bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of the metabolic profile in mediating the relationship between body mass index and left ventricular mass in adolescents: analysis of a prospective cohort study
Authors: Carter Alice R , Ferreira Diana L. Santos , Taylor Amy E , Lawlor Deborah A , Smith George Davey , Sattar Naveed , Chaturvedi Nishi , Hughes Alun D , Howe Laura D 
Published: March 2020

AbstractBackgroundWe aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure.MethodsBody mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height2.7 (LVMI), was assessed by echocardiography at age 17. The metabolic profile was quantified via nuclear magnetic resonance spectroscopy at age 15.Multivariable confounder (maternal age, parity, highest qualification, maternal smoking, pre-pregnancy BMI, pre-pregnancy height, household social class and adolescent birthweight, adolescent smoking, fruit and vegetable consumption, physical activity) -adjusted linear regression estimated the association of BMI with LVMI and mediation by metabolic traits. We considered 156 metabolomic traits individually, jointly as principal components (PCs) explaining 95% of the variance in the NMR platform, and assessed whether the PCs for the metabolic traits added to the proportion of the association explained by established cardiovascular risk factors (systolic and diastolic blood pressure, insulin, triglycerides, low density lipoprotein, and glucose).ResultsA 1kg/m2 higher BMI was associated with a 0.70 g/m2.7 (0.53, 0.88) and 0.66 g/m2.7 (0.53, 0.79) higher LVMI in males (N=437) and females (N=536), respectively. Established risk factors explained 3% (95% CI: 2% to 5%) of this association in males, increasing to 10% (95% CI: 8%, 13%) when including metabolic PCs. In females, the standard risk factors explained 3% (95% CI: 2%, 5%) of the association, and did not increase when including the metabolic PCs.ConclusionThe addition of the NMR measured metabolic traits appear to mediate more of the effect of BMI on LVMI than the established risk factors alone in adolescent males, but not females.
Spatially fractionated stereotactic body radiotherapy (Lattice SBRT) for large tumors
Authors: Duriseti Sai , Kavanaugh James , Goddu Sreekrishna , Price Alex , Knutson Nels , Reynoso Francisco , Michalski Jeff , Mutic Sasa , Robinson Clifford , Spraker Matthew B 
Published: March 2020

AbstractStereotactic body radiotherapy (SBRT) has demonstrated clinical benefit for patients with metastatic and/or unresectable cancer. Technical considerations of treatment delivery and sensitive organs at risk (OARs) limit the use of SBRT in large tumors or those in unfavorable locations. Spatially fractionated radiotherapy (SFRT) delivers high-dose radiation to discrete sub-volume vertices within a tumor target while restricting the remainder of the target to low dose. SFRT has been utilized for treatment of large tumors with reported dramatic tumor response and minimal side effects. Lattice is a modern approach to SFRT that can be delivered with arc-based therapy, which allows for the rapid dose fall-off required for high quality SBRT. In order to overcome the limitations of SBRT for large tumors, we developed Lattice SBRT. Here we report the results of a dosimetry and quality assurance (QA) feasibility study of Lattice SBRT in 11 patients with 12 tumor targets, each ≥ 10 cm in an axial dimension. Prior CT simulation scans were used to generate volumetric-modulated arc therapy (VMAT) Lattice SBRT plans that were then delivered on clinically available Linacs. QA testing included external portal imaging device (EPID) and ion chamber (IC) analysis. All generated plans were able to meet the standard SBRT dose constraints, such as those from AAPM Task Group 101. Additionally, we provide a step-by-step approach for generating and delivering Lattice SBRT plans using commercially available treatment technology. Lattice SBRT is currently being tested in a prospective trial for patients with metastatic cancer needing palliation of large tumors (NCTXXXX).
Closed-loop stimulation of the medial septum terminates epileptic seizures
Authors: Takeuchi Yuichi , Harangozó Márk , Pedraza Lizeth , Földi Tamás , Kozák Gábor , Berényi Antal 
Published: March 2020

ABSTRACTTemporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, due to its large size and irregular shape. In contrast, the medial septum (MS) is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this ‘proxy intervention’ concept and precisely timed stimulation, we report here that closed-loop MS electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell-type-specific stimulation revealed that precisely timed activation of MS GABAergic neurons underlay the effects. Our concept of phase-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and its current embodiment can be directly translated into clinical application.
Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients
Authors: Syrimi Eleni , Khan Naeem , Murray Paul , Willcox Carrie , Haigh Tracey , Willcox Benjamin , Masand Navta , Zuo Jianmin , Barone Sierra M , Irish Jonathan M , Kearns Pamela , Taylor Graham S 
Published: March 2020

AbstractSystemic immunity plays an important role in cancer immune surveillance and therapy but there is little detailed knowledge about the immune status of healthy children or children with cancer. We performed a high dimensional single cell analysis of systemic immunity in pediatric cancer patients and age-matched healthy children. In young children with cancer (age < 8years) NK cells were decreased in frequency, maturity, expression of perforin and granzyme-B, and were less cytotoxic in ex vivo assays. NK cell activity was restored after in vitro culture with interleukin-2. In contrast, older children with cancer (>8 years old) had decreased naive CD4 and CD8 T-cells with concomitant increases in effector memory and T effector memory RA-revertant (TEMRA) T-cells. These immunological changes in pediatric cancer patients are relevant to the better understanding of how cancers diagnosed in childhood interact with systemic immunity and could inform the development and application of effective immune-modulating therapies in the pediatric population.One Sentence SummaryHigh dimensional analysis of systemic immunity in pediatric cancer patients reveals clinically relevant immune changes in NK and T-cells that vary with patient age.
Alcohol-Induced Increase in the Content of CYP2E1 in Human Liver Microsomes Causes a Multifold Activation of CYP3A4 and Attenuates its Cooperativity
Authors: Dangi Bikash , Davydova Nadezhda Y. , Vavilov Nikita E. , Zgoda Victor G. , Davydov Dmitri R. 
Published: March 2020

AbstractHere we investigate the effect of alcohol-induced increase in the content of CYP2E1 in human liver microsomes (HLM) on the function of CYP3A4. In these studies we used a model that implements enrichment of HLM samples with CYP2E1 through membrane incorporation of the purified protein. Enrichment of HLM with CYP2E1 considerably increases the rate of metabolism of 7-benzyloxyquinoline (BQ) and attenuates the homotropic cooperativity observed with this CYP3A4-specific substrate. Incorporation of CYP2E1 also eliminates the activating effect of α-Naphthoflavone (ANF) on BQ metabolism seen in some untreated HLM samples. To probe the physiological relevance of these effects we compared three pooled preparations of HLM from normal donors (HLM-N) with a preparation obtained from heavy alcohol consumers (HLM-A). The composition of the P450 pool in all four samples was characterized with mass-spectrometric determination of 11 cytochrome P450 species. The molar content of CYP2E1 in HLM-A was from 2.5 to 3.3 times higher than that found in HLM-N. In contrast, the content of CYP3A4 in HLM-A was the lowest among all four HLM samples. Despite of that, HLM-A exhibited much higher rate of metabolism and lower degree of homotropic cooperativity with BQ, similar to that observed in CYP2E1-enriched HLM-N. In order to substantiate the hypothesis on the involvement of physical interactions between CYP2E1 and CYP3A4 in the observed effects we probed hetero-association of these proteins in Supersomes™ containing recombinant CYP3A4 with a technique based on homo-FRET and employing CYP2E1 labeled with BODIPY-618 maleimide. These experiments demonstrated high affinity interactions between the two enzymes and revealed an inhibitory effect of ANF on their hetero-association. Our results demonstrate that the catalytic activity and allosteric properties of CYP3A4 are fundamentally dependent on the composition of the cytochrome P450 ensemble and imply a profound impact of chronic alcohol exposure on the pharmacokinetics of drugs metabolized by CYP3A4.
A new genetic method to predict the prognostic outcome of melanoma
Authors: GuoHu Hong , Qing Guan , XinHua Luo 
Published: March 2020

AbstractCutaneous melanoma is quite often encountered in dermato-oncology. This paper describes a new genetic method to predict the prognostic outcome of melanoma. Data were collected from the TCGA databases. According to tumor progression status, the data were divided into two groups to evaluate the significant biological processes and key genes influencing the outcome of melanoma using a bioinformatics method. By adopting a statistical regression analysis method, a novel score based on the contributing genes was developed. Cox regression analysis was used to validate the effectiveness of the genetic risk score in predicting the outcome. Seven biological processes associated with melanocytes were identified. A protein-protein interactions network showed that 27 functional genes were associated with the outcome of melanoma. Among these, three genes (COL17A1, ITGA6, and SPRR2F) were used to calculate the genetic risk score, which was regarded as an independent and effective risk factor for disease progression or overall survival in melanoma.
An emergent population code in primary auditory cortex supports selective attention to spectral and temporal sound features
Authors: Downer Joshua D. , Verhein Jessica R. , Rapone Brittany C. , O’Connor Kevin N. , Sutter Mitchell L. 
Published: March 2020

ABSTRACTTextbook descriptions of primary sensory cortex (PSC) revolve around single neurons’ representation of low-dimensional sensory features, such as visual object orientation in V1, location of somatic touch in S1, and sound frequency in A1. Typically, studies of PSC measure neurons’ responses along few (1 or 2) stimulus and/or behavioral dimensions. However, real-world stimuli usually vary along many feature dimensions and behavioral demands change constantly. In order to illuminate how A1 supports flexible perception in rich acoustic environments, we recorded from A1 neurons while rhesus macaques performed a feature-selective attention task. We presented sounds that varied along spectral and temporal feature dimensions (carrier bandwidth and temporal envelope, respectively). Within a block, subjects attended to one feature of the sound in a selective change detection task. We find that single neurons tend to be high-dimensional, in that they exhibit substantial mixed selectivity for both sound features, as well as task context. Contrary to common findings in many previous experiments, attention does not enhance the single-neuron representation of attended features in our data. However, a population-level analysis reveals that ensembles of neurons exhibit enhanced encoding of attended sound features, and this population code tracks subjects’ performance. Importantly, surrogate neural populations with intact single-neuron tuning but shuffled higher-order correlations among neurons failed to yield attention-related effects observed in the intact data. These results suggest that an emergent population code not measurable at the single-neuron level might constitute the functional unit of sensory representation in PSC.SIGNIFICANCE STATEMENTThe ability to adapt to a dynamic sensory environment promotes a range of important natural behaviors. We recorded from single neurons in monkey primary auditory cortex while subjects attended to either the spectral or temporal features of complex sounds. Surprisingly, we find no average increase in responsiveness to, or encoding of, the attended feature across single neurons. However, when we pool the activity of the sampled neurons via targeted dimensionality reduction, we find enhanced population-level representation of the attended feature and suppression of the distractor feature. This dissociation of the effects of attention at the level of single neurons vs. the population highlights the synergistic nature of cortical sound encoding and enriches our understanding of sensory cortical function.
Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis
Authors: Guillotin Delphine , Taylor Adam R. , Platé Manuela , Mercer Paul F. , Edwards Lindsay M. , Haggart Ross , Miele Gino , McAnulty Robin J. , Maher Toby M. , Hynds Robert E. , Jamal-Hanjani Mariam , Marshall Richard P. , Fisher Andrew J. , Blanchard Andy D. , Chambers Rachel C. 
Published: March 2020

ABSTRACTFibroblastic foci (FF) represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling un-manipulated myo/fibroblasts within FFin situby laser capture microdissection.The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as aneigengene-based approach to identify transcriptional signatures which correlate with fibrillar collagen gene expression. WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collageneigengeneanalysis revealed that TGF-β1, RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-β1-induced mTORC1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts. These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesisin situand further identifies the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.What is the key question?Can we identify a transcriptional signature associated with collagen gene expression in the fibrotic focus, the cardinal fibrotic lesion in IPF?What is the bottom line?We herein define the major transcriptional programmes involved in fibrogenesis in IPF by profiling myo/fibroblasts within FFin situby laser capture microdissection.Why read on?The data provide strong support for a human tissue-based approach to identify critical transcriptional nodes associated with fibrogenesisin situand further identifies the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.
In vivocharacterization of chick embryo mesoderm by optical coherence tomography assisted microindentation
Authors: Marrese Marica , Antonovaité Nelda , Nelemans Ben K.A. , Ahmadzada Ariana , Iannuzzi Davide , Smit Theodoor H. 
Published: March 2020

AbstractEmbryos are growing organisms with highly heterogeneous properties in space and time. Understanding the mechanical properties is a crucial prerequisite for the investigation of morphogenesis. During the last ten years, new techniques have been developed to evaluate the mechanical properties of biological tissuesin vivo. To address this need, we employed a new instrument that, via the combination of micro-indentation with Optical Coherence Tomography (OCT), allows us to determine both, the spatial distribution of mechanical properties of chick embryos and the structural changes in real-time provided by OCT. We report here the stiffness measurements on live chicken mesoderm during somite formation, from the mesenchymal tailbud to the epithelialized somites. The storage modulus of the mesoderm increases from (176±18) Pa in the tail up to (716±117) Pa in the somitic region. The midline has a storage modulus of (947±111) Pa in the caudal presomitic mesoderm, indicating a stiff rod along the body axis, which thereby mechanically supports the surrounding tissue. The difference in stiffness between midline and presomitic mesoderm decreases as the mesoderm forms somites. The viscoelastic response of the somites develops further until somite IV, which is commensurate with the slow process of epithelization of somites between S0 and SIV.Overall, this study provides an efficient method for the biomechanical characterization of soft biological tissuesin vivoand shows that the mechanical properties strongly relate to different morphological features of the investigated regions.
A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography
Authors: Saxena Neeraj , Shaw Alexander D. , Richmond Lewys , Babic Adele , Singh Krish D. , Hall Judith E. , Wise Richard G. , Muthukumaraswamy Suresh D. 
Published: March 2020

SummaryBackgroundUnderstanding the effects of anaesthetic drugs on cortical oscillations can help to elucidate the mechanistic link between receptor physiology and their clinical effects. Propofol produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing stimulus-onset-evoked responses)1. Dexmedetomidine, an α2-adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deeper sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABAergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations.MethodsSixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visual and motor task.ResultsThe key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the M100 (27%) and M150 (52%) evoked responses, whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on motor GBR or movement related beta de-synchronisation (MRBD). However, dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%).ConclusionsDexmedetomidine and propofol, at equi-sedative doses, have contrasting effects on visual stimulus induced GBR, visual evoked responses and PMBR. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs and their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.
First complete genome sequences ofStreptococcus pyogenesNCTC 8198Tand CCUG 4207T, the type strain of the type species of the genusStreptococcus: 100% match in length and sequence identity between PacBio solo and Illumina plus Oxford Nanopore hybrid assemblies
Authors: Salvà-Serra Francisco , Jaén-Luchoro Daniel , Jakobsson Hedvig E. , Gonzales-Siles Lucia , Karlsson Roger , Busquets Antonio , Gomila Margarita , Bennasar-Figueras Antonio , Russell Julie E. , Fazal Mohammed Abbas , Alexander Sarah , Moore Edward R. B. 
Published: March 2020

AbstractWe present the first complete, closed genome sequences ofStreptococcus pyogenesstrains NCTC 8198Tand CCUG 4207T, the type strain of the type species of the genusStreptococcusand an important human pathogen that causes a wide range of infectious diseases.S. pyogenesNCTC 8198Tand CCUG 4207Tare derived from deposit of the same strain at two different culture collections. NCTC 8198Twas sequenced, using a PacBio platform; the genome sequence was assembledde novo, using HGAP. CCUG 4207Twas sequenced and ade novohybrid assembly was generated, using SPAdes, combining Illumina and Oxford Nanopore sequence reads. Both strategies, yielded closed genome sequences of 1,914,862 bp, identical in length and sequence identity. Combining short-read Illumina and long-read Oxford Nanopore sequence data circumvented the expected error rate of the nanopore sequencing technology, producing a genome sequence indistinguishable to the one determined with PacBio. Sequence analyses revealed five prophage regions, a CRISPR-Cas system, numerous virulence factors and no relevant antibiotic resistance genes.These two complete genome sequences of the type strain ofS. pyogeneswill effectively serve as valuable taxonomic and genomic references for infectious disease diagnostics, as well as references for future studies and applications within the genusStreptococcus.
Establishment ofEtv5gene knockout mice as a recipient model for spermatogonial stem cell transplantation
Authors: Zhang Xianyu , Zhao Xin , Li Guoling , Zhang Mao , Xing Pingping , Li Zicong , Chen Bin , Yang Huaqiang , Wu Zhenfang 
Published: March 2020

AbstractTransplantation of spermatogonial stem cells (SSCs) is an alternative reproductive method to achieve conservation and production of elite animals in livestock production. Creating a recipient animal without endogenous germ cells is important for effective SSC transplantation. However, natural mutants with depletion of SSCs are difficult to obtain, and drug ablation of endogenous germ cells is arduous to perform for practical use. In this study, we used mouse models to study the preparation of recipients with congenital germ cell ablation. We knocked out (KO) Ets-variant gene 5 (Etv5) in mice using the CRISPR/Cas9 system. The testicular weight ofEtv5-/-mice was significantly lower than that of wild-type (WT) mice. The germ cell layer of the seminiferous tubules gradually receded with age inEtv5-/-mice. At 12 weeks of age, the tubules ofEtv5-/-mice lacked germ cells (Sertoli cell-only syndrome), and sperm were completely absent in the epididymis. We subsequently transplanted allogeneic SSCs with enhanced green fluorescent protein (EGFP) into 3-(immature) or 7-week-old (mature)Etv5-/-mice. Restoration of germ cell layers in the seminiferous tubules and spermatogenesis was observed in all immature testes but not in mature adult testes at 2 months post-transplantation. The presence of heterologous genesEtv5andEGFPin recipient testicular tissue and epididymal sperm by PCR indicated that sperm originated from the transplanted donor cells. Our study demonstrates that, althoughEtv5-/-mice could accommodate and support foreign germ cell transplantation, this process occurs in a quite low efficiency to support a full spermatogenesis of transplanted SSCs. However, usingEtv5-/-mice as a recipient model for SSC transplantation is feasible, and still needs further investigation to establish an optimized transplantation process.