bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of two conserved cell death elicitor families from the Dothideomycete fungal pathogens Dothistroma septosporum and Fulvia fulva (syn. Cladosporium fulvum)
Authors: Tarallo Mariana , McDougal Rebecca L. , Chen Zhiyuan , Wang Yan , Bradshaw Rosie E. , Mesarich Carl H. 
Published: June 2022

AbstractDothistroma septosporum (Ds) and Fulvia fulva (Ff; previously called Cladosporium fulvum) are two closely related Dothideomycete fungal species that cause Dothistroma needle blight in pine and leaf mold in tomato, respectively. During host colonization, these pathogens secrete virulence factors termed effectors to promote infection. In the presence of corresponding host immune receptors, however, these effectors activate plant defenses, including a localized cell death response that halts pathogen growth. We identified two effector protein families, Ecp20 and Ecp32, which are conserved between the two pathogens. The Ecp20 family has four paralogues in both species, while the Ecp32 family has four paralogues in D. septosporum and five in F. fulva. Both families have members that are highly expressed during host infection. Members of the Ecp20 family have predicted structural similarity to proteins with a β-barrel fold, including the Alt a 1 allergen from Alternaria alternata, while members of the Ecp32 family have predicted structural similarity to proteins with a β-trefoil fold, such as trypsin inhibitors and lectins. Using Agrobacterium tumefaciens-mediated transient transformation assays, each family member was assessed for its ability to trigger cell death in leaves of the non-host species Nicotiana benthamiana and N. tabacum. Using this approach, FfEcp20-2, DsEcp20-3 and FfEcp20-3 from the Ecp20 family, and all members from the Ecp32 family, except for the Ds/FfEcp32-4 pair, triggered cell death in both species. This cell death was dependent on secretion of the effectors to the apoplast. In line with recognition by an extracellular immune receptor, cell death triggered by Ds/FfEcp20-3 and FfEcp32-3 was compromised in N. benthamiana silenced for BAK1 or SOBIR1, which encode extracellular co-receptors involved in transducing defense response signals following apoplastic effector recognition. We then investigated whether DsEcp20-3 and DsEcp20-4 triggered cell death in the host species Pinus radiata by directly infiltrating purified protein into pine needles. Strikingly, as in the non-host species, DsEcp20-3 triggered cell death, while DsEcp20-4 did not. Collectively, our study describes two new candidate effector families with cell death-eliciting activity from D. septosporum and F. fulva and provides evidence that members of these families are recognized by plant immune receptors.
The lingering effects of Neanderthal introgression on human complex traits
Authors: Wei Xinzhu , Robles Christopher R. , Pazokitoroudi Ali , Ganna Andrea , Gusev Alexander , Durvasula Arun , Gazal Steven , Loh Po-Ru , Reich David , Sankararaman Sriram 
Published: June 2022

AbstractThe mutations introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed mutations. We developed rigorous methods to assess the contribution of introgressed Neanderthal mutations to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal mutations and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal mutations have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.1% of heritable variation averaged across phenotypes; p = 9.59×10-9). However, the contribution of introgressed mutations tends to be significantly depleted relative to modern human mutations matched for allele frequency and linkage disequilibrium (about 57% depletion on average), consistent with purifying selection on introgressed mutations. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal mutations with 64 phenotypes (p < 1 ×10-10). Previous work (Skov 2021) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed mutations that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed mutations are highly likely to have a phenotypic effect. Examination of these mutations reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.
Strongly bactericidal all-oral β-lactam combinations for the treatment of Mycobacterium abscessus lung disease
Authors: Negatu Dereje A. , Zimmerman Matthew D. , Dartois Véronique , Dick Thomas 
Published: June 2022

ABSTRACTBioactive forms of oral β-lactams were screened in vitro against Mycobacterium abscessus with and without the bioactive form of the oral β-lactamase inhibitor avibactam-ARX1796. Sulopenem was equally active without avibactam, while tebipenem, cefuroxime and amoxicillin required avibactam for optimal activity. Systematic pairwise combination of the four β-lactams revealed strong bactericidal synergy for each of sulopenem, tebipenem and cefuroxime combined with amoxicillin in the presence of avibactam. These all-oral β-lactam combinations warrant clinical evaluation.
Impact of imperfect diagnosis in ME/CFS association studies
Authors: Malato João , Graça Luís , Sepúlveda Nuno 
Published: June 2022

ABSTRACTThe absence of an objective disease biomarker puts studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) under the curse of imperfect diagnosis. This problem leads to frequent reports that fail to reproduce prior published studies. To address the impact of imperfect diagnosis on the robustness of studies’ conclusions, we conducted a simulation study to quantify the statistical power to detect a disease association with a hypothetical binary factor in the presence of imperfect diagnosis. Using the classical case-control design, studies with sample sizes of less than 500 individuals per group could not reach the target power of at least 80% to detect realistic disease associations. We then recreated serological association studies in which the chance of imperfect diagnosis was combined with the probability of misclassifying a binary factor, as it happens in a typical serological association study. In this case, the target power of 80% could only be achieved for studies with more than 1000 individuals per group. Given the current sample sizes of ME/CFS studies, our results suggest that most studies are likely to be underpowered due to imperfect diagnosis alone. To increase reproducibility across studies, we provided some practical recommendations, such as the use of standard case definitions together with multi-centric study designs, and routine reporting of power calculations under a non-negligible chance of misdiagnosis. Our results can also inform the design of future studies under the assumption of misdiagnosis.
Luminal progenitors undergo partial epithelial-to-mesenchymal transition at the onset of basal-like breast tumorigenesis
Authors: Landragin Camille , Saichi Melissa , Prompsy Pacôme , Durand Adeline , Mesple Jérémy , Trouchet Amandine , Faraldo Marisa , Salmon Hélène , Vallot Céline 
Published: June 2022

SUMMARYDefects in double-strand repair mechanisms - both through germline or somatic inactivation of repair genes - is a hallmark of basal-like breast cancers. In this genetically-unstable context, a recurrent shift in cell identity occurs within the mammary epithelium. Basal-like tumors have indeed been proposed to originate from luminal progenitor (LP) cells yet tumor-initiating events remain poorly understood. Here, we map state transitions at the onset of basal-like tumorigenesis, using a Brca-1 deficient mouse model launching tumorigenesis in multiple LP cells. Combining single-cell transcriptomics to spatial multiplex imaging, we identify a population of cycling p16-expressing cells, emerging from the luminal progenitor compartment, undergoing partial epithelial-to-mesenchymal transition and losing luminal identity. Pseudo-temporal analyses position these cells as a transitory pre-tumoral state between aberrant Brca1-deficient luminal progenitors and growing tumor cells. In patients, the p16 pre-tumoral signature is found in early stage basal-like tumors, that rarely recur. Concomitant to p16 activation, we show that LP cells undergo an epigenomic crisis attested by the general re-organization of their heterochromatin. They accumulate multiple H3K27me3 micro-foci - reminiscent of the formation of senescence-associated heterochromatin foci (SAHFs) - and lose their inactive X (Xi). Both p16 activation and heterochromatin reorganization are hallmarks of human basal-like breast tumors; we propose that these events occur during initial LP transformation and are scars of an initial transitory senescent-like state.
Mathematical modeling and biochemical analysis support partially ordered CaM-MLCK binding
Authors: MacEwen Melissa JS , Rusnac Domnita-Valeria , Ermias Henok , Locke Timothy M , Gizinski Hayden E , Dexter Joseph P , Sancak Yasemin 
Published: June 2022

AbstractActivation of myosin light-chain kinase (MLCK) by calcium ions (Ca2+) and calmodulin (CaM) plays an important role in numerous cellular functions including vascular smooth muscle contraction and cellular motility. Despite extensive biochemical analysis of this system, aspects of the mechanism of activation remain controversial, and competing theoretical models have been proposed for the binding of Ca2+and CaM to MLCK. The models are analytically solvable for an equilibrium steady state and give rise to distinct predictions that hold regardless of the numerical values assigned to parameters. These predictions form the basis of a recently proposed, multi-part experimental strategy for model discrimination. Here we implement this strategy by measuring CaM-MLCK binding using anin vitroFRET system. This system uses the CaM-binding region of smooth muscle MLCK protein to link two fluorophores to form an MLCK FRET Reporter (FR). Biochemical and biophysical experiments have established that FR can be reliably used to analyze MLCK-CaM binding. We assessed the binding of either wild-type CaM, or mutant CaM with one or more defective EF-hand domains, to FR. Interpretation of binding data in light of the mathematical models suggests a partially ordered mechanism for binding of CaM to MLCK. Complementary data collected using orthogonal approaches that directly quantify CaM-MLCK binding further supports our conclusions.
Socio-economic disadvantage is associated with alterations in brain wiring economy
Authors: Siugzdaite Roma , Akarca Danyal , Johnson Amy , Carozza Sofia , Anwyl-Irvine Alexander L , Uh Stepheni , Smith Tess , Bignardi Giacomo , Dalmaijer Edwin , Astle Duncan E. 
Published: June 2022

AbstractThe quality of a child’s social and physical environment is a key influence on brain development, educational attainment and mental wellbeing. However, there still remains a mechanistic gap in our understanding of how environmental influences converge on changes in the brain’s developmental trajectory. In a sample of 145 children with structural diffusion tensor imaging data, we used generative network modelling to simulate the emergence of whole brain network organisation. We then applied data-driven clustering to stratify the sample according to socio-economic disadvantage, with one of the resulting clusters containing mostly children living below the poverty line. A formal comparison of the simulated networks from the generative model revealed that the computational principles governing network formation were subtly different for children experiencing socio-economic disadvantage, and that this resulted in significantly altered developmental timing of network modularity emergence. Children in the low socio-economic status (SES) group had a significantly slower time to peak modularity, relative to the higher SES group (t(69) = 3.02, P = 3.50 × 10-4, d = 0.491). In a subsequent simulation we showed that the alteration in generative properties increases the variability in wiring probabilities during network formation (KS test: D = 0.012, P < 0.001). One possibility is that multiple environmental influences such as stress, diet and environmental stimulation impact both the systematic coordination of neuronal activity and biological resource constraints, converging on a shift in the economic conditions under which networks form. Alternatively, it is possible that this stochasticity reflects an adaptive mechanism that creates “resilient” networks better suited to unpredictable environments.Author SummaryWe used generative network models to simulate macroscopic brain network development in a sample of 145 children. Within these models, network connections form probabilistically depending on the estimated “cost” of forming a connection, versus topological “value” that the connection would confer. Tracking the formation of the network across the simulation, we could establish the changes in global brain organisation measures such as integration and segregation. Simulations for children experiencing socio-economic disadvantage were associated with a shift in emergence of a topologically valuable network property, namely modularity.
Significance tests for R2 of out-of-sample prediction using polygenic scores
Authors: Momin Md. Moksedul , Lee Soohyun , Wray Naomi R , Lee S. Hong 
Published: June 2022

AbstractThe coefficient of determination (R2) is a well-established measure to indicate the predictive ability of polygenic scores (PGS). However, the sampling variance of R2 is rarely considered so that 95% confidence intervals (CI) are not usually reported. Moreover, when comparisons are made between PGS based on different discovery samples, the sampling covariance of R2 is necessary to test the difference between them. Here, we show how to estimate the variance and covariance of R2 values to assess the 95% CI and p-value of the R2 difference. We apply this approach to real data to predict into 28,880 European participants using UK Biobank (UKBB) and Biobank Japan (BBJ) GWAS summary statistics for cholesterol and BMI. We quantify the significantly higher predictive ability of UKBB PGS compared to BBJ PGS (p-value 7.6e-31 for cholesterol and 1.4e-50 for BMI). A joint model of UKBB and BBJ PGS significantly improves the predictive ability, compared to a model of UKBB PGS only (p-value 3.5e-05 for cholesterol and 1.3e-28 for BMI). The proposed approach can also be applied to testing a significant difference between R2 values across different p-value thresholds. We also show that the predictive ability of regulatory SNPs is significantly enriched than non-regulatory SNPs for cholesterol (p-value 2.6e-19 for UKBB and 8.7e-08 for BBJ). We suggest that the proposed approach (available in R package ‘r2redux’) should be used to test the statistical significance of difference between pairs of PGS, which may help to draw a correct conclusion about the predictive ability of PGS.
An intelligent synthetic bacterium with sound-integrated ability for chronological toxicant detection, degradation, and lethality
Authors: Liu Huan , Zhang Lige , Wang Weiwei , Hu Haiyang , Xu Ping , Tang Hongzhi 
Published: June 2022

AbstractModules, toolboxes, and systems of synthetic biology are being designed to solve environmental problems. However, weak and decentralized functional modules require complicated controls. To address this issue, we investigated an integrated system that can complete detection, degradation, and lethality, in chronological order without exogenous inducers. Biosensors were optimized by regulating expression of receptor and reporter to get higher sensitivity and output signal. Several stationary-phase promoters were selected and compared, while promoter Pficwas chosen to express the degradation enzyme. We created two concepts of lethal circuits by testing various toxic proteins, with a toxin/antitoxin circuit showing a potent lethal effect. Three modules were coupled, step-by-step. Detection, degradation, and lethality were sequentially completed, and the modules had partial attenuation compared to pre-integration, except for degradation. Our study provides a novel concept for integrating and controlling functional modules, which can accelerate the transition of synthetic biology from a concept to practical applications.TeaserWe provide new ideas for integration and chronological control of multiple modules in synthetic biology.
Comparison of urine proteomes from tumor-bearing mice with those from tumor-resected mice
Authors: Ziqi Heng , Chenyang Zhao , Youhe Gao 
Published: June 2022

Abstract[Objective]This study focuses on the most important concern of surgeons - whether they resected all of the tumor. Urine can reflect early changes associated with physiological or pathophysiological processes. Based on the above ideas, we conducted experiments to explore changes in the urine proteome between tumor-bearing mice and tumor-resected mice.[Method]The tumor-bearing mouse model was established with MC38 mouse colon cancer cells, and the mice were divided into the healthy control group, complete resection group, and nonresection group. Urine was collected 7 days and 30 days after resection. Liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) was used to identify the urine proteome and then analyze differentially expressed proteins and biological pathways.[Results](1) Seven days after tumor resection, there were 20 differentially expressed proteins that could distinguish between the complete resection group and the nonresection group. The biological process includes circadian rhythm, Notch signaling pathway, leukocyte cell–cell adhesion, and heterophilic cell–cell adhesion via plasma membrane cell adhesion molecules. (2) Thirty days after tumor resection, there were 33 differentially expressed proteins that could distinguish between the complete resection group and the nonresection group. The biological process includes cell adhesion, complement activation, the alternative pathway, the immune system process, and angiogenesis. (3) There was no significant difference between the two groups at 30 days after tumor resection between the complete resection group and the healthy control group.[Conclusion]Changes in the urine proteome can reflect tumors with or without complete resection.
Heterogeneity in viral replication dynamics shapes the antiviral response
Authors: Bruurs L.J.M. , Müller M. , Schipper J.G. , Rabouw H.H. , Boersma S. , van Kuppeveld F.J.M. , Tanenbaum M.E. 
Published: June 2022

AbstractIn response to virus infection, host cells can activate antiviral signaling to restrict virus replication and communicate viral infection to neighboring cells. For poorly understood reasons, antiviral response activation is highly heterogeneous among infected cells; both quantitatively (level of pathway activation) and qualitatively (transcribed antiviral gene set). Here, we used live-cell single-molecule imaging to simultaneously visualize viral infection and antiviral signaling, providing quantitative insights into antiviral response activation in single cells; first, the probability of activating an antiviral response varies throughout infection, with most efficient activation occurring several hours after the first viral replication. Second, cell-to-cell heterogeneity in viral replication rates early in infection determine the efficiency of antiviral response activation. Finally, variation in signaling strength of the viral sensing pathway result in qualitatively distinct antiviral responses. Together, this works identifies key parameters that shape the antiviral response and provides quantitative insights into the origin of heterogeneity in the antiviral response.
Benzo(a)pyrene regulates chaperone-mediated autophagy via heat shock protein 90
Authors: Su Min , Zhou Shuhong , Li Jun , Lin Nan , Chi Tao , Zhang Mengdi , Lv Xiaoli , Hu Yuxia , Bai Tuya , Chang Fuhou 
Published: June 2022

ABSTRACTThe Benzo(a)pyrene (Bap) exposure induced oxidative damage, DNA damage and autophagy. To explore the molecular mechanism of BaP-induced autophagy. In these studies, we first found that heat shock protein 90 (HSP90), heat shock cognate 70 (HSC70) and lysosomal-associated membrane protein type 2 receptor (Lamp-2a) expressions of C57BL mice lung tissue and A549 cells exposed to BaP were significant increase, as well as Bap induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by comet assay and γ-H2AX foci analysis in A549 cells. Our results demonstrated BaP induced CMA and caused DNA damage. Next, we knocked down HSP90 expression by the HSP90 Inhibitor, NVP-AUY 922, exposed or HSP90α shRNA lentivirus transduction in A549 cells. HSC70 and Lamp-2a expressions of these cells exposed to BaP were not significant increase, which showed that BaP inducted CMA was mediated by HSP90. Further, HSP90α shRNA prevented BaP induced of Bap which suggested BaP regulated CMA and caused DNA damage by HSP90. Our results elucidated a new mechanism of BaP regulated CMA through HSP90.