bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy
Authors: Wilson Parker C. , Wu Haojia , Kirita Yuhei , Uchimura Kohei , Rennke Helmut G. , Welling Paul A. , Waikar Sushrut S. , Humphreys Benjamin D. 
Published: May 2019

AbstractDiabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell-type-specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na-K+-ATPase,WNK1, mineralocorticoid receptor andNEDD4Lexpression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy.Significance StatementSingle nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.
“The flavor enhancer maltol increases pigment aggregation in dermal and neural melanophores in Xenopus laevis tadpoles”
Authors: Dahora Lara I. , Fitzgerald Ashley , Emanuel Matthew , Baiges Alexa F. , Husain Zahabiya , Thompson Christopher K. 
Published: May 2019

ABSTRACTMelanophores are pigmented cells that change the distribution of pigmented melanosomes, enabling animals to appear lighter or darker for camouflage, thermoregulation, and UV-protection. A complex series of hormonal and neural mechanisms regulates melanophore pigment distribution, making these cells a valuable tool to screen toxicants as a dynamic cell type that responds rapidly to the environment. We found that maltol, a naturally occurring flavor enhancer and fragrance agent, induces melanophore pigment aggregation in a dose-dependent manner in Xenopus laevis tadpoles. To determine if maltol affects camouflage adaptation, we placed tadpoles into maltol baths situated over either white or black background. Maltol induced pigment aggregation in a similar dose-dependent pattern regardless of background color. We also tested how maltol treatment compares to melatonin treatment and found that the degree of pigment aggregation induced by maltol is similar to treatment with melatonin, but the time course differs significantly. Last, maltol had no effect on mRNA expression of pro-opiomelanocortin or melanin concentrating hormone receptor in the brain, both of which regulate camouflage-related pigment aggregation. Our results suggest that maltol does not exert its effects via the camouflage adaptation mechanism nor via melatonin-based mechanisms. These results are the first to identify a specific toxicological effect of maltol exposure and rules out several mechanisms by which maltol may exert its effects on pigment aggregation.
Strain-aware assembly of genomes from mixed samples using flow variation graphs
Authors: Baaijens Jasmijn A. , Stougie Leen , Schönhuth Alexander 
Published: May 2019

AbstractThe goal of strain-aware genome assembly is to reconstruct all individual haplotypes from a mixed sample at the strain level and to provide abundance estimates for the strains. Given that the use of a reference genome can introduce significant biases, de novo approaches are most suitable for this task. So far, reference-genome-independent assemblers have been shown to reconstruct haplotypes for mixed samples of limited complexity and genomes not exceeding 10000 bp in length.Here, we present VG-Flow, a de novo approach that enables full-length haplotype reconstruction from pre-assembled contigs of complex mixed samples. Our method increases contiguity of the input assembly and, at the same time, it performs haplotype abundance estimation. VG-Flow is the first approach to require polynomial, and not exponential runtime in terms of the underlying graphs. Since runtime increases only linearly in the length of the genomes in practice, it enables the reconstruction also of genomes that are longer by orders of magnitude, thereby establishing the first de novo solution to strain-aware full-length genome assembly applicable to bacterial sized genomes.VG-Flow is based on the flow variation graph as a novel concept that both captures all diversity present in the sample and enables to cast the central contig abundance estimation problem as a flow-like, polynomial time solvable optimization problem. As a consequence, we are in position to compute maximal-length haplotypes in terms of decomposing the resulting flow efficiently using a greedy algorithm, and obtain accurate frequency estimates for the reconstructed haplotypes through linear programming techniques.Benchmarking experiments show that our method outperforms state-of-the-art approaches on mixed samples from short genomes in terms of assembly accuracy as well as abundance estimation. Experiments on longer, bacterial sized genomes demonstrate that VG-Flow is the only current approach that can reconstruct full-length haplotypes from mixed samples at the strain level in human-affordable runtime.
Gut microbial dysbiosis in individuals with Sjögren’s disease
Authors: Mendez Roberto , Watane Arjun , Farhangi Monika , Cavuoto Kara M. , Leith Tom , Budree Shrish , Galor Anat , Banerjee Santanu 
Published: May 2019

AbstractPurposeTo evaluate the gut microbiome in individuals with Sjögrens and correlate bacterial profiles to dry eye (DE) measures.MethodsProspective case series of individuals with confirmed (n=13) and unconfirmed (n=8) Sjögrens (n=21; total cases) as compared to healthy controls (n=10). Stool was analyzed by 16S pyrosequencing and associations between bacterial classes and DE symptoms and signs were examined.ResultsFirmicutes was the dominant phylum in the gut, comprising 40-60% of all phyla. On a phyla level, subjects with Sjögrens (confirmed and unconfirmed) had depletion of Firmicutes (1.1- fold) and an expansion of Proteobacteria (3.0-fold), Actinobacteria (1.7-fold), and Bacteroidetes (1.3-fold) compared to controls. Shannon’s diversity index showed no differences between groups with respect to the numbers of different operational taxonomic units (OTUs) encountered (diversity) and the instances these unique OTUs were sampled (evenness). On the other hand, Faith’s phylogenetic diversity showed increased diversity in cases vs controls, which reached significance when comparing confirmed Sjögrens and controls (13.57 ± 0.89 and 10.96 ± 0.76, p=0.02). Using Principle Co-ordinate Analysis, qualitative differences in microbial composition were noted with differential clustering of cases and controls. Dimensionality reduction and clustering of complex microbial data further showed differences between the three groups, with regard to microbial composition, association and clustering. Finally, differences in certain classes of bacteria correlated with DE symptoms and signs.ConclusionsIndividuals with Sjögrens have gut microbiome alterations as compared to healthy controls. Certain classes of bacteria were associated with DE measures.
Flexible mixture model approaches that accommodate footprint size variability for robust detection of balancing selection
Authors: Cheng Xiaoheng , DeGiorgio Michael 
Published: May 2019

AbstractLong-term balancing selection typically leaves narrow footprints of increased genetic diversity, and therefore most detection approaches only achieve optimal performances when sufficiently small genomic regions (i.e., windows) are examined. Such methods are sensitive to window sizes and suffer substantial losses in power when windows are large. This issue creates a tradeoff between noise and power in empirical applications. Here, we employ mixture models to construct a set of five composite likelihood ratio test statistics, which we collectively termBstatistics. These statistics are agnostic to window sizes and can operate on diverse forms of input data. Through simulations, we show that they exhibit comparable power to the best-performing current methods, and retain substantially high power regardless of window sizes. They also display considerable robustness to high mutation rates and uneven recombination landscapes, as well as an array of other common confounding scenarios. Moreover, we applied a specific version of theBstatistics, termedB2, to a human population-genomic dataset and recovered many top candidates from prior studies, including the then-uncharacterizedSTPG2andCCDC169-SOHLH2, both of which are related to gamete functions. We further appliedB2on a bonobo population-genomic dataset. In addition to theMHC-DQgenes, we uncovered several novel candidate genes, such asKLRD1, involved in viral defense, andSCN9A, associated with pain perception. Finally, we show that our methods can be extended to account for multi-allelic balancing selection, and integrated the set of statistics into open-source software namedBalLeRMixfor future applications by the scientific community.
Close-Range Interactions Favor Growth in Random-Paired Extracted Soil Bacteria
Authors: Dubey Manupriyam , Hadadi Noushin , Pelet Serge , Johnson David R. , van der Meer Jan R. 
Published: May 2019

AbstractSpecies interactions at the cellular level are thought to govern the formation and functioning of microbial communities, but direct measurements of species interactions are difficult to perform between the hundreds of different species that constitute most microbial ecosystems. We developed a methodology to examine interactive growth of random cell pairs encapsulated inside 40–70 µm diameter agarose beads. We focused on a sandy soil as a test microbial ecosystem. By using gentle washing procedures, we detached microbial cells from sand and encapsulated them either in the absence or presence of pure culture inoculants. We then tested whether inoculants had on average positive or negative effects on the growth of resident community members depending on the growth substrate. Surprisingly, all the tested inoculants (includingPseudomonas veronii1YdBTEX2,Pseudomonas putidaF1,Pseudomonas protegensCHA0 andEscherichia coliMG1655) stimulated the growth of 40-80 percent of sand-derived cells when grown pair-wise in close proximity (i.e., within the same bead). This was true essentially irrespective of the growth substrate. Beneficial inoculant-sand cell partnerships resulted in up to 100-fold increase in productivity of the sand cell partner and up to 100-fold decrease in that of the inoculant. However, the maximum productivity attained by inoculant-sand cell partners within beads did not surpass that of inoculants alone. Further surprisingly, random pairs of sand cells encapsulated within the same bead also benefited growth in comparison to individual sand cells in a mutualistic manner (i.e., productivity when grown together was greater than the sum of individual productivities), but less than productivities observed in partnerships with the tested inoculants. This suggests that partnerships between inoculants and sand cells are not so much characterized by competition for substrate as by carbon loss through metabolite provision of the inoculant to sand cells (competitive exploitation).
A Novel Type 2 Diabetes Locus in sub-Saharan Africans, ZRANB3, is Implicated in Beta Cell Proliferation
Authors: Adeyemo Adebowale A. , Chen Guanjie , Doumatey Ayo P. , Hostelley Timothy L. , Leitch Carmen C. , Zhou Jie , Bentley Amy R. , Shriner Daniel , Fasanmade Olufemi , Okafor Godfrey , Eghan Benjamin , Agyenim-Boateng Kofi , Chandrasekharappa Settara , Adeleye Jokotade , Balogun William , Owusu Samuel , Amoah Albert , Acheampong Joseph , Johnson Thomas , Oli Johnnie , Adebamowo Clement ,   South Africa Zulu Type 2 Diabetes Case-Control Study, Collins Francis , Dunston Georgia , Zaghloul Norann A. , Rotimi Charles N. 
Published: May 2019

AbstractGenome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report the largest genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyzed ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. TCF7L2 rs7903156 was the most significant locus (p=7.288 × 10−13). We identified a novel genome wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP chr2:136064024, T allele frequency=0.034, p=2.831×10−9). Knockdown of the zebrafish ortholog resulted in reduction in pancreatic beta cell number in the developing organism, suggesting a potential mechanism for its effect on glucose hemostasis. We also showed transferability in our study of 32 established T2D loci. Our findings provide evidence of a novel candidate T2D locus and advance understanding of the genetics of T2D in non-European ancestry populations.
The genetic interaction between HIV and the antibody repertoire
Authors: Strauli Nicolas , Fryer Emily Kathleen , Pham Olivia , Abdel-Mohsen Mohamed , Facente Shelley N. , Pilcher Christopher , Pennings Pleuni , Pillai Satish , Hernandez Ryan D. 
Published: May 2019

AbstractThe interaction between human immunodeficiency virus (HIV) and the antibody repertoire (AbR) during chronic infection can provide important information for HIV vaccine research, yet has not been well-characterized on a systems level. We deeply sequenced the HIV population and the AbR of ten HIV-infected, antiretroviral (ART)-naïve individuals, each with 10-20 longitudinal samples spanning 4-14 years. Our unbiased sequencing approach identified partitions of AbRs showing evidence of interaction with autologous HIV populations. We show that these HIV-associated partitions are enriched for the V gene segments of known HIV broadly neutralizing antibodies (bnAbs), indicating that the HIV-responding component of the AbR can be identified via time-series genetic data. Despite this evidence for larger-scale AbR/HIV interactions at the sub-population level, we found little to no evidence for antagonistic coevolution (i.e. an arms race). This suggests that antagonistic coevolution is either rare, or hard to detect, which has important vaccine design implications.
X-ray phase contrast imaging ofVitisspp. buds shows freezing pattern and correlation between volume and cold hardiness
Authors: Kovaleski Alisson P. , Londo Jason P. , Finkelstein Kenneth D. 
Published: May 2019

AbstractGrapevine (Vitisspp.) buds must survive winter temperatures in order to resume growth when suitable conditions return in spring. They do so by developing cold hardiness through deep supercooling, but the mechanistic process of supercooling in buds remains largely unknown. Here we use synchrotron X-ray phase contrast imaging to study cold hardiness-related characteristics ofV. amurensis, V. riparia, andV. viniferabuds: time-resolved 2D imaging was used to visualize freezing; and microtomography was used to evaluate morphological changes during deacclimation. Bud cold hardiness was determined (low temperature exotherms; LTEs) using needle thermocouples during 2D imaging as buds were cooled with a N2gas cryostream. Resolution in 2D imaging did not allow for ice crystal identification, but freezing was assessed due to movement of tissues coinciding with LTE values. Freezing was observed to propagate from the center of the bud toward the outer bud scales. The freezing events observed lasted several minutes. Additionally, loss of supercooling ability appears to be correlated with increases in bud tissue volume during the process of deacclimation, but major increases in volume occur after most of the supercooling ability is lost, suggesting growth resumption processes are limited by deacclimation state.HighlightX-ray phase contrast imaging shows freezing occurs over several minutes and propagates from center toward tip ofVitisspp. buds. Incremental increase in bud volume correlates with cold deacclimation
Adaptation to low parasite abundance affects immune investment strategy and immunopathological responses of cavefish
Authors: Peuß Robert , Box Andrew C. , Chen Shiyuan , Wang Yongfu , Tsuchiya Dai , Persons Jenna L. , Kenzior Alexander , Maldonado Ernesto , Krishnan Jaya , Scharsack Jörn P. , Slaughter Brian P. , Rohner Nicolas 
Published: May 2019

AbstractReduced parasite infection rates in the developed world are suspected to underlie the rising prevalence of autoimmune disorders. However, the long-term evolutionary consequences of decreased parasite exposure on an immune system are not well understood. We used the Mexican tetraAstyanax mexicanusto understand how loss of parasite diversity influences the evolutionary trajectory of the vertebrate immune system by comparing river with cave morphotypes. Here, we present field data that affirms a strong reduction in parasite diversity in the cave ecosystem and show that cavefish immune cells display a more sensitive proinflammatory response towards bacterial endotoxins. Surprisingly, other innate cellular immune responses, such as phagocytosis, are drastically decreased in cavefish. Using two independent single-cell approaches, we identified a shift in the overall immune cell composition in cavefish as the underlying cellular mechanism, indicating strong differences in the immune investment strategy. While surface fish invest evenly into the innate and adaptive immune system, cavefish shifted immune investment to the adaptive immune system, and here, mainly towards specific T-cell populations that promote homeostasis. Additionally, inflammatory responses and immunopathological phenotypes in visceral adipose tissue are drastically reduced in cavefish. Our data indicate that long term adaptation to low parasite diversity coincides with a more sensitive immune system in cavefish, which is accompanied by a reduction of the immune cells that play a role in mediating the proinflammatory response.
Proteostasis collapse halts G1 progression and delimits replicative lifespan
Authors: Moreno David F. , Jenkins Kirsten , Morlot Sandrine , Charvin Gilles , Csikász-Nagy Attila , Aldea Martí 
Published: May 2019

AbstractLoss of proteostasis and cellular senescence are key hallmarks of cell aging, but whether they are subject to direct cause-effect relationships is not known. We show that most yeast cells arrest in G1 before death with low nuclear levels of cyclin Cln3, a key activator of Start extremely sensitive to chaperone status. Chaperone availability is seriously compromised in aged cells, and the G1 arrest coincides with massive aggregation of a metastable chaperone-activity reporter. A mathematical model integrating autocatalytic protein aggregation and a minimal Start network recapitulates empirical observations. As key predictions, G1-cyclin overexpression increases lifespan in a chaperone-dependent manner, and lifespan reduction by enforced protein aggregation is greatly alleviated by increased expression of specific chaperones or cyclin Cln3. Overall, our data indicate the crucial role of chaperone malfunction in setting lifespan in yeast cells, and configure a molecular pathway whereby proteostasis breakdown acts as a direct effector of cell senescence.
Computational design of a modular protein sense/response system
Authors: Glasgow Anum A. , Huang Yao-Ming , Mandell Daniel J. , Thompson Michael , Ritterson Ryan , Loshbaugh Amanda L. , Pellegrino Jenna , Krivacic Cody , Pache Roland A. , Barlow Kyle A. , Ollikainen Noah , Jeon Deborah , Kelly Mark J. S. , Fraser James S. , Kortemme Tanja 
Published: May 2019

ABSTRACTSensing and responding to signals is a fundamental ability of living systems, but despite remarkable progress in computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here we describe a generalizable computational strategy for designing sensor/actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation via split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site matches the design model with atomic accuracy. Our computational design strategy opens broad avenues to link biological outputs to new signals.One Sentence SummaryAn engineering strategy to design modular synthetic signaling systems that respond to new small molecule inputs.
Age dependence of modern clinical risk groups for localized prostate cancer – a population-based study
Authors: Huynh-Le Minh-Phuong , Myklebust Tor Åge , Feng Christine H. , Karunamuni Roshan , Johannesen Tom Børge , Dale Anders M. , Andreassen Ole A. , Seibert Tyler M. 
Published: May 2019

AbstractBackgroundOptimal prostate cancer (PCa) screening strategies will focus on men most likely to have potentially-lethal, localized disease. Age-specific incidence rates (ASIRs) for clinical risk groups could guide risk-stratified screening.ObjectiveDetermine ASIRs and proportions of PCa diagnoses in Norway for modern risk-group and Gleason score categories.Design, Setting, and ParticipantsAll men diagnosed with PCa in Norway in 2014-2017 (n=20,356).Outcome Measurements and Statistical AnalysisPatients were assigned to clinical risk groups: low, favorable-intermediate, unfavorable-intermediate, high, regional, and metastatic, using Gleason score and clinical stage. Associations were assessed between age and (1) Gleason score (including Gleason 3+4 and 4+3) and (2) PCa risk group. Risk-group ASIRs were calculated by multiplying the overall Norwegian ASIR by the proportions observed for each category.ResultsOlder age was significantly associated with higher Gleason score and more advanced disease. For example, among men aged 55-59, 65-69, 75-79, and 85-89 years, the percentage with Gleason 8-10 disease was 16.5%, 23.4%, 37.2%, and 59.9%, respectively (p<0.001); the percentage with at least high-risk disease was 29.3%, 39.1%, 60.4%, and 90.6%, respectively. Corresponding percentages for low-risk PCa were 24.0%, 17.9%, 10.2%, and 4.1% (p<0.001). The respective maximum ASIRs (per 100,000 men) for low-risk, favorable-intermediate-risk, unfavorable-intermediate-risk, high-risk, regional, and metastatic disease were: 157.1, 183.8, 194.8, 408.3, 172.3, and 330.0; incidence for low-risk and favorable-intermediate-risk PCa peaked before age 70, while more advanced categories peaked after 70. At age 75-79 years, the ASIR of high-risk disease was approximately 6 times greater than at 55-59 years.ConclusionsRisk of clinically-significant, localized PCa increases with age. Healthy older men may be among those most likely to benefit from PCa screening.