bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic targets of HOP2 are enriched for features found at recombination hotspots
Authors: Daradur Jenya , Kesserwan Mohamad , Freese Nowlan H. , Loraine Ann E. , Riggs C. Daniel 
Published: January 2023

AbstractHOP2 is a conserved protein that plays a positive role in homologous chromosome pairing and a separable role in preventing illegitimate connections between nonhomologous chromosome regions during meiosis. We employed ChIP-seq to discover that Arabidopsis HOP2 binds along the length of all chromosomes, except for centromeric and nucleolar organizer regions, and no binding sites were detected in the organelle genomes. A large number of reads were assigned to the HOP2 locus itself, yet TAIL-PCR and SNP analysis of the aligned sequences indicate that many of these reads originate from the transforming T-DNA, supporting the role of HOP2 in preventing nonhomologous exchanges. The 292 ChIP-seq peaks are largely found in promoter regions and downstream from genes, paralleling the distribution of recombination hotspots, and motif analysis revealed that there are several conserved sequences that are also enriched at crossover sites. We conducted coimmunoprecipitation of HOP2 followed by LC-MS/MS and found enrichment for several proteins, including some histone variants and modifications that are also known to be associated with recombination hotspots. We propose that HOP2 may be directed to chromatin motifs near double strand breaks, where homology checks are proposed to occur.
Rescue of normal excitability in LGI1-deficient epileptic neurons
Authors: Extrémet Johanna , Ramirez-Franco Jorge , Fronzaroli-Molinieres Laure , Boumedine-Guignon Norah , Ankri Norbert , Far Oussama El , José Garrido Juan , Debanne Dominique , Russier Michaël 
Published: January 2023

AbstractLeucine-rich Glioma Inactivated 1 (LGI1) is a glycoprotein secreted by neurons, the deletion of which leads to Autosomal Dominant Lateral Temporal Lobe Epilepsy. Recently, we showed that LGI1 deficiency in a mouse model (KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release. However, the precise conditions for rescuing normal excitability in KO-Lgi1 neurons have still not been reported. Here we show that the selective expression of LGI1 in KO-Lgi1 neurons with the use of single-cell electroporation reduces intrinsic excitability, and restores both the Kv1.1 mediated D-type current and Kv1.1 immunostaining at the AIS. In addition, we show that the homeostatic shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons electroporated with the Lgi1 gene. Furthermore, we reveal a spatial gradient of both intrinsic excitability and Kv1.1 immunostaining that is centred on the electroporated neuron. We conclude that expression of LGI1 restores normal excitability through the expression of functional Kv1 channels at the AIS.
Synthetic genetic circuits to uncover and enforce the OCT4 trajectories of successful reprogramming of human fibroblasts
Authors: Ilia Katherine , Shakiba Nika , Bingham Trevor , Jones Ross D. , Kaminski Michael M. , Aravera Eliezer , Bruno Simone , Palacios Sebastian , Weiss Ron , Collins James J. , Del Vecchio Domitilla , Schlaeger Thorsten M. 
Published: January 2023

AbstractReprogramming human fibroblasts to induced pluripotent stem cells (iPSCs) is inefficient, with heterogeneity among transcription factor (TF) trajectories driving divergent cell states. Nevertheless, the impact of TF dynamics on reprogramming efficiency remains uncharted. Here, we identify the successful reprogramming trajectories of the core pluripotency TF, OCT4, and design a genetic controller that enforces such trajectories with high precision. By combining a genetic circuit that generates a wide range of OCT4 trajectories with live-cell imaging, we track OCT4 trajectories with clonal resolution and find that a distinct constant OCT4 trajectory is required for colony formation. We then develop a synthetic genetic circuit that yields a tight OCT4 distribution around the identified trajectory and outperforms in terms of reprogramming efficiency other circuits that less accurately regulate OCT4. Our synthetic biology approach is generalizable for identifying and enforcing TF dynamics for cell fate programming applications.One-sentence summaryGenetic controllers and live-cell imaging offer a versatile strategy for probing the role of transcription factor dynamics in cell fate transitions.
Ensemble Processing and Synthetic Image Generation for Abnormally Shaped Nuclei Segmentation
Authors: Han Yue , Lei Yang , Shkolnikov Viktor , Xin Daisy , Auduong Alicia , Barcelo Steven , Allebach Jan , Delp Edward J. 
Published: January 2023

ABSTRACTAbnormalities in biological cell nuclei morphology are correlated with cell cycle stages, disease states, and various external stimuli. There have been many deep learning approaches that have described nuclei segmentation and analysis of nuclear morphology. One problem with many deep learning methods is acquiring large amounts of annotated nuclei data, which is generally expensive to obtain. In this paper, we propose a system to segment abnormally shaped nuclei with a limited amount of training data. We first generate specific shapes of synthetic nuclei groundtruth. We randomly sample these synthetic groundtruth images into training sets to train several Mask R-CNNs. We design an ensemble strategy to combine or fuse segmentation results from the Mask R-CNNs. We also design an oval nuclei removal by StarDist to reduce the false positives and improve the overall segmentation performance. Our experiments indicate that our method outperforms other methods in segmenting abnormally shaped nuclei.
Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages
Authors: Zarrow Jonah E. , Alli-Oluwafuyi Abdul-Musawwir , Youwakim Cristina M. , Kim Kwangho , Jenkins Andrew N. , Suero Isabelle C. , Jones Margaret R. , Mashhadi Zahra , Mackie Kenneth P. , Waterson Alex G. , Doran Amanda C. , Sulikowski Gary A. , Davies Sean S. 
Published: January 2023

AbstractN-acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzesN-acyl-phosphatidylethanolamine (NAPEs) to formN-acyl-ethanolamides (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance,NAPEPLDexpression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators (VU534 and VU533) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced inNapepld-/-BMDM or after Nape-pld inhibition. Together these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.
Feeding Neurons Integrate Metabolic and Reproductive States in Mice
Authors: Massa Megan G. , Scott Rachel L. , Cara Alexandra L. , Cortes Laura R. , Sandoval Norma P. , Park Jae W. , Ali Sahara , Velez Leandro M. , Tesfaye Bethlehem , Reue Karen , van Veen J. Edward , Seldin Marcus , Correa Stephanie M. 
Published: January 2023

AbstractTrade-offs between metabolic and reproductive processes are important for survival, particularly in mammals that gestate their young. Puberty and reproduction, as energetically taxing life stages, are often gated by metabolic availability in animals with ovaries. How the nervous system coordinates these trade-offs is an active area of study. We identify somatostatin neurons of the tuberal nucleus (TNSST) as a node of the feeding circuit that alters feeding in a manner sensitive to metabolic and reproductive states in mice. Whereas chemogenetic activation of TNSSTneurons increased food intake across sexes, selective ablation decreased food intake only in female mice during proestrus. Interestingly, this ablation effect was only apparent in animals with a low body mass. Fat transplantation and bioinformatics analysis of TNSSTneuronal transcriptomes revealed white adipose as a key modulator of the effects of TNSSTneurons on food intake. Together, these studies point to a mechanism whereby TNSSThypothalamic neurons modulate feeding by responding to varying levels of circulating estrogens differentially based on energy stores. This research provides insight into how neural circuits integrate reproductive and metabolic signals, and illustrates how gonadal steroid modulation of neuronal circuits can be context-dependent and gated by metabolic status.
Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression
Authors: Liu Mengmeng , Hemba-Waduge Rajitha-Udakara-Sampath , Li Xiao , Huang Xiahe , Liu Tzu-Hao , Han Xianlin , Wang Yingchun , Ji Jun-Yuan 
Published: January 2023

SummaryConserved Wnt/Wingless signaling plays pivotal roles in regulating normal development and energy metabolism in metazoans, and aberrant activation of Wnt signaling drives the pathogenesis of many diseases including cancer. However, the role of Wnt signaling in regulating cellular lipid homeostasis, particularly lipid mobilization, remains poorly understood. Here we show that canonical Wg signaling inhibits lipid accumulation inDrosophilalarval adipocytes by stimulating lipid catabolism while simultaneously inhibiting lipogenesis. Using a combination of RNA-sequencing and CUT&RUN assays, we identified a battery of Wg target genes encoding key factors required for lipogenesis (such asFASN1andAcCoS), lipolysis (such as lipid droplet-associated proteinsLsd-1andLsd-2), and fatty acid β-oxidation in the mitochondria and peroxisome (e.g.,CPT1andCRAT), most of which are directly repressed by active Wg signaling. Furthermore, lipid accumulation defects caused by active Wg signaling are rescued by either ectopically expressing Lsd-1 and Lsd-2 or depleting the transcriptional repressor Aef1, whose binding motif was identified in 52% of Wg signaling-repressed genes. These findings suggest that active Wg signaling reduces intracellular lipid accumulation by inhibiting lipogenesis and fatty acid β-oxidation and by promoting lipolysis and lipid mobilization, and Wg signaling-induced transcriptional repression play a prominent role in these converging mechanisms.
Polygenic adaptation dynamics in large, finite populations
Authors: Devi Archana , Jain Kavita 
Published: January 2023

AbstractAlthough many phenotypic traits are determined by a large number of genetic variants, how a polygenic trait adapts in response to a change in the environment is not completely understood. In the framework of diffusion theory, we study the steady state and the adaptation dynamics of a large but finite population evolving under stabilizing selection and symmetric mutations when selection and mutation are moderately large. We find that in the stationary state, the allele frequency distribution at a locus is unimodal if its effect size is below a threshold effect and bimodal otherwise; these results are the stochastic analog of the deterministic ones where the stable allele frequency becomes bistable when the effect size exceeds a threshold. It is known that following a sudden shift in the phenotypic optimum, in an infinitely large population, selective sweeps at a large-effect locus are prevented and adaptation proceeds exclusively via subtle changes in the allele frequency; in contrast, we find that the chance of sweep is substantially enhanced in large, finite populations and the allele frequency at a large-effect locus can reach a high frequency at short times even for small shifts in the phenotypic optimum.
Epidemiologic transition of lung cancer mortality in Italy by sex, province of residence and birth cohort (1920-1929 to 1960-1969)
Authors: Catelan Dolores , Biggeri Annibale , Bucchi Lauro , Manno Valerio , Pappagallo Marilena , Stoppa Giorgia , Grippo Francesco , Frova Luisa , Zamagni Federica , Crialesi Roberta , Minelli Giada 
Published: January 2023

AbstractSpace-time analysis of mortality risk is useful to evaluate the epidemiologic transitions at the subnational level. In this study, we analysed the death certificate records for lung cancer in Italy in 1995-2016, obtained from the Italian National Statistics Institute. Our objective was to investigate the spatio-temporal evolution of lung cancer mortality by sex and province of residence (n = 107) using the birth cohort as relevant time axis. We built space-time Bayesian models with space-time interactions. Among men (n = 554,829), mortality peaked in the 1920-1929 cohort, followed by a generalised decline. Among women (n = 158,619), we found novel original evidence for a peak in the 1955-1964 cohort, equivalent to a 35-year delay, with a downward trend being observed thereafter. Over time, the documented north-south decreasing mortality gradient has been replaced by a west-east decreasing gradient. Naples has become the province at highest risk in Italy, both among men and women. This pattern is consistent with an epidemiologic transition of risk factors for lung cancer to the south-west of the country and raises concerns, because 5-year age-standardised net survival from the disease in this geographic area is lower than in northern and central Italy. The variability of mortality rates among provinces has changed over time, with an increasing homogeneity for men and an opposite trend for women in the more recent birth cohorts. These unprecedented observations update substantially previous knowledge on lung cancer mortality in Italy.What’s new?The epidemiologic transition of lung cancer mortality in Italy (1995-2016) was studied using space-time Bayesian models with space-time interactions. Among men, mortality peaked in the 1920-1929 cohort, followed by a decline. Among women, novel evidence was found for a peak in the 1955-1964 cohort, equivalent to a 35-year delay, with a downward trend thereafter. The north-south decreasing gradient has been replaced by a west-east decreasing gradient, with Naples currently being the province at highest risk.
Keyphrase Identification Using Minimal Labeled Data with Hierarchical Contexts and Transfer Learning
Authors: Goli Rohan , Komatineni Keerthana , Alluri Shailesh , Hubig Nina , Min Hua , Gong Yang , Sittig Dean F. , Rennert Lior , Robinson David , Biondich Paul , Wright Adam , Nøhr Christian , Law Timothy , Faxvaag Arild , Weaver Aneesa , Gimbel Ronald , Jing Xia 
Published: January 2023

ABSTRACTBackgroundInteroperable clinical decision support system (CDSS) rules provide a pathway to interoperability, a well-recognized challenge in health information technology. Building an ontology facilitates creating interoperable CDSS rules, which can be achieved by identifying the keyphrases (KP) from the existing literature. Ontology construction is traditionally a manual effort by human domain experts, and the newly advanced natural language processing techniques, such as KP identification, can be a critical complementary automatic part of building ontology. However, KP identification requires human expertise, consensus, and contextual understanding for data labeling.MethodsThis paper presents a semi-supervised KP identification framework (long short-term memory-based encoders and the conditional random fields -based decoder models, BiLSTM-CRF) using minimal human labeled data based on hierarchical attention (i.e., at word, sentence, and abstract levels) over the documents and domain adaptation. We created synthetic labels for initial training and human-labeled data for fine-tuning. We also tested different options during NLP preprocessing and ML training to optimize the ML pipeline.ResultsOur method outperforms the prior neural architectures by learning through synthetic labels for initial training, document-level contextual learning, language modeling, and fine-tuning with limited gold standard label data. After comparison, we found that the BIO encoding schema performed slightly better than Blue, and domain adaptation techniques can improve the quality of synthetic labels. In addition, document-level context, pre-trained LM, and pre-trained WE all contributed to better model performance in our tasks. Add 2 to 4 human-labeled documents for every 100 synthetic labeled documents improves the model performance without exhausting human-labeled documents too quickly.ConclusionsTo the best of our knowledge, this is the first functional framework for the CDSS sub-domain to identify KPs, which is trained on limited human labeled data. It contributes to the general natural language processing (NLP) architectures in areas such as clinical NLP, where manual data labeling is challenging, and light-weighted deep learning models play an important role in real-time KP identification as a complementary approach to human experts’ effort.
KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors
Authors: Zhang Bo , Zhao Chen , Shen Wenchen , Li Wei , Zheng Yue , Kong Xiangfei , Wang Junbao , Wu Xudong , Liu Ying , Zhou Yan 
Published: January 2023

AbstractThe hippocampus plays major roles in learning and memory. Similar to other parts of the brain, the development of hippocampus requires precise coordination of patterning, cell proliferation, differentiation, and migration, with both cell-intrinsic and extrinsic mechanisms involved. Here we genetically removed the chromatin-association capability of KDM2B - a key component of the variant Polycomb repressive complex 1 (PRC1) - in the progenitors of developing dorsal telencephalon (Kdm2bΔCxxC) to surprisingly discover that the size ofKdm2bΔCxxChippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure.Kdm2bΔCxxCmice displayed prominent defects in spatial memory, motor learning and fear conditioning. The differentiation trajectory of the developingKdm2bΔCxxChippocampus was greatly delayed, with a significant amount of TBR2-expressing intermediate progenitors stuck along the migratory/differentiation path. Transcriptome and chromatin immunoprecipitation studies of neonatal hippocampi and their progenitors indicated that genes implicated in stemness maintenance, especially components of canonical Wnt signaling, could not be properly silenced by PRC1 and PRC2. Activating the Wnt signaling disturbed hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveiled a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of hippocampus during development.Graphic AbstractLoss of KDM2B-CxxC reduces repressive histone modifications – H2AK119ub and H3K27me3 - on key Wnt signal genes, hence leading to the block of their attenuation over time. Hampered differentiation and migration of hippocampal progenitors leads to hippocampal agenesis.
The impact of innovation news coverage on illiquid stocks: the case of US market
Authors: Fedorova Elena , Stepanov Valentin 
Published: January 2023

PurposeThe purpose of this study is to determine stock market reactions to the news about innovations and other types of publications for illiquid stocks.Design/methodology/approach(1) The authors opt for machine learning techniques and expert analysis and propose their own lexicon of innovations based on the news articles published on the professional website; (2) the dataset consists of the data on 2,000 US companies for 6 years; (3) the text analysis including BERT and Top2 Vec models which are superior to Latent Dirichlet allocation (LDA) in information criteria allows for more accurate evaluation of news sentiment and idea; and (4) furthermore, random forest and gradient boosting were applied to increase validity of results and demonstrate factor importance.Findings(1) The paper presents theoretical findings adding to signalling theory and efficient market hypothesis for US illiquid stocks; (2) this study suggests that information on product innovations (unlike other types of innovations) has a direct and significant effect on the return of illiquid stocks; (3) the results also give evidence that under uncertainty innovation-related publications do not affect the return of illiquid stocks; and (4) the analysis of the news topics (narratives) demonstrates that only the narrative related to important corporate announcements has a positive impact on the return of illiquid stocks.Originality/value(1) The authors are the first to conduct a large-scale study of the impact of various information on the return of illiquid stocks; (2) the paper focuses on information on several types of innovations with regard to the return of illiquid stocks; (3) based on Top2 Vec model, this study identifies the key topics-narratives discussed by investors and assesses their impact on the return of illiquid stocks; and (4) as an information source, the authors use the sample comprising a total of 1.4m news articles released on the professional website for investors “Benzinga”.
Socio-economic effects of trade fairs on host cities from a citizens' perspective: The case of Thessaloniki, Greece
Authors: Kourkouridis Dimitris , Frangopoulos Yannis , Kapitsinis Nikolaos 
Published: January 2023

PurposeTrade fairs have crucial socio-economic, cultural and political impacts. This paper aims to explore these multi-faceted effects at the local level from a citizens' perspective.Design/methodology/approachThe economic, social, environmental and socio-cultural effects of trade fair activity are studied by employing the case study of Thessaloniki International Fair. These impacts are examined based on the views of people in the local community of the host area, conducting a fieldwork survey with questionnaires.FindingsThe analysis, based on descriptive statistics, factor analysis and induction statistics, indicates that the economic, environmental and socio-cultural effects of trade fair activity on the city are largely viewed positively by residents of Thessaloniki. Differences in representations of fair's impacts are evident in what specific groups, according to age, educational level and occupation, expect from trade fair activity.Originality/valueWhile fairs' effects have been examined by studies in economics, sociology and politics, providing useful insights about the inter-linkages between trade fairs and host cities, they tend to pay little attention to citizens' perceptions on fairs' socio-economic implications. This paper enriches the literature on trade fairs' effects by adopting a citizens' perspective, being among the first studies to focus on representations, perceptions and views of residents of the host city to examine fairs' socio-economic implications.