bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lesion-Constrained Electrical Source Imaging: A Novel Approach in Epilepsy Surgery for Tuberous Sclerosis Complex
Authors: Peters Jurriaan M. , Hyde Damon E. , Chu Catherine J. , Boom Merel , Scherrer Benoit , Madsen Joseph R. , Stone Scellig S. , Ouaalam Hakim , Prabhu Sanjay P. , Sahin Mustafa , Warfield Simon K. 
Published: July 2019

Purpose:
Electrical source imaging may yield ambiguous results in multilesional epilepsy. The aim of this study was to test the clinical utility of lesion-constrained electrical source imaging in epilepsy surgery in children with tuberous sclerosis complex.

Methods:
Lesion-constrained electrical source imaging is a novel method based on a proposed head model in which the source solution is constrained to lesions. Using a goodness of fit analysis, we rank-ordered individual tubers by their ability to approximate interictal and ictal EEG data. The overlap with the surgical resection cavity was determined qualitatively, and placed findings in the context of epilepsy surgical outcome, and compared with the low-resolution brain electromagnetic tomography solution.

Results:
Low-resolution brain electromagnetic tomography predicted the surgical cavity in only one patient with good outcome (true positive) and localized to outside of the cavity in two patients with a good outcome (false negative). In one patient with a poor outcome, the interictal low-resolution brain electromagnetic tomography solution overlapped with the cavity (false positive). Lesion-constrained electrical source imaging of ictal EEG data identified tubers concordant with the resection zone in three patients with a good surgical outcome (true positive) and appropriately discordant in three other patients with a poor outcome (true negative).

Conclusions:
Lesion-constrained electrical source imaging on low-resolution EEG data provides complementary information in the presurgical workup for patients with tuberous sclerosis complex, although further validation is required. In the appropriate clinical context, the yield of source localization on low-resolution EEG data may be increased by reduction of the solution space.
Local frustration determines loop opening during the catalytic cycle of an oxidoreductase
Authors: Stelzl Lukas L. , Mavridou Despoina A.I. , Saridakis Emmanuel , Gonzalez Diego , Baldwin Andrew J. , Ferguson Stuart J. , Sansom Mark S.P. , Redfield Christina 
Published: July 2019

AbstractLocal structural frustration, the existence of mutually exclusive competing interactions, may explain why some proteins are dynamic while others are rigid. Frustration is thought to underpin biomolecular recognition and the flexibility of protein binding sites. Here we show how a small chemical modification, the oxidation of two cysteine thiols to a disulfide bond, during the catalytic cycle of the N-terminal domain of the key bacterial oxidoreductase DsbD (nDsbD), introduces frustration ultimately influencing protein function. In oxidized nDsbD, local frustration disrupts the packing of the protective cap-loop region against the active site allowing loop opening. By contrast, in reduced nDsbD the cap loop is rigid, always protecting the active-site thiols from the oxidizing environment of the periplasm. Our results point towards an intricate coupling between the dynamics of the active-site cysteines and of the cap loop which modulates the association reactions of nDsbD with its partners resulting in optimized protein function.
Macrobdella decora: Old World Leech Gut Microbial Community Structure Conserved in a New World Leech
Authors: McClure Emily Ann , Nelson Michael C. , Lin Amy , Graf Joerg 
Published: July 2019

ABSTRACTLeeches are found in terrestrial, aquatic, and marine habitats on all continents. Sanguivorous leeches have been used in medicine for millennia. Modern scientific uses include studies of neurons, anticoagulants, and gut microbial symbioses.Hirudo verbana, the European medicinal leech, maintains a gut community dominated by two bacterial symbionts,Aeromonas veroniiandMucinivorans hirudinis, which sometimes account for as much as 97% of the total crop microbiota. The highly simplified gut anatomy and microbiome ofH. verbanamake it an excellent model organism for studying gut microbial dynamics. The North American medicinal leech,Macrobdella decora,is a hirudinid leech native to Canada and the northern U.S.A. In this study we show thatM. decorasymbiont communities are very similar to those inH. verbana.This similarity allowed for an extensive study in which wild caught animals were sampled to determine effects of geographic separation, time of collection, and feeding on the microbiome. Through 16S V4 rRNA deep sequencing we show that: i) theM. decoragut and bladder microbial communities are distinct, ii) theM. decoragut community is affected by feeding and long periods of starvation, and iii) geographic separation does not appear to affect the overall gut microbial community structure. We propose thatM. decorais a replacement forH. verbanafor studies of wild-caught animals and offer evidence for the conservation of annelid symbionts. Successful culturing and comparison of dominant symbionts fromM. decoraandH. verbenawill provide the ability to assess host-symbiont co-evolution in future work.IMPORTANCEBuilding evidence implicates the gut microbiome in regulating animal digestion, nutritional acquisition, immune regulation, development, and even mood regulation. Because of the difficulty of assigning causative relationships in complex gut microbiomes a simplified model for testing hypotheses is necessary. Previous research inHirudo verbanahas suggested this animal as a highly simplified and tractable animal model of gut symbioses. Our data show thatMacrobdella decoramay work just as well asH. verbanawithout the drawback of being an endangered organism and with the added convenience of easy access to field-caught specimens. The similarity of the microbial community structure of species from two different continents reveals the highly-conserved nature of the microbial symbionts in sanguivorous leeches and confirms the medicinal leech as a highly simplified, natural animal model in which to study gut symbioses.
Epigenetic dysregulation underpins tumorigenesis in a cutaneous tumor syndrome
Authors: Davies Helen R. , Hodgson Kirsty , Schwalbe Edward , Coxhead Jonathan , Sinclair Naomi , Zou Xueqing , Cockell Simon , Husain Akhtar , Nik-Zainal Serena , Rajan Neil 
Published: July 2019

AbstractPatients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes 1,2. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel driver mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic and methylation profiling suggest that mutated DNMT3A drives tumorigenesis mechanistically through Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm the phenomenon of benign pulmonary metastases from primary skin lesions. In malignant tumors, additional epigenetic modifiers MBD4, CREBBP, KDM6A and EP300 were mutated. We thus present epigenetic dysregulation as a driver in CCS tumorigenesis and propose this may account for the diverse histophenotypic patterns despite the paucity of mutations seen. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.
A pipeline for multidimensional confocal analysis of mitochondrial morphology, function and dynamics in pancreatic β-cells
Authors: Chaudhry Ahsen , Shi Rocky , Luciani Dan S. 
Published: July 2019

ABSTRACTLive-cell imaging of mitochondrial function and dynamics can provide vital insights into both physiology and pathophysiology, including of metabolic diseases like type 2 diabetes. However, without super-resolution microscopy and commercial analysis software it is challenging to accurately extract features from dense multi-layered mitochondrial networks, such as those in insulin-secreting pancreatic β-cells. Motivated by this, we developed a comprehensive pipeline, and associated ImageJ plugin, that enables 2D/3D quantification of mitochondrial network morphology and dynamics in mouse β-cells, and by extension other similarly challenging cell-types. The approach is based on standard confocal microscopy and shareware, making it widely accessible. The pipeline was validated using mitochondrial photo-labelling and unsupervised cluster analysis, and is capable of morphological and functional analyses on a per-organelle basis, including in 4D (xyzt). Overall, this tool offers a powerful framework for multiplexed analysis of mitochondrial state/function, and provides a valuable resource to accelerate mitochondrial research in health and disease.
A role of cellular translation regulation associated with toxic Huntingtin protein
Authors: Joag Hiranmay , Ghatpande Vighnesh , Sarkar Maitheli , Raina Anshu , Desai Meghal , Shinde Mrunalini , Bose Tania , Majumdar Amitabha 
Published: July 2019

AbstractHuntington’s disease (HD) is a severe neurodegenerative disorder caused by poly Q repeat expansion in the Huntingtin (Htt) gene. While the Htt amyloid aggregates are known to affect many cellular processes, its role in translation is not addressed. Here we report pathogenic Htt expression causes protein synthesis deficit in cells. We find a functional prion-like protein, the translation regulator Orb2 to be sequestered by Htt aggregates. Coexpression of Orb2 can partially rescue the lethality associated with poly Q expanded Htt. These findings can be relevant for HD as human homologs of Orb2 also can be sequestered by pathogenic Htt aggregates. Our work suggests that translation dysfunction could be one of the contributors in the pathogenesis of HD and new therapies targeting protein synthesis pathways might help alleviate disease symptoms.
A near-full-length HIV-1 genome from 1966 recovered from formalin-fixed paraffin-embedded tissue
Authors: Gryseels Sophie , Watts Thomas D. , Kabongo Jean-Marie M. , Larsen Brendan B. , Lemey Philippe , Muyembe-Tamfum Jean-Jacques , Teuwen Dirk E. , Worobey Michael 
Published: July 2019

AbstractAlthough estimated to have emerged in humans in Central Africa in the early 1900s, HIV-1, the main causative agent of AIDS, was only discovered in 1983. With very little direct biological data of HIV-1 from before the 1980s, far-reaching evolutionary and epidemiological inferences regarding the long pre-discovery phase of this pandemic are based on extrapolations by phylodynamic models of HIV-1 genomic sequences gathered mostly over recent decades. Here, using a very sensitive multiplex RT-PCR assay, we screened 1,652 formalin-fixed paraffin-embedded tissue specimens collected for pathology diagnostics in Kinshasa, Democratic Republic of Congo (DRC), between 1959 and 1967. We report the near-complete genome of one positive from 1966 (“DRC66”)—a non-recombinant sister lineage to subtype C that constitutes the oldest HIV-1 near-full-length genome recovered to date. Root-to-tip plots showed the DRC66 sequence is not an outlier as would be expected if dating estimates from more recent genomes were systematically biased; and inclusion of DRC66 sequence in tip-dated BEAST analyses did not significantly alter root and internal node age estimates based on post-1978 HIV-1 sequences. There was larger variation in divergence time estimates among datasets that were subsamples of the available HIV-1 genomes from 1978-2015, showing the inherent phylogenetic stochasticity across subsets of the real HIV-1 diversity. In conclusion, this unique archival HIV-1 sequence provides direct genomic insight into HIV-1 in 1960s DRC, and, as an ancient-DNA calibrator, it validates our understanding of HIV-1 evolutionary history.SignificanceInferring the precise timing of the origin of the HIV/AIDS pandemic is of great importance because it offers insights into which factors did—or did not—facilitate the emergence of the causal virus. Previous estimates have implicated rapid development during the early 20th century in Central Africa, which wove once-isolated populations into a more continuous fabric. We recovered the first HIV-1 genome from the 1960s, and it provides direct evidence that HIV-1 molecular clock estimates spanning the last half-century are remarkably reliable. And, because this genome itself was sampled only about a half-century after the estimated origin of the pandemic, it empirically anchors this crucial inference with high confidence.
POT-1 telomere binding protein promotes a novel form of Transgenerational Epigenetic Inheritance
Authors: Lister-Shimauchi Evan H. , Dinh Michael , Maddox Paul , Ahmed Shawn 
Published: July 2019

SummaryTransgenerational Epigenetic Inheritance occurs when gametes transmit forms of information without altering genomic DNA1. Although deficiency for telomerase in human families causes transgenerational shortening of telomeres2, a role for telomeres in Transgenerational Epigenetic Inheritance is unknown. Here we show that Protection Of Telomeres 1 (Pot1) proteins, which interact with single-stranded telomeric DNA3,4, function in gametes to regulate developmental expression of telomeric foci for multiple generations. C. elegans POT-1 and POT-25,6 formed abundant telomeric foci in adult germ cells that vanished in 1-cell embryos and gradually accumulated during development. pot-2 mutants displayed abundant POT-1::mCherry foci throughout development. pot-2 mutant gametes created F1 cross-progeny with constitutively abundant POT-1::mCherry and mNeonGreen::POT-2 foci, which persisted for 6 generations but did not alter telomere length. pot-1 mutant and pot-2; pot-1 double mutant gametes gave rise to progeny with constitutively diminished Pot1 foci. Genomic silencing and small RNAs potentiate many transgenerational effects7 but did not affect Pot1 foci. We conclude that C. elegans POT-1 functions at telomeres of pot-2 mutant gametes to create constitutively high levels of Pot1 foci in future generations. As regulation of telomeres and Pot1 have been tied to cancer8,9, this novel and highly persistent form of Transgenerational Epigenetic Inheritance could be relevant to human health.
First Attempt to Identify and Map QTLs Associated with Promiscuous Nodulation in Soybean
Authors: Agoyi Eric E. , Tumuhairwe John B. , Chigeza Godfree , Tukamuhabwa Phinehas , Diers Brian W. 
Published: July 2019

ABSTRACTTo inform possibility of conducting marker assisted breeding of promiscuous soybean varieties, this study used 92 F2 lines from biparental cross to identify QTLs associated with promiscuous nodulation in soybean. GBS; genotyping by sequencing platform was used to generate SNPs through the pipeline 2 in TASSEL 5.0, Bowtie2 version 2.2.8 for tag alignment, Beagle version 4.1 to impute missing SNPs and R-QTL package in R for QTL identification. Four nodulation traits were assessedviznumber of nodules (NN), percent of effective nodules (NE), fresh weight and dry weight of nodules (NFW and NDW). Two QTLs were identified on chromosomes 10 and 13. Both QTLs were associated with NN, only QTL13 was associated NE and only QTL10 was associated with nodule ‘weights. It was observed that NN, NFW and NDW shared QTL10 and NN and NE share QTL13 allowing hypothetize on the existence of pleiotropic genes in those those two regions. Over dominance effect was observed for QTL10 and non additive effect for QTL13. The paper recommend investigations be pursued to validate those QTLs and set foundation for marker assisted selection of promiscuous soybean varieties. Also these findings could serve as starting point for gene cloning to better understand nodulation trait in soybean.
ALI-1, candidate gene of B1 locus, is associated with awn length and grain weight in common wheat
Authors: Wang Dongzhi , Yu Kang , Jin Di , Sun Linhe , Chu Jinfang , Wu Wenying , Xin Peiyong , Li Xin , Sun Jiazhu , Yang Wenlong , Zhan Kehui , Zhang Aimin , Liu Dongcheng 
Published: July 2019

AbstractAwn plays a vital role in the photosynthesis, grain production and drought tolerance of common wheat; however, works on the systematic identification or cloning of genes controlling wheat awn length (AL) were seldom reported. Here, we conducted the Genome-wide association study (GWAS) in 364 wheat accessions and identified 25 loci involved in the AL, including dominant awn suppressors B1, B2 and four homologs of awn controlling genes in rice and barley. Furthermore, the B1 locus was mapped to a 125-kb physical interval harboring two genes on chromosome 5AL through map-based cloning. As the candidate gene for B1 locus, a C2H2 zinc finger gene Awn Length Inhibitor 1 (ALI-1) expressed predominantly in the developing spike of awnless individuals and suppresses downstream genes transcriptionally. ALI-1 reduces cytokinin content and simultaneously restrains cytokinin signal transduction, which leads to a stagnation of cell proliferation and reduction of cell number in awn. Noteworthily, ali-1 was the first awn controlling locus that observed increasing grain length in wheat, which is a valuable supplemental attribution of awn on grain weight besides photosynthesis. Thus, ALI-1 pleiotropically regulates awn and grain development, and this work provides a strategy to achieve improved grain yield and address future extreme climate.HighlightALI-1, candidate gene of awn suppressing B1 locus, associates with awn length and grain length, providing a reacquaint of the effect of wheat awn on grain production.
Intestinal delta-6-desaturase activity determines host range forToxoplasmasexual reproduction
Authors: Di Genova Bruno Martorelli , Wilson Sarah K. , Dubey J.P. , Knoll Laura J. 
Published: July 2019

AbstractMany eukaryotic microbes have complex lifecycles that include both sexual and asexual phases with strict species-specificity. While the asexual cycle of the protistan parasiteToxoplasma gondiican occur in any warm-blooded mammal, the sexual cycle is restricted to the feline intestine1. The molecular determinants that identify cats as the definitive host forT. gondiiare unknown. Here, we defined the mechanism of species specificity forT. gondiisexual development and break the species barrier to allow the sexual cycle to occur in mice. We determined thatT. gondiisexual development occurs when cultured feline intestinal epithelial cells are supplemented with linoleic acid. Felines are the only mammals that lack delta-6-desaturase activity in their intestines, which is required for linoleic acid metabolism, resulting in systemic excess of linoleic acid2, 3. We found that inhibition of murine delta-6-desaturase and supplementation of their diet with linoleic acid allowedT. gondiisexual development in mice. This mechanism of species specificity is the first defined for a parasite sexual cycle. This work highlights how host diet and metabolism shape coevolution with microbes. The key to unlocking the species boundaries for other eukaryotic microbes may also rely on the lipid composition of their environments as we see increasing evidence for the importance of host lipid metabolism during parasitic lifecycles4, 5. Pregnant women are advised against handling cat litter as maternal infection withT. gondiican be transmitted to the fetus with potentially lethal outcomes. Knowing the molecular components that create a conducive environment forT. gondiisexual reproduction will allow for development of therapeutics that prevent shedding ofT. gondiiparasites. Finally, given the current reliance on companion animals to studyT. gondiisexual development, this work will allow theT. gondiifield to use of alternative models in future studies.
Sleep prevents catastrophic forgetting in spiking neural networks by forming joint synaptic weight representations
Authors: Golden Ryan , Delanois Jean Erik , Sanda Pavel , Bazhenov Maxim 
Published: July 2019

AbstractArtificial neural networks overwrite previously learned tasks when trained sequentially, a phenomenon known as catastrophic forgetting. In contrast, the brain learns continuously, and typically learns best when new learning is interleaved with periods of sleep for memory consolidation. In this study, we used spiking network to study mechanisms behind catastrophic forgetting and the role of sleep in preventing it. The network could be trained to learn a complex foraging task but exhibited catastrophic forgetting when trained sequentially on multiple tasks. New task training moved the synaptic weight configuration away from the manifold representing old tasks leading to forgetting. Interleaving new task training with periods of off-line reactivation, mimicking biological sleep, mitigated catastrophic forgetting by pushing the synaptic weight configuration towards the intersection of the solution manifolds representing multiple tasks. The study reveals a possible strategy of synaptic weights dynamics the brain applies during sleep to prevent forgetting and optimize learning.