bluuebunny/crossref_metadata_2025 huggingface dataset:
SEQdata-BEACON: a comprehensive database of sequencing performance and statistical tools for performance evaluation and yield simulation in BGISEQ-500
Authors: Zhou Yanqiu , Liu Chen , Zhou Rongfang , Lu Anzhi , Huang Biao , Liu Liling , Chen Ling , Luo Bei , Huang Jin , Tian Zhijian
Published: May 2019

Background

BGISEQ-500 is based on DNBSEQ™ technology and superior in providing high outputs and requiring less cost. This sequencer has been widely used in various areas of scientific and clinical research. A better understanding of the sequencing process and sequencer performance is essential for stabilizing sequencing process, accurately interpreting sequencing results and efficiently solving sequencing troubles. To solve these problems, a comprehensive database SEQdata-BEACON was constructed to accumulate sequencing performance data in BGISEQ-500.

Methods

Totally 60 BGISEQ-500 sequencers in BGI-Wuhan lab were used to collect the sequencing performance data. Those lanes in paired-end 100 sequencing using 10bp barcode were chosen, and each lane containing 66 metrics was assigned a unique entry number as ID. The database was constructed in MySQL server 8.0 and the website was built on Apache (2.4.33 win64 VC15 server). The statistical analysis and linear regression models were generated by R program based on the data from November 2018 to April 2019.

Results

A total of 2236 entries were recorded in the database, including sample ID, yield, quality, machine state and supplies information. According to correlation matrix, the 52 numerical metrics were clustered into three groups signifying yield-quality, machine state and sequencing calibration. The metrics distributions also delivered some patterns and rendered clues for further explanation or analysis of the sequencing process. Using the data of total 200 cycles, the linear regression model well simulated the final outputs. Moreover, the predicted final yield could be provided in the 15th cycle of the early stage of sequencing and the corresponding coefficient of determination R2 of the 200th and 15th cycle models were 0.97 and 0.81 respectively. The data source, statistical findings and application tools were all available in our website http://seqBEACON.genomics.cn:443/home.html. These resources can be used as a constantly updated reference for BGISEQ-500 users to comprehensively understand DNBSEQ™ technology, solve sequencing problems and optimize the sequencing process.
Genome sequence of the model rice variety KitaakeX
Authors: Jain Rashmi , Jenkins Jerry , Shu Shengqiang , Chern Mawsheng , Martin Joel A. , Copetti Dario , Duong Phat Q. , Pham Nikki T. , Kudrna David A. , Talag Jayson , Schackwitz Wendy S. , Lipzen Anna M. , Dilworth David , Bauer Diane , Grimwood Jane , Nelson Catherine R. , Xing Feng , Xie Weibo , Barry Kerrie W. , Wing Rod A. , Schmutz Jeremy , Li Guotian , Ronald Pamela C.
Published: May 2019

Here, we report the de novo genome sequencing and analysis of Oryza sativa ssp. japonica variety KitaakeX, a Kitaake plant carrying the rice XA21 immune receptor. Our KitaakeX sequence assembly contains 377.6 Mb, consisting of 33 scaffolds (476 contigs) with a contig N50 of 1.4 Mb. Complementing the assembly are detailed gene annotations of 35,594 protein coding genes. We identified 331,335 genomic variations between KitaakeX and Nipponbare (ssp. japonica), and 2,785,991 variations between KitaakeX and Zhenshan97 (ssp. indica). We also compared Kitaake resequencing reads to the KitaakeX assembly and identified 219 small variations. The high-quality genome of the model rice plant KitaakeX will accelerate rice functional genomics.
Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago
Authors: Tatara Eric , Gutfraind Alexander , Collier Nicholson T. , Echevarria Desarae , Cotler Scott J. , Major Marian , Ozik Jonathan , Dahari Harel , Boodram Basmattee
Published: May 2019

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and mortality worldwide. Direct-acting antiviral (DAA) therapy leads to high cure rates. However, persons who inject drugs (PWID) are at risk for reinfection after cure and may require multiple DAA treatments to reach the World Health Organization’s (WHO) goal of HCV elimination by 2030. Using an agent-based model (ABM) that accounts for the complex interplay of demographic factors, risk behaviors, social networks, and geographic location for HCV transmission among PWID, we examined the combination(s) of DAA enrollment (2.5%, 5%, 7.5%, 10%), adherence (60%, 70%, 80%, 90%) and frequency of DAA treatment courses needed to achieve the WHO’s goal of reducing incident chronic infections by 90% by 2030 among a large population of PWID from Chicago, IL and surrounding suburbs. We also estimated the economic DAA costs associated with each scenario. Our results indicate that a DAA treatment rate of >7.5% per year with 90% adherence results in 75% of enrolled PWID requiring only a single DAA course; however19% would require 2 courses, 5%, 3 courses and <2%, 4 courses), with an overall DAA cost of $325 million to achieve the WHO goal in metropolitan Chicago. We estimate a 28% increase in the overall DAA cost under low adherence (70%) compared to high adherence (90%). Our modeling results have important public health implications for HCV elimination among U.S. PWID. Using a range of feasible treatment enrollment and adherence rates, we report robust findings supporting the need to address re-exposure and reinfection among PWID to reduce HCV incidence.
Saving Old Bones: a non-destructive method for bone collagen prescreening
Authors: Sponheimer Matt , Ryder Christina M. , Fewlass Helen , Smith Erin K. , Pestle William J. , Talamo Sahra
Published: May 2019

Bone collagen is an important material for radiocarbon, paleodietary, and paleoproteomic analyses, but it degrades over time. Various methods have been employed to prescreen bone for collagen preservation, but these are often destructive and/or require exportation for analysis. Here we show that near-infrared spectroscopy can be used to determine bone collagen content quickly and non-destructively on site.r
New kinship andFSTestimates reveal higher levels of differentiation in the global human population
Authors: Ochoa Alejandro , Storey John D.
Published: May 2019

Kinship coefficients andFST, which measure genetic relatedness and the overall population structure, respectively, have important biomedical applications. However, existing estimators are only accurate under restrictive conditions that most natural population structures do not satisfy. We recently derived new kinship andFSTestimators for arbitrary population structures [1, 2]. Our estimates on human datasets reveal a complex population structure driven by founder effects due to dispersal from Africa and admixture. Notably, our new approach estimates largerFSTvalues of 26% for native worldwide human populations and 23% for admixed Hispanic individuals, whereas the existing approach estimates 9.8% and 2.6%, respectively. While previous work correctly measuredFSTbetween subpopulation pairs, our generalizedFSTmeasures genetic distances among all individuals and their most recent common ancestor (MRCA) population, revealing that genetic differentiation is greater than previously appreciated. This analysis demonstrates that estimating kinship andFSTunder more realistic assumptions is important for modern population genetic analysis.
Restored tactile sensation improves neuroprosthetic arm control
Authors: Flesher Sharlene N , Downey John E , Weiss Jeffrey M , Hughes Christopher L , Herrera Angelica J , Tyler-Kabara Elizabeth C , Boninger Michael L , Collinger Jennifer L , Gaunt Robert A
Published: May 2019

Summary paragraph

The sense of touch is critical for skillful hand control1–3, but is largely missing for people who use prosthetic devices. Instead, prosthesis users rely heavily on visual feedback, even though state transitions that are necessary to skillfully interact with objects, such as object contact, are relayed more precisely through tactile feedback4–6. Here we show that restoring tactile sensory feedback, through intracortical microstimulation of the somatosensory cortex7, enables a person with a bidirectional intracortical brain-computer interface to improve their performance on functional object transport tasks completed with a neurally-controlled prosthetic limb. The participant had full visual feedback and had practiced the task for approximately two years prior to these experiments. Nevertheless, successful trial times on a commonly used clinical upper limb assessment task were reduced from a median time of 20.9 s (13.1 - 40.5 s interquartile range) to 10.2 s (5.4 - 18.1 s interquartile range) when vision was supplemented with microstimulation-evoked cutaneous percepts that were referred to different fingers and were graded in intensity based on real-time prosthesis contact forces. Faster completion times were primarily due to a reduction in the amount of time spent attempting to grasp objects. These results demonstrate the importance of tactile sensations in upper-limb control and the utility of creating bidirectional brain-computer interfaces to restore this stream of information using intracortical microstimulation.
Intertwined Functions of Separase and Caspase in Cell Division and Programmed Cell Death
Authors: Jeong Pan-Young , Kumar Ashish , Joshi Pradeep , Rothman Joel H.
Published: May 2019

Timely sister chromatid separation, promoted by separase, is essential for faithful chromosome segregation. Separase is a member of the CD clan of cysteine proteases, which also includes the pro-apoptotic enzymes known as caspases. We report that theC. elegansseparase SEP-1, primarily known for its role in cell division, is required for apoptosis when the predominant pro-apoptotic caspase CED-3 is compromised. Loss of SEP-1 results in extra surviving cells in a weakced-3(−)mutant, and suppresses the embryonic lethality of a mutant defective for the apoptotic suppressorced-9/Bcl-2. We also report apparent non-apoptotic roles for CED-3 in promoting germ cell proliferation and germline meiotic chromosome disjunction and the normal rate of embryonic development. Moreover, loss of the soma-specific (CSP-3) and germline-specific (CSP-2) caspase inhibitors results in CED-3-dependent suppression of embryonic lethality and meiotic chromosome non-disjunction respectively, when separase function is compromised. Thus, while caspases and separases have evolved different substrate specificities associated with their specialized functions in apoptosis and cell division respectively, they appear to have retained the residual ability to participate in both processes, supporting the view that co-option of components in cell division may have led to the innovation of programmed cell suicide early in metazoan evolution.
A protein-centric approach for exome variant aggregation enables sensitive association analysis with clinical outcomes
Authors: Li Ginny X.L. , Munro Dan , Fermin Damian , Vogel Christine , Choi Hyungwon
Published: May 2019

Somatic mutations are early drivers of tumorigenesis and tumor progression. However, the mutations typically occur at variable positions across different individuals, resulting in the data being too sparse to test meaningful associations between variants and phenotypes. To overcome this challenge, we devised a novel approach called Gene-to-Protein-to-Disease (GPD) which accumulates variants into new sequence units as the degree of genetic assault on structural or functional units of each protein. The variant frequencies in the sequence units were highly reproducible between two large cancer cohorts. Survival analysis identified 247 sequence units in which somatic mutations had deleterious effects on overall survival, including consensus driver mutations obtained from multiple calling algorithms. By contrast, around 75% of the survival predictive units had been undetected by conventional gene-level analysis. We demonstrate the ability of these signatures to separate patient groups according to overall survival, therefore providing novel prognostic tools for various cancers. GPD also identified sequence units with somatic mutations whose impact on survival was modified by the occupancy of germline variants in the surrounding regions. The findings indicate that a patient’s genetic predisposition interacts with the effect of somatic mutations on survival outcome in some cancers.
Ventral Pallidum is Essential for Cocaine Reinstatement After Voluntary Abstinence
Authors: Farrell Mitchell R. , Ruiz Christina M. , Castillo Erik , Faget Lauren , Khanbijian Christine , Liu Siyu , Schoch Hannah , Rojas Gerardo , Hnasko Thomas S. , Mahler Stephen V.
Published: May 2019

Addiction is a chronic relapsing disorder, and during recovery many people experience several relapse events as they attempt to voluntarily abstain from drug. New preclinical relapse models have emerged which capture this common human experience of relapse after voluntary abstinence, and mounting evidence indicates that reinstatement of drug seeking after voluntary abstinence recruits neural circuits distinct from reinstatement following experimenter-imposed abstinence, or abstinence due to extinction training. Ventral pallidum (VP), a key limbic node involved in drug seeking, has well-established roles in conventional reinstatement models tested following extinction training, but it is unclear whether this region also participates in more translationally-relevant models of relapse. Here we show that chemogenetic inhibition of VP neurons strongly attenuates cocaine-, context-, and cue-induced reinstatement tested after voluntary, punishment-induced abstinence. This effect was strongest in the most compulsive, punishment-resistant rats, and reinstatement was associated with neural activity in anatomically-defined VP subregions. VP inhibition also attenuated the propensity of rats to display ‘hesitations,’ a risk assessment behavior seen during punished drug taking that is likely due to concurrent approach and avoidance motivations. These results indicate that VP, unlike other connected limbic brain regions, is essential for reinstatement of drug seeking after voluntary abstinence. Since VP inhibition effects were strongest in the most compulsively cocaine-seeking individuals, this could indicate that VP plays a particularly important role in the most pathological, addiction-like behavior, making it an attractive target for future therapeutic interventions.
Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis
Authors: Walsh Carolyn M. , Hill Rose Z. , Schwendinger-Schreck Jamie , Deguine Jacques , Brock Emily C. , Kucirek Natalie , Rifi Ziad , Wei Jessica , Gronert Karsten , Brem Rachel B. , Barton Gregory M. , Bautista Diana M.
Published: May 2019

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.
Multi-ethnic genome-wide association study of decomposed cardioelectric phenotypes illustrates strategies to identify and characterize evidence of shared genetic effects for complex traits
Authors: Baldassari Antoine R. , Sitlani Colleen M. , Highland Heather M. , Arking Dan E. , Buyske Steve , Darbar Dawood , Gondalia Rahul , Graff Misa , Guo Xiuqing , Heckbert Susan R. , Hindorff Lucia A. , Hodonsky Chani J. , Ida Chen Yii-Der , Kaplan Robert C. , Peters Ulrike , Post Wendy , Reiner Alex P. , Rotter Jerome I. , Shohet Ralph V. , Seyerle Amanda A. , Sotoodehnia Nona , Tao Ran , Taylor Kent D. , Wojcik Genevieve L , Yao Jie , Kenny Eimear E. , Lin Henry J. , Soliman Elsayed Z. , Whitsel Eric A. , North Kari E. , Kooperberg Charles , Avery Christy L.
Published: May 2019

Background

Published genome-wide association studies (GWAS) are mainly European-centric, examine a narrow view of phenotypic variation, and infrequently interrogate genetic effects shared across traits. We therefore examined the extent to which a multi-ethnic, combined trait GWAS of phenotypes that map to well-defined biology can enable detection and characterization of complex trait loci.

Methods

With 1000 Genomes Phase 3 imputed data in 34,668 participants (15% African American; 3% Chinese American; 51% European American; 30% Hispanic/Latino), we performed covariate-adjusted univariate GWAS of six contiguous electrocardiogram (ECG) traits that decomposed an average heartbeat and two commonly reported composite ECG traits that summed contiguous traits. Combined phenotype testing was performed using the adaptive sum of powered scores test (aSPU).

Results

We identified six novel and 87 known ECG trait loci (aSPU p-value < 5E-9). Lead SNP rs3211938 at novel locus CD36 was common in African Americans (minor allele frequency=10%) and near-monomorphic in European Americans, with effect sizes for the composite trait, QT interval, among the largest reported. Only one novel locus was detected for the composite traits, due to opposite directions of effects across contiguous traits that summed to near-zero. Combined phenotype testing did not detect novel loci unapparent by univariate testing. However, this approach aided locus characterization, particularly when loci harbored multiple independent signals that differed by trait.

Conclusions

Despite including one-third as few participants as the largest published GWAS of ECG traits, our study identifies multiple novel ECG genetic loci, emphasizing the importance of ancestral diversity and phenotype measurement in this era of ever-growing GWAS.

AUTHOR SUMMARY

We leveraged a multiethnic cohort with precise measures of cardioelectric function to identify novel genetic loci affecting this complex, multifaceted phenotype. The success of our approach stresses the importance of phenotypic precision and participant diversity for future locus discovery and characterization efforts, and cautions against compromises made in genome-wide association studies to pursue ever-growing sample sizes.
HBV seroepidemiology data for Africa provides insights into transmission and prevention
Authors: McNaughton Anna L , Lourenço José , Bester Phillip Armand , Mokaya Jolynne , Lumley Sheila F , Forde Donall , Maponga Tongai G , Katumba Kenneth R , Goedhals Dominique , Gupta Sunetra , Seeley Janet , Newton Robert , Ocama Ponsiano , Matthews Philippa C
Published: May 2019

International goals for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In many African populations, HBV prevalence remains high (≥8%) despite the roll-out of infant HBV immunisation from the mid-1990’s onwards. Enhanced efforts are now urgently required to improve an understanding of population epidemiology, in order to determine which interventions are most likely to be effective in advancing populations towards elimination goals. In populations with a high prevalence of infection, catch-up HBV vaccination of adults has sometimes been deployed as a preventive strategy. An alternative approach of ‘test and treat’ could be applied as a tool to interrupt transmission. We used a systematic approach to investigate the relationship between prevalence of HBV infection (HBsAg) and exposure (anti-HBc) in Africa, and then applied a mathematical model to investigate the impact of catch-up vaccination and a ‘test and treat’ strategy in Uganda, representing a high prevalence setting. We demonstrate a strong relationship between the prevalence of HBsAg and anti-HBc (p<0.0001), but with region-specific differences that may reflect different patterns of transmission. In high prevalence settings, catch-up vaccination may have a transient effect but this intervention does not contribute to a sustained decline in prevalence. In contrast, diagnosing and treating infection has a marked impact on reducing prevalence, equivalent to that of infant immunisation. Conclusion: We have developed a high-resolution picture of HBV epidemiology across Africa. Developing insights into regional differences provides an evidence base for the most effective interventions. In combination with robust neonatal immunisation programmes, testing and treating infection is likely to be of most impact in making advances towards elimination targets.
Predicting spread and effective control measures for African swine fever– should we blame the boars?
Authors: Taylor Rachel A. , Podgórski Tomasz , Simons Robin R. L. , Ip Sophie , Gale Paul , Kelly Louise A. , Snary Emma L.
Published: May 2019

African swine fever (ASF) has been causing multiple outbreaks in Russia, Poland and the Baltic countries in recent years and is currently spreading westwards throughout Europe and eastwards into China, with cases occurring in wild boar and domestic pigs. Curtailing further spread of ASF requires full understanding of the transmission pathways of the disease. Wild boars have been implicated as a potential reservoir for the disease and one of the main modes of transmission within Europe. We developed a spatially explicit model to estimate the risk of infection with ASF in boar and pigs due to the natural movement of wild boar that is applicable across the whole of Europe. We demonstrate the model by using it to predict the probability that early cases of ASF in Poland were caused by wild boar dispersion. The risk of infection in 2015 is computed due to wild boar cases in Poland in 2014, compared against the reported cases in 2015 and then the procedure is repeated for 2015-2016. We find that long- and medium-distance spread of ASF (i.e. >30km) is very unlikely to have occurred due to boar dispersal, due in part to the generally short distances boar will travel (<20km on average). We also predict what the relative success of different control strategies would have been in 2015, if they were implemented in 2014. Results suggest that hunting of boar reduces the number of new cases, but a larger region is at risk of ASF compared to no control measure. Alternatively, introducing boar-proof fencing reduces the size of the region at risk in 2015, but not the total number of cases. Overall, our model suggests wild boar movement is only responsible for local transmission of disease, thus other pathways are more dominant in medium and long distance spread of the disease.
Sensitive detection of circular DNAs at single-nucleotide resolution using guided realignment of partially aligned reads
Authors: Prada-Luengo Iñigo , Krogh Anders , Maretty Lasse , Regenberg Birgitte
Published: May 2019

Circular DNA has recently been identified across different species including human normal and cancerous tissue, but short-read mappers are unable to align many of the reads crossing circle junctions and hence limits their detection from short-read sequencing data. Here, we propose a new method, Circle-Map, that guides the realignment of partially aligned reads using information from discordantly mapped reads. We demonstrate how this approach dramatically increases sensitivity for detection of circular DNA on both simulated and real data while retaining high precision.
The Avocado Genome Informs Deep Angiosperm Phylogeny, Highlights Introgressive Hybridization, and Reveals Pathogen-Influenced Gene Space Adaptation
Authors: Rendón-Anaya Martha , Ibarra-Laclette Enrique , Méndez Bravo Alfonso , Lan Tianying , Zheng Chunfang , Carretero-Paulet Lorenzo , Perez-Torres Claudia Anahí , Chacón-López Alejandra , Hernandez-Guzmán Gustavo , Chang Tien-Hao , Farr Kimberly M. , Barbazuk W. Brad , Chamala Srikar , Mutwil Marek , Shivhare Devendra , Alvarez-Ponce David , Mitter Neena , Hayward Alice , Fletcher Stephen , Rozas Julio , Sánchez Gracia Alejandro , Kuhn David , Barrientos-Priego Alejandro F. , Salojärvi Jarkko , Librado Pablo , Sankoff David , Herrera-Estrella Alfredo , Albert Victor A. , Herrera-Estrella Luis
Published: May 2019

The avocado,Persea americana, is a fruit crop of immense importance to Mexican agriculture with an increasing demand worldwide. Avocado lies in the anciently-diverged magnoliid clade of angiosperms, which has a controversial phylogenetic position relative to eudicots and monocots. We sequenced the nuclear genomes of the Mexican avocado race,P. americanavar.drymifolia, and the most commercially popular hybrid cultivar, Hass, and anchored the latter to chromosomes using a genetic map. Resequencing of Guatemalan and West Indian varieties revealed that ∼39% of the Hass genome represents Guatemalan source regions introgressed into a Mexican race background. Some introgressed blocks are extremely large, consistent with the recent origin of the cultivar. The avocado lineage experienced two lineage-specific polyploidy events during its evolutionary history. Although gene-tree/species-tree phylogenomic results are inconclusive, syntenic ortholog distances to other species place avocado as sister to the enormous monocot and eudicot lineages combined. Duplicate genes descending from polyploidy augmented the transcription factor diversity of avocado, while tandem duplicates enhanced the secondary metabolism of the species. Phenylpropanoid biosynthesis, known to be elicited byColletotrichum(anthracnose) pathogen infection in avocado, is one enriched function among tandems. Furthermore, transcriptome data show that tandem duplicates are significantly up- and down-regulated in response to anthracnose infection, whereas polyploid duplicates are not, supporting the general view that collections of tandem duplicates contribute evolutionarily recent “tuning knobs” in the genome adaptive landscapes of given species.

SIGNIFICANCE STATEMENT

Avocado is a nutritious, economically important fruit species that occupies an unresolved position near the earliest evolutionary branchings of flowering plants. Our nuclear genome sequences of Mexican and Hass variety avocados inform ancient evolutionary relationships and genome doublings, the admixed nature of Hass, and provide a look at how pathogen interactions have shaped avocado’s more recent genomic evolutionary history.
Hepatitis C Virus Regulates its Replication by Maturing miR-122 Through Akt-Dependent Phosphorylation of KSRP
Authors: Baudesson Camille , Amadori Céline , Danso Hassan , Donati Flora , Nevers Quentin , Durand Tony , Lemasson Matthieu , Rosenberg Arielle R. , Trabucchi Michele , Ahmed-Belkacem Abdelhakim , Bruscella Patrice , Pawlotsky Jean-Michel , Féray Cyrille
Published: May 2019

The liver-specific micro-RNA-122 (miR-122) is required for the replication of hepatitis C virus (HCV). The direct interaction between miR-122 and the 5’ untranslated region of the HCV genome promotes viral replication and protects HCV RNA from degradation. Because HCV RNA is its own substrate for replication, infected cells are submitted to the sequestration of increasing levels of miR-122 and to global de-repression of host miR-122 mRNA targets. Whether and how HCV regulates miR-122 maturation to create an environment favorable to its replication remains unexplored. We discovered that Akt-dependent phosphorylation of KSRP host protein at Serine residue 193 is essential for miR-122 maturation in hepatocytes. Moreover, we showed the existence of a reciprocal regulation loop where HCV replication can modulate the proviral effect mediated by KSRP-dependent maturation of miR-122. These data support a mechanism by which HCV regulates the expression of miR-122 by hijacking KSRP, thereby fueling its own replication.
Mitonuclear interactions influence Alzheimer’s disease risk
Authors: Andrews Shea J , Fulton-Howard Brian , Patterson Christopher , McFall G Peggy , Gross Alden , Michaelis Elias K , Goate Alison , Swerdlow Russell H , Pa Judy ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: May 2019

We examined the associations between mitochondrial DNA haplogroups (MT-hg) and their interactions with a polygenic risk score based on nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset of dementia (AOO). Logistic regression was used to determine the effect of MT-hgs and nMT-PRS on dementia at baseline (332 controls / 204 cases). Cox proportional hazards models were used to model dementia AOO (n=1047; 433 incident cases). Additionally, we tested for interactions between MT-hg and nMT-PRS in the logistic and Cox models. MT-hg K and a one SD larger nMT-PRS were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K and T were observed. Individual MT-hg were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T and a synergistic interaction between the nMT-PRS and MT-hg V. These results suggest that MT-hgs influence dementia risk, and that variants in the nuclear and mitochondrial genome interact to influence the age of onset of dementia.

Highlights

Mitochondrial dysfunction has been proposed to influence dementia risk

MT-hg K and T interacted with a genetic risk score to reduce dementia risk

MT-hg T and V interacted with a genetic risk score to influence dementia age of onset
Neglectful maternal caregiving involves altered brain plasticity in empathy-related areas
Authors: Rodrigo María José , León Inmaculada , García Lorna , Hernández-Cabrera Juan Andrés , Quiñones Ileana
Published: May 2019

The maternal brain undergoes functional and structural adaptations to sensitive caregiving that are critical for ensuring infant wellbeing. This study investigates brain structural alterations in neglectful caregiving and their impact on mother-child interactive behavior. High-resolution 3D volumetric images were obtained on 25 neglectful (NM) and 23 non-neglectful control (CM) mothers. Using Voxel-Based Morphometry, we compared gray and white matter volume (GMV/WMV) between the two groups. Mothers also completed an empathy scale and participated with their children in a standardized play task (Emotional Availability Scale, EA). NM, as compared to CM, showed GMV reductions in right insula, anterior/middle cingulate, and right inferior frontal gyrus (IFG), as well as WMV reductions in bilateral frontal regions. A GMV increase was observed in the right fusiform and cerebellum. Regression analyses showed a negative effect of fusiform GMV and a positive effect of right frontal WMV on EA Mediation analyses showed the mediating role of emotional empathy in the positive effect of insula and IFG, and the negative effect of cerebellum on EA. Neglectful mothering involves an altered plasticity in emotional empathy-related areas and in frontal areas associated with poor mother-child interactive bonding, indicating how critical the structural changes in these areas are for infant wellbeing.
The Impact of Pathway Database Choice on Statistical Enrichment Analysis and Predictive Modeling
Authors: Mubeen Sarah , Hoyt Charles Tapley , Gemünd Andre , Hofmann-Apitius Martin , Fröhlich Holger , Domingo-Fernández Daniel
Published: May 2019

Background

Pathway-centric approaches are widely used to interpret and contextualize -omicsdata. However, databases contain different representations of the same biological pathway, which may lead to different results of statistical enrichment analysis and predictive models in the context of precision medicine.

Results

We have performed an in-depth benchmarking of the impact of pathway database choice on statistical enrichment analysis and predictive modeling. We analyzed five cancer datasets using three major pathway databases and developed an approach to merge several databases into a single integrative database: MPath. Our results show that equivalent pathways from different databases yield disparate results in statistical enrichment analysis. Moreover, we observed a significant dataset-dependent impact on performance of machine learning models on different prediction tasks. Further, MPath significantly improved prediction performance and reduced the variance of prediction performances in some cases. At the same time, MPath yielded more consistent and biologically plausible results in the statistical enrichment analyses. Finally, we implemented a software package designed to make our comparative analysis with these and additional databases fully reproducible and to facilitate the update of our integrative pathway resource in the future.

Conclusion

This benchmarking study demonstrates that pathway database choice can influence the results of statistical enrichment analysis and prediction modeling. Therefore, we recommend the use of multiple pathway databases or the use of integrative databases.
MolNetEnhancer: enhanced molecular networks by integrating metabolome mining and annotation tools
Authors: Ernst Madeleine , Kang Kyo Bin , Caraballo-Rodríguez Andrés Mauricio , Nothias Louis-Felix , Wandy Joe , Wang Mingxun , Rogers Simon , Medema Marnix H. , Dorrestein Pieter C. , van der Hooft Justin J.J.
Published: May 2019

Metabolomics has started to embrace computational approaches for chemical interpretation of large data sets. Yet, metabolite annotation remains a key challenge. Recently, molecular networking and MS2LDA emerged as molecular mining tools that find molecular families and substructures in mass spectrometry fragmentation data. Moreover, in silico annotation tools obtain and rank candidate molecules for fragmentation spectra. Ideally, all structural information obtained and inferred from these computational tools could be combined to increase the resulting chemical insight one can obtain from a data set. However, integration is currently hampered as each tool has its own output format and efficient matching of data across these tools is lacking. Here, we introduce MolNetEnhancer, a workflow that combines the outputs from molecular networking, MS2LDA, in silico annotation tools (such as Network Annotation Propagation or DEREPLICATOR) and the automated chemical classification through ClassyFire to provide a more comprehensive chemical overview of metabolomics data whilst at the same time illuminating structural details for each fragmentation spectrum. We present examples from four plant and bacterial case studies and show how MolNetEnhancer enables the chemical annotation, visualization, and discovery of the subtle substructural diversity within molecular families. We conclude that MolNetEnhancer is a useful tool that greatly assists the metabolomics researcher in deciphering the metabolome through combination of multiple independent in silico pipelines.
Reverse engineering neural networks to characterise their cost functions
Authors: Isomura Takuya , Friston Karl
Published: May 2019

This work considers a class of biologically plausible cost functions for neural networks, where the same cost function is minimised by both neural activity and plasticity. We show that such cost functions can be cast as a variational bound on model evidence under an implicit generative model. Using generative models based on Markov decision processes (MDP), we show, analytically, that neural activity and plasticity perform Bayesian inference and learning, respectively, by maximising model evidence. Using mathematical and numerical analyses, we then confirm that biologically plausible cost functions—used in neural networks—correspond to variational free energy under some prior beliefs about the prevalence of latent states that generate inputs. These prior beliefs are determined by particular constants (i.e., thresholds) that define the cost function. This means that the Bayes optimal encoding of latent or hidden states is achieved when, and only when, the network’s implicit priors match the process that generates the inputs. Our results suggest that when a neural network minimises its cost function, it is implicitly minimising variational free energy under optimal or sub-optimal prior beliefs. This insight is potentially important because it suggests that any free parameter of a neural network’s cost function can itself be optimised—by minimisation with respect to variational free energy.
PPPred: Classifying Protein-phenotype Co-mentions Extracted from Biomedical Literature
Authors: Shahri Morteza Pourreza , Roe Mandi M. , Reynolds Gillian , Kahanda Indika
Published: May 2019

The MEDLINE database provides an extensive source of scientific articles and heterogeneous biomedical information in the form of unstructured text. One of the most important knowledge present within articles are the relations between human proteins and their phenotypes, which can stay hidden due to the exponential growth of publications. This has presented a range of opportunities for the development of computational methods to extract these biomedical relations from the articles. However, currently, no such method exists for the automated extraction of relations involving human proteins and human phenotype ontology (HPO) terms. In our previous work, we developed a comprehensive database composed of all co-mentions of proteins and phenotypes. In this study, we present a supervised machine learning approach called PPPred (Protein-Phenotype Predictor) for classifying the validity of a given sentence-level co-mention. Using an in-house developed gold standard dataset, we demonstrate that PPPred significantly outperforms several baseline methods. This two-step approach of co-mention extraction and classification constitutes a complete biomedical relation extraction pipeline for extracting protein-phenotype relations.

CCS CONCEPTS

•Computing methodologies → Information extraction; Supervised learning by classification; •Applied computing →Bioinformatics;
A deletion in theSTA1promoter determines maltotriose and starch utilization inSTA1+Saccharomyces cerevisiaestrains
Authors: Krogerus Kristoffer , Magalhães Frederico , Kuivanen Joosu , Gibson Brian
Published: May 2019

Diastatic strains ofSaccharomyces cerevisiaeare common contaminants in beer fermentations and are capable of producing an extracellularSTA1-encoded glucoamylase. Recent studies have revealed variable diastatic ability in strains tested positive forSTA1,and here we elucidate genetic determinants behind this variation. We show that poorly diastatic strains have a 1162 bp deletion in the promoter ofSTA1. With CRISPR/Cas9-aided reverse engineering, we show that this deletion greatly decreases the ability to grow in beer and consume dextrin, and the expression ofSTA1. New PCR primers were designed for differentiation of highly and poorly diastatic strains based on the presence of the deletion in theSTA1promoter. In addition, using publically available whole genome sequence data, we show that theSTA1gene is prevalent in among the ‘Beer 2’/’Mosaic Beer’ brewing strains. These strains utilize maltotriose efficiently, but the mechanisms for this have been unknown. By deletingSTA1from a number of highly diastatic strains, we show here that extracellular hydrolysis of maltotriose throughSTA1appears to be the dominant mechanism enabling maltotriose use during wort fermentation inSTA1+strains. The formation and retention ofSTA1seems to be an alternative evolutionary strategy for efficient utilization of sugars present in brewer’s wort. The results of this study allow for the improved reliability of molecular detection methods for diastatic contaminants in beer, and can be exploited for strain development where maltotriose use is desired.
Tissue Engineered Axon Tracts Serve as Living Scaffolds to Accelerate Axonal Regeneration and Functional Recovery Following Peripheral Nerve Injury in Rats
Authors: Katiyar Kritika S. , Struzyna Laura A. , Morand Joseph P. , Burrell Justin C. , Clements Basak , Laimo Franco A. , Browne Kevin D. , Kohn Joachim , Ali Zarina , Ledebur Harry C. , Smith Douglas H. , Cullen D. Kacy
Published: May 2019

Although regeneration of damaged axons in peripheral nerves has long been observed, the mechanisms facilitating this growth are not well characterized. Recently, we demonstrated that host axon regeneration could be greatly enhanced by transplanting engineered living axon tracts to guide outgrowth. Here, we used a model of rat sciatic nerve transection to explore potential mechanisms of this facilitated regeneration and its efficacy in comparison with nerve guidance tubes (NGTs) and autografts. Tissue engineered nerve grafts (TENGs) were developed via “stretch-growth” in mechanobioreactors and consisted of centimeter-scale aligned axonal tracts. Either TENGs, NGTs or autografts (reversed nerve) were then transplanted to bridge a 1 cm segmental gap in the sciatic nerve with the mechanisms of axonal regrowth assessed at 2 weeks and the extent of functional recovery assessed at 16 weeks. We observed numerous host axons growing directly along and intertwining with pre-formed axonal tracts in TENGs. This behavior appears to mimic the action of “pioneer” axons in developmental pathfinding by providing living cues for directed and accelerated outgrowth. Indeed, we found that the rates of axon regeneration were 3-4 fold faster than NGTs and equivalent to autografts. It was also observed that infiltration of host Schwann cells – traditional drivers of peripheral axon regeneration – was both accelerated and progressed directly along TENG axonal tracts. These TENG repairs resulted in levels of functional recovery equivalent to autografts, with each being several fold superior to NGT repairs. This new mechanism – which we term “axon-facilitated axon-regeneration” – may be further exploited to enhance axonal regeneration and functional recovery following neurotrauma.
Brain-synthesized estrogens regulate cortical migration in a sexually divergent manner
Authors: Sellers Katherine J. , Denley Matthew C.S. , Saito Atsushi , Kamiya Atsushi , Srivastava Deepak P.
Published: May 2019

Estrogens play an important role in the sexual dimorphisms that occur during brain development, including the neural circuitry that underlies sex-typical and socio-aggressive behaviors. Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is expressed at high levels during early development in both male and female cortices, suggesting a role for brain-synthesized estrogens during corticogenesis. This study investigated how the local synthesis of estrogens affects neurodevelopment of the cerebral cortex, and how this differs in males and females by knockdown expression of the Cyp19a1 gene, which encodes aromatase, between embryonic day 14.5 and postnatal day 0 (P0). The effects of Cyp19a1 knockdown on neural migration was then assessed. Aromatase was expressed in the developing cortex of both sexes, but at significantly higher levels in male than female mice. Under basal conditions, no obvious differences in cortical migration between male and female mice were observed. However, knockdown of Cyp19a1 increased the number GFP-positive cells in the cortical plate, with a concurrent decrease in the subventricular zone/ventricular zone in P0 male mice. The opposite effect was observed in females, with a significantly reduced number of GFP-positive cells migrating to the cortical plate. These findings have important implications for our understanding of the role of fetal steroids for neuronal migration during cerebral cortex development. Moreover, these data indicate that brain-synthesized estrogens regulate radial migration through distinct mechanisms in males and females.
Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection
Authors: Kazer Samuel W. , Aicher Toby P. , Muema Daniel M. , Carroll Shaina L. , Ordovas-Montanes Jose , Ziegler Carly G. K. , Nyquist Sarah K. , Wong Emily B. , Ismail Nasreen , Dong Mary , Moodley Amber , Dong Krista L. , Ndhlovu Zaza M. , Ndung’u Thumbi , Walker Bruce D. , Shalek Alex K.
Published: May 2019

Cellular immunity is critical for controlling intracellular pathogens, but the dynamics and cooperativity of the evolving host response to infection are not well defined. Here, we apply single-cell RNA-sequencing to longitudinally profile pre- and immediately post-HIV infection peripheral immune responses of multiple cell types in four untreated individuals. Onset of viremia induces a strong transcriptional interferon response integrated across most cell types, with subsequent pro-inflammatory T cell differentiation, monocyte MHC-II upregulation, and cytolytic killing. With longitudinal sampling, we nominate key intra- and extracellular drivers that induce these programs, and assign their multi-cellular targets, temporal ordering, and duration in acute infection. Two individuals studied developed spontaneous viral control, associated with initial elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated proliferating natural killer (NK) cell subset. Our study presents a unified framework for characterizing immune evolution during a persistent human viral infection at single-cell resolution, and highlights programs that may drive response coordination and influence clinical trajectory.
Codon Pairs are Phylogenetically Conserved: Codon pairing as a new class of phylogenetic characters
Authors: Miller Justin B. , McKinnon Lauren M. , Whiting Michael F. , Ridge Perry G.
Published: May 2019

Identical codon pairing and co-tRNA codon pairing increase translational efficiency within genes when two codons that encode the same amino acid are located within a ribosomal window. By examining both identical and co-tRNA codon pairing across 23 423 species, we determined that both pairing techniques are phylogenetically informative across all domains of life using either an alignment-free or parsimony framework. We also determined that conserved codon pairing typically has a smaller window size than the length of a ribosome. We also analyzed frequencies of codon pairing for each codon to determine which codons are most likely to pair. The alignment-free method does not require orthologous gene annotations and recovers species relationships that are comparable to other alignment-free techniques. Parsimony generally recovers phylogenies that are more congruent with the established phylogenies than the alignment-free method. However, four of the ten taxonomic groups do not have sufficient ortholog annotations and are therefore recoverable using only the alignment-free methods. Since the recovered phylogenies using only codon pairing largely match established phylogenies and are comparable to other algorithms, we propose that codon pairing biases are phylogenetically conserved and should be considered in conjunction with current techniques in future phylogenomic studies. Furthermore, the phylogenetic conservation of codon pairing indicates that codon pairing plays a greater role in the speciation process than previously acknowledged.

Availability

All scripts used to recover and compare phylogenies, including documentation and test files, are freely available on GitHub athttps://github.com/ridgelab/codon_pairing.