bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type-I interferon signaling is essential for robust metronomic chemo-immunogenic tumor regression in murine triple-negative breast cancer
Authors: Vergato Cameron , Doshi Kshama A. , Roblyer Darren , Waxman David J. 
Published: December 2021

AbstractTriple-negative breast cancer (TNBC) is characterized by poor prognosis and aggressive growth, with limited therapeutic options for many patients. Here, we use two syngeneic mouse TNBC models, 4T1 and E0771, to investigate the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I interferon (IFN) signaling to therapeutic activity.Chemically-activated cyclophosphamide induced robust IFNα/β receptor-1-dependent signaling linked to hundreds of IFN-stimulated gene responses in both TNBC lines. Further, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by extensive downstream gene responses, robust immune cell infiltration and prolonged tumor regression. The immune dependence of these effective anti-tumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFNα/β receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these TNBC tumors to cyclophosphamide administered on a metronomic schedule.SignificanceTNBC has poor prognosis and few therapeutic options. We show that cyclophosphamide treatment can induces extensive tumor regression in syngeneic mouse models of TNBC via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust anti-tumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving TNBC treatment efficacy.
Bat teeth illuminate the diversification of mammalian tooth classes
Authors: Sadier Alexa , Anthwal Neal , Krause Andrew L. , Dessalles Renaud , Lake Michael , Bentolila Laurent , Haase Robert , Nieves Natalie , Santana Sharlene , Sears Karen 
Published: December 2021

AbstractTooth classes are a mammalian innovation that has contributed to the evolutionary success of mammals. However, our understanding of how tooth classes have evolved and diversified remains limited. Here, we use the evolutionary radiation of noctilionoid bats, the most diverse clade of mammals in terms of diet type, as a model system to show how the tooth developmental program evolved during the adaptation to new diet types. We combined morphological, developmental, cellular, and modeling approaches, to investigate the developmental differences between two tooth classes, molars and premolars and the mechanisms driving their diversification. We demonstrate that tooth classes develop through independent developmental cascades that deviate from classical models. Then we showed that the dramatic diversification of tooth number and size is driven by the modulation of the growth rate of the jaw, explaining the rapid gain/loss of teeth during the evolution of this clade. Finally, we propose a mathematical model that recapitulates the successive appearance of tooth buds and supports the hypothesis that growth acts as a key driver of the evolution of tooth number and size by tinkering with reaction/diffusion processes. Our results demonstrate developmental independence between mammalian tooth classes and provide a mechanism to explain their rapid diversification. More broadly, these results reveal how simple modifications of one developmental mechanism by another can drive the evolution of repeated structures during adaptive radiations.
Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencing
Authors: Pan Feng , Yu Shuai-Xia , Wang Xuan , Huang He-Cheng , Cai Zeng-Ying , Wang Jia-Min , Lin Shu-Yuan , Gao Yu-Lin , Li En-Min , Xu Li-Yan 
Published: December 2021

AbstractEsophageal carcinoma is a common and aggressive malignancy, and its patients have dismal clinical outcomes. The epigenetic dysregulation in both major subtypes, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), awaits further characterization. Here, we perform whole-genome bisulfite sequencing (WGBS) on a total of 43 esophageal cancer and normal samples, generating one of the largest WGBS datasets in this cancer to date. Focusing on hypomethylated regions in cancer, we show that they are associated with increased chromatin activity and enhancer RNA expression. Using this large collection of WGBS dataset, we reveal and validate novel clusters in both ESCC and EAC. We further identify specific molecular features in each cluster, with potential clinical implications. These data together advance our understanding of the epigenetic alterations in esophageal cancer and provide a rich resource for the research community of this disease.
Association of Egg Consumption, Metabolic Markers, and Risk of Cardiovascular Diseases
Authors: Pan Lang , Chen Lu , Lv Jun , Pang Yuanjie , Guo Yu , Pei Pei , Du Huaidong , Yang Ling , Millwood Iona Y. , Walters Robin G. , Chen Yiping , Gong Weiwei , Chen Junshi , Yu Canqing , Chen Zhengming , Li Liming ,   the China Kadoorie Biobank Collaborative Group
Published: December 2021

AbstractObjectiveTo simultaneously explore the associations of self-reported egg consumption with plasma metabolic markers and these markers with CVD risk.MethodsTotally 4,778 participants (3,401 CVD cases subdivided into subtypes and 1,377 controls) aged 30-79 were selected from a nested case-control study based on the China Kadoorie Biobank. Targeted nuclear magnetic resonance was used to quantify 225 metabolites and derived traits in baseline plasma samples. Linear regression was conducted to assess associations between self-reported egg consumption and metabolic markers, which were further compared with associations between metabolic markers and CVD risk.ResultsEgg consumption was associated with 24 out of 225 markers, including positive associations for apolipoprotein A1, acetate, mean HDL diameter, and lipid profiles of very large and large HDL, and inverse associations for total cholesterol and cholesterol esters in small VLDL. Among these 24 markers, 14 of them were associated with CVD risk. In general, the associations of metabolic markers with egg consumption and of metabolic markers with CVD risk showed opposite patterns.ConclusionsIn the Chinese population, egg consumption is associated with several metabolic markers, which may partially explain the protective effect of egg consumption on CVD.
Ubiquitination regulates cytoophidium assembly in Schizosaccharomyces pombe
Authors: Andreadis Christos , Li Tianhao , Liu Ji-Long 
Published: December 2021

AbstractCTP synthase (CTPS), a metabolic enzyme responsible for the de novo synthesis of CTP, can form filamentous structures termed cytoophidia, which are evolutionarily conserved from bacteria to humans. Here we used Schizosaccharomyces pombe to study the cytoophidium assembly regulation by ubiquitination. We tested the CTP synthase’s capacity to be epigenetically modified by ubiquitin or be affected by the ubiquitination state of the cell, showed that CTPS is immunoprecipitated with ubiquitin, and that ubiquitination is important for the maintenance of the CTPS filamentous structure in fission yeast. We have identified proteins which are in complex with CTPS, including specific ubiquitination regulators which significantly affect CTPS filamentation, and mapped probable ubiquitination targets on CTPS. Furthermore, we discovered that a cohort of deubiquitinating enzymes is significant for the regulation of cytoophidium morphology. Our study provides a framework for the analysis of the effects that ubiquitination and deubiquitination have on the formation of CTPS filaments.
Tailer: A Pipeline for Sequencing-Based Analysis of Non-Polyadenylated RNA 3’ End Processing
Authors: Nicholson-Shaw Tim , Lykke-Andersen Jens 
Published: December 2021

AbstractPost-transcriptional trimming and tailing of RNA 3’ ends play key roles in the processing and quality control of non-coding RNAs (ncRNAs). However, bioinformatic tools to examine changes in the RNA 3’ “tailome” are sparse and not standardized. Here we present Tailer, a bioinformatic pipeline in two parts that allows for robust quantification and analysis of tail information from next generation sequencing experiments that preserve RNA 3’ end information. The first part of Tailer, Tailer-Processing, uses genome annotation or reference FASTA gene sequences to quantify RNA 3’ ends from SAM-formatted alignment files or FASTQ sequence read files produced from sequencing experiments. The second part, Tailer-Analysis, uses the output of Tailer-Processing to identify statistically significant RNA targets of trimming and tailing and create graphs for data exploration. We apply Tailer to RNA 3’ end sequencing experiments from three published studies and find that it accurately and reproducibly recapitulates key findings. Thus, Tailer should be a useful and easily accessible tool to globally investigate tailing dynamics of non-polyadenylated RNAs and conditions that perturb them.
Tissue-specific inhibition of protein sumoylation uncovers diverse SUMO functions during C. elegans vulval development
Authors: Fergin Aleksandra , Boesch Gabriel , Greter Nadja R. , Berger Simon , Hajnal Alex 
Published: December 2021

AbstractThe sumoylation (SUMO) pathway is involved in a variety of processes during C. elegans development, such as gonadal and vulval fate specification, cell cycle progression and maintenance of chromosome structure. The ubiquitous expression of the sumoylation machinery and its involvement in many essential processes has made it difficult to dissect the tissue-specific roles of protein sumoylation and identify the specific target proteins. To overcome these challenges, we have established tools to block protein sumoylation and degrade sumoylated target proteins in a tissue-specific and temporally controlled manner. We employed the auxin-inducible protein degradation system (AID) to down-regulate AID-tagged SUMO E3 ligase GEI-17 or the SUMO ortholog SMO-1, either in the vulval precursor cells (VPCs) or in the gonadal anchor cell (AC). Tissue-specific inhibition of GEI-17 and SMO-1 revealed diverse roles of the SUMO pathway during vulval development, such as AC positioning, basement membrane (BM) breaching, vulval cell fate specification and epithelial morphogenesis. Inhibition of sumoylation in the VPCs resulted in an abnormal shape of the vulval toroids and ectopic cell fusions. Sumoylation of the ETS transcription factor LIN-1 at K169 mediates a subset of these SUMO functions, especially the proper contraction of the ventral vulA toroids. Thus, the SUMO pathway plays diverse roles throughout vulval development.
FPCountR: Absolute protein quantification using fluorescence measurements
Authors: Csibra Eszter , Stan Guy-Bart 
Published: December 2021

AbstractThis paper presents a generalisable method for the calibration of fluorescence readings on microplate readers, in order to convert arbitrary fluorescence units into absolute units. FPCountR relies on the generation of bespoke fluorescent protein (FP) calibrants, assays to determine protein concentration and activity, and a corresponding analytical workflow. We systematically characterise the assay protocols for accuracy, sensitivity and simplicity, and describe a novel ‘ECmax’ assay that outperforms the others and even enables accurate calibration without requiring the purification of FPs. To obtain cellular protein concentrations, we consider methods for the conversion of optical density to either cell counts or alternatively to cell volumes, as well as examining how cells can interfere with protein counting via fluorescence quenching, which we quantify and correct for the first time. Calibration across different instruments, disparate filter sets and mismatched gains is demonstrated to yield equivalent results. It also reveals that mCherry absorption at 600nm does not confound cell density measurements unless expressed to over 100,000 proteins per cell. FPCountR is presented as pair of open access tools (protocol and R package) to enable the community to use this method, and ultimately to facilitate the quantitative characterisation of synthetic microbial circuits.
Graphsite: Ligand-binding site classification using Deep Graph Neural Network
Authors: Shi Wentao , Singha Manali , Pu Limeng , Ramanujam J. , Brylinski Michal 
Published: December 2021

AbstractBinding sites are concave surfaces on proteins that bind to small molecules called ligands. Types of molecules that bind to the protein determine its biological function. Meanwhile, the binding process between small molecules and the protein is also crucial to various biological functionalities. Therefore, identifying and classifying such binding sites would enormously contribute to biomedical applications such as drug repurposing. Deep learning is a modern artificial intelligence technology. It utilizes deep neural networks to handle complex tasks such as image classification and language translation. Previous work has proven the capability of deep learning models handle binding sites wherein the binding sites are represented as pixels or voxels. Graph neural networks (GNNs) are deep learning models that operate on graphs. GNNs are promising for handling binding sites related tasks - provided there is an adequate graph representation to model the binding sties. In this communication, we describe a GNN-based computational method, GraphSite, that utilizes a novel graph representation of ligand-binding sites. A state-of-the-art GNN model is trained to capture the intrinsic characteristics of these binding sites and classify them. Our model generalizes well to unseen data and achieves test accuracy of 81.28% on classifying 14 binding site classes.
Power laws govern the abundance distribution of birds by rank
Authors: Da Silva Sergio , Matsushita Raul 
Published: December 2021

AbstractOnly a few bird species are abundant. According to new data, a log left-skewed distribution, rather than a lognormal distribution, better adjusts to the abundance distribution of bird species. We look at the rank abundance distribution rather than the species abundance distribution and find three power laws that fit the tails using the same data.
Endowing Universal CAR T-cell with Immune-Evasive Properties using TALEN-Gene Editing
Authors: Jo Sumin , Das Shipra , Williams Alan , Chretien Anne-Sophie , Pagliardini Thomas , Le Roy Aude , Postigo Fernandez Jorge , Le Clerre Diane , Jahangiri Billal , Chion-Sotinel Isabelle , Gouble Agnes , Dusséaux Mathilde , Galetto Roman , Duclert Aymeric , Marcenaro Emanuela , Devillier Raynier , Olive Daniel , Duchateau Philippe , Poirot Laurent , Valton Julien 
Published: December 2021

AbstractUniversal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive CAR T-cells scaffold that evades NK cell and alloresponsive T-cell attacks and imparts efficient antitumor activityin vitroandin vivo. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for future powerful clinical applications.
Integration host factor regulates colonization factors in the bee gut symbiontFrischella perrara
Authors: Schmidt K. , Santos-Matos G. , Leopold-Messer S. , El-Chazli Y. , Emery O. , Steiner T. , Piel J. , Engel P. 
Published: December 2021

AbstractBacteria colonize specific niches in the animal gut. However, the genetic basis of these associations is often unclear. The proteobacteriumFrischella perrarais a widely distributed gut symbiont of honey bees. It colonizes a specific niche in the hindgut and causes a characteristic melanization response. Genetic determinants required for the establishment of this association, or its relevance for the host, are unknown. Here, we independently isolated three point mutations in genes encoding the DNA-binding protein integration host factor (IHF) inF. perrara. These mutants abolished the production of an aryl polyene metabolite causing the yellow colony morphotype ofF. perrara. Inoculation of microbiota-free bees with one of the mutants drastically decreased gut colonization ofF. perrara. Using RNAseq we found that IHF affects the expression of potential colonization factors, including genes for adhesion (Type 4 pili), interbacterial competition (Type 6 secretion systems), and secondary metabolite production (colibactin and aryl polyene biosynthesis). Gene deletions of these components revealed different colonization defects depending on the presence of other bee gut bacteria. Interestingly, one of the T6SS mutants did not induce the scab phenotype anymore, despite colonizing at high levels, suggesting an unexpected role in bacteria-host interaction. IHF is conserved across many bacteria and may also regulate host colonization in other animal symbionts.
Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)
Authors: Barry Lucy A. , Kay Graham W. , Mitchell Nadia L. , Murray Samantha J. , Jay Nigel P. , Palmer David N. 
Published: December 2021

AbstractThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles.Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras.This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.
Using simulated temperature regimes to test growth and development of an invasive forest insect under climate change
Authors: Walter Jonathan A. , Thompson Lily M. , Powers Sean D. , Parry Dylan , Agosta Salvatore J. , Grayson Kristine L. 
Published: December 2021

AbstractTemperature and its impact on fitness are fundamental for understanding range shifts and population dynamics under climate change. Geographic climate heterogeneity, behavioural and physiological plasticity, and thermal adaptation to local climates makes predicting the responses of species to climate change complex. Using larvae from seven geographically distinct wild populations in the eastern United States of the non-native forest pestLymantria dispar dispar(L.), we conducted a simulated reciprocal transplant experiment in environmental chambers using six custom temperature regimes representing contemporary conditions near the southern and northern extremes of the US invasion front and projections under two climate change scenarios for the year 2050. Larval growth rates increased with climate warming compared to current thermal regimes and responses differed by population. A significant population-by-treatment interaction indicated that growth rates increased more when a source population experienced the warming scenarios for their region, especially for southern populations. Our study demonstrates the utility of simulating thermal regimes under climate change in environmental chambers and emphasizes how the impacts from future increases in temperature can be heterogeneous due to geographic differences in climate-related performance among populations.
Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with loss of proteostasis
Authors: Paxman Julie , Zhou Zhen , O’Laughlin Richard , Li Yang , Tian Wanying , Su Hetian , Jiang Yanfei , Holness Shayna E. , Stasiowski Elizabeth , Tsimring Lev S. , Pillus Lorraine , Hasty Jeff , Hao Nan 
Published: December 2021

SummaryChromatin instability and loss of protein homeostasis (proteostasis) are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of S.cerevisiae, proteostasis decline occurred specifically in the fraction of cells with decreased stability at the ribosomal DNA (rDNA) region. A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)- binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability. We further found that loss of rDNA stability contributes to age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates negatively impact nucleolar integrity and global proteostasis and hence limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis decline and highlight the importance of cell-to-cell variability in aging processes.
A Scaling Law for PCR Positivity in the COVID Second Wave
Authors: Johnson Keith 
Published: December 2021

AbstractIn this preliminary report, PCR positivity data in the second wave of the COVID pandemic (September-January 2020) are shown to obey a scaling law given by:

where % P0 and Σ0 are the y- and x-intercepts of a plot of positivity, %P, against the number of tests, Σ. The law holds across international, regional and local boundaries, as demonstrated for Great Britain, Austria, Germany and Sweden, the nine English regions, London - Yorkshire & Humber, and various Local Health Authorities in England. One possible explanation for scaling might be Dorfman pooling.The scaling law can be used to remove a systematic or false positive (FP) component from the daily number of positive tests, or cases, to yield the real number of cases. The results correlate strongly with the ZOE survey for London (R2=0.787) and Excess Deaths for England (R2=0.833). The cumulative total of FPs can be estimated as 1.4M by the beginning of 2021, in line with other estimates.