bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-sectional volumes and trajectories of the human brain, gray matter, white matter and cerebrospinal fluid in 9,473 typically aging adults
Authors: Irimia Andrei
Published: January 2020

Accurate knowledge of adult human brain volume (BV) is critical for studies of aging- and disease-related brain alterations, and for monitoring the trajectories of neural and cognitive functions in conditions like Alzheimer’s disease and traumatic brain injury. This scoping meta-analysis aggregates normative reference values for BV and three related volumetrics—gray matter volume (GMV), white matter volume (WMV) and cerebrospinal fluid volume (CSFV)—from typically-aging adults studied cross-sectionally using magnetic resonance imaging (MRI). Drawing from an aggregate sample of 9,473 adults, this study provides (A) regression coefficientsβdescribing the age-dependent trajectories of volumetric measures by sex within the range from 20 to 70 years based on both linear and quadratic models, and (B) average values for BV, GMV, WMV and CSFV at the representative ages of 20 (young age), 45 (middle age) and 70 (old age). The results provided synthesize ∼20 years of brain volumetrics research and allow one to estimate BV at any age between 20 and 70. Importantly, however, such estimates should be used and interpreted with caution because they depend on MRI hardware specifications (e.g. scanner manufacturer, magnetic field strength), data acquisition parameters (e.g. spatial resolution, weighting), and brain segmentation algorithms. Guidelines are proposed to facilitate future meta- and mega-analyses of brain volumetrics.

Disclosure statement

The author declares that he has no actual or potential conflicts of interest.
Patch size distribution and network connectivity affect species invasion dynamics in dendritic networks
Authors: Holenstein Kathrin , Harvey Eric , Altermatt Florian
Published: January 2020

Biological invasions are globally affecting ecosystems, causing local species loss and altering ecosystem functioning. Understanding the success and unfolding of such biological invasions is thus of high priority. Both local properties and the spatial network structure have been shown to be determinants of invasion success, and the identification of spatial invasion hubs directly promoting invasion dynamics is gaining attention. Spatial dynamics, however, could also indirectly alter invasion success by shaping local community structure: in many ecosystems, such as riverine networks, regional properties such as patch size distribution are known drivers of local community structures, which themselves may affect the establishment success of invading species. Using microcosm experiments in dendritic networks, we disentangled how patch size distribution and dispersal along specific network topologies shaped local communities, and, subsequently, affected the establishment success of invading species. We find that inherent patch size distributions shaped composition and diversity of local communities, and, subsequently, modulated invasion success. Specifically, the relationship between local diversity and invasion success changed across an increasing patch size gradient from a negative to a positive correlation, while overall increasing patch size reduced invasion success. Connectivity did not have a direct effect on invasion success but indirectly affected invasions by shaping diversity patterns in the whole network. Our results emphasize the relevance of indirect, landscape-level effects on species invasions, which need to be considered in the management of spatial habitat networks.
Spatially organized genomic and physiological heterogeneity of the olfactory bulb mitral cell layer
Authors: Paseltiner Daniel , Loeffler Henry , Andonian Alex , Leberman Abigail , Gould Travis J. , Castro Jason B.
Published: January 2020

Sensory inputs to the dorsal vs ventral olfactory bulb derive from distinct receptor families, and drive distinct behaviors. To address whether second-order OB neurons and circuits exhibit matching heterogeneity for input-specific readout, we clustered spatial expression profiles of >2,000 genes from the mitral cell layer (MCL). We observed clear dorsal and ventral clusters, together with dorsoventral differences in mitral cell physiology. Bulbar circuits may therefore be tuned for zone-specific computation.
Toward an understanding of the relation between gene regulation and 3D genome organization
Authors: Tian Hao , Yang Ying , Liu Sirui , Quan Hui , Gao Yi Qin
Published: January 2020

The development and usage of chromosome conformation capture technologies have provided great details on 3D genome organization and provide great opportunities to understand how gene regulation is affected by the 3D chromatin structure. Previously, we identified two types of sequence domains, CGI forest and CGI prairie, which tend to segregate spatially, but to different extent in different tissues/cell states. To further quantify the association of domain segregation with gene regulation and differentiation, we analyzed in this study the distribution of genes of different tissue specificities along the linear genome, and found that the distribution patterns are distinctly different in forests and prairies. The tissue-specific genes (TSGs) are significantly enriched in the latter but not in the former and genes of similar expression profiles among different cell types (co-activation/repression) also tend to cluster in specific prairies. We then analyzed the correlation between gene expression and the spatial contact revealed in Hi-C measurement. Tissue-specific forest-prairie contact formation was found to correlate with the regulation of the TSGs, in particular those in the prairie domains, pointing to the important role gene positioning, in the linear DNA sequence as well as in 3D chromatin structure, plays in gene regulatory network formation.
Deep Evolutionary History of the Phox and Bem1 (PB1) Domain Across Eukaryotes
Authors: Mutte Sumanth Kumar , Weijers Dolf
Published: January 2020

Protein oligomerization is a fundamental process to build complex functional modules. Domains that facilitate the oligomerization process are diverse and widespread in nature across all kingdoms of life. One such domain is the Phox and Bem1 (PB1) domain, which is functionally (relatively) well understood in the animal kingdom. However, beyond animals, neither the origin nor the evolutionary patterns of PB1-containing proteins are understood. While PB1 domain proteins have been found in other kingdoms, including plants, it is unclear how these relate to animal PB1 proteins.

To address this question, we utilized large transcriptome datasets along with the proteomes of a broad range of species. We discovered eight PB1 domain-containing protein families in plants, along with three each in Protozoa and Chromista and four families in Fungi. Studying the deep evolutionary history of PB1 domains throughout eukaryotes revealed the presence of at least two, but likely three, ancestral PB1 copies in the Last Eukaryotic Common Ancestor (LECA). These three ancestral copies gave rise to multiple orthologues later in evolution. Tertiary structural models of these plant PB1 families, combined with Random Forest based classification, indicated family-specific differences attributed to the length of PB1 domain and the proportion of β-sheets.

This study identifies novel PB1 families and reveals considerable complexity in the protein oligomerization potential at the origin of eukaryotes. The newly identified relationships provide an evolutionary basis to understand the diverse functional interactions of key regulatory proteins carrying PB1 domains across eukaryotic life.
Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesis
Authors: Xue Yue , Yang Ying , Tian Hao , Quan Hui , Liu Sirui , Zhang Ling , Gao Yi Qin
Published: January 2020

The three-dimensional (3D) chromatin structure, together with DNA methylation and other epigenetic marks, profoundly affects gene expression and displays abnormal behaviors in cancer cells. We elucidated the chromatin architecture remodeling in carcinogenesis from the perspective of spatial interactions between CGI forest and prairie domains, which are two types of megabase-sized domains defined by different sequence features but show distinct epigenetic and transcriptional patterns. DNA sequence strongly affects chromosome spatial interaction, DNA methylation and gene expression. Globally, forests and prairies show enhanced spatial segregation in cancer cells and such structural changes are accordant with the alteration of CGI interactions and domain boundary insulation, which could affect vital cancer-related properties. As the cancer progresses, a gradual increase of the DNA methylation difference between the two types of DNA domains is also observed for many different types of cancers. These observations are consistent with the change of transcriptional level differences of genes in these two domains, suggesting a highly-connected global structural, epigenetic and transcriptional activity changes in carcinogenesis.
A genome-wide association study highlights a regulatory role forIFNG-AS1contributing to cutaneous leishmaniasis in Brazil
Authors: Castellucci Léa C. , Almeida Lucas , Cherlin Svetlana , Fakiola Michaela , Carvalho Edgar , Figueiredo Amanda B. , Cavalcanti Clara M. , Alves Natalia S. , Dutra Walderez O. , Gollob Kenneth J. , Cordell Heather J. , Blackwell Jenefer M.
Published: January 2020

Background

Cutaneous leishmaniasis (CL) caused byLeishmania braziliensisremains an important public health problem in Brazil. The goal of this study was to identify genetic risk factors for CL.

Methods

Genome-wide analysis was undertaken using DNAs from 956 CL cases and 868 controls (phase 1) and 1110 CL cases and 1178 controls (phase 2) genotyped using Illumina HumanCoreExome BeadChips. Imputation against 1000G data provided 4,498,586 quality-controlled single nucleotide variants (SNVs) common across phase 1 and phase 2 samples. Linear mixed models in FastLMM were used to take account of genetic diversity/ethnicity/admixture. Cellular cytokines were measured using flow cytometry.

Results

Combined analysis across cohorts found no associations that achieved genome-wide significance, commonly accepted asP<5×10-8. Support for variants at wound-healing genes previously studied as candidate genes for CL includedSMAD2(rs115582038/rs75753347;Pimputed_1000G=1.47×10-4). Top novel GWAS hits at P<5×10-5in plausible candidate genes for CL includedSERPINB10(rs62097497;Pimputed_1000G=2.67×10-6),CRLF3(rs75270613;Pimputed_1000G=5.12×10-6),STX7(rs144488134;Pimputed_1000G=6.06×10-6),KRT80(rs10783496Pimputed_1000G=6.58×10-6),LAMP3(rs74285558;Pimputed_1000G=6.54×10-6) andIFNG-AS1(rs4913269;Pimputed_1000G=1.32×10-5). Of these,LAMP3(Padjusted=9.25×10-12; +6-fold),STX7(Padjusted=7.62×10-3; +1.3-fold) andCRLF3(Padjusted=9.19×10-9; +1.97-fold) were all expressed more highly in CL biopsies compared to normal skin, whereas expression ofKRT80(Padjusted=3.07×10-8; −3-fold) was lower. Notably, the percent peripheral blood CD3+T cells making interferon-γ in response toLeishmaniaantigen differed significantly byIFNG-AS1genotype.

Conclusions

In addition to supporting variants in wound-healing genes as genetic risk factors for CL, our GWAS results provide important novel leads to understanding pathogenesis of CL including through the regulation of interferon-γ responses.
Mate selection provides similar genetic progress and average inbreeding than optimum contribution selection in the long-term
Authors: Yoshida Grazyella Massako , Yáñez José Manuel , Queiroz Sandra Aidar de , Carvalheiro Roberto
Published: January 2020

Optimum contribution selection (OCS) and mate selection (MS) are alternative strategies to maximize genetic gain under controlled rates of inbreeding. There is evidence in the literature that MS outperforms OCS in controlling inbreeding under the same expected genetic gain in the short-term. It is unclear, however, if the same would occur in the long-term. This study aimed to compare OCS and MS regarding short and long-term genetic progress and inbreeding, using simulated data. The structure of the simulated population aimed to mimic an aquaculture breeding program. Twenty discrete generations were simulated, considering 50 families and 2,000 offspring per generation, and a trait with a heritability of 0.3. OCS and MS were applied using a differential evolution (DE) algorithm, under an objective function that accounted for genetic merit, inbreeding of the future progeny and coancestry among selection candidates. For OCS, the optimization process consisted of selection based on optimum contribution followed by minimum inbreeding mating. Objective functions using different weights on coancestry were tested. For each application, 20 replicates were simulated and the results were compared based on their average. Both strategies, OCS and MS, were very effective in controlling inbreeding over the generations. In the short-term, MS was more efficient than OCS in controlling inbreeding under the same genetic gain. In the long-term, OCS and MS resulted in similar genetic progress and average inbreeding, under the same penalty on coancestry.
Effect of Cysteine, Yeast Extract, pH Regulation and Gas Flow on Acetate and Ethanol Formation and Growth Profiles ofClostridium ljungdahliiSyngas Fermentation
Authors: Infantes Alba , Kugel Michaela , Neumann Anke
Published: January 2020

The fermentation of synthesis gas, or syngas, which consists mainly of CO, CO2and H2by acetogenic bacteria has the potential to help in transitioning from a fossil-fuel-based to a renewable bio-economy.Clostridium ljungdahlii, one of such microorganisms, has as main fermentation products acetate and ethanol. Multiple research efforts have been directed towards understanding how the metabolism and the product formation of this, and other acetogenic bacteria, can be directed towards increasing productivities and yields; nonetheless, transferring those findings to a particular set-up can prove challenging. This study used a well-established and robust fed-batch fermentation system withC. ljungdahliito look into the effects of different fermentation pH profiles, gas flow, and the supplementation with additional yeast extract or cysteine on growth, product formation ratios, yields, and productivities, as well as gas consumption. Neither yeast extract nor cysteine supplementation had a noticeable impact on cell growth, product formation or overall gas consumption. The lowering of the pH proved mainly detrimental, with decreased productivities and no improvement in ethanol ratios. The most notable shift towards ethanol was achieved by the combination of lowering both the pH and the gas flow after 24 h, but with the caveat of lower productivity. The obtained results, unexpected to some extent, highlight the necessity for a better understanding of the physiology and the metabolic regulation of acetogenic bacteria in order for this process to become more industrially relevant.
Early EEG and behavioral alterations in Dravet mice
Authors: Fadila Saja , Quinn Shir , Maia Ana Turchetti , Yakubovich Daniel , Anderson Karen L. , Rubinstein Moran
Published: January 2020

Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stage-related alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated. Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype.

Highlights

Reduction in background EEG power in Dravet

Low EEG power correlates with the risk of premature death

Motor deficits and hyperactivity are evident as early as the febrile stage

Cognitive deficits and detection of increased anxiety begin at the worsening stage
Differential functional connectivity underlying asymmetric reward-related activity in human and non-human primates
Authors: Lopez-Persem Alizée , Roumazeilles Léa , Folloni Davide , Marche Kévin , Fouragnan Elsa F. , Khalighinejad Nima , Rushworth Matthew F. S. , Sallet Jérôme
Published: January 2020

The orbitofrontal cortex (OFC) is a key brain region involved in complex cognitive functions such as reward processing and decision-making. Neuroimaging studies have shown unilateral OFC response to reward-related variables, however, those studies rarely discussed the lateralization of this effect. Yet, some lesion studies suggest that the left and right OFC contribute differently to cognitive processes. We hypothesized that the OFC asymmetrical response to reward could reflect underlying hemispherical difference in OFC functional connectivity. Using restingstate and reward-related MRI data from humans and from rhesus macaques, we first identified a specific asymmetrical response of the lateral OFC to reward in both species. Crucially, the subregion showing the highest reward-related asymmetry (RRA) overlapped with the region showing the highest functional connectivity asymmetry (FCA). Furthermore, the two types of functional asymmetries were found to be significantly correlated across humans. Altogether, our results suggest a similar pattern of functional specialization between the left and right OFC is present in two primate species.
The completeness and stratification in yeast genotype-phenotype space
Authors: Wang Jianguo , He Xionglei
Published: January 2020

Genotype and phenotype are two themes of modern biology. While the running principles in genotype has been well understood (e.g., DNA double helix structure, genetic code, central dogma, etc.), much less is known about the rules in phenotype. In this study we examine a yeast phenotype space that is represented by 405 quantitative traits. We show that the space is convergent with limited latent dimensions, which form surprisingly long-distance chains such that all traits are interconnected with each other. As a consequence, statistically uncorrelated traits are linearly dependent in the multi-dimensional phenotype space and can be precisely inferred from each other. Meanwhile, the performance is much poorer for similar trait inferences but from the genotype space (including DNA and mRNA), highlighting the dimension stratification between genotype space and phenotype space. Since the world we’re living is primarily phenotypic and what we truly care is phenotype, these findings call for phenotype-centered biology as a complement for the cross-space genetic thinking in current biology.
SIMPLEs: a single-cell RNA sequencing imputation strategy preserving gene modules and cell clusters variation
Authors: Hu Zhirui , Zu Songpeng , Liu Jun S.
Published: January 2020

A main challenge in analyzing single-cell RNA sequencing (scRNASeq) data is to reduce technical variations yet retain cell heterogeneity. Due to low mRNAs content per cell and molecule losses during the experiment (called “dropout”), the gene expression matrix has substantial zero read counts. Existing imputation methods either treat each cell or each gene identically and independently, which oversimplifies the gene correlation and cell type structure. We propose a statistical model-based approach, called SIMPLEs, which iteratively identifies correlated gene modules and cell clusters and imputes dropouts customized for individual gene module and cell type. Simultaneously, it quantifies the uncertainty of imputation and cell clustering. Optionally, SIMPLEs can integrate bulk RNASeq data for estimating dropout rates. In simulations, SIMPLEs performed significantly better than prevailing scRNASeq imputation methods by various metrics. By applying SIMPLEs to several real data sets, we discovered gene modules that can further classify subtypes of cells. Our imputations successfully recovered the expression trends of marker genes in stem cell differentiation and can discover putative pathways regulating biological processes.
Crystal structure of NirF: Insights into its role in hemed1biosynthesis
Authors: Klünemann Thomas , Nimtz Manfred , Jänsch Lothar , Layer Gunhild , Blankenfeldt Wulf
Published: January 2020

Certain facultative anaerobes such as the opportunistic human pathogenPseudomonas aeruginosacan respire on nitrate, a process generally known as denitrification. This enables denitrifying bacteria to survive in anoxic environments and contributes e.g. to the formation of biofilm, hence increasing difficulties in eradicatingP. aeruginosainfections. A central step in denitrification is the reduction of nitrite to nitrous oxide by nitrite reductase NirS, an enzyme that requires the unique cofactor hemed1. While hemed1biosynthesis is mostly understood, the role of the essential periplasmatic protein NirF in this pathway remains unclear. Here, we have determined crystal structures of NirF and its complex with dihydrohemed1, the last intermediate of hemed1biosynthesis. We found that NirF forms a bottom-to-bottom β-propeller homodimer and confirmed this by multi-angle light and small-angle X-ray scattering. The N-termini are immediately neighbored and project away from the core structure, which hints at simultaneous membrane anchoringviaboth N-termini. Further, the complex with dihydrohemed1allowed us to probe the importance of specific residues in the vicinity of the ligand binding site, revealing residues not required for binding or stability of NirF but essential for denitrification in experiments with complemented mutants of a ΔnirFstrain ofP. aeruginosa. Together, these data implicate that NirF possesses a yet unknown enzymatic activity and is not simply a binding protein of hemed1derivatives.
How quickly can we predict trimethoprim resistance using alchemical free energy methods?
Authors: Fowler Philip W
Published: January 2020

The emergence of antimicrobial resistance (AMR) threatens modern medicine and necessitates more personalised treatment of bacterial infections. Sequencing the whole genome of the pathogen(s) in a clinical sample offers one way to improve clinical microbiology diagnostic services, and has already been adopted for tuberculosis in some countries. A key weakness of a genetics clinical microbiology is it cannot return a result for rare or novel genetic variants and therefore predictive methods are required. Non-synonymous mutations in the S. aureus dfrB gene can be successfully classified as either conferring resistance (or not) by calculating their effect on the binding free energy of the antibiotic, trimethoprim. The underlying approach, alchemical free energy methods, requires large numbers of molecular dynamics simulations to be run.

We show that a large number (N=15) of binding free energies calculated from a series of very short (50 ps) molecular dynamics simulations are able to satisfactorily classify all seven mutations in our clinically-derived testset. A result for a single mutation could therefore be returned in less than an hour, thereby demonstrating that this or similar methods are now sufficiently fast and reproducible for clinical use.
Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation
Authors: Liang Dan , Elwell Angela L. , Aygün Nil , Lafferty Michael J. , Krupa Oleh , Cheek Kerry E. , Courtney Kenan P. , Yusupova Marianna , Garrett Melanie E. , Ashley-Koch Allison , Crawford Gregory E. , Love Michael I. , de la Torre-Ubieta Luis , Geschwind Daniel H. , Stein Jason L.
Published: January 2020

Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, the mechanisms mediating the effects of genetic variants on gene regulation are poorly understood. To determine the functional impact of common genetic variation on the non-coding genome longitudinally during human cortical development, we performed a chromatin accessibility quantitative trait loci (caQTL) analysis in neural progenitor cells and their differentiated neuronal progeny from 92 donors. We identified 8,111 caQTLs in progenitors and 3,676 caQTLs in neurons, with highly temporal, cell-type specific effects. A subset (∼20%) of caQTLs were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type specific caQTLs and brain-relevant genome-wide association data, we were able to fine-map loci and identify regulatory mechanisms underlying non-coding neuropsychiatric disorder risk variants.

Highlights

Genetic variation alters chromatin architecture during human cortical development

Genetic effects on chromatin accessibility are highly cell-type specific

Alleles disrupting TF motifs generally decrease accessibility, except for repressors

caQTLs facilitate fine-mapping and inference of regulatory mechanisms of GWAS loci
Regulated repression, and not activation, governs the cell fate promoter controlling yeast meiosis
Authors: Tam Janis , van Werven Folkert J.
Published: January 2020

Intrinsic signals and cues from the external environment drive cell fate decisions. In budding yeast, the decision to enter meiosis is controlled by nutrient and mating-type signals that regulate expression of the master transcription factor for meiotic entry,IME1. How nutrient signals controlIME1expression remains poorly understood. Here we show thatIME1transcription is regulated by multiple sequence-specific transcription factors that mediate association of Tup1-Cyc8 co-repressor to its promoter. We find that at least eight transcription factors bind theIME1promoter when nutrients are ample. Remarkably, association of these transcription factors is highly regulated by different nutrient cues. Mutant cells lacking three transcription factors (Sok2/Phd1/Yap6) displayed reduced Tup1-Cyc8 association, increasedIME1expression and earlier onset of meiosis. Our data demonstrate that the promoter of a master regulator is primed for rapid activation while repression by multiple transcription factors mediating Tup1-Cyc8 recruitment dictates the fate decision to enter meiosis.
Heterosis of leaf and rhizosphere microbiomes in field-grown maize
Authors: Wagner Maggie R. , Roberts Joe H. , Balint-Kurti Peter , Holland James B.
Published: January 2020

Macroorganisms’ genotypes shape their phenotypes, which in turn shape the habitat available to potential microbial symbionts. This influence of host genotype on microbiome composition has been demonstrated in many systems; however, most previous studies have either compared unrelated genotypes or delved into molecular mechanisms. As a result, it is currently unclear whether the heritability of host-associated microbiomes follows similar patterns to the heritability of other complex traits.

We take a new approach to this question by comparing the microbiomes of diverse maize inbred lines and their F1hybrid offspring, which we quantified in both rhizosphere and leaves of field-grown plants using 16S-v4 and ITS1 amplicon sequencing.

We show that inbred lines and hybrids differ consistently in composition of bacterial and fungal rhizosphere communities, as well as leaf-associated fungal communities. A wide range of microbiome features display heterosis within individual crosses, consistent with patterns for non-microbial maize phenotypes. For leaf microbiomes, these results were supported by the observation that broad-sense heritability in hybrids was substantially higher than narrow-sense heritability.

Our results support our hypothesis that at least some heterotic host traits affect microbiome composition in maize.
Genetic effects on educational attainment in Hungary
Authors: Ujma Péter P. , Eszlári Nóra , Millinghoffer András , Bruncsics Bence , Petschner Péter , Antal Péter , Deakin Bill , Breen Gerome , Bagdy György , Juhász Gabriella
Published: January 2020

Educational attainment is a substantially heritable trait, and it has recently been linked to specific genetic variants by genome-wide association studies (GWASs). However, the effects of such genetic variants are expected to vary across environments, including countries and historical eras. We used polygenic scores (PGSs) to assess molecular genetic effects on educational attainment in Hungary, a country in the Central Eastern European region where behavioral genetic studies are in general scarce and molecular genetic studies of educational attainment have not been previously published. We found that the PGS is significantly associated with highest educational level attained as well as the number of years in education in a sample of Hungarian volunteers (N=829). In an English (N=976) comparison sample with identical measurement protocols the same PGS had a stronger association with educational level, but not with years in education. In line with previous Estonian findings, we found higher PGS effect sizes in Hungarian, but not in English participants who attended higher education after the fall of Communism, although we lacked statistical power for this effect to reach significance. Our results provide evidence that polygenic scores for educational attainment are valid in diverse European populations.
Algorithmic Learning for Auto-deconvolution of GC-MS Data to Enable Molecular Networking within GNPS
Authors: Aksenov Alexander A. , Laponogov Ivan , Zhang Zheng , Doran Sophie LF , Belluomo Ilaria , Veselkov Dennis , Bittremieux Wout , Nothias Louis Felix , Nothias-Esposito Mélissa , Maloney Katherine N. , Misra Biswapriya B. , Melnik Alexey V. , Jones Kenneth L. , Dorrestein Kathleen , Panitchpakdi Morgan , Ernst Madeleine , van der Hooft Justin J.J. , Gonzalez Mabel , Carazzone Chiara , Amézquita Adolfo , Callewaert Chris , Morton James , Quinn Robert , Bouslimani Amina , Albarracín Orio Andrea , Petras Daniel , Smania Andrea M. , Couvillion Sneha P. , Burnet Meagan C. , Nicora Carrie D. , Zink Erika , Metz Thomas O. , Artaev Viatcheslav , Humston-Fulmer Elizabeth , Gregor Rachel , Meijler Michael M. , Mizrahi Itzhak , Eyal Stav , Anderson Brooke , Dutton Rachel , Lugan Raphaël , Boulch Pauline Le , Guitton Yann , Prevost Stephanie , Poirier Audrey , Dervilly Gaud , Bizec Bruno Le , Fait Aaron , Persi Noga Sikron , Song Chao , Gashu Kelem , Coras Roxana , Guma Monica , Manasson Julia , Scher Jose U. , Barupal Dinesh , Alseekh Saleh , Fernie Alisdair , Mirnezami Reza , Vasiliou Vasilis , Schmid Robin , Borisov Roman S. , Kulikova Larisa N. , Knight Rob , Wang Mingxun , Hanna George B , Dorrestein Pieter C. , Veselkov Kirill
Published: January 2020

Gas chromatography-mass spectrometry (GC-MS) represents an analytical technique with significant practical societal impact. Spectral deconvolution is an essential step for interpreting GC-MS data. No public GC-MS repositories that also enable repository-scale analysis exist, in part because deconvolution requires significant user input. We therefore engineered a scalable machine learning workflow for the Global Natural Product Social Molecular Networking (GNPS) analysis platform to enable the mass spectrometry community to store, process, share, annotate, compare, and perform molecular networking of GC-MS data. The workflow performs auto-deconvolution of compound fragmentation patternsviaunsupervised non-negative matrix factorization, using a Fast Fourier Transform-based strategy to overcome scalability limitations. We introduce a “balance score” that quantifies the reproducibility of fragmentation patterns across all samples. We demonstrate the utility of the platform with breathomics analysis applied to the early detection of oesophago-gastric cancer, and by creating the first molecular spatial map of the human volatilome.
Plastid genomics of Nicotiana (Solanaceae): insights into molecular evolution, positive selection and the origin of the maternal genome of Aztec tobacco (Nicotiana rustica)
Authors: Mehmood Furrukh , Abdullah  , Ubaid Zartasha , Shahzadi Iram , Ahmed Ibrar , Waheed Mohammad Tahir , Poczai Péter , Mirza Bushra
Published: January 2020

The genus Nicotiana of the family Solanaceae, commonly referred to as tobacco plants, are a group cultivated as garden ornamentals. Besides their use in the worldwide production of tobacco leaves, they are also used as evolutionary model systems due to their complex development history, which is tangled by polyploidy and hybridization. Here, we assembled the plastid genomes of five tobacco species, namely N. knightiana, N. rustica, N. paniculata, N. obtusifolia and N. glauca. De novo assembled tobacco plastid genomes showed typical quadripartite structure, consisting of a pair of inverted repeats (IR) regions (25,323–25,369 bp each) separated by a large single copy (LSC) region (86,510 –86,716 bp) and a small single copy (SSC) region (18,441–18,555 bp). Comparative analyses of Nicotiana plastid genomes showed similar GC content, gene content, codon usage, simple sequence repeats, oligonucleotide repeats, RNA editing sites and substitutions with currently available Solanaceae genomes sequences. We identified twenty highly polymorphic regions mostly belonging to intergenic spacer regions (IGS), which could be appropriate for the development of robust and cost-effective markers to infer the phylogeny of genus Nicotiana and family Solanaceae. Our comparative plastid genome analysis revealed that the maternal parent of the tetraploid N. rustica was the common ancestor of N. paniculata and N. knightiana, and the later species is more closely related to N. rustica. The relaxed molecular clock analyses estimated that the speciation event between N. rustica and knightiana appeared 0.56 Ma (HPD 0.65–0.46). The biogeographical analysis showed a south-to-north range expansion and diversification for N. rustica and related species, where N. undulata and N. paniculata evolved in North/Central Peru, while N. rustica developed in Southern Peru and separated from N. knightiana, which adapted to the Southern coastal climatic regimes. We further inspected selective pressure on protein-coding genes among tobacco species to determine if this adaptation process affected the evolution of plastid genes. These analyses indicated that four genes involved in different plastid functions, such as DNA replication (rpoA) and photosynthesis (atpB, ndhD and ndhF), came under positive selective pressure as a result of specific environmental conditions. Genetic mutations of the following genes might have contributed to the survival and better adaptation during the evolutionary history of tobacco species.
Characterizing dysbiosis of gut microbiome in PD: Evidence for overabundance of opportunistic pathogens
Authors: Wallen Zachary D , Appah Mary , Dean Marissa N , Sesler Cheryl L , Factor Stewart A , Molho Eric , Zabetian Cyrus P , Standaert David G , Payami Haydeh
Published: January 2020

In Parkinson’s disease (PD), gastrointestinal features are common and often precede the motor signs. Braak and colleagues proposed that PD may start in the gut, triggered by a pathogen, and spread to the brain. Numerous studies have examined the gut microbiome in PD, all found it to be altered, but found inconsistent results on associated microorganisms. Studies to date have been small (N=20 to 306) and are difficult to compare or combine due to varied methodology. We conducted a microbiome-wide association study (MWAS) with two large datasets for internal replication (N=333 and 507). We used uniform methodology when possible, interrogated confounders, and applied two statistical tests for concordance, followed by correlation network analysis to infer interactions. Fifteen genera were associated with PD at a microbiome-wide significance level, in both datasets, with both methods, with or without covariate adjustment. The associations were not independent, rather represented 3 clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens; all were elevated in PD. Cluster 2 were short-chain-fatty-acid producing bacteria; all were reduced in PD. Cluster 3 were carbohydrate-metabolizing probiotics; elevated in PD. Depletion of anti-inflammatory short-chain-fatty-acid producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is a novel finding and their identity provides a lead to experimentally test their role in PD.
Regulation of perceptual learning by chronic chemogenetic manipulation of parvalbumin-positive interneurons
Authors: Cisneros-Franco J. Miguel , Thomas Maryse E. , Regragui Itri , Lane Conor P. , Ouellet Lydia , de Villers-Sidani Étienne
Published: January 2020

Parvalbumin-positive (PV+) interneurons are major regulators of adult experience-dependent plasticity. Acute manipulation of PV+ cell activity before learning alters the rate of acquisition of new skills, whereas transient inactivation of PV+ cells interferes with retrieval of previously learned information. However, the effects of sustained PV+ cell manipulation throughout training remain largely unknown. Using chemogenetics in rat auditory cortex during an adaptive sound disrimination task, here we show that PV+ cells exert bidirectional control over the rate of perceptual learning. Down-regulation of PV+ cell activity accelerated learning, but increasing their activity resulted in slower learning. However, both interventions led to reduced gains in perceptual acuity by the end of training relative to controls. Furthermore, longitudinal training performance was functionally correlated with measures of neural synchrony and stimulus-specific adaptation. These findings suggest that, whereas restricting PV+ cell activity may initially facilitate training-induced plasticity, a subsequent increase in PV+ cell activity is necessary to prevent further plastic changes and consolidate learning.
Hypercluster: a python package and SnakeMake pipeline for flexible, parallelized unsupervised clustering optimization
Authors: Blumenberg Lili , Ruggles Kelly V.
Published: January 2020

Unsupervised clustering is a common and exceptionally useful tool for large biological datasets. However, clustering requires upfront algorithm and hyperparameter selection, which can introduce bias into the final clustering labels. It is therefore advisable to obtain a range of clustering results from multiple models and hyperparameters, which can be cumbersome and slow. To streamline this process, we present hypercluster, a python package and SnakeMake pipeline for flexible and parallelized clustering evaluation and selection. Hypercluster is available on bioconda; installation, documentation and example workflows can be found at:https://github.com/ruggleslab/hypercluster.

Author summary

Unsupervised clustering is a technique for grouping similar samples within a dataset. It is extremely common when analyzing big data from patient samples, or high throughput techniques like single cell RNA-seq. When researchers use unsupervised clustering, they have to select parameters that affect the final result—for instance, how many groups they expect to find or what the smallest group is allowed to be. Some methods require setting even less intuitive parameters. For most applications, it is extremely challenging to guess what the values of these parameters should be; therefore to prevent introducing bias into the final results, researchers should test many different parameters and methods to find the best groups. This process is cumbersome, slow and challenging to perform in a reproducible way. We developed hypercluster, a tool that automates this process, make it much faster, and presenting the results in a reproducible and helpful manner.
Protein Corona Composition and Dynamics on Carbon Nanotubes in Blood Plasma and Cerebrospinal Fluid
Authors: Pinals Rebecca L. , Yang Darwin , Rosenberg Daniel J. , Chaudhary Tanya , Crothers Andrew R. , Iavarone Anthony T. , Hammel Michal , Landry Markita P.
Published: January 2020

When a nanoparticle enters a biological environment, the surface is rapidly coated with proteins to form a “protein corona”. Presence of the protein corona surrounding the nanoparticle has significant implications for applying nanotechnologies within biological systems, affecting outcomes such as biodistribution and toxicity. Herein, we measure protein corona formation on single-stranded DNA wrapped single-walled carbon nanotubes (ssDNA-SWCNTs), a high-aspect ratio nanoparticle ideal for sensing and delivery applications, and polystyrene nanoparticles, a model nanoparticle system. The protein corona of each nanoparticle is studied in human blood plasma and cerebrospinal fluid. We characterize corona composition by proteomic mass spectrometry to determine abundant and differentially enriched vs. depleted corona proteins. High-binding corona proteins on ssDNA-SWCNTs include proteins involved in lipid binding and transport (clusterin and apolipoprotein A-I), complement activation (complement C3), and blood coagulation (fibrinogen). Of note, albumin is the most common blood protein (55% w/v), yet exhibits low-binding affinity towards ssDNA-SWCNTs, displaying 1300-fold lower bound concentration relative to native plasma. We investigate the role of electrostatic and entropic interactions driving selective protein corona formation, and find that hydrophobic interactions drive inner corona formation, while shielding of electrostatic interactions allows for outer corona formation. Lastly, we study real-time binding of proteins on ssDNA-SWCNTs and find relative agreement between proteins that are enriched and bind strongly, such as fibrinogen, and proteins that are depleted and bind marginally, such as albumin. Interestingly, certain proteins express contrary behavior in single-protein experiments than within the whole biofluid, highlighting the importance of cooperative mechanisms driving selective corona adsorption on the SWCNT surface. Knowledge of the protein corona composition, dynamics, and structure informs translation of engineered nanoparticles fromin vitrodesign to effectivein vivoapplication.
Intraspinal stimulation with silicon-based 3D microelectrode array for bladder voiding in cats before and after spinal cord injury
Authors: Pikov Victor , McCreery Douglas B. , Han Martin
Published: January 2020

Bladder dysfunction is a significant and largely unaddressed problem for people living with spinal cord injury. Intermittent catheterization does not provide volitional control of micturition and has numerous side effects. Targeted electrical microstimulation of the spinal cord has been previously explored for restoring such volitional control in the animal model of experimental spinal cord injury. In this study, the development of the intraspinal microstimulation array technology was continued and evaluated in the feline animal model for its ability to provide more focused and reliable bladder control after a complete spinal cord transection. For the first time, the intraspinal multisite silicon array wad built using novel microfabrication processes to provide custom-designed tip geometry and 3D electrode distribution, better cost efficiency, reproducibility, scalability, and on-the-probe integration of active electronics. Long-term implantation was performed in 8 animals for a period up to 6 months, targeting the dorsal gray commissure area in the S1 sacral cord that is known to be involved in the coordination between the bladder detrusor and the external urethral sphincter. About one third of the electrode sites in the that area produced micturition-related responses. The effectiveness of stimulation increased starting from one month after spinal cord transection (as evaluated in one animal), likely due to supraspinal disinhibition of the spinal circuitry and/or hypertrophy and hyperexcitability of the spinal bladder afferents. Further studies are required to assess longer-term reliability of the developed intraspinal microstimulation array technology in preparation for eventual human translation.
BNrich: A Bayesian network approach to the pathway enrichment analysis
Authors: Maleknia Samaneh , Sharifi-Zarchi Ali , Tabar Vahid Rezaei , Namazi Mohsen , Kavousi Kaveh
Published: January 2020

Motivation

One of the most popular techniques in biological studies for analyzing high throughput data is pathway enrichment analysis (PEA). Many researchers apply the existing methods without considering the topology of pathways or at least they have overlooked a significant part of the structure, which may reduce the accuracy and generalizability of the results. Developing a new approach while considering gene expression data and topological features like causal relations regarding edge directions will help the investigators to achieve more accurate results.

Results

We proposed a new pathway enrichment analysis based on Bayesian network (BNrich) as an approach in PEA. To this end, the cycles were eliminated in 187 KEGG human signaling pathways concerning intuitive biological rules and the Bayesian network structures were constructed. The constructed networks were simplified by the Least Absolute Shrinkage Selector Operator (LASSO), and their parameters were estimated using the gene expression data. We finally prioritize the impacted pathways by Fisher’s Exact Test on significant parameters. Our method integrates both edge and node related parameters to enrich modules in the affected signaling pathway network. In order to evaluate the proposed method, consistency, discrimination, false positive rate and empirical P-value criteria were calculated, and the results are compared to well-known enrichment methods such as signaling pathway impact analysis (SPIA), bi-level meta-analysis (BLMA) and topology-based pathway enrichment analysis (TPEA).

Availability

The R package is available oncarn.