolensiswhereas three relatives ofP. angolensiswere detectable by LAMP. The diagnostic sensitivities of LAMP (93%) and microscopy (100%) were significantly different (X2= 8.38,P= 0.0038) unlike the diagnostic specificities (90%) and (100%), respectively (X2= 3.37,P= 0.066). Microscopy was significantly more sensitive than PCR (32.6%) (X2= 149.26,P< 2.2e-16) and equally specific as PCR (P=NA). The positive predictive values of PCR and LAMP were 100% and 96.5% respectively whereas the negative predictive values were 33.1% and 81.8% respectively. The LAMP assay developed in this study offers a great tool for routine screening sweet orange samples forP. angolensis.
Surveillance of genetic diversity and evolution in locally transmitted SARS-CoV-2 in Pakistan during the first wave of the COVID-19 pandemic
Authors: Shakeel Muhammad , Irfan Muhammad , Zaibunnisa  , Rashid Muhammad , Ansari Sabeeta Kanwal , Khan Ishtiaq Ahmad 
Published: January 2021

AbstractSurveillance of genetic diversity in the SARS-CoV-2 is extremely important to detect the emergence of more infectious and deadly strains of the virus. In this study, we monitored mutational events in the SARS-CoV-2 genome through whole genome sequencing. The samples (n=48) were collected from the hot spot regions of the metropolitan city Karachi, Pakistan during the four months (May 2020 to August 2020) of first wave of the COVID-19 pandemic. The data analysis highlighted 122 mutations, including 120 single nucleotide variations (SNV), and 2 deletions. Among the 122 mutations, there were 71 singletons, and 51 recurrent mutations. A total of 16 mutations, including 5 nonsynonymous mutations, were detected in spike protein. Notably, the spike protein missense mutation D614G was observed in 31 genomes. The phylogenetic analysis revealed majority of the genomes (36) classified as B lineage, where 2 genomes were from B.6 lineage, 5 genomes from B.1 ancestral lineage and remaining from B.1 sub-lineages. It was noteworthy that three clusters of B.1 sub-lineages were observed, including B.1.36 lineage (10 genomes), B.1.160 lineage (11 genomes), and B.1.255 lineage (5 genomes), which represent independent events of SARS-CoV-2 transmission within the city. The sub-lineage B.1.36 had higher representation from the Asian countries and the UK, B.1.160 correspond to the European countries with highest representation from the UK, Denmark, and lesser representation from India, Saudi Arabia, France and Switzerland, and the third sub-lineage (B.1.255) correspond to the USA. Collectively, our study provides meaningful insight into the evolution of SARS-CoV-2 lineages in spatio-temporal local transmission during the first wave of the pandemic.
Listeria monocytogenesfaecal carriage is common and driven by microbiota
Authors: Garcia-Garcera Marc , Hafner Lukas , Burucoa Christophe , Moura Alexandra , Pichon Maxime , Lecuit Marc 
Published: January 2021

AbstractListeriagenus comprises two opportunistic pathogenic species,L. monocytogenes(Lm) andL. ivanovii, and several non-pathogenic species. All can thrive as saprophytes, whereas only pathogenic species cause systemic infections in human and cattle. IdentifyingListeriaspecies’ respective biotopes is critical to understand the ecological contribution ofListeriapathogenic potential. Here, we aimed at detectingListeriain samples of diverse origins, to highlight ecological differences between pathogenic and non-pathogenic species. We retrieved 16S rDNA datasets from the metagenomics MG-RAST database and determined the prevalence and abundance ofListeriaspecies in various sources. Overall,Listeriawas detected in 14% of datasets.Lmwas the most prevalent species, most abundant both in soil and host-associated environments, including in 5% of human stools.Lmwas also detected in 10% of human stool samples from an independent cohort of 900 healthy asymptomatic donors. A specific microbiota signature was associated withLmfaecal carriage in human, as well as in experimentally inoculated mice, in which it precededLmlong-term gut colonization, indicating that gut microbiota composition influencesLmfaecal carriage. These results suggest that asymptomatic faecal carriage, rather than disease, exerts purifying selection onLm“virulence genes”.
Effects of forced cohesin eviction and retention on X-inactivation and autosomes
Authors: Kriz Andrea J. , Colognori David , Sunwoo Hongjae , Nabet Behnam , Lee Jeannie T. 
Published: January 2021

SUMMARYDepletion of architectural factors globally alters chromatin structure, but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Interestingly, cohesin loss disrupts Xi superstructure, unveiling superloops between escapee genes, with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure and compromises spreading of Xist RNA-Polycomb complexes, attenuating Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with theXistlocus are weakened. Surprisingly, cohesin loss created an “Xi superloop” and cohesin retention created “Xi megadomains” on the active X. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X-inactivation and inter-chromosomal interactions across the genome.
Constitutive high expression of NOXA sensitizes human embryonic stem cells for rapid cell death
Authors: Basundra Richa , Kapoor Sahil , Hollville Emilie , Kiapour Nazanin , Lopez Adriana Beltran , Melchiorre Nicole Marie , Deshmukh Mohanish 
Published: January 2021

AbstractHuman embryonic stem (hES) cells are highly sensitive to apoptotic stimuli such as DNA damage, which allows for rapid elimination of mutated cells during development. However, the mechanisms that maintain hES cells in the primed apoptotic state are not completely known. Key activators of apoptosis, the BH3-only proteins, are present at low levels in most cell types. In contrast, hES cells have constitutive high levels of the BH3-only protein, NOXA. We examined the importance of NOXA for enabling apoptosis in hES cells. hES cells deleted forNOXAshowed remarkable protection against multiple apoptotic stimuli. NOXA was constitutively localized to the mitochondria, where it interacted with MCL1. Strikingly, inhibition of MCL1 inNOXAknockout cells was sufficient to sensitize these cells to DNA damage, and subsequently, cell death. Our study demonstrates, an essential function of constitutive high levels of NOXA in hES cells is to effectively antagonize MCL1 to permit rapid apoptosis.Significance statementHuman embryonic stem (hES) cells give rise to the entire organism, hence understanding how these cells regulate their survival and death is important. These cells undergo rapid death in response to DNA damage thereby removing mutated cells from the developing embryo. We focused on identifying the mechanism underlying the sensitivity of these cells to DNA damage. We discovered that the protein NOXA is essential for cell death in hES cells. Further, the crucial function of NOXA is to neutralize high levels of antiapototic protein, MCL1, thus enabling hES cells to respond rapidly to DNA damage.
Structural mechanism of CARD8 regulation by DPP9
Authors: Sharif Humayun , Hollingsworth L. Robert , Griswold Andrew R. , Hsiao Jeffrey C. , Wang Qinghui , Bachovchin Daniel A. , Wu Hao 
Published: January 2021

SUMMARYCARD8 is a germline-encoded pattern recognition receptor that detects intracellular danger signals. Like the related inflammasome sensor NLRP1, CARD8 undergoes constitutive autoprocessing within its function-to-find domain (FIIND), generating two polypeptides that stay associated and autoinhibited. Certain pathogen- and danger-associated activities, including the inhibition of the serine dipeptidases DPP8 and DPP9 (DPP8/9), induce the proteasome-mediated degradation of the N-terminal (NT) fragment, releasing the C-terminal (CT) fragment to form a caspase-1 activating inflammasome. DPP8/9 also bind directly to the CARD8 FIIND, but the role that this interaction plays in CARD8 inflammasome regulation is not yet understood. Here, we solved several cryo-EM structures of CARD8 bound to DPP9, with or without the DPP inhibitor Val-boroPro (VbP), which revealed a ternary complex composed of one DPP9, the full-length CARD8, and one CARD8-CT. Through structure-guided biochemical and cellular experiments, we demonstrated that DPP9’s structure restrains CARD8-CT after proteasomal degradation. Moreover, although DPP inhibitors do not directly displace CARD8 from DPP9in vitro, we show that they can nevertheless destabilize this complex in cells. Overall, these results demonstrate that DPP8/9 inhibitors cause CARD8 inflammasome activation via at least two distinct mechanisms, one upstream and one downstream of the proteasome.
Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex
Authors: Koike Yuka , Sugai Akihiro , Hara Norikazu , Ito Junko , Yokoseki Akio , Ishihara Tomohiko , Yamagishi Takuma , Tsuboguchi Shintaro , Tada Mari , Ikeuchi Takeshi , Kakita Akiyoshi , Onodera Osamu 
Published: January 2021

AbstractIn amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43), which is encoded byTARDBP, forms aggregates in the motor cortex. This aggregate formation may be triggered by an increase in the TDP-43 level with aging. However, the amount of TDP-43 is autoregulated by alternative splicing of theTARDBP3’UTR, and how this autoregulation is affected by aging remains to be elucidated. We found that DNA demethylation in the autoregulatory region in the TARDBP 3′UTR reduced alternative splicing and increasedTARDBPmRNA expression. Furthermore, in the human motor cortex, we found that this region was demethylated with aging, resulting in increased expression ofTARDBPmRNA. The acceleration of DNA demethylation in the motor cortex was associated with the age of ALS onset. In summary, the dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and motor system selectivity in ALS.
The termite fungal cultivarTermitomycescombines diverse enzymes and oxidative reactions for plant biomass conversion
Authors: Schalk Felix , Gostinčar Cene , Kreuzenbeck Nina B. , Conlon Benjamin H. , Sommerwerk Elisabeth , Rabe Patrick , Burkhardt Immo , Krüger Thomas , Kniemeyer Olaf , Brakhage Axel A. , Gunde-Cimerman Nina , de Beer Z. Wilhelm , Dickschat Jeroen S. , Poulsen Michael , Beemelmanns Christine 
Published: January 2021

AbstractMacrotermitine termites have domesticated fungi in the genusTermitomycesas their primary food source using pre-digested plant biomass. To access the full nutritional value of lignin-enriched plant biomass, the termite-fungus symbiosis requires the depolymerization of this complex phenolic polymer. While most previous work suggests that lignocellulose degradation is accomplished predominantly by the fungal cultivar, our current understanding of the underlying biomolecular mechanisms remains rudimentary. Here, we provide conclusive OMICs and activity-based evidence thatTermitomycespartially depolymerizes lignocellulose through the combined actions of high-redox potential oxidizing enzymes (laccases, aryl-alcohol oxidases and a manganese peroxidase), the production of extracellular H2O2and Fenton-based oxidative degradation, which is catalyzed by a newly described 2-methoxybenzoquinone/hydroquinone redox shuttle system and mediated by secreted chelating dicarboxylic acids. In combination, our approaches reveal a comprehensive depiction of how the efficient biomass degradation mechanism in this ancient insect agricultural symbiosis is accomplished through a combination of white- and brown-rot mechanisms.ImportanceFungus-growing termites have perfected the decomposition of recalcitrant plant biomass to access valuable nutrients by engaging in a tripartite symbiosis with complementary contributions from a fungal mutualist and a co-diversified gut microbiome. This complex symbiotic interplay makes them one of the most successful and important decomposers for carbon cycling in Old World ecosystems. To date, most research has focused on the enzymatic contributions of microbial partners to carbohydrate decomposition. Here we provide genomic, transcriptomic and enzymatic evidence thatTermitomycesalso employs redox mechanisms, including diverse ligninolytic enzymes and a Fenton-based hydroquinone-catalyzed lignin-degradation mechanism, to break down lignin-rich plant material. Insights into these efficient decomposition mechanisms open new sources of efficient ligninolytic agents applicable for energy generation from renewable sources.
Knowledge of and Attitudes on Artificial Intelligence in Healthcare: A Provincial Survey Study of Medical Students
Authors: Mehta Nishila , Harish Vinyas , Bilimoria Krish , Morgado Felipe , Ginsburg Shiphra , Law Marcus , Das Sunit 
Published: January 2021

ABSTRACTBackgroundThere has been growing acknowledgement that undergraduate medical education (UME) must play a formal role in instructing future physicians on the promises and limitations of artificial intelligence (AI), as these tools are integrated into medical practice.MethodsWe conducted an exploratory survey of medical students’ knowledge of AI, perceptions on the role of AI in medicine, and preferences surrounding the integration of AI competencies into medical education. The survey was completed by 321 medical students (13.4% response rate) at four medical schools in Ontario.ResultsMedical students are generally optimistic regarding AI’s capabilities to carry out a variety of healthcare functions, from clinical to administrative, with reservations about specific task types such as personal counselling and empathetic care. They believe AI will raise novel ethical and social challenges. Students are concerned about how AI will affect the medical job market, with 25% responding that it was actively impacting their choice of specialty. Students agree that medical education must do more to prepare them for the impact of AI in medicine (79%), and the majority (68%) believe that this training should begin at the UME level.ConclusionsMedical students expect AI will be widely integrated into healthcare and are enthusiastic to obtain AI competencies in undergraduate medical education.