bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Reevaluation of the Effect of Dietary Restriction on Different Recombinant Inbred (RI) Lines of Male and Female Mice
Authors: Unnikrishnan Archana , Matyi Stephanie , Garrett Karla , Ranjo-Bishop Michelle , Allison David B , Ejima Keisuke , Chen Xiwei , Dickinson Stephanie , Richardson Arlan 
Published: June 2021

AbstractDietary restriction (DR) was reported to either have no effect or reduced the lifespan of the majority of the 41-recombinant inbred (RI)-lines studied (Liao et al., 2010). In an appropriately power longevity study (n > 30 mice/group), we measured the lifespan of the four RI-lines (115-RI, 97-RI, 98-RI, and 107-RI) that were reported to have the greatest decrease in lifespan when fed 40% DR. DR increased the median lifespan of female and male 115-RI mice and female 97-RI and 107-RI mice. DR had little effect (less than 4%) on the median lifespan of female and male 98-RI mice and male 97-RI mice and reduced the lifespan of male 107-RI mice over 20%. While our study was unable to replicate the effect of DR on the lifespan of the RI-mice (except male 107-RI mice) reported by Liao et al. (2010), we found that the genotype of a mouse had a major impact on the effect of DR on lifespan, with the effect of DR ranging from a 50% increase to a 22% decrease. No correlation was observed between the changes in either body composition or glucose tolerance induced by DR and the changes observed in lifespan of the four RI-lines of male and female mice. These four RI-lines of mice give the research community a unique resource where investigators for the first time can study the anti-aging mechanism of DR by comparing mice in which DR increases lifespan to mice where DR has either no effect or reduces lifespan.Graphical AbstractBrief AbstractIn this study we reevaluate the effect of the genotype and sex of the recombinant inbred strains of mice on their response to dietary restriction. Out of the eight lines studied, half of the groups showed an increase in lifespan when the diet was restricted by 40% and the other half either did not respond or showed a decrease in lifespan. The recombinant inbred lines used in this study are potentially important resource for aging research to identify pathways and understand the mechanism involved in the anti-aging action of DR.
Pan-cancer landscape of AID-related mutations, composite mutations and its potential role in the ICI response
Authors: Verdin Isaias Hernández , Akdemir Kadir C. , Ramazzotti Daniele , Caravagna Giulio , Labreche Karim , Mokhtari Karima , Hoang-Xuan Khê , Peyre Matthieu , Bielle Franck , Touat Mehdi , Idbaih Ahmed , Duval Alex , Sanson Marc , Alentorn Agustí 
Published: June 2021

AbstractActivation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family, may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome or targeted sequencing. AID synergizes initial hotspot mutations by a second composite mutation. Analysis of 2.5 million cells, normal and oncogenic, revealed AICDA expression activation after oncogenic transformation and cell cycle regulation loss. AID mutational load was found to be independently associated with favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2,000 samples. Finally, we found that AID related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity and T-cell exhaustion, which may increase ICI sensitivity.In BriefA combined bulk and single cell multi-omic analysis of over 50,000 patients and 2.5 million cells across 80 tumor types reveals oncogenic acquired AICDA expression inducing composite mutations and clonal immunogenic neoepitopes that are associated with favorable outcome in patients treated by immune-checkpoint inhibitors.Highlights•Pan-cancer analysis of AID mutations using > 50,000 samples, 2,000 ICI treated cases and 2.5 million cells with genome, exome and transcriptome data•Oncogenic transient AICDA expression induces mutations mainly during transcription of its off-target genes in virtually all cancers•AID is implicated in composite mutations on weakly functional alleles and immunogenic clonal neoepitopes at hotspots with greater positive selection•AID mutational load predicts response and is associated with favorable outcome in ICI treated patients
Patient-derived tumor spheroid cultures as a promising tool to assist personalized therapeutic decisions in breast cancer
Authors: Hofmann Sarah , Cohen-Harazi Raichel , Maizels Yael , Koman Igor 
Published: June 2021

AbstractBreast cancer is the most common cause of cancer related death in women. Treatment of breast cancer has many limitations including a lack of accurate biomarkers to predict success of chemotherapy and intrinsic resistance of a significant group of patients to the gold standard of therapy. Therefore, new tools are needed to provide doctors with guidance in choosing the most effective treatment plan for a particular patient and thus to increase the survival rate for breast cancer patients.Here, we present a successful method to grow in vitro spheroids from primary breast cancer tissue. Samples were received in accordance with relevant ethical guidelines and regulations. After tissue dissociation, in vitro spheroids were generated in a scaffold-free 96-well plate format. Spheroid composition was investigated by immunohistochemistry (IHC) of epithelial (Pan Cytokeratin (panCK)), stromal (Vimentin) and breast cancer-specific markers (ER, PR, HER2, GATA-3). Growth and cell viability of the spheroids were assessed upon treatment with multiple anti-cancer compounds. Student’s t-test and two-way ANOVA test were used to determine statistical significance.We were able to successfully grow spheroids from 27 out of 31 samples from surgical resections of breast cancer tissue from previously untreated patients. Recapitulation of the histopathology of the tissue of origin was confirmed. Furthermore, a drug panel of standard first- and second-line chemotherapy drugs used to treat breast cancer was applied to assess the viability of the patient-derived spheroids and revealed variation between samples in the response of the spheroids to different drug treatments.We investigated the feasibility and the utility of an in vitro patient-derived spheroid model for breast cancer therapy, and we conclude that spheroids serve as a highly effective platform to explore cancer therapeutics and personalized treatment efficacy. These results have significant implications for the application of this model in clinical personalized medicine.
HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65
Authors: Fink Douglas L. , Cai James , Whelan Matthew V. X. , Monit Christopher , de Motes Carlos Maluquer , Towers Greg J. , Sumner Rebecca P. 
Published: June 2021

AbstractThe NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins aimed at varied NF-κB pathway targeted to mitigate the anti-viral effects of NF-κB-dependent host immunity. In this study we have demonstrated using numerous assays, in a number of different cell types, that plasmid-encoded or virus-delivered Simian Immunodeficiency Virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65 and not NF-κB transcription factor proteins p50 or p100, preventing nuclear translocation of p65, a novel mechanism of NF-κB antagonism by lentiviruses. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity.ImportanceBroad antagonism of NF-κB activation has been described for HIV-1, but not for Vpx-encoding lentiviruses such as HIV-2. Here we extend our understanding of lentiviral antagonism by identifying an interaction between Vpx and transcription factor NF-κB p65, leading to inhibition of its nuclear translocation and broad NF-κB antagonism. This further evidences a requirement for lentiviruses to target universal regulators of immunity, including NF-κB, to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists, such as lipopolysaccharide translocation, during disruption of the gut microbiome barrier during HIV-1 infection. Further structural studies of p65 targeting by Vpx may yield translational insights in the form of novel pan-NF-κB inhibitors for pathologies characterised by excessive NF-κB activity. Our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of other pathways such as NF-κB.
Conservation of locomotion-induced oculomotor activity through evolution in higher tetrapods
Authors: França de Barros Filipa , Bacqué-Cazenave Julien , Taillebuis Coralie , Courtand Gilles , Manuel Marin , Bras Hélène , Tagliabue Michele , Combes Denis , Lambert François M , Beraneck Mathieu 
Published: June 2021

SummaryEfference copies are neural replicas of motor outputs used to anticipate the sensory consequences of a self-generated motor action or to coordinate neural networks involved in distinct motor behaviors1. An established example of this motor-to-motor coupling is the efference copy of the propulsive motor command that supplements classical visuo-vestibular reflexes to ensure gaze stabilization during amphibian larval locomotion2. Such feedforward replica from spinal pattern-generating circuits produces a spino-extraocular motor coupled activity that evokes eye movements, spatio-temporally coordinated to tail undulation independently of any sensory signal3,4. Exploiting the evolutionary-development characteristic of the frog1, studies in metamorphing Xenopus demonstrated the persistence of this spino-extraocular motor command in adults, and its developmental adaptation to tetrapodal locomotion5,6. Here, we demonstrate for the first time the existence of a comparable locomotor-to-ocular motor coupling in the mouse. In neonates, ex vivo nerve recordings from brainstem-spinal cord preparation reveals a spino-extraocular motor coupled activity similar to the one described in Xenopus. In adult mice, trans-synaptic rabies injection in lateral rectus eye muscle labels cervical spinal cord neurons projecting directly to abducens motor neurons. Finally, treadmill-elicited locomotion in decerebrated preparations7 evokes rhythmic eye movements in synchrony with the limb gait pattern. Overall, our data are evidence for the conservation of locomotor-induced eye movements in higher tetrapods. Thus, in mammals as in amphibians, during locomotion CPG-efference copy feedforward signals might interact with sensory feedback to ensure efficient gaze control.HighlightsSpino-extraocular motor coupling is evidenced from newborn mice ex vivo preparationsAdult decerebrated mice exhibit conjugated rhythmic eye movements during treadmill locomotionLocomotor-induced oculomotor activity occurs in absence of visuo-vestibular inputsConserved CPG-based efference copy signal in vertebrates with common features.eTOC blurbWe report a functional coupling between spinal locomotor and oculomotor networks in the mouse, similar to the one previously described in Amphibians. This is the first evidence for the direct contribution of locomotor networks to gaze control in mammals, suggesting a conservation of the spino-extraocular coupling in higher tetrapods during sustained locomotion.
Transcriptional activation of auxin biosynthesis drives developmental reprogramming of differentiated cells
Authors: Sakamoto Yuki , Kawamura Ayako , Suzuki Takamasa , Segami Shoji , Maeshima Masayoshi , Polyn Stefanie , De Veylder Lieven , Sugimoto Keiko 
Published: June 2021

AbstractPlant cells exhibit remarkable plasticity of their differentiation states, enabling regeneration of whole plants from differentiated somatic cells. How they revert cell fate and express pluripotency, however, remains unclear. Here we show that transcriptional activation of auxin biosynthesis is crucial for reprogramming differentiated Arabidopsis leaf cells. We demonstrate that interfering with the activity of histone acetyltransferases dramatically reduces callus formation from leaf mesophyll protoplasts. Impaired histone acetylation predominantly affects transcription of auxin biosynthesis genes. Auxin biosynthesis is in turn required to accomplish initial cell division through the activation of G2/M phase genes mediated by MYB DOMAIN PROTEIN 3-RELATED (MYB3Rs). We further show that the AUXIN RESPONSE FACTOR 7 (ARF7)/ARF19 and INDOLE-3-ACETIC ACID INDUCIBLE 3 (IAA3)/IAA18-mediated auxin signaling pathway is responsible for cell cycle reactivation in protoplasts. These findings provide novel mechanistic model of how differentiated plant cells can revert their fate and reinitiate the cell cycle to become pluripotent.
Resolving the structure of phage-bacteria interactions in the context of natural diversity
Authors: Kauffman Kathryn M. , Chang William K. , Brown Julia M. , Hussain Fatima A. , Yang Joy Y. , Polz Martin F. , Kelly Libusha 
Published: June 2021

AbstractMicrobial communities are shaped by viral predators1. Yet, resolving which viruses (phages) and bacteria are interacting is a major challenge in the context of natural levels of microbial diversity2. Thus, fundamental features of how phage-bacteria interactions are structured and evolve in “the wild” remain poorly resolved3, 4. Here we use large-scale isolation of environmental marineVibriobacteria and their phages to obtain quantitative estimates of strain-level phage predator loads, and use all-by-all host range assays to discover how phage and host genomic diversity shape interactions. We show that killing in environmental interaction networks is sparse - with phage predator loads low for most bacterial strains and phages host-strain-specific in their killing. Paradoxically, we also find that although overlap in killing is generally rare between phages, recombination is common. Together, these results indicate that the number of hosts that phages infect is often larger than the number that they kill and suggest that recombination during cryptic co-infections is an important mode of phage evolution in microbial communities. In the development of phages for bioengineering and therapeutics it will be important to consider that nucleic acids of introduced phages may spread into local phage populations through recombination, and that the likelihood of transfer is not predictable based on killing host range.
Inhibition of cancer cells in culture. The effects of treatment with ketone bodies and/or rapamycin treatment
Authors: Miller Anna , Lin Bo , Pincus Matthew R. , Fine Eugene J. , Feinman Richard D. 
Published: June 2021

AbstractBackgroundThe potential for ketogenic diets or administration of exogenous ketone bodies to treat or prevent to cancer remains encouraging. Of particular interest is the possibility that, whatever the effect of a nutritional intervention alone, the diet might enhance the effect of existing cancer drugs, thereby requiring lower doses and a reduction in toxicity and side effects.MethodsSW480, a human cell line derived from colon, was treated with ketone bodies (sodium 3-hydroxy butyrate (common name, □-hydroxy butyrate) or with sodium acetoacetate in the presence or absence of rapamycin. Cells were incubated for 96 hours in DMEM with 10 mM glucose medium. HSF2617, a human epithelial fibroblast line served as control and cells were subjected to similar treatment as the SW480 cells. Cell proliferation and glucose consumption were determined with standard reagents.ResultsThe ketone bodies inhibited proliferation of SW480 cells in culture. Rapamycin also inhibited proliferation and its action was enhanced by the ketone bodies although there was little synergistic effect under these conditions. Human fibroblast controls were not inhibited by the ketone bodies. Both SW480 and control lines showed consumption of glucose during a 96 hour incubation period, suggesting that normal controls can switch to ketogenic metabolism while the cancer cells, which proliferate poorly, cannot. Results are consistent with recent reports of a mouse model showing the synergy of rapamycin and a ketogenic diet (Zou Y,et al. (2020)PLoS ONE15(5)) as well as earlier publications describing additive or synergistic effects of ketogenic diets with other modalities of cancer treatment.ConclusionsThe results show that the growth of a cancer cell line in culture can be inhibited by the addition of ketone bodies or rapamycin to the growth medium. The combination of treatments was found to be additive, consistent with results from a previously published mouse model. The data demonstrate the potential for a strategy whereby doses of anti-cancer agents that have detrimental or toxic side-effects can be reduced if coupled to an appropriate source of ketone bodies.
Fishing for biodiversity by balanced harvesting
Authors: Law Richard , Plank Michael J 
Published: June 2021

AbstractFisheries are damaging, and seemingly incompatible with the conservation of marine ecosystems. Yet fish are an important source of food, and support the lives of many people in coastal communities. This paper considers an idea that a moderate intensity of fishing, appropriately scaled across species, could help in maintaining biodiversity, rather than reducing it. The scaling comes from an intuition that rates of fishing mortality of species should be kept in line with production rates of the species, a notion known as balanced harvesting. This places species conservation and exploitation on an equal footing in a single equation, showing quantitatively the relative levels of fishing mortality that species of different abundance can support. Using a dynamic model of a marine ecosystem, we give numerical evidence showing for the first time that fishing, if scaled in this way, can protect rarer species, while allowing some exploitation of species with greater production. This works because fishing mortality rates, when scaled by production, are density-dependent. Such fishing, operating adaptively to follow species’ production rates over time, contains a feedback that would help to protect species from overfishing in the presence of uncertainty about how marine ecosystems work.
Population structure and reproduction of the alvinocaridid shrimp Rimicaris exoculata on the Mid-Atlantic Ridge: variations between habitats and vent fields
Authors: Hernández-Ávila Iván , Cambon-Bonavita Marie-Anne , Sarrazin Jozée , Pradillon Florence 
Published: June 2021

AbstractRimicaris exoculata is a dominant species of deep Mid-Atlantic Ridge (MAR) vent fields and inhabits areas close to vent emissions at depths below 2000 m. Its high abundance and strong genetic connectivity along the MAR point at a remarkable ability to produce dispersing larval stages. However, the reproduction of this species long remained enigmatic because brooding females were rarely observed. Here, we describe the population structure and reproduction of R. exoculata at the Snake Pit and TAG vent fields (3600m depth) for the months of January-February. We observed major differences in population structure between habitats within a single vent field: females widely dominate the large swarms near active venting while inactive peripheries are inhabited by large males. Low temperature diffusion zones are mainly colonized by small juveniles of R. chacei instead of R. exoculata. Size structure of populations from dense active areas is polymodal at both fields, suggesting discontinuous recruitment. Male and female sizes did not vary across habitats and vent fields, with sexually mature female being slightly larger than males. In contrast to previous studies, hundreds of ovigerous females were observed at both vent fields, suggesting seasonal reproduction. Proportion of ovigerous females among sexually mature females were similar between vent fields (36.7 %). However, reproductive output was lower at TAG, where ovigerous females had smaller size-specific fecundity and egg size, and more aborted broods. Broods were colonized by the dirivultid copepod Stygiopontius pectinatus at both vent fields, apparently without deleterious effect on egg development. In the light of the observed variability in R. exoculata population structure, we propose a hypothetical scenario depicting its mating system and brooding behavior, and discuss more generally intraspecific interactions during its benthic life stages.
Contrasting a reference cranberry genome to a crop wild relative provides insights into adaptation, domestication, and breeding
Authors: Kawash Joseph , Colt Kelly , Hartwick Nolan T. , Abramson Bradley W. , Vorsa Nicholi , Polashock James J. , Michael Todd P. 
Published: June 2021

AbstractCranberry (Vaccinium macrocarpon) is a member of the Heath family (Ericaceae) and is a temperate low-growing woody perennial native to North America that is both economically important and has significant health benefits. While some native varieties are still grown today, breeding programs over the past 50 years have made significant contributions to improving disease resistance, fruit quality and yield. An initial genome sequence of an inbred line of the wild selection ‘Ben Lear,’ which is parent to multiple breeding programs, provided insight into the gene repertoire as well as a platform for molecular breeding. Recent breeding efforts have focused on leveraging the circumborealV. oxycoccos, which forms interspecific hybrids withV. macrocarpon, offering to bring in novel fruit chemistry and other desirable traits. Here we present an updated, chromosome-resolvedV. macrocarponreference genome, and compare it to a high-quality draft genome ofV. oxycoccos. Leveraging the chromosome resolved cranberry reference genome, we confirmed that the Ericaceae has undergone two whole genome duplications that are shared with blueberry and rhododendron. Leveraging resequencing data for ‘Ben Lear’ inbred lines, as well as several wild and elite selections, we identified common regions that are targets of improvement. These same syntenic regions inV. oxycoccos, were identified and represent environmental response and plant architecture genes. These data provide insight into early genomic selection in the domestication of a native North American berry crop.