bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the lower thermal limits for transmission of human malaria, Plasmodium falciparum
Authors: Waite Jessica L. , Suh Eunho , Lynch Penelope A. , Thomas Matthew B. 
Published: April 2019

AbstractThe rate of malaria transmission is strongly determined by parasite development time in the mosquito, known as the extrinsic incubation period (EIP), since the quicker parasites develop, the greater the chance that the vector will survive long enough for the parasite to complete development and be transmitted. EIP is known to be temperature dependent but this relationship is surprisingly poorly characterized. There is a single degree-day model for EIP of Plasmodium falciparum that derives from a limited number of poorly controlled studies conducted almost a century ago. Here, we show that the established degree-day model greatly underestimates the rate of development of P. falciparum in both Anopheles stephensi and An. gambiae mosquitoes at temperatures in the range of 17-20°C. We also show that realistic daily temperature fluctuation further speeds parasite development. These novel results challenge one of the longest standing models in malaria biology and have potentially important implications for understanding the impacts of climate change.
Generative network models identify biological mechanisms of altered structural brain connectivity in schizophrenia
Authors: Zhang Xiaolong , Braun Urs , Harneit Anais , Zang Zhenxiang , Geiger Lena S. , Betzel Richard F. , Chen Junfang , Schweiger Janina , Schwarz Kristina , Reinwald Jonathan Rochus , Fritze Stefan , Witt Stephanie , Rietschel Marcella , Nöthen Markus M. , Degenhardt Franziska , Schwarz Emanuel , Hirjak Dusan , Meyer-Lindenberg Andreas , Bassett Danielle S. , Tost Heike 
Published: April 2019

AbstractBackgroundAlterations in the structural connectome of schizophrenia patients have been widely characterized, but the mechanisms leading to those alterations remain largely unknown. Generative network models have recently been introduced as a tool to test the biological underpinnings of the formation of altered structural brain networks.MethodsWe evaluated different generative network models to investigate the formation of structural brain networks in healthy controls (n=152), schizophrenia patients (n=66) and their unaffected first-degree relatives (n=32), and we identified spatial and topological factors contributing to network formation. We further investigated the association of these factors to cognition and to polygenic risk for schizophrenia.ResultsStructural brain networks can be best accounted for by a two-factor model combining spatial constraints and topological neighborhood structure. The same wiring model explained brain network formation for all groups analyzed. However, relatives and schizophrenia patients exhibited significantly lower spatial constraints and lower topological facilitation compared to healthy controls. The model parameter for spatial constraint was correlated with the polygenic risk for schizophrenia and predicted reduced cognitive performance.ConclusionsOur results identify spatial constraints and local topological structure as two interrelated mechanisms contributing to normal brain development as well as altered connectomes in schizophrenia. Spatial constraints were linked to the genetic risk for schizophrenia and general cognitive functioning, thereby providing insights into their biological basis and behavioral relevance.
Chromatin co-accessibility is highly structured, spans entire chromosomes, and mediates long range regulatory genetic effects
Authors: Young Greenwald William W. , D’Antonio-Chronowska Agnieszka , Benaglio Paola , Matsui Hiroko , Smith Erin N. , D’Antonio Matteo , Frazer Kelly A. 
Published: April 2019

AbstractChromatin accessibility identifies active regions of the genome, often at transcription factor (TF) binding sites, enhancers, and promoters, and contains regulatory genetic variation. Functionally related accessible sites have been reported to be co-accessible; however, the prevalence and range of co-accessibility is unknown. We perform ATAC-seq in induced pluripotent stem cells from 134 individuals and integrate it with RNA-seq, WGS, and ChIP-seq, providing the first long-range chromosome-length analysis of co-accessibility. We show that co-accessibility is highly connected, with sites having a median of 24 co-accessible partners up to 250Mb away. We also show that co-accessibility can de novo identify known and novel co-expressed genes, and co-regulatory TFs and chromatin states. We perform a cis and trans-caQTL, a trans-eQTL, and examine allelic effects of co-accessibility, identifying tens of thousands of trans-caQTLs, and showing that trans genetic effects can be propagated through co-accessibility to gene expression for cell-type and disease relevant genes.
Start from Scratch: Precisely Identify Massive Active Enhancers by Sequencing
Authors: Zhu Xiusheng , Huang Lei , Li Qing , Zhang Yubo 
Published: April 2019

AbstractEnhancer loci identified by ChIP-Seq or other experimental methods occupy hundreds of base pairs on the genome. It is the paradox comparing with the motif analysis, which usually contains only a few or tens nucleotides, achieved by bioinformatics analysis. To address this issue, we develop an experimental method, termed as massive active enhancer sequencing (MAE-Seq), to designate active enhancer sequences from arbitrary sources of 25bp random DNA libraries. These sequences are constructed in a mini-promoter vector with fluorescent reporter. After transfection, positive cells are sorted out and for sequencing. With the results, we successfully identify hundreds known accurate active enhancer sequences as expected. Besides that, large amounts of unmarked regulatory elements (UREs) without epigenetic features are also been spotted. In conclusion, MAE-Seq would be useful to refine enhancer sequences and precisely annotate the genome in eukaryotes.
A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine
Authors: von Frieling Jakob , Faisal Muhammed Naeem , Sporn Femke , Pfefferkorn Roxana , Nolte Stella Solveig , Sommer Felix , Rosenstiel Philip , Roeder Thomas 
Published: April 2019

AbstractOver-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here, we show that a HFD triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and preceded by induction of JNK signaling in enterocytes. JNK (basket) within enterocytes was essential for activation of stem cells in response to a HFD. Moreover, this nutritional intervention leads to upregulation of the cytokine upd3 in enterocytes, a reaction that is known to trigger STAT signaling in intestinal stem cells followed by their activation. We also showed that the indigenous microbiota was essential for HFD-induced stem cell activation because this response was blunted in germ-free flies lacking a microbiota. Moreover, chronic HFD feeding of flies markedly altered both the microbiota composition and bacterial load. Although HFD-induced stem cell activity was transient, long-lasting changes to the cellular composition, including a substantial increase in the number of enteroendocrine cells, were observed. Taken together, a HFD enhances stem cell activity in the Drosophila gut and this effect is completely reliant on the indigenous microbiota and also dependent on JNK signaling within intestinal enterocytes.Author summaryHigh-fat diets have been associated with a plethora of morbidities. The major research focus has been on its effects on obesity related disorders, mostly omitting the intestine, although it is the organ that makes the first contact with all diet components. Here, we aimed to understand the direct effects of HFD on the intestine itself. Using Drosophila as a model, we showed that HFD induced a transient activation of intestinal stem cells. This response completely depended on JNK signaling in enterocytes. Mechanistically, we found that HFD induces JNK signaling in enterocytes, which triggers production of the cytokine upd3. This, in turn activates STAT signaling in intestinal stem cells, leading to their activation. Surprisingly, we found that a HFD triggered induced stem cell activation critically depends on the indigenous microbiota, as in germ free flies this reaction was completely abolished. Moreover, HFD changed both, composition and abundance of the microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we assume that the increased bacterial load is the major cause for the HFD triggered stem cell activation in the intestine.
Host developmental stage is associated with shifts in the exosphere microbiome of urban-farmed Asian green leafy vegetables
Authors: Pavagadhi Shruti , Bandla Aditya , Hong Miko Poh Chin , Umashankar Shivshankar , Ting Yeap Yoon , Swarup Sanjay 
Published: April 2019

AbstractGreen leafy vegetables (GLV’s) comprise a significant part of urban South-East Asian (SEA) diets and are intensively farmed in SEA cities, including Singapore. Urban farming practices and urban-adapted vegetable cultivars likely select for specific above- and below-ground microbial communities – microbiomes – that assemble in close proximity to the plant tissues – the exosphere. A healthy exosphere microbiome is important for plant growth and safe human consumption. Using 16S rDNA gene amplicon sequencing compositional analyses, we show here that the exosphere microbiome of two commonly-consumed GLV’s – Choy Sum (Brassica oleracea Alboglabra Group) and Gai Lan (Brassica chinensis var. parachinensis) – dominated by Gammaproteobacteria, Alphaproteobacteria, Bacteroidia and Actinobacteria. Shifts in exosphere microbiome composition were strongly associated with plant developmental stage. Finally, microbial taxa consistently detected in the exosphere comprise a small subset, which are predicted to harbour plant-beneficial traits.SignificanceAmong plant crops, GLVs form an integral part of the Asian diet, especially so in Southeast Asia. Some of these GLVs have short life-cycles (∽30-45 days), which makes them suitable for urban farms in terms of cost advantage as short cycle crops are preferred in urban farms. From a food-security perspective, GLVs forms an important target food group and efforts are being made to increase its productivity to meet the increasing food demands. Current farming practices often place lot of importance on chemical fertilizers and nutrient inputs to improve the fertility of non-arable urban lands to increase the crop productivity. Furthermore, farms in urban settings are also associated with anthropogenic inputs and eutrophic conditions. These together, contribute to negative environmental externalities questioning the sustainability and eco-sustenance of urban farming. Microbial based management systems can not only resolve these challenging issues, but can also enhance plant growth, nutrient use efficiency and disease tolerance. However, their use as microbial adjuncts to agricultural practices is currently limited in urban environments, which could possibly be due to the restricted knowledge-base on these urban phytobiomes.
ATM and ATR Influence Meiotic Crossover Formation Through Antagonistic and Overlapping Functions inC. elegans
Authors: Li Wei , Yanowitz Judith 
Published: April 2019

ABSTRACTDuring meiosis, formation of double-strand breaks (DSBs) and repair by homologous recombination between homologs creates crossovers (COs) that facilitate chromosome segregation. CO formation is tightly regulated to ensure the integrity of this process. The DNA damage response kinases, Ataxia-telangiectasia mutated (ATM) and RAD3-related (ATR) have emerged as key regulators of CO formation in yeast, flies, and mice, influencing DSB formation, repair pathway choice, and cell cycle progression. The molecular networks that ATM and ATR influence during meiosis are still being resolved in other organisms. Here we show thatCaenorhabditis elegansATM and ATR homologs, ATM-1 and ATL-1 respectively, act at multiple steps in CO formation to ultimately ensure that COs are formed on all chromosomes. We show a role for ATM-1 in regulating the choice of repair template, biasing use of the homologous chromosome instead of the sister chromatid. Our data suggests a model in which ATM-1 and ATL-1 have antagonistic roles in very early repair processing, but are redundantly required for accumulation of the RAD-51 recombinase at DSB sites. We propose that these features of ATM-1 and ATL-1 ensure both CO formation on all chromosomes and accurate repair of additional DSBs.Article SummaryCrossovers formed during meiosis connect homologs and properly align them for cell division. The central importance of crossovers is underscored by the existence of extensive regulatory processes that ensures the proper execution of these events. This paper explores the evolutionary conserved roles of the central DNA damage response kinases, ATM and ATR, in crossover formation. The authors show that these kinases function together as rheostats to promote timely formation of crossovers on all chromosomes but to limit extensive DNA damage. This work provides a platform for identifying conserved meiotic targets of ATM and ATR that affect fertility across species.
Dynamic changes in the urine proteome in two ovarian cancer rat models
Authors: Li Yuqiu , Zhang Linpei , Meng Wenshu , Gao Youhe 
Published: April 2019

AbstractOvarian cancer is the most lethal gynecological malignancy in women, and it is likely to metastasize and has a poor prognosis. The early and reliable diagnosis and monitoring of ovarian cancer is very important. Without a homeostasis mechanism, urine can reflect early systemic changes in the body and has a great potential to be used for the early detection of cancer. This study tested whether early changes could be detected in two ovarian cancer rat models. Two rat models were established by either intraperitoneal (i.p.) or orthotopic (o.t.) injection of NuTu-19 ovarian cancer cells in female Fischer344 rats. Urine samples from ovarian cancer rats were collected at five time points during cancer development, and urinary proteins from the rats were profiled by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Compared with pre-injection samples, 49 differential proteins that have human orthologues were significantly changed in the orthotopically injected model. Among them, 24 of the differential proteins have previously been reported to be associated with ovarian cancer, six of which were reported to be biomarkers of ovarian cancer. On the 7th day after orthotopic injection, four differential proteins (APOA1, OX2G, CHMP5, HEXB) were identified before obvious metastases appeared. In the intraperitoneal injection model, 76 differential proteins were changed during the course of ovarian cancer development. The results show that urine proteins could enable the early detection and monitoring of ovarian cancer progression and could lay a foundation for further exploration of the biomarkers of ovarian cancer.
Post-ictal neuronal network remodeling and Wnt pathway dysregulation in the intra-hippocampal kainate mouse model of temporal lobe epilepsy
Authors: Gupta Kunal , Schnell Eric 
Published: April 2019

AbstractMouse models of mesial temporal lobe epilepsy recapitulate aspects of human epilepsy, which is characterized by neuronal network remodeling in the hippocampal dentate gyrus. Observational studies suggest that this remodeling is associated with altered Wnt pathway signaling, although this has not been experimentally examined. We used the well-characterized mouse intrahippocampal kainate model of temporal lobe epilepsy to examine associations between post-seizure hippocampal neurogenesis and altered Wnt signaling. Tissue was analyzed using immunohistochemistry and confocal microscopy, and transcriptome analysis was performed on RNA extracted from anatomically micro-dissected dentate gyri. Seizures increased neurogenesis and dendritic arborization of newborn hippocampal dentate granule cells in peri-ictal regions, and decreased neurogenesis in the ictal zone, 2-weeks after kainate injection. Interestingly, administration of the novel canonical Wnt pathway inhibitor XAV939 daily for 2-weeks after kainate injection further increased dendritic arborization in peri-ictal regions after seizure, without an effect on baseline neurogenesis in control animals. Transcriptome analysis of dentate gyri demonstrated significant canonical Wnt gene dysregulation in kainate-injected mice across all regions for Wnt3, 5a and 9a. Intriguingly, certain Wnt genes demonstrated differential patterns of dysregulation between the ictal and peri-ictal zones, most notably Wnt5B, 7B and DKK-1. Together, these results demonstrate regional variation in Wnt pathway dysregulation in the early post-ictal period, and surprisingly, suggest that some Wnt-mediated effects might actually temper aberrant neurogenesis after seizures. The Wnt pathway may therefore provide suitable targets for novel therapies that prevent network remodeling and the development of epileptic foci in high-risk patients.
Targeting against HIV/HCV Co-infection using Machine Learning-based multitarget-quantitative structure-activity relationships (mt-QSAR) Methods
Authors: Wei Yu , Li Wei , Du Tengfei , Hong Zhangyong , Lin Jianping 
Published: April 2019

ABSTRACTCo-infection between HIV-1 and HCV is common today in certain populations. However, treatment of co-infection is full of challenges with special consideration for potential hepatic safety and drug-drug interactions. Multitarget inhibitors with less toxicity may provide a promising therapeutic strategy for HIV/HCV co-infection. However, identification of one molecule acting on multiple targets simultaneously by experimental evaluation is costly and time-consuming. In silico target prediction tools provide more opportunities for the development of multitarget inhibitors. In this study, by combining naive Bayesian (NB) and support vector machine (SVM) algorithms with two types of molecular fingerprints (MACCS and ECFP6), 60 classification models were constructed to predict the active compounds toward 11 HIV-1 targets and 4 HCV targets based on the multitarget-quantitative structure-activity relationships (mt-QSAR). 5-fold cross-validation and test set validation was performed to confirm the performance of 60 classification models. Our results show that 60 mt-QSAR models appeared to have high classification accuracy in terms of ROC-AUC values ranging from 0.83 to 1 with a mean value of 0.97 for HIV-1 models, and ROC-AUC values ranging from 0.84 to 1 with a mean value of 0.96 for HCV. Furthermore, the 60 models were applied to comprehensively predict the potential targets for additional 46 compounds including 27 approved HIV-1 drugs, 10 approved HCV drugs and 9 selected compounds known to be active on one or more targets of HIV-1 or those of HCV. Finally, 18 hits including 7 HIV-1 approved drugs, 4 HCV approved drugs and 7 compounds were predicted to be HIV/HCV co-infection multitarget inhibitors. The reported bioactivity data confirmed that 7 compounds actually interacted with HIV-1 and HCV targets simultaneously with diverse binding affinities. Of those remaining predicted hits and chemical-protein interaction pairs involving the potential ability to suppress HIV/HCV co-infection deserve further investigation by experiments. This investigation shows that the mt-QSAR method is available to predict chemical-protein interaction for discovering multitarget inhibitors and provide a unique perspective on HIV/HCV co-infection treatment.
Resistance toCandidatusLiberibacter solanacearum in tomato landraces from Mexico
Authors: Garzón-Tiznado José A. , López-Orona Carlos A. , Castro-Espinoza Luciano , Velarde-Félix Sixto , Figueroa-Pérez Marely G. , Retes-Manjarrez Jesús E. 
Published: April 2019

AbstractCandidatusLiberibacter solanacearum (CLso) is an economically important plant-pathogen of tomato (Solanum lycopersicum) crops in the United States, Mexico, Central America, and New Zealand. Currently, there are no reports of resistance toCLsoin tomato cultivars. Identification and development ofCLso-resistant cultivars may offer the most efficient way to manage this tomato disease. Resistance of 46 tomato landraces collected in different regions of Mexico, representing a wide range of genetic variability from this country was evaluated. Two assays were done in consecutively years to assess the resistance toCLsounder greenhouse conditions. Plants from both tests were inoculated withCLsothrough 20Bactericera cockerelliinsects per plant. In the first trial, landraces FC22 and FC44 showed a significantly higher proportion of resistant plants, less symptoms severity, and longer incubation time, followed by landraces FC40 and FC33 compared with the rest of the 42 landraces and 2 susceptible cultivars 60 days post inoculation (dpi). In the second assay, only landraces FC22 and FC44 had again significantly higher proportion of resistant plants, less symptoms severity, relative lowerCLsotiters, and longer incubation time in comparison with landraces FC40 and FC33 and the two susceptible cultivars 60 dpi, corroborating their resistance toCLso. Presence ofCLsoDNA in all resistant plants from both assays discards scape plants and indicates that the methodology used was adequate to discriminate between resistant and susceptible plants. These results confirm that landraces FC22 and FC44 are promising resistant sources for the development ofCLso-resistant cultivars of tomato.Author summaryThe bacterium “CandidatusLiberibacter solanacearum” (CLso) is an important plant-pathogen of tomato crops in the United States, Mexico, Central America, and New Zealand. Tomato growers are lacking of cultivars with resistance to this pathogen and the development of resistant cultivars of this crop would make a sustainable business for these growers and healthy tomato consumption for humans. Tomato landraces from countries that are center of domestication of cultivated crops like Mexico, are potentially sources of resistance to plant-pathogens. Therefore, two tests were done looking for resistance sources to this pathogen and we found two tomato landraces (FC22 and FC44) showing high level of resistance toCLsobecause they had significantly higher resistant plants, less symptoms severity, lowerCLsoDNA concentration, and delay of the first symptoms in the inoculated plants in comparison with the two commercial cultivars and 44 tomato landraces collected from Mexico 60 days post infection. These landraces are promising resistant sources for the development ofCLso-resistant cultivars of tomato.