bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of early murine leukemia virus titer and H-2 type with spontaneous leukemia in mice of the BALB/c times AKR cross: a genetic analysis.
Authors: Lilly F , Duran-Reynals M L , Rowe W P
Published: May 2018

Tissue extracts from 6-wk old mice of the AKR strain (H-K) show high levels of infectious murine leukemia virus, and these mice show a near 100% incidence of spontaneous leukemia. In F1 mice of the cross, BALB/c times AKR (H-2K/H-2K), both the occurrence of virus and the incidence of spontaneous leukemia are suppressed to very low values, due largely to the presence of the FV-1b allele inherited from the BALB/c parent. Mice of the (BALB/c times AKR) F-1 times AKR backcross generation were observed for possible correlations between virus expressions at 6 wk of age, H-2 type and leukemia incidence. H-2 type showed at most a weak influence on the occurrence of infectious virus, but there was a very strong correlation between the level of virus expression and the occurrence of leukemia and a strong correlation between H-2 type and leukemia. In addition, there was a highly significant nonrandom distribution of virus-negative mice among the backcross litters, suggesting a maternal effect on virus expression.
Elevated ribonuclease activity in the thymus and white blood cells of genetically cancer prone mice.
Authors: Drake W P , Pokorney D R , Chipman S , Levy C C , Mardiney M R
Published: May 2018

Ribonuclease activity in cell-free thymus homogenates was elevated for five strains of mice genetically predisposed toward leukemia or reticulum cell neoplasms (AKR, C58, PL, RF, and SJL). Such increased activity was directed against polyuridylic acid and was observed in 8-wk old mice, well before the onset of neoplastic transformation. Similarly, white blood cell ribonuclease activity was elevated in mice of the strains AKR, C2H/He, PL and RF. Statistical analysis indicated that such elevated activity in these strains related to their high incidence of spontaneous neoplastic disease. Elevated ribonuclease activity thus represents a new biochemical marker relating to the genetic propensity of some strains of mice to die prematurely of spontaneous neoplasia.
Evaluation of mutant muscle Ca2+ channel properties using two different expression systems
Authors: Allard Bruno
Published: May 2018

Allard appraises recent studies investigating the pathological mechanism of hypokalemic periodic paralysis mutations.
Sustainable development goals as the basis of university management towards global competitiveness
Authors: Utama Yos Johan , Ambariyanto Ambariyanto , Zainuri Muhammad , Darsono Darsono , Setyono Budi , Widowati  , Putro Sapto Purnomo
Published: May 2018

Sustainable Development Goals are international agreements of many countries under UN initiation that have certain goals and targets. Achieving these goals and targets of the SDG requires a broad and focused effort from various sectors including higher education. Some of the goals associated with higher education are education, sanitation, innovation and global partnership. Given that higher education is one of the main drivers of the progress of a country, it gives university opportunities to play a bigger role. In addition, the rapid development and changes that occur today also require universities to respond quickly and appropriately. This can be done by developing university management based on the principle of SDG. This paper provides a brief description of the strategies that higher education institutions can take, particularly in responding to the changing world and in achieving the target of the SDGs. Five strategis for the university to encourage faster achievement of the targeted SDGs are proposed, i.e. Improvement of higher education quality, improvement of higher education equity, improvement of sanitarian and environment, improvement of research and innovation, and global partnership.
Axe: rapid, competitive sequence read demultiplexing using a trie
Authors: Murray Kevin D , Borevitz Justin O
Published: May 2018

We describe a rapid algorithm for demultiplexing DNA sequence reads with in-read indices. Axe selects the optimal index present in a sequence read, even in the presence of sequencing errors. The algorithm is able to handle combinatorial indexing, indices of differing length and several mismatches per index sequence.

Availability and implementation

Axe is implemented in C, and is used as a command-line program on Unix-like systems. Axe is available online at https://github.com/kdmurray91/axe, and is available in Debian/Ubuntu distributions of GNU/Linux as the package axe-demultiplexer.

Supplementary information

Supplementary data are available at Bioinformatics online
PREQUAL: detecting non-homologous characters in sets of unaligned homologous sequences
Authors: Whelan Simon , Irisarri Iker , Burki Fabien
Published: May 2018

Phylogenomic datasets invariably contain undetected stretches of non-homologous characters due to poor-quality sequences or erroneous gene models. The large-scale multi-gene nature of these datasets renders impractical or impossible detailed manual curation of sequences, but few tools exist that can automate this task. To address this issue, we developed a new method that takes as input a set of unaligned homologous sequences and uses an explicit probabilistic approach to identify and mask regions with non-homologous adjacent characters. These regions are defined as sharing no statistical support for homology with any other sequence in the set, which can result from e.g. sequencing errors or gene prediction errors creating frameshifts. Our methodology is implemented in the program PREQUAL, which is a fast and accurate tool for high-throughput filtering of sequences. The program is primarily aimed at amino acid sequences, although it can handle protein coding DNA sequences as well. It is fully customizable to allow fine-tuning of the filtering sensitivity.

Availability and implementation

The program PREQUAL is written in C/C++ and available through a GNU GPL v3.0 at https://github.com/simonwhelan/prequal.

Supplementary information

Supplementary data are available at Bioinformatics online.
Lost in translation: bioinformatic analysis of variations affecting the translation initiation codon in the human genome
Authors: Abad-Navarro Francisco , de la Morena-Barrio María Eugenia , Fernández-Breis Jesualdo Tomás , Corral Javier
Published: May 2018

Motivation

Translation is a key biological process controlled in eukaryotes by the initiation AUG codon. Variations affecting this codon may have pathological consequences by disturbing the correct initiation of translation. Unfortunately, there is no systematic study describing these variations in the human genome. Moreover, we aimed to develop new tools for in silico prediction of the pathogenicity of gene variations affecting AUG codons, because to date, these gene defects have been wrongly classified as missense.

Results

Whole-exome analysis revealed the mean of 12 gene variations per person affecting initiation codons, mostly with high (>0.01) minor allele frequency (MAF). Moreover, analysis of Ensembl data (December 2017) revealed 11 261 genetic variations affecting the initiation AUG codon of 7205 genes. Most of these variations (99.5%) have low or unknown MAF, probably reflecting deleterious consequences. Only 62 variations had high MAF. Genetic variations with high MAF had closer alternative AUG downstream codons than did those with low MAF. Besides, the high-MAF group better maintained both the signal peptide and reading frame. These differentiating elements could help to determine the pathogenicity of this kind of variation.

Availability and implementation

Data and scripts in Perl and R are freely available at https://github.com/fanavarro/hemodonacion.

Supplementary information

Supplementary data are available at Bioinformatics online.
Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions
Authors: Lionakis Michail S , Lewis Russell E , Kontoyiannis Dimitrios P
Published: May 2018

Although the widespread use of mold-active agents (especially the new generation of triazoles) has resulted in reductions of documented invasive mold infections (IMIs) in patients with hematological malignancies and allogeneic hematopoietic stem cell transplantation (HSCT), a subset of such patients still develop breakthrough IMIs (bIMIs). There are no data from prospective randomized clinical trials to guide therapeutic decisions in the different scenarios of bIMIs. In this viewpoint, we present the current status of our understanding of the clinical, diagnostic, and treatment challenges of bIMIs in high-risk adult patients with hematological cancer and/or HSCT receiving mold-active antifungals and outline common clinical scenarios. As a rule, managing bIMIs demands an individualized treatment plan that takes into account the host, including comorbidities, certainty of diagnosis and site of bIMIs, local epidemiology, considerations for fungal resistance, and antifungal pharmacological properties. Finally, we highlight areas that require future investigation in this complex area of clinical mycology.
Human Cytomegalovirus Enhances Placental Susceptibility and Replication of Human Immunodeficiency Virus Type 1 (HIV-1), Which May Facilitate In Utero HIV-1 Transmission
Authors: Johnson Erica L , Boggavarapu Sahithi , Johnson Elan S , Lal Asim A , Agrawal Parth , Bhaumik Siddhartha Kumar , Murali-Krishna Kaja , Chakraborty Rana
Published: May 2018

Co-pathogens that threaten the fetus during gestation, including human cytomegalovirus (HCMV), may contribute to mother-to-child transmission of HIV-1. We show that HCMV infection of placental macrophages may promote HIV replication and transmission as a consequence of inflammation and inhibition of intrinsic antiviral responses.
Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation
Authors: Iwasaki Kenta , Kitahata Nana , Hiramitsu Takahisa , Yamamoto Takayuki , Noda Takayuki , Okada Manabu , Narumi Shunji , Watarai Yoshihiko , Miwa Yuko , Uchida Kazuharu , Matsuoka Yutaka , Horimi Kosei , Kobayashi Takaaki
Published: May 2018

It is unclear to what extent the development of follicular helper T cells (Tfh) and de novo donor-specific human leukocyte antigen antibody (DSA) production could be influenced by immunosuppressive agents, particularly calcineurin inhibitor (CNI; cyclosporine or tacrolimus), after kidney transplantation. Here, the effects of immunosuppressive agents on Tfh-mediated B-cell activation and antibody production were investigated. In vitro circulating Tfh (cTfh; memory CD4+CXCR5+)/B-cell (CD19+) co-culture assays revealed that CNI considerably inhibited cTfh-mediated B-cell activation and IgG antibody secretion through the suppression of IL-21 and IL-2. Both IL-21 and CD40L up-regulated IL-2 receptors (CD25) on B cells, and anti-CD25 antibody induced apoptosis of activated B cells, resulting in the inhibition of IgG production. The frequency of cTfh-expressed CD40L and PD-1 was elevated in patients with de novo DSA 1 year after transplantation. The degree of inhibition by CNI was dependent on Staphylococcal enterotoxin B-induced CD40L+PD-1+ cTfh up-regulation level. Our data demonstrate that CD40L+PD-1+cTfh could be a marker to implicate individual difference in CNI sensitivity for Tfh-mediated B-cell activation in kidney transplantation.
Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials
Authors: Idzerda Nienke M A , Pena Michelle J , Parving Hans-Henrik , de Zeeuw Dick , Heerspink Hiddo J L
Published: May 2018

Background

Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline.

Methods

The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14 weeks and whether these responses were predictive of eGFR decline during the subsequent 9 months of follow-up.

Results

UPCR and TC response varied between individuals: mean UPCR response was −1.3% (5th–95th percentile −59.9 to 141.8) and mean TC response was −93.9 mg/dL (−169.1 to −26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) −1.6 to 0.9; P = 0.54] and TC responders (0.3; 95% CI −1.8 to 1.1; P = 0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6–3.0; P = 0.004 and 1.7; 95% CI 0.5–2.9; P = 0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5–3.7; P = 0.01). These findings were not different for rosuvastatin or atorvastatin.

Conclusions

Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.
Arterial spin labeling MR imaging for differentiation between high- and low-grade glioma—a meta-analysis
Authors: Falk Delgado Alberto , De Luca Francesca , van Westen Danielle , Falk Delgado Anna
Published: May 2018

Background

Arterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) non-invasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma.

Methods

Cochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed.

Results

In total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79–0.90) and specificity 0.80 (0.72–0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71–0.91) and specificity 0.83 (0.69–0.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79–0.91) and specificity 0.80 (0.65–0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered.

Conclusion

Arterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.
Inertial Measurement Unit-Assisted Implantation of Pedicle Screws in Combination With an Intraoperative 3-Dimensional/2-Dimensional Visualization of the Spine
Authors: Jost Gregory F , Walti Jonas , Mariani Luigi , Schaeren Stefan , Cattin Philippe
Published: May 2018

BACKGROUND

Inertial measurement units (IMUs) are microelectromechanical systems used to track orientation and motion.

OBJECTIVE

To use instruments mounted with IMUs in combination with a 3- and 2-dimensional (3D/2D) rendering of the computed-tomography scan (CT) to guide implantation of pedicle screws.

METHODS

Pedicle screws were implanted from T1 to S1 in 2 human cadavers. A software application enabled the surgeon to select the starting points and trajectories on a 3D/2D image of the spine, then locate these starting points on the exposed spine and apply the IMU-mounted instruments to reproduce the trajectories. The position of the screws was evaluated on the postoperative CT scan.

RESULTS

A total of 72 pedicle screws were implanted. Thirty-seven (77%) of the thoracic screws were within the pedicle (Heary I), 7 (15%) showed a lateral breach of the pedicle, and 4 (8%) violated the anterior or lateral vertebral body (Heary III). In the lumbar spine and S1, 21 screws (88%) were within the pedicle (Gertzbein 0), 2 (8%) screws had a pedicle wall breach < 2 mm (Gertzbein 1), and 1 > 2 to < 4 mm (Gertzbein 2). In the second cadaver, the position was compared to the intraoperatively shown virtual position. The median offset was 3°(mean 3° ± 2°, variance 5, range 0°–9°) in the sagittal plane and 3° (mean 4° ± 3°, variance 9, range 0°–12°) in the axial plane.

CONCLUSION

IMU-assisted implantation of pedicle screws combined with an intraoperative 3D/2D visualization of the spine enabled the surgeon to precisely implant pedicle screws on the exposed spine.
“Interlocking” Clipping of an Irregular Middle Cerebral Artery Bifurcation Aneurysm: 2-Dimensional Operative Video
Authors: Sorenson Thomas J , Marcellino Chris , Acciarri Nicola , Rangel Castilla Leonardo , Lanzino Giuseppe
Published: May 2018

Middle cerebral artery (MCA) aneurysms often have an irregular morphology that might require creative clipping techniques even in the case of small aneurysms. In this video, we illustrate the case of a patient with an incidental but very irregular MCA aneurysm. The presence of 2 separate, asymmetric lobes was dealt with by utilizing the “interlocking” clip technique in which a regular clip is used to obliterate 1 portion of the aneurysm and a fenestrated clip, with the ring of the fenestration circling the body of the first clip, is used to obtain obliteration of the other lobe. This patient also had a contralateral internal carotid artery occlusion, and we discuss the pitfalls of temporary clipping in such a situation.
Coevolution of a Persistent Plant Virus and Its Pepper Hosts
Authors: Safari Maliheh , Roossinck Marilyn J.
Published: May 2018

There are many nonpathogenic viruses that are maintained in a persistent lifestyle in plants. Plant persistent viruses are widespread, replicating in their hosts for many generations. So far, Endornaviridae is the only family of plant persistent viruses with a single-stranded RNA genome, containing one large open reading frame. Bell pepper endornavirus (BPEV), Hot pepper endornavirus, Capsicum frutescens endornavirus 1 (CFEV 1) have been identified from peppers. Peppers are native to Central and South America and, as domesticated plants, human selection accelerated their evolution. We investigated the evolution of these endornaviruses in different peppers including Capsicum annuum, C. chacoense, C. chinense, C. frutescens, C. baccutum, and C. pubescens using two fragments from the viral helicase (Hel) and RNA dependent RNA polymerase (RdRp) domains. In addition, using single nucleotide polymorphisms, we analyzed the pepper host populations and phylogenies. The endornaviruses phylogeny was correlated with its Capsicum species host. In this study, BPEV was limited to C. annuum species, and the RdRp and Hel phylogenies identified two clades that correlated with the host pungency. No C. annuum infected with CFEV 1 was found in this study, but the CFEV 1 RdRp fragment was recovered from C. chinense, C. frutescens, C. baccutum, and C. pubescens. Hence, during pepper speciation, the ancestor of CFEV 1 may have evolved as a new endornavirus, BPEV, in C. annuum peppers.
The Distribution and Detection ofGrapevine red blotch virusin its Host Depend on Time of Sampling and Tissue Type
Authors: Setiono Felicia J. , Chatterjee Debotri , Fuchs Marc , Perry Keith L. , Thompson Jeremy R.
Published: May 2018

Grapevine red blotch virus (GRBV) is the causal agent of grapevine red blotch, an emerging disease that affects cultivated grapevine such as Vitis vinifera. The ability to detect viruses in grapevine is often hindered by low virus titers compounded by a variable distribution in the plant and seasonal variations. In order to examine these two variables in relation to GRBV, we developed a quantitative polymerase chain reaction (qPCR) method that incorporates both internal and external references to enhance assay robustness. In greenhouse-grown vines infected with GRBV, qPCR identified highest virus titers in the petioles of fully expanded leaves and significantly reduced levels of virus in the shoot extremities. In vineyard-grown vines infected with GRBV, the virus titer in July and October 2016 followed a pattern similar to that found for the greenhouse-grown plants but, most strikingly, close to half (44%) of the samples analyzed in June 2015 tested negative for infection. The technique presented and results obtained highlight the variability of virus distribution in its host and provide a useful guide for selecting the best tissues for optimal GRBV diagnosis.
New Sources of Adult Plant and Seedling Resistance to Puccinia coronata f. sp. avenae Identified among Avena sativa Accessions From the National Small Grains Collection
Authors: Admassu-Yimer Belayneh , Gordon Tyler , Harrison Stephen , Kianian Shahryar , Bockelman Harold , Bonman J. Michael , Esvelt Klos Kathy
Published: May 2018

Accessions of cultivated oat (Avena sativa L.) from the United States Department of Agriculture–Agricultural Research Service Small Grains Collection in Aberdeen, ID were characterized for adult plant resistance (APR) and seedling resistance to crown rust, caused by Puccinia coronata f. sp. avenae. Initially, 607 oat accessions with diverse geographic origins were evaluated in field tests in Baton Rouge, LA. Of those, 97 accessions were not fully susceptible and were tested in the field in St. Paul, MN against a diverse P. coronata f. sp. avenae population. Thirty-six accessions that had some level of resistance in both field tests and mean coefficients of infection of ≤20 were further evaluated for APR and seedling resistance. Among these, four accessions (PI 193040, PI 194201, PI 237090, and PI 247930) were resistant to eight P. coronata f. sp. avenae races as seedlings. Twenty-nine accessions had resistance to at least one of the P. coronata f. sp. avenae races. Three accessions (CIav 2272, CIav 3390, and PI 285583) were fully susceptible to all eight P. coronata f. sp. avenae races as seedlings. Further evaluation of the three seedling-susceptible accessions at the flag leaf stage in a growth chamber resulted in moderately susceptible to moderately resistant responses. The resistance sources presented here may contain genes not deployed in elite oat varieties, and may be useful for future crown rust resistance breeding. The adult and seedling resistance found in accessions of the cultivated oat species is especially valuable because it avoids problems associated with the transfer of genes from wild species to cultivated oat.
Tobramycin-impregnated calcium sulfate pellets for the treatment of chronic osteomyelitis in children and adolescents
Authors: Andreacchio Antonio , Alberghina Flavia , Paonessa Matteo , Cravino Mattia , De Rosa Vincenzo , Canavese Federico
Published: May 2018

The aim of this work was to evaluate the outcome and efficacy of treatment in a homogeneous group of skeletally immature patients with chronic osteomyelitis of the long bones managed by a combination of radical debridement and insertion of tobramycin-impregnated calcium sulfate pellets to fill the bone defect in a single-stage procedure. Between 2011 and 2016, 12 skeletally immature patients were treated surgically by the reported technique. Single-stage surgery using tobramycin-impregnated calcium sulfate pellets in association with systemic antibiotic therapy yields satisfactory outcomes in skeletally immature children presenting chronic osteomyelitis by reducing the risk of occurrence of comorbidities, hospital stays, and healthcare costs.
Sorptive removal of phenanthrene from aqueous solutions using magnetic and non-magnetic rice husk-derived biochars
Authors: Guo Wei , Wang Shujuan , Wang Yunkai , Lu Shaoyong , Gao Yue
Published: May 2018

A magnetically modified rice husk biochar (MBC) was successfully prepared by a hydrothermal method from original biochar (BC) and subsequently used to remove phenanthrene (PHE) from aqueous solutions. The porosity, specific surface area and hydrophobicity of BC were significantly improved (approx. two times) after magnetic modification. The adsorption data fitted well to pseudo-second-order kinetic and Langmuir models. Compared with BC, MBC had a faster adsorption rate and higher adsorption capacity of PHE. The adsorption equilibrium for PHE on MBC was achieved within 1.0 h. The maximum adsorption capacity of PHE on MBC was 97.6 mg g
−1
based on the analysis of the Sips model, which was significantly higher than that of other sources of BCs. The adsorption mechanism of the two BCs was mainly attributed to the action of surface functional groups and π–π-conjugated reactions. The adsorption of PHE on MBC mainly occurred in the functional groups of C–O and Fe
3
O
4
, but that on BC was mainly in the functional groups of –OH, N–H, C=C and C–O.
Genomic Analysis of a Transcriptional Networks Directing Progression of Cell States During MGE development
Authors: Sandberg Magnus , Taher Leila , Hu Jiaxin , Black Brian L. , Nord Alex , Rubenstein John L.R.
Published: May 2018

Background

Homeodomain (HD) transcription factor (TF) NKX2-1 critical for the regional specification of the medial ganglionic eminence (MGE) as well as promoting the GABAergic and cholinergic neuron fates via the induction of TFs such as LHX6 and LHX8. NKX2-1 defines MGE regional identity in large part through transcriptional repression, while specification and maturation of GABAergic and cholinergic fates is mediated in part by transcriptional activation via TFs such as LHX6 and LHX8. Here we analyze the signaling and TF pathways, downstream of NKX2-1, required for GABAergic and cholinergic neuron fate maturation.

Methods

Differential ChIP-seq analysis was used to identify regulatory elements (REs) where chromatin state was sensitive to change in theNkx2-1cKO MGE at embryonic day (E) 13.5. TF motifs in the REs were identified using RSAT. CRISPR-mediated genome editing was used to generate enhancer knockouts. Differential gene expression in these knockouts was analyzed through RT-qPCR and in situ hybridization. Functional analysis of motifs within hs623 was analyzed via site directed mutagenesis and reporter assays in primary MGE cultures.

Results

We identified 4782 activating REs (aREs) and 6391 repressing REs (rREs) in theNkx2-1conditional knockout (Nkx2-1cKO) MGE. aREs are associated with basic-Helix-Loop-Helix (bHLH) TFs. Deletion of hs623, an intragenicTcf12aRE, caused a reduction ofTcf12expression in the sub-ventricular zone (SVZ) and mantle zone (MZ) of the MGE. Mutation of LHX, SOX and octamers, within hs623, caused a reduction of hs623 activity in MGE primary cultures.

Conclusions

Tcf12expression in the sub-ventricular zone (SVZ) of the MGE is mediated through aRE hs623. The activity of hs623 is dependent on LHX6, SOX and octamers. Thus, maintaining the expression ofTcf12in the SVZ involves on TF pathways parallel and genetically downstream of NKX2-1.
Sex differences along the Autism Continuum: A twin study of brain structure
Authors: Cauvet Élodie , Westeinde Annelies van’t , Toro Roberto , Kuja-Halkola Ralf , Neufeld Janina , Mevel Katell , Bölte Sven
Published: May 2018

Females might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N=148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.
Quantitative assessment of cell population diversity in single-cell landscapes
Authors: Liu Qi , Herring Charles A. , Sheng Quanhu , Ping Jie , Simmons Alan J. , Chen Bob , Banerjee Amrita , Gu Guoqiang , Coffey Robert J. , Shyr Yu , Lau Ken S.
Published: May 2018

Single-cell RNA-sequencing (scRNA-seq) has become a powerful tool for the systematic investigation of cellular diversity. As a number of computational tools have been developed to identify and visualize cell populations within a single scRNA-seq dataset, there is a need for methods to quantitatively and statistically define proportional shifts in cell population structures across datasets, such expansion or shrinkage, or emergence or disappearance of cell populations. Here we present sc-UniFrac, a framework to statistically quantify compositional diversity in cell populations between single-cell transcriptome landscapes. sc-UniFrac enables sensitive and robust quantification in simulated and experimental datasets in terms of both population identity and quantity. We have demonstrated the utility of sc-UniFrac in multiple applications, including assessment of biological and technical replicates, classification of tissue phenotypes, identification and definition of altered cell populations, and benchmarking batch correction tools. sc-UniFrac provides a framework for quantifying diversity or alterations in cell populations across conditions, and has broad utility for gaining insight on how cell populations respond to perturbations.
Atxn2-CAG100-knock-in affects mouse lifespan and vestibulo-cerebellar function via neural disconnection
Authors: Halbach Melanie V. , Sen Nesli-Ece , Canet-Pons Júlia , Kuppens Bram W. , Segers Mandy , Schonewille Martijn , Rollmann Ewa , Seidel Kay , Rüb Udo , Meierhofer David , Mittelbronn Michel , Harter Patrick , De Zeeuw Chris I. , Almaguer-Mederos Luis E. , Gispert Suzana , Bosman Laurens W.J. , Auburger Georg
Published: May 2018

Unstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable.

We generated a novel knock-in mouse line with CAG100 expansion inAtxn2, transmitted unstably. The mutant protein accumulated in neuronal cytosolic aggregates, with a characteristic pattern of multi-system-atrophy. Loss-of-function phenotypes included less mutant offspring, initial weight gain and motor hyperactivity. Progressive toxic aggregation effects started around 20 weeks in homozygous animals showing weight loss, reduced muscle strength and gait ataxia. Lifespan was decreased. In the cerebellum, neuronal soma and dendrites were remarkably spared. However, myelin proteins MBP, CNP, PLP1 and transcriptsMal, Mobp, Rtn4decreased markedly, especially adhesion factors MAG and MOG. In neurons, strong reductions were found for mRNAs of perineuronal elementsHaplnl, Hapln2, Hapln4, of axonal myelin interactorsPrnpandKlk6. At protein level, the adhesion factor neuroplastin and neurofilaments were strongly reduced, while presynaptic alpha-synuclein increased two-fold.

Overall, this authentic SCA2 mouse model elucidates how altered function and aggregation toxicity of ATXN2 conspire to trigger axon-myelin disconnection. This model will promote the development of neuroprotective therapies and disease biomarkers.
Analysing the structure of pathways and its influence on the interpretation of biomedical datasets
Authors: Burger Bram , Hernández Sánchez Luis Francisco , Lereim Ragnhild Reehorst , Barsnes Harald , Vaudel Marc
Published: May 2018

Biochemical pathways are commonly used as a reference to conduct functional analysis on biomedical omics datasets, where experimental results are mapped to knowledgebases comprising known molecular interactions collected from the literature. Due to their central role, the content of the functional knowledgebases directly influences the outcome of pathway analyses. In this study, we investigate the structure of the current pathway knowledge, as exemplified by Reactome, discuss the consequences for biological interpretation, and outline possible improvements in the use of pathway knowledgebases. By providing a view of the underlying network structure, we aim to help pathway analysis users manage their expectations and better identify possible artefacts in the results.
Nuclear and mitochondrial phylogenomics of the Diplostomoidea and Diplostomida (Digenea, Platyhelminthes)1
Authors: Locke Sean A. , Dam Alex Van , Caffara Monica , Pinto Hudson Alves , López-Hernández Danimar , Blanar Christopher
Published: May 2018

Higher systematics within the Digenea, Carus 1863 have been relatively stable since a phylogenetic analysis of partial nuclear ribosomal markers (rDNA) led to the erection of the Diplostomida Olson, Cribb, Tkach, Bray, and Littlewood, 2003. However, recent mitochondrial (mt) genome phylogenies suggest this order might be paraphyletic. These analyses show members of two diplostomidan superfamilies are more closely related to the Plagiorchiida La Rue, 1957 than to other members of the Diplostomida. In one of the groups implicated, the Diplostomoidea Poirier, 1886, a recent phylogeny based on mt DNA also indicates the superfamily as a whole is non-monophyletic. To determine if these results were robust to additional taxon sampling, we analyzed mt genomes from seven diplostomoids in three families. To choose between phylogenetic alternatives based on mt genomes and the prior rDNA-based topology, we also analyzed hundreds of ultra-conserved elements (UCEs) assembled from shotgun sequencing. The Diplostomida was paraphyletic in the mt genome phylogeny, but supported in the UCE phylogeny. We speculate this mitonuclear discordance is related to ancient, rapid radiation in the Digenea. Both UCEs and mt genomes support the monophyly of the Diplostomoidea and show congruent relationships within it. The Cyathocotylidae Mühling, 1898 are early diverging descendants of a paraphyletic clade of Diplostomidae Poirier, 1886, in which were nested members of the Strigeidae Railliet, 1919; the results support prior suggestions that the Crassiphialinae Sudarikov, 1960 will rise to the family level. Morphological traits of diplostomoid metacercariae appear to be more useful for differentiating higher taxa than those of adults. We describe a new species of Cotylurus Szidat, 1928, resurrect a species of Hysteromorpha Lutz, 1931, and find support for a species of Alaria Schrank, 1788 of contested validity. Complete rDNA operons are provided as a resource for future studies.
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
Authors: Cortés-Ciriano Isidro , Lee June-Koo , Xi Ruibin , Jain Dhawal , Jung Youngsook L. , Yang Lixing , Gordenin Dmitry , Klimczak Leszek J. , Zhang Cheng-Zhong , Pellman David S. , Park Peter J. ,   on behalf of the PCAWG Structural Variation Working Group,   the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
Published: May 2018

Chromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.
Ancient ancestry informative markers for identifying fine-scale ancient population structure in Eurasians
Authors: Esposito Umberto , Das Ranajit , Pirooznia Mehdi , Elhaik Eran
Published: May 2018

The rapid accumulation of ancient human genomes from various areas and time periods potentially allows the expansion of studies of biodiversity, biogeography, forensics, population history, and epidemiology into past populations. However, most ancient DNA (aDNA) data were generated through microarrays designed for modern-day populations known to misrepresent the population structure. Past studies addressed these problems using ancestry informative markers (AIMs). However, it is unclear whether AIMs derived from contemporary human genomes can capture ancient population structure and whether AIM finding methods are applicable to ancient DNA (aDNA) provided that the high missingness rates in ancient, oftentimes haploid, DNA can also distort the population structure. Here, we define ancient AIMs (aAIMs) and develop a framework to evaluate established and novel AIM-finding methods in identifying the most informative markers. We show that aAIMs identified by a novel principal component analysis (PCA)-based method outperforms all competing methods in classifying ancient individuals into populations and identifying admixed individuals. In some cases, predictions made using the aAIMs were more accurate than those made with a complete marker set. We discuss the features of the ancient Eurasian population structure and strategies to identify aAIMs. This work informs the design of population microarrays and the interpretation of aDNA results.
Convolving Pre-Trained Convolutional Neural Networks at Various Magnifications to Extract Diagnostic Features for Digital Pathology
Authors: Sidhom John-William , Baras Alexander S.
Published: May 2018

Deep learning is an area of artificial intelligence that has received much attention in the past few years due to both an increase in computational power with the increased use of graphics processing units (GPU’s) for computational analyses and the performance of these class of algorithms on visual recognition tasks. They have found utility in applications ranging from image search to facial recognition for security and social media purposes. Their continued success has propelled their use across many new domains including the medical field, in areas of radiology and pathology in particular, as these fields are thought to be driven by visual recognition tasks. In this paper, we present an application of deep learning, termed ‘transfer learning’, using ResNet50, a pre-trained convolutional neural network (CNN) to act as a ‘feature-detector’ at various magnifications to identify low and high level features in digital pathology images of various breast lesions for the purpose of classifying them correctly into the labels of normal, benign, in-situ, or invasive carcinoma as provided in the ICIAR 2018 Breast Cancer Histology Challenge (BACH).
sppIDer: a species identification tool to investigate hybrid genomes with high-throughput sequencing
Authors: Langdon Quinn K. , Peris David , Kyle Brian , Hittinger Chris Todd
Published: May 2018

The genomics era has expanded our knowledge about the diversity of the living world, yet harnessing high-throughput sequencing data to investigate alternative evolutionary trajectories, such as hybridization, is still challenging. Here we present sppIDer, a pipeline for the characterization of interspecies hybrids and pure species,that illuminates the complete composition of genomes. sppIDer maps short-read sequencing data to a combination genome built from reference genomes of several species of interest and assesses the genomic contribution and relative ploidy of each parental species, producing a series of colorful graphical outputs ready for publication. As a proof-of-concept, we use the genus Saccharomyces to detect and visualize both interspecies hybrids and pure strains, even with missing parental reference genomes. Through simulation, we show that sppIDer is robust to variable reference genome qualities and performs well with low-coverage data. We further demonstrate the power of this approach in plants, animals, and other fungi. sppIDer is robust to many different inputs and provides visually intuitive insight into genome composition that enables the rapid identification of species and their interspecies hybrids. sppIDer exists as a Docker image, which is a reusable, reproducible, transparent, and simple-to-run package that automates the pipeline and installation of the required dependencies (https://github.com/GLBRC/sppIDer).
WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids
Authors: Yoney Anna , Etoc Fred , Ruzo Albert , Metzger Jakob J. , Martyn Iain , Li Shu , Kirst Christoph , Carroll Thomas , Siggia Eric D. , Brivanlou Ali H.
Published: May 2018

Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9 live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WNT, however, endows cells with the competence to respond to graded levels of ACTIVIN, which induces differentiation without changing SMAD2 dynamics. This cellular memory of WNT signaling is necessary for ACTIVIN morphogen activity. A re-evaluation of the evidence gathered over decades in model systems, re-enforces our conclusions and points to an evolutionarily conserved mechanism.
Optogenetic manipulation of medullary neurons in the locust optic lobe
Authors: Wang Hongxia , Dewell Richard B. , Ehrengruber Markus U. , Segev Eran , Reimer Jacob , Roukes Michael L. , Gabbiani Fabrizio
Published: May 2018

Locust is a widely used animal model for studying sensory processing and its relation to behavior. Due to the lack of genomic information, genetic tools to manipulate neural circuits in locusts are not yet available. We examined whether Semliki Forest virus is suitable to mediate exogenous gene expression in neurons of the locust optic lobe. We subcloned a channelrhodopsin variant and the yellow fluorescent protein Venus into a Semliki Forest virus vector and injected the virus into the optic lobe of locusts (Schistocerca americana). Fluorescence was observed in all injected optic lobes. Most neurons that expressed the recombinant proteins were located in the first two neuropils of the optic lobe, the lamina and medulla. Extracellular recordings demonstrated that laser illumination increased the firing rate of medullary neurons expressing channelrhodopsin. The optogenetic activation of the medullary neurons also triggered firing of a postsynaptic, looming-sensitive neuron, the Lobula Giant Movement Detector (LGMD). These results indicate that Semliki Forest virus is efficient at mediating transient exogenous gene expression and provides a tool to manipulate neural circuits in the locust nervous system and likely other insects.

New and Noteworthy

Using Semliki Forest virus, we efficiently delivered channelrhodopsin into neurons of the locust optic lobe. We demonstrate that laser illumination increases the firing of the medullary neurons expressing channelrhodopsin and of an identified postsynaptic target neuron, the LGMD neuron. This technique allows to manipulate the neuronal activity in locust neural circuits using optogenetics.
Transcriptome-wide analysis of auxin-induced carotenoid accumulation in Chlorella microalgae
Authors: Alsenani Faisal , Wass Taylor J. , Ma Ruijuan , Eltanahy Eladl , Netzel Michael E. , Schenk Peer M.
Published: May 2018

Microalgae are a commercially viable route for the production of carotenoids, including β-carotene and astaxanthin. In the current study, the commercially relevant microalga, Chlorella sp. BR2 was treated with four plant hormones: indole-3-acetic acid, salicylic acid, abscisic acid and methyl jasmonate, over a range of dosages and screened for enhanced carotenoid production. Indole-3-acetic acid was the only hormone with an inductive effect on carotenoid accumulation. As such, the transcriptome under the condition with the highest carotenoid increase was profiled using RNA-Seq and expressed sequences reconstructed with de novo assembly. This allowed for the profiling of transcriptome-wide changes following auxin treatment, revealing the active pathway components of auxininduced carotenogenesis. Data analysis specified the differentially expressed genes involved in auxin biosynthesis and signal transduction, which suggest a close relationship to equivalent pathways in higher plants. However unlike in plants, the ancient ABP1/SCFSKP2A/IBR5-mediated pathways for auxin response likely acted as the primary signaling route in Chlorella. As carotenoids are precursors for abscisic acid, the findings suggest a causative link between auxin signaling and abiotic stress tolerance.

Highlight

Transcriptomics of plant hormone-treated Chlorella revealed the active pathway components of auxin-induced carotenogenesis and included the ancient ABP1/SCFSKP2A/IBR5-mediated pathways. The manuscript presents the first documented transcriptomic data of auxin-treated microalgae.