bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel conditional Sgsh knockout mouse model recapitulates phenotypic and neuropathic deficits of Sanfilippo syndrome
Authors: Lau Adeline A. , King Barbara M. , Thorsen Carly L. , Hassiotis Sofia , Beard Helen , Trim Paul J. , Whyte Lauren S. , Tamang Sarah J. , Duplock Stephen K. , Snel Marten F. , Hopwood John J. , Hemsley Kim M. 
Published: April 2017

AbstractMucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal storage disorder caused by a deficiency of the lysosomal enzyme N‐sulfoglucosamine sulfohydrolase (SGSH), involved in the catabolism of heparan sulfate. The clinical spectrum is broad and the age of symptom onset and the degree of preservation of cognitive and motor functions appears greatly influenced by genotype. To explore this further, we generated a conditional knockout (SgshKO) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous SgshD31N MPS‐IIIA mouse model. Phenotypic deficits were noted in SgshKO mice prior to SgshD31N mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein‐II expression, reactive astrocytosis and appearance of ubiquitin‐positive inclusions) were also comparable between affected mouse strains. This suggests that gross substrate storage and these neuropathological markers are neither primary determinants, nor good biomarkers/indicators of symptom generation, confirming similar observations made recently in MPS‐IIIA patients. The SgshKO mouse will be a useful tool for elucidation of the neurological basis of disease and assessment of the clinical efficacy of new treatments for Sanfilippo syndrome.
Risk factors for poor bone health in primary mitochondrial disease
Authors: Gandhi Shifa S. , Muraresku Colleen , McCormick Elizabeth M. , Falk Marni J. , McCormack Shana E. 
Published: April 2017

AbstractIntroductionPrimary mitochondrial disease is caused by either mitochondrial or nuclear DNA mutations that impact the function of the mitochondrial respiratory chain. Individuals with mitochondrial disorders have comorbid conditions that may increase their risk for poor bone health. The objective of this retrospective electronic medical record (EMR) review was to examine risk factors for poor bone health in children and adults with primary mitochondrial disease.MethodsEighty individuals with confirmed clinical and genetic diagnoses of primary mitochondrial disease at the Children's Hospital of Philadelphia (CHOP) were included in this study. Risk factors and bone health outcomes were collected systematically, including: anthropometrics (low BMI), risk‐conferring co‐morbidities and medications, vitamin D status, nutrition, immobility, fracture history, and, where available, dual energy x‐ray absorptiometry (DXA) bone mineral density (BMD) results.ResultsOf patients 73% (n = 58) had at least one risk factor and 30% (n = 24) had four or more risk factors for poor bone health. The median number of risk factors per participant was 2, with an interquartile interval (IQI 0–4). In the subset of the cohort who were known to have sustained any lifetime fracture (n = 11), a total of 16 fractures were reported, six of which were fragility fractures, indicative of a clinically significant decrease in bone strength.ConclusionsThe prevalence of risk factors for poor bone health in primary mitochondrial disease is high. As part of supportive care, practitioners should address modifiable risk factors to optimize bone health, and have a low threshold to evaluate clinical symptoms that could suggest occult fragility fracture.
The effect of selective opioid receptor agonists and antagonists on epileptiform activity in morphine‐dependent infant mice hippocampal slices
Authors: Panahi Yousef , Saboory Ehsan , Rassouli Ali , Sadeghi‐Hashjin Goudarz , Roshan‐Milani Shiva , Derafshpour Leila , Rasmi Yousef 
Published: April 2017

AbstractHippocampal slices of mouse brain were used to estimate how selective agonist and antagonist of opioid receptors alter Low‐Mg+2 artificial cerebrospinal fluid (LM‐ACSF)‐induced epileptiform activities in normal and morphine‐dependent mice. Brain slices were obtained from control and morphine‐dependent mice. The morphine‐dependent group received morphine once a day for 5 consecutive days, and the control group received saline. All injections were administered subcutaneously (s.c) in a volume of 0.1 mL on postnatal days 14–18. Brain slices were perfused with LM‐ACSF along with selective agonist and antagonist of μ, κ and δ opioid receptors. Changes in spike count per unit of time were used as indices to quantify the effects of LM‐ACSF exposure in the slices. In both groups, DAMGO (selective μ opioid receptor agonist) and DPDPE (selective δ opioid receptor agonist) suppressed while Dyn‐A (selective κ opioid receptor agonist) potentiated the epileptiform activity. Meanwhile, BFN‐A (selective μ opioid receptor antagonist) recovered epileptiform activity in normal brain slices but not in morphine‐dependent ones. NTI (selective δ opioid receptor antagonist) and nor‐BNI (selective κ opioid receptor antagonist) decreased epileptiform activity. It seems that the excitatory effect of morphine on epileptiform activity was mediated through kappa receptors and its inhibitory effect was mediated via the mu receptor and, to a lesser degree, through the delta receptor. The pattern of effect was similar in normal and morphine‐dependent slices, but the intensity of the effect was significantly stronger in normal mice. Finding of this study might be considered for further research and attention in epilepsy treatment.
Destabilisation and modification of Tollmien–Schlichting disturbances by a three-dimensional surface indentation
Authors: Xu Hui , Mughal Shahid M. , Gowree Erwin R. , Atkin Chris J. , Sherwin Spencer J. 
Published: April 2017

We consider the influence of a smooth three-dimensional (3-D) indentation on the instability of an incompressible boundary layer by linear and nonlinear analyses. The numerical work was complemented by an experimental study to investigate indentations of approximately $11\unicode[STIX]{x1D6FF}_{99}$ and $22\unicode[STIX]{x1D6FF}_{99}$ width at depths of 45 %, 52 % and 60 % of $\unicode[STIX]{x1D6FF}_{99}$, where $\unicode[STIX]{x1D6FF}_{99}$ indicates 99% boundary layer thickness. For these indentations a separation bubble confined within the indentation arises. Upstream of the indentation, spanwise-uniform Tollmien–Schlichting (TS) waves are assumed to exist, with the objective to investigate how the 3-D surface indentation modifies the 2-D TS disturbance. Numerical corroboration against experimental data reveals good quantitative agreement. Comparing the structure of the 3-D separation bubble to that created by a purely 2-D indentation, there are a number of topological changes particularly in the case of the widest indentation; more rapid amplification and modification of the upstream TS waves along the symmetry plane of the indentation is observed. For the shortest indentations, beyond a certain depth there are then no distinct topological changes of the separation bubbles and hence on flow instability. The destabilising mechanism is found to be due to the confined separation bubble and is attributed to the inflectional instability of the separated shear layer. Finally for the widest width indentation investigated ($22\unicode[STIX]{x1D6FF}_{99}$), results of the linear analysis are compared with direct numerical simulations. A comparison with the traditional criteria of using $N$-factors to assess instability of properly 3-D disturbances reveals that a general indication of flow destabilisation and development of strongly nonlinear behaviour is indicated as $N=6$ values are attained. However $N$-factors, based on linear models, can only be used to provide indications and severity of the destabilisation, since the process of disturbance breakdown to turbulence is inherently nonlinear and dependent on the magnitude and scope of the initial forcing.
Estimating the real incidence of invasive listeriosis through an integrated surveillance model in use in Lombardy (Italy, 2006–2014)
Authors: ZOLIN A. , AMATO E. , D'AURIA M. , GORI M. , HUEDO P. , BOSSI A. , PONTELLO M. 
Published: April 2017

SUMMARYThe annual incidence of listeriosis in Italy is lower (0·19–0·27 per 100 000 inhabitants per year) than in Europe (0·34–0·52 per 100 000 inhabitants per year). Since the observed incidence of listeriosis may be biased downward for underdiagnosis or under-reporting, this work aims to estimate the real incidence of listeriosis during a 9-year period in the Lombardy region, Italy. Data on listeriosis cases were collected from national mandatory notification system (MAINF) and Laboratory-based Surveillance System (LabSS). The two sources were cross-matched and capture–recapture method was applied to estimate the number of undetected cases and the real incidence of invasive listeriosis. Five hundred and eighty invasive listeriosis cases were detected by the two sources between 2006 and 2014: 50·2% were identified only via MAINF, 16·7% were recorded only via LabSS, overlaps occurred in 192 cases (33·1%). The mean annual incidence detected only by MAINF was 0·56 per 100 000 inhabitants, which rose to 0·67 per 100 000 considering also the cases detected by LabSS. The capture–recapture method allowed to estimate an incidence of 0·84 per 100 000. The high incidence of listeriosis may be due to improved sensitivity of the surveillance system, but also reflect a real increase, associated with an increased population at risk.
Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence
Authors: SIGNORELLI C. , ODONE A. , CIORBA V. , CELLA P. , AUDISIO R. A. , LOMBARDI A. , MARIANI L. , MENNINI F. S. , PECORELLI S. , REZZA G. , ZUCCOTTI G.V. , PERACINO A. 
Published: April 2017

SUMMARYIn 2014, the Food and Drug Administration approved a new human papillomavirus 9-valent vaccine (9vHPV), targeting nine HPV types: HPV types 6, 11, 16, and 18, which are also targeted by the quadrivalent HPV vaccine (qHPV), plus five additional high cancer risk HPV types (HPV types 31, 33, 45, 52, and 58). The aim of the current study was to systematically retrieve, qualitatively and quantitatively pool, as well as critically appraise all available evidence on 9vHPV from randomized controlled trials (RCTs). We conducted a systematic review of the literature on 9vHPV efficacy, immunogenicity and safety, as well as a systematic search of registered, completed, and ongoing RCTs. We retrieved and screened 227 records for eligibility. A total of 10 publications reported on RCTs’ results on 9vHPV and were included in the review. Sixteen RCTs on 9vHPV have been registered on RCT registries. There is evidence that 9vHPV generated a response to HPV types 6, 11, 16 and 18 that was non-inferior to qHPV. Vaccine efficacy against five additional HPV type-related diseases was directly assessed on females aged 16–26 years (risk reduction against high-grade cervical, vulvar or vaginal disease = 96·7%, 95% CI 80·9%–99·8%). Bridging efficacy was demonstrated for males and females aged 9–15 years and males aged 16–26 years (the lower bound of the 95% CIs of both the geometric mean titer ratio and difference in seroconversion rates meeting the criteria for non-inferiority for all HPV types). Overall, 9vHPV has been proved to be safe and well tolerated. Other RCTs addressed: 9vHPV co-administration with other vaccines, 9vHPV administration in subjects that previously received qHPV and 9vHPV efficacy in regimens containing fewer than three doses. The inclusion of additional HPV types in 9vHPV offers great potential to expand protection against HPV infection. However, the impact of 9vHPV on reducing the global burden of HPV-related disease will greatly depend on vaccine uptake, coverage, availability, and affordability.
Seed ecology: a diverse and vibrant field of study
Authors: Baskin Carol C. 
Published: April 2017

AbstractMy purpose is to introduce a special issue of Seed Science Research devoted to papers resulting from material presented at Seed Ecology V held in Caeté, Brazil on 21–25 August 2016. An overview of the field of seed ecology is presented that includes a short summary of what I consider to be the eight basic subcategories of this field, and the five new areas of investigation that have developed as extensions and/or recombinations of basic areas. Seed ecology conferences allow researchers to communicate with each other and build new collaborative relationships. At Seed Ecology V, information was presented that related to each area of seed ecology. The nine papers in this special issue are a small sample of the information presented at the meeting, and each paper is briefly described and placed into one of the subcategories of seed ecology research.
Two-dimensional Mo1.33C MXene with divacancy ordering prepared from parent 3D laminate with in-plane chemical ordering
Authors: Tao Quanzheng , Dahlqvist Martin , Lu Jun , Kota Sankalp , Meshkian Rahele , Halim Joseph , Palisaitis Justinas , Hultman Lars , Barsoum Michel W. , Persson Per O.Å. , Rosen Johanna 
Published: April 2017

AbstractThe exploration of two-dimensional solids is an active area of materials discovery. Research in this area has given us structures spanning graphene to dichalcogenides, and more recently 2D transition metal carbides (MXenes). One of the challenges now is to master ordering within the atomic sheets. Herein, we present a top-down, high-yield, facile route for the controlled introduction of ordered divacancies in MXenes. By designing a parent 3D atomic laminate, (Mo2/3Sc1/3)2AlC, with in-plane chemical ordering, and by selectively etching the Al and Sc atoms, we show evidence for 2D Mo1.33C sheets with ordered metal divacancies and high electrical conductivities. At ∼1,100 F cm−3, this 2D material exhibits a 65% higher volumetric capacitance than its counterpart, Mo2C, with no vacancies, and one of the highest volumetric capacitance values ever reported, to the best of our knowledge. This structural design on the atomic scale may alter and expand the concept of property-tailoring of 2D materials.
Exploiting induced pluripotent stem cell-derived macrophages to unravel host factors influencing Chlamydia trachomatis pathogenesis
Authors: Yeung Amy T. Y. , Hale Christine , Lee Amy H. , Gill Erin E. , Bushell Wendy , Parry-Smith David , Goulding David , Pickard Derek , Roumeliotis Theodoros , Choudhary Jyoti , Thomson Nick , Skarnes William C. , Dougan Gordon , Hancock Robert E. W. 
Published: April 2017

AbstractChlamydia trachomatis remains a leading cause of bacterial sexually transmitted infections and preventable blindness worldwide. There are, however, limited in vitro models to study the role of host genetics in the response of macrophages to this obligate human pathogen. Here, we describe an approach using macrophages derived from human induced pluripotent stem cells (iPSdMs) to study macrophage–Chlamydia interactions in vitro. We show that iPSdMs support the full infectious life cycle of C. trachomatis in a manner that mimics the infection of human blood-derived macrophages. Transcriptomic and proteomic profiling of the macrophage response to chlamydial infection highlighted the role of the type I interferon and interleukin 10-mediated responses. Using CRISPR/Cas9 technology, we generated biallelic knockout mutations in host genes encoding IRF5 and IL-10RA in iPSCs, and confirmed their roles in limiting chlamydial infection in macrophages. This model can potentially be extended to other pathogens and tissue systems to advance our understanding of host-pathogen interactions and the role of human genetics in influencing the outcome of infections.
Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer
Authors: Carstens Julienne L. , Correa de Sampaio Pedro , Yang Dalu , Barua Souptik , Wang Huamin , Rao Arvind , Allison James P. , LeBleu Valerie S. , Kalluri Raghu 
Published: April 2017

AbstractThe exact nature and dynamics of pancreatic ductal adenocarcinoma (PDAC) immune composition remains largely unknown. Desmoplasia is suggested to polarize PDAC immunity. Therefore, a comprehensive evaluation of the composition and distribution of desmoplastic elements and T-cell infiltration is necessary to delineate their roles. Here we develop a novel computational imaging technology for the simultaneous evaluation of eight distinct markers, allowing for spatial analysis of distinct populations within the same section. We report a heterogeneous population of infiltrating T lymphocytes. Spatial distribution of cytotoxic T cells in proximity to cancer cells correlates with increased overall patient survival. Collagen-I and αSMA+fibroblasts do not correlate with paucity in T-cell accumulation, suggesting that PDAC desmoplasia may not be a simple physical barrier. Further exploration of this technology may improve our understanding of how specific stromal composition could impact T-cell activity, with potential impact on the optimization of immune-modulatory therapies.
Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
Authors: Pan Feng , Wingo Thomas S. , Zhao Zhigang , Gao Rui , Makishima Hideki , Qu Guangbo , Lin Li , Yu Miao , Ortega Janice R. , Wang Jiapeng , Nazha Aziz , Chen Li , Yao Bing , Liu Can , Chen Shi , Weeks Ophelia , Ni Hongyu , Phillips Brittany Lynn , Huang Suming , Wang Jianlong , He Chuan , Li Guo-Min , Radivoyevitch Tomas , Aifantis Iannis , Maciejewski Jaroslaw P. , Yang Feng-Chun , Jin Peng , Xu Mingjiang 
Published: April 2017

AbstractTET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2−/− mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2−/− tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2−/− Lin−c-Kit+ cells shows higher mutation frequencies in Tet2−/− cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.
DNA replication licensing factor Cdc6 and Plk4 kinase antagonistically regulate centrosome duplication via Sas-6
Authors: Xu Xiaowei , Huang Shijiao , Zhang Boyan , Huang Fan , Chi Wangfei , Fu Jingyan , Wang Gang , Li Si , Jiang Qing , Zhang Chuanmao 
Published: April 2017

AbstractCentrosome number is tightly controlled during the cell cycle to ensure proper spindle assembly and cell division. However, the underlying mechanism that controls centrosome number remains largely unclear. We show herein that the DNA replication licensing factor Cdc6 is recruited to the proximal side of the centrioles via cyclin A to negatively regulate centrosome duplication by binding and inhibiting the cartwheel protein Sas-6 from forming a stable complex with another centriole duplication core protein, STIL. We further demonstrate that Cdc6 colocalizes with Plk4 at the centrosome, and interacts with Plk4 during S phase. Plk4 disrupts the interaction between Sas-6 and Cdc6, and suppresses the inhibitory role of Cdc6 on Sas-6 by phosphorylating Cdc6. Overexpressing wild-type Cdc6 or Plk4-unphosphorylatable Cdc6 mutant 2A reduces centrosome over-duplication caused by Plk4 overexpression or hydroxyurea treatment. Taken together, our data demonstrate that Cdc6 and Plk4 antagonistically control proper centrosome duplication during the cell cycle.
Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes
Authors: Woodbury-Smith Marc , Nicolson Rob , Zarrei Mehdi , Yuen Ryan K. C. , Walker Susan , Howe Jennifer , Uddin Mohammed , Hoang Ny , Buchanan Janet A. , Chrysler Christina , Thompson Ann , Szatmari Peter , Scherer Stephen W. 
Published: April 2017

AbstractAutism spectrum disorder is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to autism spectrum disorder, showing de novo and inherited unbalanced copy number variants and smaller insertions and deletions (indels), more complex structural variants, as well as single-nucleotide variants deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two copy number variant microdeletions, which affect regions of NRXN1 and MBD5—each well-established in association with risk of autism spectrum disorder and other neurodevelopmental disorders. Although each copy number variant would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.
Implantable strain sensor to monitor fracture healing with standard radiography
Authors: Pelham Hunter , Benza Donald , Millhouse Paul W. , Carrington Nathan , Arifuzzaman Md. , Behrend Caleb J. , Anker Jeffrey N. , DesJardins John D. 
Published: April 2017

AbstractCurrent orthopaedic clinical methods do not provide an objective measure of fracture healing or weight bearing for lower extremity fractures. The following report describes a novel approach involving in-situ strain sensors to objectively measure fracture healing. The sensor uses a cantilevered indicator pin that responds to plate bending and an internal scale to demonstrate changes in the pin position on plain film radiographs. The long lever arm amplifies pin movement compared to interfragmentary motion, and the scale enables more accurate measurement of position changes. Testing with a human cadaver comminuted metaphyseal tibia fracture specimen demonstrated over 2.25 mm of reproducible sensor displacement on radiographs with as little as 100 N of axial compressive loading. Finite element simulations determined that pin displacement decreases as the fracture callus stiffens and that pin motion is linearly related to the strain in the callus. These results indicate that an implanted strain sensor is an effective tool to help assess bone healing after internal fixation and could provide an objective clinical measure for return to weight bearing.