bluuebunny/crossref_metadata_2025_split huggingface dataset:
The erythrocyte membrane properties of beta thalassaemia heterozygotes and their consequences for Plasmodium falciparum invasion
Authors: Introini Viola , Marin-Menendez Alejandro , Nettesheim Guilherme , Lin Yen-Chun , Kariuki Silvia N. , Smith Adrian L , Jean Letitia , Brewin John N. , Rees David C. , Cicuta Pietro , Rayner Julian C. , Penman Bridget S. 
Published: January 2022

AbstractMalaria parasites such as Plasmodium falciparum have exerted formidable selective pressures on the human genome. Of the human genetic variants associated with malaria protection, beta thalassaemia (a haemoglobinopathy) was the earliest to be associated with malaria prevalence. However, the malaria protective properties of beta thalassaemic erythrocytes remain unclear. Here we studied the mechanics and surface protein expression of beta thalassaemia heterozygous erythrocytes, measured their susceptibility to P. falciparum invasion, and calculated the energy required for merozoites to invade them. We found invasion-relevant differences in beta thalassaemic cells versus matched controls, specifically: elevated membrane tension, reduced bending modulus, and higher levels of expression of the major invasion receptor basigin. However, these differences acted in opposition to each other with respect to their likely impact on invasion, and overall we did not observe beta thalassaemic cells to have lower P. falciparum invasion efficiency for any of the strains tested.
Multi-omic data helps improve prediction of personalised tumor suppressors and oncogenes
Authors: Sudhakar Malvika , Rengaswamy Raghunathan , Raman Karthik 
Published: January 2022

ABSTRACTThe progression of tumorigenesis starts with a few mutational and structural driver events in the cell. Various cohort-based computational tools exist to identify driver genes but require a large number of samples to produce reliable results. Many studies use different methods to identify driver mutations/genes from mutations that have no impact on tumour progression; however, a small fraction of patients show no mutational events in any known driver genes. Current unsupervised methods map somatic and expression data onto a network to identify the perturbation in the network. Our method is the first machine learning model to classify genes as tumour suppressor gene (TSG), oncogene (OG) or neutral, thus assigning the functional impact of the gene in the patient. In this study, we develop a multi-omic approach, PIVOT (Personalised Identification of driVer OGs and TSGs), to train on experimentally or computationally validated mutational and structural driver events. Given the lack of any gold standards for the identification of personalised driver genes, we label the data using four strategies and, based on classification metrics, show gene-based labelling strategies perform best. We build different models using SNV, RNA, and multi-omic features to be used based on the data available. Our models trained on multi-omic data improved predictions compared to mutation and expression data, achieving an accuracy ≥ 0.99 for BRCA, LUAD and COAD datasets. We show network and expression-based features contribute the most to PIVOT. Our predictions on BRCA, COAD and LUAD cancer types reveal commonly altered genes such as TP53, and PIK3CA, which are predicted drivers for multiple cancer types. Along with known driver genes, our models also identify new driver genes such as PRKCA, SOX9 and PSMD4. Our multi-omic model labels both CNV and mutations with a more considerable contribution by CNV alterations. While predicting labels for genes mutated in multiple samples, we also label rare driver events occurring in as few as one sample. We also identify genes with dual roles within the same cancer type. Overall, PIVOT labels personalised driver genes as TSGs and OGs and also identifies rare driver genes.PIVOT is available at https://github.com/RamanLab/PIVOT.
Imaging with spatio-temporal modelling to characterize the dynamics of plant-pathogen lesions
Authors: Leclerc Melen , Jumel Stéphane , Hamelin Frédéric M. , Treilhaud Rémi , Parisey Nicolas , Mammeri Youcef 
Published: January 2022

AbstractWithin-host spread of pathogens is an important process for the study of plant-pathogen interactions. However, the development of plant-pathogen lesions remains practically difficult to characterize beyond the common traits such as lesion area. Here, we address this question by combining image-based phenotyping with mathematical modelling. We consider the spread ofPeyronellaea pinodeson pea stipules that were monitored daily with visible imaging. We assume that pathogen propagation on host-tissues can be described by the Fisher-KPP model where lesion spread depends on both a logistic growth and an homogeneous diffusion. Model parameters are estimated using a variational data assimilation approach on sets of registered images. This modelling framework is used to compare the spread of an aggressive isolate on two pea cultivars with contrasted levels of partial resistance. We show that the expected slower spread on the most resistant cultivar is actually due to a significantly lower diffusion coefficient. This study shows that combining imaging with spatial mechanistic models can offer a mean to disentangle some processes involved in host-pathogen interactions and further development may allow a better identification of quantitative traits thereafter used in genetics and ecological studies.
Reaction time sensitivity to spectrotemporal modulations of sound
Authors: Veugen Lidwien C.E. , van Opstal A. John , van Wanrooij Marc M. 
Published: January 2022

AbstractWe tested whether sensitivity to acoustic spectrotemporal modulations can be observed from reaction times for normal-hearing and impaired-hearing conditions. In a manual reaction-time task, normal-hearing listeners had to detect the onset of a ripple (with density between 0-8 cycles/octave and a fixed modulation depth of 50%), that moved up or down the log-frequency axis at constant velocity (between 0-64 Hz), in an otherwise-unmodulated broadband white-noise. Spectral and temporal modulations elicited band-pass filtered sensitivity characteristics, with fastest detection rates around 1 cycle/oct and 32 Hz for normal-hearing conditions. These results closely resemble data from other studies that typically used the modulation-depth threshold as a sensitivity criterion. To simulate hearing-impairment, stimuli were processed with a 6-channel cochlear-implant vocoder, and a hearing-aid simulation that introduced separate spectral smearing and low-pass filtering. Reaction times were always much slower compared to normal hearing, especially for the highest spectral densities. Binaural performance was predicted well by the benchmark race model of binaural independence, which models statistical facilitation of independent monaural channels. For the impaired-hearing simulations this implied a “best-of-both-worlds” principle in which the listeners relied on the hearing-aid ear to detect spectral modulations, and on the cochlear-implant ear for temporal-modulation detection. Although singular-value decomposition indicated that the joint spectrotemporal sensitivity matrix could be largely reconstructed from independent temporal and spectral sensitivity functions, in line with time-spectrum separability, a substantial inseparable spectral-temporal interaction was present in all hearing conditions. These results suggest that the reaction-time task yields a valid and effective objective measure of acoustic spectrotemporal-modulation sensitivity.
Building programmable multicompartment artificial cells incorporating remotely activated protein channels using microfluidics and acoustic levitation
Authors: Li Jin , Jamieson William D. , Dimitriou Pantelitsa , Xu Wen , Rohde Paul , Martinac Boris , Baker Matthew , Drinkwater Bruce W. , Castell Oliver K. , Barrow David A. 
Published: January 2022

AbstractIntracellular compartments are functional units that support the metabolic processes within living cells, through spatiotemporal regulation of chemical reactions and biological processes. Consequently, as a step forward in the bottom-up creation of artificial cells, building analogous intracellular architectures is essential for the expansion of cell-mimicking functionality. Herein, we report the development of a droplet laboratory platform to engineer customised complex emulsion droplets as a multicompartment artificial cell chassis, using multiphase microfluidics and acoustic levitation. Such levitated constructs provide free-standing, dynamic, definable droplet networks for the encapsulation and organisation of chemical species. Equally, they can be remotely operated with pneumatic, heating, and magnetic elements for post-processing, including the incorporation of membrane proteins; alpha-hemolysin; and large-conductance mechanosensitive channel (MscL) and their activation. The assembly of droplet networks is three-dimensionally patterned with fluidic inputs configurations determining droplet contents and connectivity. Whilst acoustic manipulation can be harnessed to reconfigure the droplet network in situ. In addition, a mechanosensitive channel, MscL, can be repeatedly activated and deactivated in the levitated artificial cell by the application of acoustic and magnetic fields to modulate membrane tension on demand. This offers possibilities beyond one-time chemically mediated activation to provide repeated, non-contact control of membrane protein function. Collectively, this will expand our capability to program and operate increasingly sophisticated artificial cells as life-like materials.
The role of LHCBM1 in non-photochemical quenching in Chlamydomonas reinhardtii
Authors: Liu Xin , Nawrocki Wojciech , Croce Roberta 
Published: January 2022

AbstractNon-photochemical quenching (NPQ) is the process that protects photosynthetic organisms from photodamage by dissipating the energy absorbed in excess as heat. In the model green alga Chlamydomonas reinhardtii, NPQ was abolished in the knock-out mutants of the pigment-protein complexes LHCSR3 and LHCBM1. However, while LHCSR3 was shown to be a pH sensor and switching to a quenched conformation at low pH, the role of LHCBM1 in NPQ has not been elucidated yet. In this work, we combine biochemical and physiological measurements to study short-term high light acclimation of npq5, the mutant lacking LHCBM1. We show that while in low light in the absence of this complex, the antenna size of PSII is smaller than in its presence, this effect is marginal in high light, implying that a reduction of the antenna is not responsible for the low NPQ. We also show that the mutant expresses LHCSR3 at the WT level in high light, indicating that the absence of this complex is also not the reason. Finally, NPQ remains low in the mutant even when the pH is artificially lowered to values that can switch LHCSR3 to the quenched conformation. It is concluded that both LHCSR3 and LHCBM1 need to be present for the induction of NPQ and that LHCBM1 is the interacting partner of LHCSR3. This interaction can either enhance the quenching capacity of LHCSR3 or connect this complex with the PSII supercomplex.
Covariance predicts conserved protein residue interactions important to the emergence and continued evolution of SARS-CoV-2 as a human pathogen
Authors: Robins William P. , Mekalanos John J. 
Published: January 2022

AbstractSARS-CoV-2 is one of three recognized coronaviruses (CoVs) that have caused epidemics or pandemics in the 21st century and that likely emerged from animal reservoirs. Differences in nucleotide and protein sequence composition within related β-coronaviruses are often used to better understand CoV evolution, host adaptation, and their emergence as human pathogens. Here we report the comprehensive analysis of amino acid residue changes that have occurred in lineage B β-coronaviruses that show covariance with each other. This analysis revealed patterns of covariance within conserved viral proteins that potentially define conserved interactions within and between core proteins encoded by SARS-CoV-2 related β-coranaviruses. We identified not only individual pairs but also networks of amino acid residues that exhibited statistically high frequencies of covariance with each other using an independent pair model followed by a tandem model approach. Using 149 different CoV genomes that vary in their relatedness, we identified networks of unique combinations of alleles that can be incrementally traced genome by genome within different phylogenic lineages. Remarkably, covariant residues and their respective regions most abundantly represented are implicated in the emergence of SARS-CoV-2 are also enriched in dominant SARS-CoV-2 variants.
The RNA polymerase gene specificity factor σ54 is required for homogeneous non-planktonic growth of uropathogenic Escherichia coli
Authors: Switzer Amy , Burchell Lynn , Mitsidis Panagiotis , Wigneshweraraj Sivaramesh 
Published: January 2022

AbstractThe canonical function of a bacterial sigma (σ) factor is to determine the gene specificity of the RNA polymerase (RNAP). In several diverse bacterial species, the σ54 factor uniquely confers distinct functional and regulatory properties on the RNAP. A hallmark feature of the σ54-RNAP is the obligatory requirement for an activator ATPase to allow transcription initiation. The genes that rely upon σ54 for their transcription have a wide range of different functions suggesting that the repertoire of functions performed by genes, directly or indirectly affected by σ54, is not yet exhaustive. By comparing the non-planktonic growth properties of prototypical enteropathogenic, uropathogenic and non-pathogenic Escherichia coli strains devoid of σ54, we uncovered σ54 as a determinant of homogenous non-planktonic growth specifically in the uropathogenic strain. Notably, bacteria devoid of individual activator ATPases of the σ54-RNAP do not phenocopy the σ54 mutant strain. It seems that σ54’s role as a determinant of homogenous non-planktonic growth represents a putative non-canonical function of σ54 in regulating genetic information flow.
Inflammatory signals from fatty bone marrow supports the early stages of DNMT3a driven clonal hematopoiesis
Authors: Zioni N , Bercovich A , Chapal-Ilani N , Solomon A , Kopitman E , Sacma M , Hartmut G , Scheller M , Müller-Tidow C , Lipka D , Shlush E , Minden M , Kaushansky N , Shlush LI 
Published: January 2022

AbstractAge related cancer is not only due to the random accumulation of mutations, but also how phenotypes are selected by the aging environment. While fatty bone marrow (FBM), is one of the hallmarks of bone marrow ageing, it is unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established FBM mice models and transplanted both human and mice preleukemic hematopoietic stem cells (PreL-HSCs) carrying DNMT3A mutations. We demonstrate that castration which models age related andropenia result in FBM. A significant increase in self-renewal was found when DNMT3AMut - preL-HSPCs were exposed to FBM. To better understand the mechanisms of the FBM-preL-HSPCs interaction, we performed single cell RNA-sequencing on HSPCs three days after FBM exposure. A 20-50 fold increase in DNMT3AMut-preL-HSCs was observed under FBM conditions in comparison to other conditions. PreL-HSPCs exposed to FBM exhibited an activated inflammatory signaling (IL-6 and INFγ). Cytokine analysis of BM fluid demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of DNMT3AMut-preL-HSPCs exposed to FBM. Overall, age related paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.
Activated MST2 kinase is free of kinetic regulation
Authors: Koehler Thomas J. , Tran Thao , Kavran Jennifer M. 
Published: January 2022

ABSTRACTCanonically, MST1/2 functions as a core kinase of the Hippo pathway and non-canonically is both activated during apoptotic signaling and acts in concert with RASSFs in T-cells. Faithful signal transduction relies on both appropriate activation and regulated substrate phosphorylation by the activated kinase. Considerable progress has been made understanding the molecular mechanisms regulating activation of MST1/2 and identifying downstream signaling events. Here we present a kinetic analysis analyzing how the ability of MST1/2 to phosphorylate substrates is regulated. Using a steady state kinetic system, we parse the contribution of different factors including the domains of MST2, phosphorylation, caspase cleavage, and complex formation to MST2 activity. In the unphosphorylated state, we find the SARAH domain stabilizes substrate binding. Phosphorylation, we also determine, drives activation of MST2 and that once activated the kinase domain is free of regulation. The binding partners SAV1, MOB1A, and RASSF5 do not alter the kinetics of phosphorylated MST2. We also show that the caspase cleaved MST2 fragment is as active as full-length suggesting that the linker region of MST2 does not inhibit the catalytic activity of the kinase domain but instead regulates MST2 activity through non-catalytic mechanisms. This kinetic analysis helps establish a framework for interpreting how signaling events, mutations, and post-translational modifications contribute to signaling of MST2 in vivo.
Genomic Biomarker Heterogeneities Between SARS-CoV-2 and COVID-19
Authors: Zhang Zhengjun 
Published: January 2022

SummaryGenes functionally associated with SARS-CoV-2 infection and genes functionally related to COVID-19 disease can be different, whose distinction will become the first essential step for successfully fighting against the COVID-19 pandemic. Unfortunately, this first step has not been completed in all biological and medical research. Using a newly developed maxcompeting logistic classifier, two genes, ATP6V1B2 and IFI27, stand out to be critical in transcriptional response to SARS-CoV-2 infection with differential expressions derived from NP/OP swab PCR. This finding is evidenced by combining these two genes with one another gene in predicting disease status to achieve better-indicating accuracy than existing classifiers with the same number of genes. In addition, combining these two genes with three other genes to form a five-gene classifier outperforms existing classifiers with ten or more genes. These two genes can be critical in fighting against the COVID-19 pandemic as a new focus and direction with their exceptional predicting accuracy. Comparing the functional effects of these genes with a five-gene classifier with 100% accuracy identified and tested from blood samples in our earlier work, genes and their transcriptional response and functional effects to SARS-CoV-2 infection and genes and their functional signature patterns to COVID-19 antibody are significantly different, which can be interpreted as the former is the point of a phenomenon, and the latter is the essence of the disease. We will use a total of fourteen cohort studies (including breakthrough infections and omicron variants) with 1481 samples to justify our results. Such significant findings can help explore the causal and pathological clue between SARS-CoV-2 infection and COVID-19 disease and fight against the disease with more targeted genes, vaccines, antiviral drugs, and therapies.
GhCO and GhCRY1 accelerate floral meristem initiation in response to increased blue light to shorten cotton breeding
Authors: Li Xiao , Wu Yuanlong , Liu Zhenping , Li Zhonghua , Chi Huabin , Wang Pengcheng , Yan Feilin , Yang Yang , Qin Yuan , Tian Xuehan , Wei Hengling , Wu Aimin , Wang Hantao , Zhang Xianlong , Yu Shuxun 
Published: January 2022

AbstractThe shoot apical meristem (SAM) is a special category of tissue with pluripotency that forms new organs and individuals, especially floral individuals. However, little is known about the fate of cotton SAMs as a tunica corpus structure. Here, we demonstrate that cotton SAM fate decisions depend on light signals and circadian rhythms, and the genes GhFKF1, GhGI, GhCRY1 and GhCO were responsible for SAM fate decisions and highlighted via RNA sequencing (RNA-seq) analysis of different cotton cultivars, as confirmed by genetic analysis via the CRISPR–Cas9 system. In situ hybridization (ISH) analysis showed that the GhCO gene, induced by a relatively high blue light proportion, was highly upregulated during the initiation of floral meristems (FMs). Further blue light treatment analysis showed that the transition from vegetative to reproductive growth of SAM was promoted by a high proportion of blue light, coupled with high expression of the blue light-responsive genes GhCO and GhCRY1. Taken together, our study suggests that blue light signalling plays a key role in the fate decision of cotton SAM. These results provide a strategy to regulate the SAM differentiation of cotton by using the CRISPR–Cas9 system to change the ratio of red and blue light absorption to breed early-maturity cotton.One-sentence summaryThe SAM differentiation especially the initiation of floral meristem of upland cotton were mediated by genes GhCO and GhCRY1 which in response to blue light.
Location bias contributes to functionally selective responses of biased CXCR3 agonists
Authors: Eiger Dylan Scott , Boldizsar Noelia , Honeycutt Christopher Cole , Gardner Julia , Kirchner Stephen , Hicks Chloe , Choi Issac , Pham Uyen , Zheng Kevin , Warman Anmol , Smith Jeffrey , Zhang Jennifer , Rajagopal Sudarshan 
Published: January 2022

SUMMARYSome G protein-coupled receptor (GPCR) ligands act as “biased agonists” which preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the chemokine GPCR CXCR3. The signaling profile of CXCR3 changed as it trafficked from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling was critical for biased activation of G proteins, β-arrestins, and ERK1/2. In CD8+ T cells, the chemokines promoted unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation was dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.
Interactive effect matters: a combination of herbivory degree and the ratio of generalist to specialist better predicts evolution of plant defense
Authors: Pan Yuanfei , Pan Xiaoyun , Faria Lucas Del Bianco , Li Bo 
Published: January 2022

AbstractHerbivory degree and the ratio of generalist to specialist herbivores have long been treated as two important but independent factors in shaping the evolution of plant defense. However, this assumption of independency is poorly supported and has resulted in great controversy in explaining the patterns of plant defense. Here we investigated the possible interaction between herbivory degree and generalist-to-specialist ratio using a cost-benefit model of defense evolution in plants. Our results showed that, with increasing generalist herbivore proportion, plant defense investment increases when herbivory degree is low and decreases when herbivory degree is high. These results provide the first theoretical support for the interactive effect of herbivory degree and ratio of generalist/specialist affecting plant defense, which integrate many of the previous results (e.g. latitudinal patterns of plant defense and defense evolution of invasive plants) and put them into a more general theoretical context.