bluuebunny/crossref_metadata_2025 huggingface dataset:
Internet-Enabled Behaviors in Older Adults During the Pandemic: Patterns of Use, Psychosocial Impacts, and Plans for Continued Utilization
Authors: Benge Jared F , Aguirre Alyssa , Scullin Michael K , Kiselica Andrew M , Hilsabeck Robin C , Paydarfar David , Douglas Michael
Published: August 2022

In response to social distancing measures during the COVID-19 pandemic, there was a need to increase the frequency of internet enabled behaviors (IEBs). To date, little is known about how the pandemic impacted IEBs in older adults, a population that has historically been linked to lower digital literacy and utilization. We administered an online survey between April and July 2021 to 298 adults who were over age 50 (mean age = 73 years; 93.5% non-Hispanic white; 94% smart phone owners; 83.5% retired). Older adults self-reported IEBs for social, shopping, medical, and leisure activities during the pandemic, plans for continued use of these behaviors, and completed measures of psychosocial functioning. 66.8% of respondents reported an overall increase in IEBs during the pandemic, most notably for online meeting attendance. More frequent online meeting use was associated with less depression (r = −0.12, p = .04) and less loneliness (r = −0.14, p = .02). With regard to plans for continued use, 82.5% of the sample reported at least one IEB (M = 2.18, SD = 1.65) that they increased during the pandemic and planned to maintain over time (e.g., online shopping for household goods). Plans for continued use were more likely in participants who used IEBs more overall during the pandemic (r = 0.56, p < .001), and who frequently sought technical support on search engines (r = 0.22, p < .001), or online video sites (r = 0.16, p = .006). In summary, IEBs during the pandemic were associated with favorable psychosocial functioning and expectations for continued use in this sample of predominantly white older adults who had some baseline technological familiarity.
Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study
Authors: Almramhi Mona M. , Finan Chris , Storm Catherine S. , Schmidt Amand F. , Kia Demis A. , Coneys Rachel , Chopade Sandesh , Hingorani Aroon D. , Wood Nicholas W.
Published: August 2022

Background

There has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to their capacity to inhibit the isoprenylation of Rho small guanosine triphosphatases (Rho GTPases). We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity.

Method

We employed two-sample Mendelian randomization (MR) to: (1) investigate the causal role of lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels in MS risk and severity, (2) genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity.

Results

The results of MR using the inverse variance weighted method show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk, but LDL-C and TG were not. MR results also show that genetically predicted RAC2 (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids.

Conclusions

Evidence from this study suggests that HDL-C is a risk factor for MS development. The MR findings suggest that RAC2 (a member of Rho GTPases) is a potent genetic modifier of MS risk. Since RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins reduce MS risk via a RAC2-related mechanism(s) (i.e., cholesterol-independent pathway).
A Role for the Fornix in Temporal Sequence Memory
Authors: Read Marie-Lucie , Umla-Runge Katja , Lawrence Andrew D. , Costigan Alison G. , Hsieh Liang-Tien , Chamberland Maxime , Ranganath Charan , Graham Kim S.
Published: August 2022

Converging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind sequentially occurring items. The fornix is a white matter pathway containing the major input and output pathways of the hippocampus, including projections from medial septum, and to diencephalon, striatum, and prefrontal cortex. If the fornix meaningfully contributes to hippocampal function, then individual differences in fornix microstructure might predict sequence memory. Here, we tested this prediction by performing tractography in 51 healthy adults who had undertaken a sequence memory task. Microstructure properties of the fornix were compared with those of tracts connecting medial temporal lobe regions, but not predominantly the hippocampus: the Parahippocampal Cingulum bundle (PHC) (conveying retrosplenial projections to parahippocampal cortex) and the Inferior Longitudinal Fasciculus (ILF) (conveying occipital projections to perirhinal cortex). Using principal components analysis, we combined Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging measures obtained from multi-shell diffusion MRI into two informative indices, the first (PC1) capturing axonal packing/myelin, the second (PC2) capturing microstructural complexity. We found a significant correlation between fornix PC2 and implicit reaction-time indices of sequence memory, indicating that greater fornix microstructural complexity is associated with better sequence memory. No such relationship was found with measures from the PHC and ILF. This study highlights the importance of the fornix in aiding memory for objects within a temporal context, potentially reflecting a role in mediating network communication within an extended hippocampal system.
Oncogenic EFNA4 amplification promotes lung adenocarcinoma lymph node metastasis
Authors: Zhao Xiangyu , Chen Yuxing , Sun Xiaoqin , He Zaoke , Wu Tao , Wu Chenxu , Chen Jing , Wang Jinyu , Diao Kaixuan , Liu Xue-Song
Published: August 2022

Lymph nodes metastases are common in patients with lung cancer. And those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. So-matic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are a major type of DNA alteration that promotes lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung cancer metastasis related gene, EFNA4. EFNA4 genome locus was significantly amplified and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 over-expression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis and suggests EFNA4 as a potential target in metastatic lung cancer therapy.

Simple Summary

Lymph nodes are likely to be the first stop for lung cancer metastasis. To further investigate the mechanism of lung cancer lymph node metastasis, we performed cancer genome analysis and found that EFNA4, a member of the ephrin (EPH) family, is amplified and up-regulated in lung tumor patients, especially in patients with lymph node metastases. In vitro and in vivo experiments show that overexpression of EFNA4 promotes lung tumor cell proliferation and migration, while knockdown or knockout of EFNA4 inhibits cell proliferation and migration. Altogether, our results suggest that the DNA amplification of EFNA4 genome locus could play an oncogenic function in promoting lung cancer lymph node metastasis.
Helicobacter chronic stage inflammation undergoes fluctuations that are altered in tlpA mutants
Authors: Johnson Kevin S. , Yang Christina , Carter J. Elliot , Worthington Atesh K. , Robinson Elektra K. , Lopez-Magaña Raymond , Salgado Frida , Arnold Isabelle , Ottemann Karen M.
Published: August 2022

Helicobacter pylori colonizes half of the world’s population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an eight month mouse infection time course and comparison of wild type and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from wild type at some time points. tlpA mutants have equivalent total and gland colonization at late stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to WT. Our results suggest the chronic inflammation setting is dynamic, and may be influenced by colonization properties of early infection.

Importance

Helicobacter pylori established chronic infection in half of the world’s population. This infection initiates during childhood, and leads to later life gastric diseases including gastritis, peptic ulcers, and gastric cancer. These diseases are driven by host inflammation, with more severe inflammation leading to more severe disease. It is not fully understood how H. pylori controls inflammation. In this work, we used an H. pylori mouse infection model and characterized inflammation and colonization of wild-type H. pylori and a mutant that was known to cause elevated inflammation. We found that inflammation in the chronic stage undergoes surprising fluctuations, with related changes in Th17 numbers. H. pylori tlpA mutants caused offset inflammation dynamics, suggesting that H. pylori infection underlies this dynamism. Although there were not colonization dynamics at the time of inflammation fluctuations, there were differences between WT and tlpA mutant colonization at early time points. Our results suggest the chronic inflammation setting is more dynamic than previously thought and may be influenced by colonization properties of early infection.
Observations on Paleospecies Determination, With Additional Data on Tyrannosaurus Including Its Highly Divergent Species Specific Supraorbital Display Ornaments That Give T. rex a New and Unique Life Appearance
Authors: Paul Gregory S.
Published: August 2022

Intrageneric dinosaur species have been being named for decades without either significant examination of the methods and standards used to do so, or widely publicized controversy over the results. The long standing assumption that all large known specimens of the iconic North American Tyrannosaurus consisted of just the one popular species T. rex was recently challenged with the first comprehensive test of the question. The result was the diagnosing and naming of two additional taxa, T. imperator and T. regina, based on a number of species levels characters regarding robustness and tooth proportions in the context of their stratigraphic distribution. In association a rare in-depth look was taken at the current state of naming vertebrate paleospecies, which it turns out are not highly rigorous because of inherent problems with the species concept and other matters. The results of the paper were severely criticized in in a manner never seen before for new dinosaur species even when based on less evidence. This study takes another look as the determination of paleospecies, and shows that many of the claims made in the criticisms regarding the Tyrannosaurus species work were inaccurate. New data on the proportions of strength bars in Tyrannosaurus skulls reinforces the basing of the three species in part on robustness factors, and allows all but one skull to be assigned to one of the species. These results allow the first detailed systematic examination of the supraorbital display bosses of the genus. They sort out as visually distinctive species specific ornaments based on both stratigraphic and taxonomic factors, strongly affirm that Tyrannosaurus was multispecific, and the species probably dimorphic. New skulls of T. rex show that the species sported – males probably -- striking display bosses not yet observed in other tyrannosaurids.
Annotation-free discovery of functional groups in microbial communities
Authors: Shan Xiaoyu , Goyal Akshit , Gregor Rachel , Cordero Otto X.
Published: August 2022

Recent studies have shown that microbial communities are composed of groups of functionally cohesive taxa, whose abundance is more stable and better associated with metabolic fluxes than that of any individual taxon. However, identifying these functional groups in a manner that is independent from error-prone functional gene annotations remains a major open problem. Here, we develop a novel approach that identifies functional groups of taxa in an unsupervised manner, solely based on the patterns of statistical variation in species abundance and environmental parameters. We demonstrate the power of this approach on three distinct data sets. On data of replicate microcosm with heterotrophic soil bacteria, our unsupervised algorithm recovered experimentally validated functional groups that divide metabolic labor and remain stable despite large variation in species composition. When leveraged against the ocean microbiome data, our approach discovered a functional group that combines aerobic and anaerobic ammonia oxidizers, whose summed abundance tracks closely with nitrate concentrations in the water column. Finally, we show that our framework can enable the detection of species groups that are likely responsible for the production or consumption of metabolites abundant in animal gut microbiomes, serving as a hypothesis generating tool for mechanistic studies. Overall, this work advances our understanding of structure-function relationships in complex microbiomes and provides a powerful approach to discover functional groups in an objective and systematic manner.
Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer
Authors: Galbraith Madeline , Levine Herbert , Onuchic José N. , Jia Dongya
Published: August 2022

Cancer metastasis relies on an orchestration of multiple traits driven by different functional interacting modules including metabolism and epithelial-mesenchymal transition (EMT). Cancer cells can adjust their metabolism during metastasis by increasing oxidative phosphorylation without compromising glycolysis, acquiring a hybrid metabolic phenotype (W/O). Often required by metastasis, cancer cells engage EMT and can acquire a hybrid epithelial/mesenchymal (E/M) phenotype. Both the W/O and E/M states are associated with high metastatic potentials. Many regulatory links coupling metabolism and EMT have been identified, but how these two modules regulate each other remains largely unexplored. Here, we investigate the coupled decision-making networks of metabolism and EMT, and systematically analyzed the effect of their crosstalk. This crosstalk can exhibits synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states availability in individual metabolism or EMT modules. To acquire an E/M-W/O state, the W/O state emerges first, followed by the E/M state, suggesting metabolism can drive EMT. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step towards understanding the multi-faceted nature of cancer metastasis.
An adhesion signaling axis involving Dystroglycan, β1-Integrin and Cas adaptor proteins regulates the establishment of the cortical glial scaffold
Authors: Wong Wenny , Estep Jason A. , Treptow Alyssa M. , Rajabli Niloofar , Jahncke Jennifer N. , Ubina Teresa , Wright Kevin M. , Riccomagno Martin M.
Published: August 2022

The mature mammalian cortex is composed of six architecturally and functionally distinct layers. Two key steps in the assembly of this layered structure are the initial establishment of the glial scaffold and the subsequent migration of post-mitotic neurons to their final position. These processes involve the precise and timely regulation of adhesion and detachment of neural cells from their substrates. Although much is known about the roles of adhesive substrates during neuronal migration and the formation of the glial scaffold, less is understood about how these signals are interpreted and integrated within these neural cells. Here, we providein vivoevidence that Cas proteins, a family of cytoplasmic adaptors, serve a functional and redundant role during cortical lamination.Castriple conditional knock-out (CasTcKO) mice display severe cortical phenotypes that feature cobblestone malformations. Molecular epistasis and genetic experiments suggest that Cas proteins act downstream of transmembrane Dystroglycan and β1-Integrin in a radial glial cell-autonomous manner. Overall, these data establish a new and essential role for Cas adaptor proteins during the formation of cortical circuits and reveal a signaling axis controlling cortical scaffold formation.
Subcellular spatially resolved gene neighborhood networks in single cells
Authors: Fang Zhou , Ford Adam J. , Hu Thomas , Zhang Nicholas , Mantalaris Athanasios , Coskun Ahmet F.
Published: August 2022

Mesenchymal stem cell (MSC)-based therapies have offered promising treatments against several disorders. However, the clinical efficacy and consistency remain underdeveloped. Single-cell and bulk molecular analyses have provided considerable heterogeneity of MSCs due to origin, expansion, and microenvironment. Image-based cellular omics methods elucidate ultimate variability in stem cell colonies, otherwise masked by bulk omics approaches. Here, we present a spatially resolved Gene Neighborhood Network (spaGNN) method to produce transcriptional density maps and analyze neighboring RNA distributions in single human MSCs and chondrocytes cultured on 2D collagen-coated substrates. This proposed strategy provides cell classification based on subcellular spatial features and gene neighborhood networks. Machine learning-based clustering of resultant data yields subcellular density classes of 20-plex biomarkers containing diverse transcript and protein features. The spaGNN reveals tissue-source-specific MSC transcription and spatial distribution characteristics. Multiplexed spaGNN analysis allows for rapid examination of spatially resolved subcellular features and activities in a broad range of cells used in pre-clinical and clinical research.
Multi-organ functions of yolk sac during human early development
Authors: Botting Rachel A , Goh Issac , Rose Antony , Webb Simone , Engelbert Justin , Gitton Yorick , Stephenson Emily , Quiroga Londoño Mariana , Mather Michael , Mende Nicole , Imaz-Rosshandler Ivan , Horsfall Dave , Basurto-Lozada Daniela , Chipampe Nana-Jane , Rook Victoria , Mazin Pavel , Vijayabaskar MS , Hannah Rebecca , Gambardella Laure , Green Kile , Ballereau Stephane , Inoue Megumi , Tuck Liz , Lorenzi Valentina , Kwakwa Kwasi , Alsinet Clara , Olabi Bayanne , Miah Mohi , Admane Chloe , Popescu Dorin-Mirel , Acres Meghan , Dixon David , Coulthard Rowen , Lisgo Steven , Henderson Deborah J , Dann Emma , Suo Chenqu , Kinston Sarah J , Park Jong-eun , Polanski Krzysztof , Van Dongen Stijn , Meyer Kerstin B , de Bruijn Marella , Palis James , Behjati Sam , Laurenti Elisa , Wilson Nicola K , Vento-Tormo Roser , Chédotal Alain , Bayraktar Omer , Roberts Irene , Jardine Laura , Göttgens Berthold , Teichmann Sarah A , Haniffa Muzlifah
Published: August 2022

The yolk sac (YS) represents an evolutionarily-conserved extraembryonic structure that ensures timely delivery of nutritional support and oxygen to the developing embryo. However, the YS remains ill-defined in humans. We therefore assemble a complete single cell 3D map of human YS from 3-8 post conception weeks by integrating multiomic protein and gene expression data. We reveal the YS as a site of primitive and definitive haematopoiesis including a YS-specific accelerated route to macrophage production, a source of nutritional/metabolic support and a regulator of oxygen-carrying capacity. We reconstruct the emergence of primitive haematopoietic stem and progenitor cells from YS hemogenic endothelium and their decline upon stromal support modulation as intraembryonic organs specialise to assume these functions. The YS therefore functions as ‘three organs in one’ revealing a multifaceted relay of vital organismal functions as pregnancy proceeds.

One Sentence Summary

Human yolk sac is a key staging post in a relay of vital organismal functions during human pregnancy.
SNP discovery by exome capture and resequencing in a pea genetic resource collection
Authors: Aubert G. , Kreplak J. , Leveugle M. , Duborjal H. , Klein A. , Boucherot K. , Vieille E. , Chabert-Martinello M. , Cruaud C. , Bourion V. , Lejeune-Hénaut I. , Pilet-Nayel M.L. , Bouchenak-Khelladi Y. , Francillonne N. , Tayeh N. , Pichon J.P. , Rivière N. , Burstin J.
Published: August 2022

Background & Summary

In addition to being the model plant used by Mendel1to establish genetic laws, pea (Pisum sativumL., 2n=14) is a major pulse crop cultivated in many temperate regions of the world. In order to face new challenges imposed particularly by global climate change and new regulations targeted at reducing chemical inputs, pea breeders have to take advantage of the genetic diversity present in thePisumgenepool to develop improved, resilient varieties. The aim of this study was to assess the genetic diversity of a pea germplasm collection and allow genome-wide association studies using this collection.

To be able to perform genome-wide association approaches with high resolution, genotyping with a large set of genetic markers such as Single Nucleotide Polymorphism (SNP) markers well-spread over the genome is required. Rapid advances in second-generation sequencing technologies and the development of bioinformatic tools have revolutionized the access to and the characterization of available genetic diversity. High-density, high-throughput genotyping has been possible for a large number of species, including those with large and complex genomes2such as pea (2n=14) which genome size is estimated to be 4.45 Gb3. In this study, which is part of the PeaMUST project4, we used a target capture technology based on pea transcriptome sequences to generate exome-enriched genomic libraries that were further subjected to Illumina sequencing in paired-end mode. This methodology was chosen because whole-genome resequencing is relatively expensive for species with large genomes and because capturing genetic variations in repeated non-coding regions is difficult to achieve or to interpret5. Whole-exome sequencing represented an interesting alternative that focused on coding regions only6,7. Mapping the obtained reads on the reference pea genome sequence enabled the discovery of an abundant set of SNPs. The development of this resource is a crucial cornerstone in research and breeding projects towards boosting the improvement of pea production and quality.
Metabolomic-Genomic prediction drastically improves prediction accuracy of breeding values in crop breeding
Authors: Guo Xiangyu , Sarup Pernille , Jahoor Ahmed , Jensen Just , Christensen Ole Fredslund
Published: August 2022

Metabolomics is intermediate stage between genotype and phenotype, and therefore useful for breeding. Objective was to investigate heritabilities and accuracies of genetic evaluation of malting quality (MQ) traits by integrating both genomic and metabolomic information. In total, 2,430 plots of 562 malting spring barley lines from three years and two locations were included. Five MQ traits were measured in wort produced from each plot. Metabolomic features used were 24,018 Nuclear Magnetic Resonance intensities measured on each wort sample. Methods for statistical analyses were genomic best linear unbiased prediction (GBLUP) and metabolomic-genomic best linear unbiased prediction (MGBLUP). Accuracies of predicted breeding values were compared using two cross-validation strategies: leave-one-year-out (LOYO) and leave-one-line-out (LOLO). Plot heritabilities ranged from 0.060 to 0.279 for GBLUP, and increased to range from 0.123 to 0.283 for MGBLUP. LOLO scheme yielded higher accuracies than LOYO scheme, and MGBLUP yielded higher accuracies than GBLUP regardless of cross-validation scheme.

Author Summary

Metabolomics is intermediate stage between genotype and phenotype, and therefore useful for breeding. We carried out a study on 2,430 plots of 562 malting spring barley lines and 24,018 Nuclear Magnetic Resonance intensities measured on each wort sample, to investigate the prediction of breeding values of five malting quality traits by integrating genomic and metabolomic information using a metabolomics-genomic model. Results showed an increase in prediction accuracy for this model compared to a genomic model.
α-Arrestins maintain phospholipid balance and Atg18 distribution to permit efficient autophagy
Authors: Bowman Ray W. , Davis Sydnie , Jordahl Eric M. , Chera Karandeep , Ozbaki-Yagan Nejla , Franks Jonathan , Hawbaker Sarah , Chiang Annette , Acar Omer , Beer-Stoltz Donna , O’Donnell Allyson F.
Published: August 2022

Cells selectively reorganize their membrane proteome in response to stressors via selective protein trafficking. The α-arrestins, a family of conserved protein trafficking adaptors, bind to select membrane proteins and interact with the ubiquitin ligase Rsp5. The α-arrestins recruit Rsp5 to its membrane protein substrates, permitting their ubiquitination and endocytosis. To identify new α-arrestin functions, we performed a genetic screen to isolate mutants that alter α-arrestin-mediated resistance to rapamycin, a drug that inhibits TORC1. Interestingly, loss of many of the ATG genes, which encode the machinery needed for the self-degradative process of autophagy, disrupted α-arrestins’ ability to promote growth on rapamycin. Herein we define a genetic network linking α-arrestins to autophagy. We show autophagy impairment in the absence of select α-arrestins, with increased autophagosome lifetimes and delayed/reduced delivery of autophagosomes to the vacuole. The α-arrestin mutants that impeded autophagy had vacuole morphology defects and increased vacuolar retention of Atg18, a member of the PROPPIN family that is needed to maintain vacuole shape and facilitate lipid transfer to expanding autophagosomes. Atg18 binds phosphatidylinositol 3 phosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), and we observed increased PI3P on the vacuole membrane in α-arrestin mutants. The levels of Vps34 and Fab1, the kinases responsible for the generation of PI3P and PI(3,5)P2, respectively, were also elevated at vacuole membranes in cells lacking α-arrestins. We posit that altered phospholipids in the vacuolar membrane form the basis for the Atg18-Atg2 mislocalization and autophagy defect. These data demonstrate a previously unappreciated link between the α-arrestins and autophagy, expanding the functional impact of these trafficking adaptors in responding to nutrient stress.

Author Summary

Cells survive nutrient starvation by degrading parts of themselves through the process of autophagy. During autophagy, cells make a double membrane, known as an autophagosome (AP), around bits of cytoplasm or organelles. The AP and its engulfed material are delivered to the vacuole, an organelle that helps break down proteins and lipids. These materials can then be used as building blocks to generate the essential components needed for the cell to survive starvation. For cells to undergo efficient autophagy, they need α-arrestins, a group of proteins important for deciding where membrane proteins localize. In cells lacking α-arrestins, the AP forms slowly, likely due to a problem in growing the AP membrane. This results in less material being delivered to the vacuole via APs when cells do not have α-arrestins. This study defines a new role for α-arrestins in promoting AP formation and starvation survival.
Elucidating the systemic response of wheat plants under waterlogging based on transcriptomic and metabolic approaches
Authors: Cid Geeisy , Francioli Davide , Kolb Steffen , Tandron Moya Yudelsy Antonia , von Wirén Nicolaus , Hajirezaei Mohammad-Reza
Published: August 2022

Extreme weather conditions lead to significant imbalances in crop productivity, which in turn affect food security. Flooding events cause serious problems to many crop species such as wheat. Although metabolic readjustments under flooding are important for plant regeneration, underlying processes remain poorly understood. Here, we investigated the systemic response of wheat to waterlogging using metabolomics and transcriptomics. A 12-day exposure to excess water triggered nutritional imbalances and disruption of metabolite synthesis and translocation, reflected by reduction of plant biomass and growth performance. Metabolic and transcriptomic profiling in roots, xylem, and leaves indicated anaerobic fermentation processes as a local response occurring in roots. Differentially expressed genes and ontological categories revealed that carbohydrate metabolism plays an important role as a systemic response. Analysis of the translocation rate of specific compounds in the xylem showed how waterlogging alters the composition of xylem exudates and thus the root to shoot communication. Interestingly, among all metabolites determined in our study, alanine was the most abundant transported in the xylem. Our results suggest an important role of this amino acid not only as amino-nitrogen source but also as the major root-to-shoot translocated and systemically acting metabolite crucial for balancing C/N between roots and shoots during waterlogging.

The relevance of this study relies on the basis to characterize the important role of alanine as

Highlight

Metabolic and transcriptomic changes in wheat highlight alanine as the major root-to-shoot translocated and systemically acting metabolite crucial for balancing C/N between roots and shoots.
Statistical characterization of tactile scenes in three-dimensional environments reveals filter properties of somatosensory cortical neurons
Authors: Zweifel Nadina O. , Solla Sara A. , Hartmann Mitra J. Z.
Published: August 2022

Natural scenes statistics have been studied extensively using collections of natural images and sound recordings. These studies have yielded important insights about how the brain might exploit regularities and redundancies in visual and auditory stimuli. In contrast, natural scenes for somatosensation have remained largely unexplored. Here we use three-dimensional scans of natural and human-made objects to quantify natural scene statistics at the scale of the human fingertip. Using measurements of distance, slope, and curvature from the object surfaces, we show that the first order statistics follow similar trends as have been observed for images of natural and human-made environments. In addition, independent component analysis of curvature measurements reveals Gabor-like basis vectors similar to those found in natural images. A simple neural model using these filters showed responses that accurately capture the statistics of responses in primate primary somatosensory cortex.
Behavioural foundation of a massive mitochondrial introgression in the fire salamander,Salamandra salamandra
Authors: Chiocchio Andrea , de Rysky Erica , Carere Claudio , Nascetti Giuseppe , Bisconti Roberta , Canestrelli Daniele
Published: August 2022

Patterns of mito-nuclear discordance across secondary contact zones have been reported in a wide range of animal and plant organisms. They consist of a spatial mismatch between nuclear and mitochondrial genomes, in terms of the geographic location and/or extension of the secondary contact zone between distinct evolutionary lineages. Several theoretical and empirical studies have identified massive mitochondrial introgression as the putative source of these mismatches. Yet, we still lack a clear understanding of the potential phenotypic underpinnings of these instances of massive introgression. In this study, we addressed the hypothesis that mtDNA variation across a contact zone could be associated with variation at phenotypic traits affecting dispersal propensity. We analyzed patterns of behavioural and genetic variation across a mtDNA secondary contact zone of the fire salamanderSalamandra salamandrain central Italy, which is over 600 km displaced from its nuclear counterpart. We found distinct behavioral profiles associated with the two mitotypes co-occurring in the mtDNA secondary contact zone. Counterintuitively, we found a ‘slow-thorough’ dispersal profile associated with the massively introgressed mitotype. This dispersal profile was characterized by shy, less active and less exploratory personality traits, and this pattern was consistent across life-stages and contexts (i.e., aquatic larvae and terrestrial juveniles). Our results provide experimental evidence supporting the intriguing hypothesis that personality traits associated with distinct mitotypes could promote differential mitochondrial introgression within alternative nuclear backgrounds.
Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice
Authors: Zekri Yanis , Guyot Romain , Suñer Inés Garteizgogeascoa , Canaple Laurence , Gautier-Stein Amandine , Vily-Petit Justine , Aubert Denise , Richard Sabine , Flamant Frédéric , Gauthier Karine
Published: August 2022

Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3-signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.

Significance Statement

Thyroid hormones (TH) increase energy expenditure by regulating the expression of target genes in many metabolic tissues. Among them, brown adipose tissue (BAT) dissipates biochemical energy into heat production to notably prevent hypothermia during cold exposure. Hypothyroid mice display inefficient BAT thermogenesis suggesting that TH are crucial for this process. Here, we eliminated TH signaling specifically in brown adipocytes and expose the mice to different physiological stressors. We showed that TH signaling is crucial for BAT thermogenesis as it controls the expression of genes involved in proliferation and in the metabolism of lipids and glucose, the main energy resources for BAT thermogenesis. This study provides an unprecedented view on the pathways by which T3 activates energy expenditure the BAT.
Brain de novo transcriptome assembly of a toad species showing polymorphic anti-predatory behavior
Authors: Chiocchio Andrea , Libro Pietro , Martino Giuseppe , Bisconti Roberta , Castrignanò Tiziana , Canestrelli Daniele
Published: August 2022

Understanding the genomic underpinnings of antipredatory behaviors is a hot topic in eco-evolutionary research. Yellow-bellied toad of the genus Bombina are textbook examples of the deimatic display, a time-structured behavior aimed at startling predators. Here, we generated the first de novo brain transcriptome of the Apennine yellow-bellied toad Bombina pachypus, a species showing inter-individual variation in the deimatic display. Through Rna-Seq experiments on a set of individuals showing distinct behavioral phenotypes, we generated 316,329,573 reads, which were assembled and annotated. The high-quality assembly was confirmed by assembly validators and by aligning the contigs against the de novo transcriptome with a mapping percentage higher than 91.0%. The homology annotation with DIAMOND (blastx) led to 77,391 contigs annotated on Nr, Swiss Prot and TrEMBL, whereas the domain and site protein prediction made with InterProScan led to 4747 GO-annotated and 1025 KEGG-annotated contigs. The B. pachypus transcriptome described here will be a valuable resource for further studies on the genomic underpinnings of behavioral variation in amphibians.
Blocking necroptosis reduces inflammation and tumor incidence in a mouse model of diet-induced hepatocellular carcinoma
Authors: Mohammed Sabira , Thadathil Nidheesh , Tran Albert L , Van Der Veldt Michael , Georgescu Constantin , Haritha Nair H , Ohene-Marfo Phoebe , Oh Sangphil , Nicklas Evan H , Wang Dawei , Luo Wenyi , Janknecht Ralf , Miller Benjamin F , Wren Jonathan D. , Freeman Willard , Deepa Sathyaseelan S
Published: August 2022

Background & Aims

Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. As necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis- induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet- induced HCC.

Methods

Male and female wild-type (WT) mice or mouse models where necroptosis is blocked (Ripk3-/- or Mlkl-/- mice) were fed a control diet or choline-deficient low fat diet (CD-LFD) or CD-high fat diet (CD-HFD) for 6 months. Changes in inflammation, immune cell infiltration, activation of oncogenic pathways, and tumor incidence were assessed by gene expression analysis, western blotting, and flow cytometry. RNA sequencing (RNA-seq) was performed to assess the changes in liver transcriptome.

Results

Blocking necroptosis by deleting either Ripk3 or Mlkl reduced markers of inflammation [proinflammatory cytokines (TNFα, IL-6, and IL-1β), F4/80+ve macrophages, CCR2+ve infiltrating monocytes], inflammation associated oncogenic pathways (JNK, PD-L1/PD-1, β-catenin), and HCC in male mice. In female mice, blocking necroptosis reduced HCC independent of inflammation. Blocking necroptosis reduced cell senescence markers in males and females, suggesting a novel cross-talk between necroptosis and cell senescence.

Conclusions

Our data show that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. In female mice necroptosis contributes to HCC independent of inflammation. Thus, our study suggests that necroptosis is a valid target for NAFLD-mediated HCC.

Synopsis

Necroptosis is a cell death pathway that mediate inflammation. Blocking necroptosis attenuated chronic inflammation by reducing recruitment and activation of liver macrophages, which in turn reduced activation of oncogenic pathways and progression of NAFLD to HCC in mice.

Graphical Abstract
The solution path of the Li-Stephens haplotype copying model
Authors: Jin Yifan , Terhorst Jonathan
Published: August 2022

The Li-Stephens (LS) haplotype copying model forms the basis of a number of important statistical inference procedures in genetics. LS is a probabilistic generative model which supposes that a sampled chromosome is an imperfect mosaic of other chromosomes found in a population. In the frequentist setting which is the focus of this paper, the output of LS is a “copying path” through chromosome space. The behavior of LS depends crucially on two user-specified parameters, θ and ρ, which are respectively interpreted as the rates of mutation and recombination. However, because LS is not based on a realistic model of ancestry, the precise connection between these parameters and the biological phenomena they represent is unclear. Here, we offer an alternative perspective, which considers θ and ρ as tuning parameters, and seeks to understand their impact on the LS output. We derive an algorithm which, for a given dataset, efficiently partitions the (θ, ρ) plane into regions where the output of the algorithm is constant, thereby enumerating all possible solutions to the LS model at one go. We extend this approach to the “diploid LS” model commonly used for phasing. We demonstrate the usefulness of our method by studying the effects changing of θ and ρ when using LS for common bioinformatic tasks. Our findings indicate that using the conventional (i.e., population-scaled) values for θ and ρ produces near optimal results for imputation, but may systematically inflate switch error in the case of phasing diploid genotypes.
FAK-SFK Signaling Integrates ECM Rigidity Sensing and Engagement of ERBB2 to Activate YAP and Promote Invasive Growth and Metastasis in Breast Cancer
Authors: Wang Xiaobo , Wang Shimin
Published: August 2022

We have examined the mechanism through which fibrotic extracellular matrices promote tumor progression and metastasis in HER2+ breast cancer. We found that integrin-mediated mechano-transduction and engagement of ERBB2/ERBB3 cooperate to induce activation of YAP and invasive growth in stiff 3D Matrigel-Collagen I. Mechanistic studies revealed that joint activation of SRC Family Kinases (SFKs) by FAK and ERBB2/3 results in tyrosine phosphorylation and inactivation of LATS1/2 and MOB1. The ensuing activation of YAP enables HER2+ breast cancer cells to proliferate and invade in 3D Matrigel-Collagen I. In addition, tyrosine phosphorylation of LATS1/2 and MOB1 and activation of YAP are required for v-SRC-mediated transformation of fibroblasts. Finally, preclinical studies indicated that FAK-SRC signaling is required for primary tumor growth and lung metastasis in the MMTV-Neumouse model of HER2+ breast cancer. Congruently, administration of dasatinib significantly increased the capacity of lapatinib to inhibit primary tumor growth and lung colonization in MMTV-Neu mice. These findings indicate that integrin-mediated mechano-transduction functions as a rheostat to regulate ERBB2 signaling to YAP and suggest that co-targeting ERBB2 and SFKs may exhibit therapeutic efficacy in HER2+ breast cancer.

Significance statement

Stromal stiffness, which ensues from increased deposition and crosslinking of linear collagens, promotes oncogenesis and tumor progression in the breast. Moreover, tumor fibrosis is increased in the more aggressive subtypes of breast cancer, such as Triple Negative (TN) and HER2+ breast cancer. However, the mechanisms through which extracellular matrix stiffness regulates intracellular signaling are poorly understood. In this study, we show that the Focal Adhesion Kinase (FAK)-SRC Family Kinase (SFK) complex integrates the sensing of matrix rigidity by integrins and the activation of ERBB2/3 to promote activation of YAP and that YAP is required for breast cancer growth and invasion. Mechanistic studies demonstrate that SFKs can phosphorylate and inhibit LATS1 and MOB1, leading to activation of YAP. Simultaneous inhibition of ERBB2/3 with lapatinib and SFKs with dasatinib profoundly inhibits primary tumor growth and metastasis in a mouse model of HER2+ breast cancer. These findings suggest that the therapeutic efficacy of combinatorial blockade of ERBB2 and integrin-mediated mechano-transduction should be tested in biomarker-driven clinical trials.
Successful reproduction of a large EEG study across software packages
Authors: Kabbara Aya , Forde Nina , Maumet Camille , Hassan Mahmoud
Published: August 2022

As an active field of research and with the development of state-of-the-art algorithms to analyze EEG datasets, the parametrization of Electroencephalography (EEG) analysis workflows has become increasingly flexible and complex, with a great variety of methodological options and tools to be selected at each step. This high analytical flexibility can be problematic as it can yield to variability in research outcomes. Therefore, growing attention has been recently paid to understand the potential impact of different methodological decisions on the reproducibility of results.

In this paper, we aim to examine how sensitive the results of EEG analyses are to variations in preprocessing with different software tools. We reanalyzed the shared EEG data (N=500) from (Williams et al. 2021) using three of the most commonly used EEG software tools: EEGLAB, Brainstorm and FieldTrip. After reproducing the same original preprocessing workflow in each software, the resulting evoked-related potentials (ERPs) were qualitatively and quantitatively compared in order to examine the degree of consistency/discrepancy between softwares. Our findings show a good degree of convergence in terms of the general profile of ERP waveforms, peak latencies and effect size estimates related to specific signal features. However, considerable variability was also observed in the magnitude of the absolute voltage observed with each software package as reflected by the similarity values and observed statistical differences at particular channels and time instants. In conclusion, we believe that this study provides valuable clues to better understand the impact of the software tool on the analysis of EEG results.
Electrical potential spiking of kombucha zoogleal mats
Authors: Adamatzky Andrew
Published: August 2022

A kombucha is a sugared tea fermented by a symbiotic community of over twenty species of bacteria and yeasts. The community produces and inhabits cellulosic gelatinous zoogleal mats. We studied electrical activity of the kombucha mats using pairs of differential electrodes. We discovered that the mats produce action like spikes of electrical potential. The spikes are often grouped in the trains of spikes. Characteristics of the spikes and trains of spikes are presented. We demonstrated that electrical responses of kombucha mats to chemical, electrical and optical stimulation are distinctive and therefore the mats can be used as sensors, or even unconventional computing devices.
Most High Throughput Expression Data Sets Are Underpowered
Authors: Trostle Alexander J. , Wang Jiasheng , Li Lucian , Wan Ying-Wooi , Liu Zhandong
Published: August 2022

Researchers handicap their high-throughput sequencing experiments when they do not perform enough biological replicates. Given that biological tissues can be highly variable, too few replicates will lead to false negatives, false positives, irreproducibility, and failure to detect real biological signatures. We propose that at least six biological replicates per condition becomes the standard for high-throughput expression datasets.