bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic and transcriptomic analysis reveals early stress responses in transgenic rice expressing Arabidopsis DREB1a
Authors: Berchembrock Yasmin Vasques , Pathak Bhuvan , Maurya Chandan , Barbosa Silva Botelho Flávia , Srivastava Vibha 
Published: January 2022

AbstractOverexpression of Arabidopsis Dehydration Response Element Binding 1a (DREB1a) is a well-known approach for developing salinity, cold and/or drought stress tolerance. However, understanding of the genetic mechanisms associated with DREB1a expression in rice is generally limited. In this study, DREB1a associated early responses were investigated in a transgenic rice line harboring cold-inducible DREB1a at a gene stacked locus. While the function of other genes in the stacked locus was not relevant to stress tolerance, this study demonstrates DREB1a can be colocalized with other genes for multigenic trait enhancement. As expected, the transgenic lines displayed improved tolerance to salinity stress and water withholding when compared to non-transgenic controls. RNA sequencing and transcriptome analysis showed upregulation of complex transcriptional networks and metabolic reprogramming as DREB1a expression led to the upregulation of multiple transcription factor gene families, suppression of photosynthesis and induction of secondary metabolism. In addition to the detection of previously described mechanisms such as production of protective molecules, potentially novel pathways were also revealed. These include jasmonate, auxin, and ethylene signaling, induction of JAZ and WRKY regulons, trehalose synthesis and polyamine catabolism. These genes regulate various stress responses and ensure timely attenuation of the stress signal. Furthermore, genes associated with heat stress response were downregulated in DREB1a overexpressing lines, suggesting antagonism between heat and dehydration stress pathways. In summary, through a complex transcriptional network, multiple stress signaling pathways are induced by DREB1a that presumably lead to early perception and rapid response towards stress tolerance as well as attenuation of the signal to prevent deleterious effects of the runoff response.
Cross-linking of the Endolysosomal System Reveals Flotillin Structures and Putative Cargo
Authors: Singh Jasjot , Elhabashy Hadeer , Muthukottiappan Pathma , Stepath Markus , Eisenacher Martin , Kohlbacher Oliver , Gieselmann Volkmar , Winter Dominic 
Published: January 2022

SUMMARYLysosomes are well-established as the main cellular organelles for the degradation of macromolecules and emerging as regulatory centers of metabolism. They are of crucial importance for cellular homeostasis, which is exemplified by a plethora of disorders related to alterations in lysosomal function. In this context, protein complexes play a decisive role, regulating not only metabolic lysosomal processes, but also lysosome biogenesis, transport, and interaction with other organelles. Using cross-linking mass spectrometry, we analyzed lysosomes and early endosomes. Based on the identification of 5,376 cross-links, we investigated protein-protein interactions and structures of lysosome- and endosome-related proteins. In particular, we present evidence for a tetrameric assembly of the lysosomal hydrolase PPT1 and heterodimeric/- multimeric structures of FLOT1/FLOT2 at lysosomes and early endosomes. For FLOT1-/FLOT2- positive early endosomes, we identified >300 proteins presenting putative cargo, and confirm the latrophilin family of adhesion G protein-coupled receptors as substrates for flotillin-dependent endocytosis.
An ancestral genomic sequence that serves as a nucleation site for de novo gene birth
Authors: Delihas Nicholas 
Published: January 2022

AbstractA short non-coding sequence present between the gamma-glutamyltransferase 1 (GGT1) and gamma-glutamyltransferase 5 (GGT5) genes, termed a spacer sequence has been detected in the genomes of Mus musculus, the house mouse and in Philippine tarsier, a primitive ancestral primate. It is highly conserved during primate evolution with certain sequences being totally invariant from mouse to humans. Evidence is presented to show this intergenic sequence serves as a nucleation site for the initiation of diverse genes. We also outline the birth of the human lincRNA gene BCRP3 (BCR activator of RhoGEF and GTPase 3 pseudogene) during primate evolution. The gene developmental process involves sequence initiation, addition of a complex of tandem transposable elements and addition of a segment of another gene. The sequence, initially formed in the Old World Monkeys such as the Rhesus monkey (Macaca mulatta) and the baboon (Papio anubis), develops into different primate genes before evolving into the human BCRP3 gene; it appears to also include trial and error during sequence/gene formation. The protein gene, GGT5 may have also formed by spacer sequence initiation in an ancient ancestor such as zebrafish, but spacer and GGT5 gene sequence drift during evolution produced a divergence that precludes further assessment.Author summaryFor a number of decades researchers have been interested in how genes evolve and a number of mechanisms of gene formation have been defined. This manuscript describes a different process of gene formation, that of a small DNA sequence that does not code for a gene but serves as a nucleation site for the initiation of de novo gene formation. This non-coding DNA sequence appears to have been in existence for about hundred million years or more and has formed the basis for the birth of diverse genes during evolution of the primates. The questions of how and why new genes are born are important in terms of revealing how organisms, especially primates, progress to greater complexity during evolution; the question of “how” is particularly relevant to the creation of biological information ab initio during prebiotic and early cellular evolution.
Comparison of dsDNA and ssDNA-based NGS library construction methods for targeted genome and methylation profiling of cfDNA
Authors: Zheng Jianchao , Li Zhilong , Zhang Xiuqing , Zhang Hongyun , Zhu Shida , Sun Jianlong , Wang Yuying 
Published: January 2022

AbstractCell-free DNA (cfDNA) profiling by next generation sequencing (NGS) has wide applications in cancer diagnosis, prognosis, and therapy response monitoring. One key step of cfDNA deep sequencing workflow is NGS library construction, whose efficiency determines effective sequencing depth, sequencing quality, and accuracy. In this study, we compared two different cfDNA library construction methods for the applications of mutation detection and methylation profiling: the conventional method which captures double-stranded DNA (dsDNA) molecules, namely the dsLib workflow, and an alternative method which captures single-stranded DNA (ssDNA), namely the ssLib workflow. Our results suggest that the dsLib method was preferrable for mutation detection while the ssLib method proved more efficient for methylation analysis. Our findings could help researchers choose more appropriate library construction method for corresponding downstream sequencing applications.
GNN-SubNet: disease subnetwork detection with explainable Graph Neural Networks
Authors: Pfeifer Bastian , Secic Afan , Saranti Anna , Holzinger Andreas 
Published: January 2022

AbstractThe tremendous success of graphical neural networks (GNNs) has already had a major impact on systems biology research. For example, GNNs are currently used for drug target recognition in protein-drug interaction networks as well as cancer gene discovery and more. Important aspects whose practical relevance is often underestimated are comprehensibility, interpretability, and explainability. In this work, we present a graph-based deep learning framework for disease subnetwork detection via explainable GNNs. In our framework, each patient is represented by the topology of a protein-protein network (PPI), and the nodes are enriched by molecular multimodal data, such as gene expression and DNA methylation. Therefore, our novel modification of the GNNexplainer for model-wide explanations can detect potential disease subnetworks, which is of high practical relevance. The proposed methods are implemented in the GNN-SubNet Python program, which we have made freely available on our GitHub for the international research community (https://github.com/pievos101/GNN-SubNet).
Localized Cardiolipin Synthesis is Required for the Assembly of MreB During the Polarized Cell Division ofChlamydia trachomatis
Authors: Ouellette Scot P. , Fisher-Marvin Laura A. , Harpring McKenna , Lee Junghoon , Rucks Elizabeth A. , Cox John V. 
Published: January 2022

AbstractPathogenicChlamydiaspecies are coccoid bacteria that use the rod-shape determining protein MreB to direct septal peptidoglycan synthesis during their polarized cell division process. How the site of polarized budding is determined in this bacterium, where contextual features like membrane curvature are seemingly identical, is unclear. We hypothesized that the accumulation of the phospholipid, cardiolipin (CL), in specific regions of the cell membrane induces localized membrane changes that trigger the recruitment of MreB to the site where the bud will arise. To test this, we ectopically expressed cardiolipin synthase (Cls) and observed a polar distribution for this enzyme inChlamydia trachomatis. In early division intermediates, Cls was restricted to the bud site where MreB is localized and peptidoglycan synthesis is initiated. The localization profile of Cls throughout division mimicked the distribution of lipids that stain with NAO, a dye that labels CL. Treatment ofChlamydiawith 3’,6-dinonylneamine (diNN), an antibiotic targeting CL-containing membrane domains, resulted in redistribution of Cls and NAO-staining phospholipids. In addition, MreB localization was altered by diNN treatment, suggesting an upstream regulatory role for CL-containing membranes in directing the assembly of MreB. This hypothesis is consistent with the observation that the clustered localization of Cls is not dependent upon MreB function or peptidoglycan synthesis. Furthermore, expression of a CL-binding protein at the inner membrane ofC. trachomatisdramatically inhibited bacterial growth supporting the importance of CL in the division process. Our findings implicate a critical role for localized CL synthesis in driving MreB assembly at the bud site during the polarized cell division ofChlamydia.
Individual variation in dispersal, and its sources, shape the fate of pushed vs. pulled range expansions
Authors: Dahirel Maxime , Guicharnaud Chloé , Vercken Elodie 
Published: January 2022

AbstractEcological and evolutionary dynamics of range expansions are shaped by both dispersal and population growth. Accordingly, density-dependence in either dispersal or growth can determine whether expansions are pulled or pushed, i.e. whether expansion velocities and genetic diversity are mainly driven by recent, low-density edge populations, or by older populations closer to the core. Despite this and despite abundant evidence of dispersal evolution during expansions, the impact of density-dependent dispersal and its evolution on expansion dynamics remains understudied. Here, we used simulation models to examine the influence of individual trait variation in both dispersal capacity and dispersal density- dependence on expansions, and how it impacts the position of expansions on the pulled-pushed continuum. First, we found that knowing about the evolution of density-dependent dispersal at the range edge can greatly improve our ability to predict whether an expansion is (more) pushed or (more) pulled. Second, we found that both dispersal costs and the sources of variation in dispersal (genetic or non-genetic, in dispersal capacity versus in density- dependence) greatly influence how expansion dynamics evolve. Among other scenarios, pushed expansions tended to become more pulled with time only when density-dependence was highly heritable, dispersal costs were low and dispersal capacity could not evolve. When, on the other hand, variation in density-dependence had no genetic basis, but dispersal capacity could evolve, then pushed expansions tended to become more pushed with time, and pulled expansions more pulled. More generally, our results show that trying to predict expansion velocities and dynamics using trait information from non-expanding regions only may be problematic, that both dispersal variation and its sources play a key role in determining whether an expansion is and stays pushed, and that environmental context (here dispersal costs) cannot be neglected. Those simulations suggest new avenues of research to explore, both in terms of theoretical studies and regarding ways to empirically study pushed vs. pulled range expansions.
A bacterial secretosome for regulated envelope biogenesis and quality control
Authors: Watkins Daniel W. , Collinson Ian 
Published: January 2022

SUMMARYAs the first line of defence against antibiotics, the Gram-negative bacterial envelope and its biogenesis are of considerable interest to the microbiological and biomedical communities. All bacterial proteins are synthesised in the cytosol, so inner- and outer-membrane proteins, and periplasmic residents have to be transported to their final destinationsviaspecialised protein machinery. The Sec translocon, a ubiquitous integral inner-membrane (IM) complex, is key to this process as the major gateway for protein transit from the cytosol to the cell envelope; this can be achieved during their translation, or afterwards. Proteins need to be directed to the inner-membrane (usually co-translational), otherwise SecA utilises ATP and the proton-motive-force (PMF) to drive proteins across the membrane post-translationally. These proteins are then picked up by chaperones for folding in the periplasm or delivered to the β-barrel assembly machinery (BAM) for incorporation into the outer-membrane. The core heterotrimeric SecYEG-complex forms the hub for an extensive network of interactions that regulate protein delivery and quality control. Here, we conduct a biochemical exploration of this ‘secretosome’ – a very large, versatile and inter-changeable assembly with the Sec-translocon at its core; featuring interactions that facilitate secretion (SecDF), inner- and outer-membrane protein insertion (respectively, YidC and BAM), protein folding and quality control (e.g. PpiD, YfgM and FtsH). We propose the dynamic interplay amongst these and other factors act to ensure efficient whole envelope biogenesis, regulated to accommodate the requirements of cell elongation and division. This organisation would be essential for cell wall biogenesis and remodelling and thus its perturbation would be a good strategy for the development of anti-microbials.
Histone H3K4 methyltransferase DcATX1 promotes ethylene induced petal senescence in carnation
Authors: Feng Shan , Wang Ruiming , Tan Hualiang , Zhong Linlin , Cheng Yunjiang , Bao Manzhu , Qiao Hong , Zhang Fan 
Published: January 2022

AbstractPetal senescence is controlled by a complex regulatory network. Epigenetic regulation like histone modification influences chromatin state and gene expression. However, involvement of histone methylation in regulating petal senescence is still largely unknown. Here, we found that the trimethylation of histone H3 at Lysine 4 (H3K4me3) is increased during the ethylene induced petal senescence in carnation (Dianthus caryophyllus L.). The H3K4me3 levels are positively associated with the expression of transcription factor DcWRKY75, ethylene biosynthetic genes DcACS1 and DcACO1, and senescence associated genes (SAGs) DcSAG12 and DcSAG29. Further, we identified that carnation DcATX1 (ARABIDOPSIS HOMOLOG OF TRITHORAX1) encodes a histone lysine methyltransferase which can methylate H3K4. Knockdown of DcATX1 delays ethylene induced petal senescence in carnation, which is associated with the downregulated expression of DcWRKY75, DcACO1 and DcSAG12. While overexpression of DcATX1 exhibits the opposite effects. DcATX1 promotes the transcription of DcWRKY75, DcACO1 and DcSAG12 by targeting to their promoters to elevate the H3K4me3 levels. Overall, our results demonstrate that DcATX1 is a H3K4 methyltransferase that promotes the expression of DcWRKY75, DcACO1 and DcSAG12 by regulating H3K4me3 levels, thereby accelerating ethylene induced petal senescence in carnation. This study further indicates that epigenetic regulation is important for plant senescence process.One sentence summaryA histone methyltransferase promotes ethylene induced petal senescence in cut flower
Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation
Authors: Aggarwal Geetika , Banerjee Subhashis , Jones Spencer A. , Benchaar Yousri , Bélanger Jasmine , Sévigny Myriam , Smith Denise M. , Niehoff Michael L. , Pavlack Monica , de Vera Ian Mitchelle S. , Petkau Terri L. , Leavitt Blair R. , Ling Karen , Jafar-Nejad Paymaan , Rigo Frank , Morley John E. , Farr Susan A. , Dutchak Paul A. , Sephton Chantelle F. , Nguyen Andrew D. 
Published: January 2022

AbstractHeterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3’ UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3’ UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by ribosomal profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.
A survey on antimicrobial resistance genes of frequently used bacteria in kefir and yoghurt
Authors: Judge Maura Fiona , Tóth Adrienn Gréta , Nagy Sára Ágnes , Papp Márton , Solymosi Norbert 
Published: January 2022

ABSTRACTAntimicrobial resistance (AMR) is one of the foremost threats facing the treatment of infectious diseases worldwide. Recent studies have highlighted the potential for antimicrobial resistance genes (ARGs) in fermented foods to contribute to AMR via horizontal gene transfer (HGT). The focus of our study was investigating the ARG content (resistome) and mobility potential of the ARGs (mobilome) of bacterial strains commonly used in probiotic products, namely yoghurt and kefir. We performed metagenomic analyses on freely available data sets (n=584) originating from various kefir and yoghurt strains using next generation sequencing (NGS) in order to gain an insight into the ARG diversity, frequency and mobility. Our study shows that kefir and yoghurt products carry diverse and significant amounts of ARGs and that these genes may often be associated with iMGEs or plasmids, conferring mobility. Certain bacteria species such as Bifidobacterium animalis and Streptococcus thermophilus were found to have higher ARG content. Overall, our results support the hypothesis that ARGs are present in fermented foods, namely yoghurt and kefir, and have the potential to contribute to AMR.
Dynamical Latent State Computation in the Posterior Parietal Cortex
Authors: Lakshminarasimhan Kaushik J , Avila Eric , Pitkow Xaq , Angelaki Dora E 
Published: January 2022

SummarySuccess in many real-world tasks depends on our ability to dynamically track hidden states of the world. To understand the underlying neural computations, we recorded brain activity in posterior parietal cortex (PPC) of monkeys navigating by optic flow to a hidden target location within a virtual environment, without explicit position cues. In addition to sequential neural dynamics and strong interneuronal interactions, we found that the hidden state – monkey’s displacement from the goal – was encoded in single neurons, and could be dynamically decoded from population activity. The decoded estimates predicted navigation performance on individual trials. Task manipulations that perturbed the world model induced substantial changes in neural interactions, and modified the neural representation of the hidden state, while representations of sensory and motor variables remained stable. The findings were recapitulated by a task-optimized recurrent neural network model, suggesting that neural interactions in PPC embody the world model to consolidate information and track task-relevant hidden states.
Bulk and Single-nucleus Transcriptomics Highlight Intra-telencephalic and Somatostatin Neurons in Alzheimer’s Disease
Authors: Consens Micaela E , Chen Yuxiao , Menon Vilas , Wang Yanling , Schneider Julie A , De Jager Philip L , Bennett David A , Tripathy Shreejoy J , Felsky Daniel 
Published: January 2022

AbstractBackgroundCortical neuron loss is a pathological hallmark of late-onset Alzheimer’s disease (AD). However, it remains unclear which neuronal subtypes are most vulnerable to degeneration and contribute most to cognitive decline.MethodsWe analyzed postmortem bulk brain RNA-sequencing (RNAseq) data collected from three studies of aging and AD comprising six neocortical regions (704 individuals; 1037 samples). We estimated relative cell type proportions from each brain sample using neuronal subclass-specific marker genes derived from ultra-high depth single-nucleus RNAseq data (snRNAseq). We associated cell type proportions with AD across all samples using mixed-effects mega-analyses. Bulk tissue analyses were complemented by analyses of three AD snRNAseq datasets using the same cell type definitions and diagnostic criteria (51 individuals). Lastly, we identified cell subtype associations with specific neuropathologies, cognitive decline, and residual cognition.ResultsIn our mega-analyses, we identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β=−0.48, pbonf=8.98×10−9) and intra-telencephalic (IT) excitatory neurons (β=−0.45, pbonf =4.32×10−7). snRNAseq-based cell type proportion analyses especially supported the association of SST neurons. Analyses of cell type proportions with specific AD-related phenotypes in ROS/MAP consistently implicated fewer SST neurons with greater brain-wide postmortem tau and beta amyloid (β=−0.155, pFDR=3.1×10−4) deposition, as well as more severe cognitive decline prior to death (β=0.309, pFDR=3.9×10−6). Greater IT neuron proportions were associated strongly with improved cognition (β=0.173, pFDR=8.3×10−5) and residual cognition (β=0.175, pFDR=1.2×10−5), but not canonical AD neuropathology.ConclusionsProportionally fewer SST and IT neurons were significantly associated with AD diagnosis across multiple studies and cortical regions. These findings support seminal work implicating somatostatin and pyramidal neurons in the pathogenesis of AD and improves our current understanding of neuronal vulnerability in AD.