bluuebunny/crossref_metadata_2025 huggingface dataset:
White matter injury induced by diabetes in acute stroke is clinically relevant: A preliminary study
Authors: Yu Xinfeng , Song Ruirui , Jiaerken Yerfan , Yuan Lixia , Huang Peiyu , Lou Min , Jiang Quan , Zhang Minming
Published: November 2016

The importance of white matter injury induced by diabetes in stroke severity and prognosis is largely unknown. We aimed to investigate the relationship between diabetes-related white matter injury beyond stroke lesions with acute neurological deficits and clinical outcome after stroke. In total, 36 stroke patients within 3–7 days after onset were enrolled. Neurological deficits on admission were assessed by National Institute of Health Stroke Score, and poor outcome at 3 months was defined as modified Rankin score >2. White matter tracts were compared between patients with diabetic and non-diabetic stroke using fractional anisotropy from diffusion tensor imaging. Regional white matter abnormality with decreased fractional anisotropy was observed in diabetic patients ( n = 18) when compared to non-diabetic patients ( n = 18). Decreased fractional anisotropy in ipsilesional distal corticospinal tract was independently associated with higher National Institute of Health Stroke Score motor component score ( β = −0.444, p = 0.005), and decreased fractional anisotropy in contralesional superior longitudinal fasciculus I was independently related to poor outcome (odds ratio, 0.900; p = 0.033). Our findings suggested that only white matter injury induced by diabetes in specific tracts like corticospinal tract and superior longitudinal fasciculus beyond stroke lesions has clinically relevant, providing insight into the mechanism of stroke recovery under the diabetic condition.
Force, Fraud, and Coercion—What Do They Mean? A Study of Victimization Experiences in a New Destination Latino Sex Trafficking Network
Authors: Sabon Lauren Copley
Published: November 2016

In response to increasing Latino new destination migration in the United States, Latino sex trafficking networks have emerged in many of these areas. This article examines victimization experiences of Latina immigrants trafficked by a regional network operating in the Eastern United States drawn from law enforcement records and interviews with legal actors involved in the criminal case. The stories shared with law enforcement by the Latina victims gives insight into their lives, experiences in prostitution, and the operation of a trafficking/prostitution network (all lacking in the literature). Through the analytical frame of social constructionism, this research highlights how strict interpretation of force, fraud, coercion, and agency used to define “severe forms of trafficking” in the TVPA limits its ability to recognize many victimization experiences in trafficking situations at the hands of traffickers. The forms of coercion used in the criminal enterprise under study highlights the numerous ways it can be wielded (even without a physical presence) and its malleability as a concept despite legal definitional rigidity. The lack of legal recognition of the plurality of lived experiences in which agency and choice can be mitigated by social forces, structural violence, intersectional vulnerabilities, and the actions of others contributes to the scholarly critique of issues prosecuting trafficking cases under the TVPA and its strict legal definitions.
Gender-Responsive Intervention for Female Juvenile Offenders: A Quasi-Experimental Outcome Evaluation
Authors: Anderson Valerie R. , Walerych Brinn M. , Campbell Nordia A. , Barnes Ashlee R. , Davidson William S. , Campbell Christina A. , Onifade Eyitayo , Petersen Jodi L.
Published: November 2016

The increasing proportion of girls in the juvenile justice system has prompted courts to develop gender-responsive services. The present study examined data from a mid-sized county juvenile court to examine the effects of a group home intervention for girls. The study compared group home participants ( n = 172) with girls who did not receive group home treatment ( n = 814) using propensity score matching (PSM). Girls who received group home treatment were significantly less likely to re-offend in the 2-year follow-up period. Policy and practice implications for gender-responsive services as well as future directions for research are discussed.
Understanding the participation experience of the top contributors in a crowdsourcing of inventive activities context
Authors: Innocent Morgane , Gabriel Patrick , Divard Ronan
Published: November 2016

The aim of this research is to identify the dimensions of the lived experience of contributors in a crowdsourcing of inventive activities context. The study is based on 93 online interviews from three major crowdsourcing platforms with contributors who have won at least one contest. The results reveal a participation experience with six dimensions. In addition to the praxeological, hedonic-sensory, rhetorical and temporal dimensions, the participation experience also includes eudemonic and liberating components. The six dimensions observed are found to be combined in an experiential system, which is organised around cross-dimensional themes such as learning and social interaction. These results encourage the development of an experiential context that fosters the emergence of the six dimensions in order to enhance the richness, diversity and memorability of participation.
Shoulder Arthroplasty Outcomes in Patients With Multiple Reported Drug Allergies
Authors: Rosenthal Brett D. , Knesek Michael J. , Kahlenberg Cynthia A. , Mai Harry , Saltzman Matthew D.
Published: November 2016

Background:

The presence of multiple allergies has been correlated with worse outcomes for patients undergoing hip and knee arthroplasty, but the effect of allergies has not yet been elucidated with respect to shoulder arthroplasty.

Purpose/Hypothesis:

The purpose of this study is to identify any discrepancies in shoulder arthroplasty outcomes with respect to reported drug allergies. We hypothesized that patients with multiple drug allergies would have inferior outcomes.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

Included in the analysis were a single surgeon’s cases between 2009 and 2014 of primary total shoulder arthroplasty with a minimum of 180 days of follow-up. Cases with fracture as the indication were excluded. Preoperative and postoperative metrics included visual analog scale (VAS) for pain, forward flexion range of motion, and Simple Shoulder Test (SST) results, and postoperative patient satisfaction scores were also collected. Chi-square and 1-way analysis of variance with Tukey post hoc analyses were performed when appropriate.

Results:

A total of 98 patients were included (no allergies, n = 51; single allergy, n = 21; multiple allergies, n = 26). The proportion of females was greater with increasing number of allergies (no allergies, 31%; single allergies, 47%; multiple allergies, 88%; Pearson χ2 = 22.5; P < .0001). Both preoperatively and postoperatively, no difference was found between cohorts with respect to SST score, VAS score, or forward flexion. There was also no difference in postoperative satisfaction between cohorts. No difference between cohorts was identified when comparing the pre- to postoperative change in SST scores, VAS scores, or forward flexion.

Conclusion:

The presence of single or multiple allergies is not correlated with worse outcomes after primary anatomic total shoulder arthroplasty.
Expectancy-Value Beliefs of Early-Adolescent Hispanic and Non-Hispanic Youth
Authors: Safavian Nayssan , Conley AnneMarie
Published: November 2016

This study used the Eccles et al. expectancy-value (E-V) theory to test the influence of motivation on mathematics achievement and enrollment using data from a cohort of 926 seventh-grade prealgebra students (49% male, 76% Hispanic, 76% low income, and 55% English learner). E-V beliefs were assessed in seventh grade along with achievement, and enrollment was measured in eighth grade. Differential associations of motivation, achievement, and enrollment were examined across Hispanic and non-Hispanic populations. Expectancy for success and task value uniquely predicted seventh-grade achievement and eighth-grade algebra enrollment after controlling for prior achievement and a full set of demographic controls, including low socioeconomic status and English fluency. The association of interest value and achievement differentiated across Hispanic and non-Hispanic youth, suggesting that the effect of interest value on mathematics achievement was weaker for Hispanic youth than for non-Hispanics after accounting for success expectations and prior achievement.
(Un)Commonly Connected
Authors: Hodge Emily M. , Salloum Serena J. , Benko Susanna L.
Published: November 2016

As states continue to implement the Common Core State Standards (CCSS), state educational agencies (SEAs) are providing professional development and curricular resources to help districts and teachers understand the standards. However, little is known about the resources SEAs endorse, the states and/or organizations sponsoring these resources, and how states and organizations are connected. This study investigates the secondary English/language arts resources provided by 51 SEAs (2,023 resources sponsored by 51 SEAs and 262 intermediary organizations). Social network analysis of states and sponsoring organizations revealed a core-periphery network in which certain states and organizations were frequently named as the sponsors of resources, while other organizations were named as resource sponsors by only one state. SEAs are providing a variety of types of resources, including professional development, curriculum guidelines, articles, and instructional aids. This study offers insight into the most influential actors providing CCSS resources at the state level, as well as how SEAs are supporting instructional capacity through the resources they provide for teachers.
Impact of Pharmacist Follow-up Intervention on Patient Return to a Community Pharmacy From a Convenient Care Clinic
Authors: Schroeder Michelle N. , Potter Johanna , DiDonato Kristen , Lengel Aaron J. , Powers Mary F.
Published: November 2016

Background: Convenient Care Clinics (CCCs) located within the same facility as a retail pharmacy offer the opportunity for immediate fill of prescriptions from the CCC and may also provide a source of new customers for the pharmacy. Objective: To assess the impact of a follow-up intervention on new patients seen at a CCC returning to the pharmacy for subsequent prescription fills compared to the control group. Methods: New patients who filled a prescription from the CCC in November and December 2015 received an initial follow-up telephone call or letter, respectively, from the pharmacist within 10 days of their prescription fill date. The primary end point of the percentage of patient return was assessed for 3 months following the initial fill date. Secondary end points included number of prescriptions transferred and customer satisfaction scores. Results: Thirty-four out of 214 patients in the control group returned to the pharmacy for subsequent prescription fills (15.9%). Fourteen out of 52 patients in the telephone group returned to the pharmacy for additional prescription fills following a telephone call from the pharmacist. (26.9%, P = .063) Sixteen out of 77 patients in the letter group returned to the pharmacy after their first prescription. (20.8%, P = .329). Conclusions: Following-up with new patients to the pharmacy in the form of a personalized telephone call increases the likelihood of patients continuing to utilize the pharmacy for their prescription needs.
GEN3VA: aggregation and analysis of gene expression signatures from related studies
Authors: Gundersen Gregory W. , Jagodnik Kathleen M. , Woodland Holly , Fernandez Nicholas F. , Sani Kevin , Dohlman Anders B. , Ung Peter Man-Un , Monteiro Caroline D. , Schlessinger Avner , Ma’ayan Avi
Published: November 2016

Background

Genome-wide gene expression profiling of mammalian cells is becoming a staple of many published biomedical and biological research studies. Such data is deposited into data repositories such as the Gene Expression Omnibus (GEO) for potential reuse. However, these repositories currently do not provide simple interfaces to systematically analyze collections of related studies.

Results

Here we present GENE Expression and Enrichment Vector Analyzer (GEN3VA), a web-based system that enables the integrative analysis of aggregated collections of tagged gene expression signatures identified and extracted from GEO. Each tagged collection of signatures is presented in a report that consists of heatmaps of the differentially expressed genes; principal component analysis of all signatures; enrichment analysis with several gene set libraries across all signatures, which we term enrichment vector analysis; and global mapping of small molecules that are predicted to reverse or mimic each signature in the aggregate. We demonstrate how GEN3VA can be used to identify common molecular mechanisms of aging by analyzing tagged signatures from 244 studies that compared young vs. old tissues in mammalian systems. In a second case study, we collected 86 signatures from treatment of human cells with dexamethasone, a glucocorticoid receptor (GR) agonist. Our analysis confirms consensus GR target genes and predicts potential drug mimickers.

Conclusions

GEN3VA can be used to identify, aggregate, and analyze themed collections of gene expression signatures from diverse but related studies. Such integrative analyses can be used to address concerns about data reproducibility, confirm results across labs, and discover new collective knowledge by data reuse. GEN3VA is an open-source web-based system that is freely available at: http://amp.pharm.mssm.edu/gen3va.
Nutrition surveillance using a small open cohort: experience from Burkina Faso
Authors: Altmann Mathias , Fermanian Christophe , Jiao Boshen , Altare Chiara , Loada Martin , Myatt Mark
Published: November 2016

Background

Nutritional surveillance remains generally weak and early warning systems are needed in areas with high burden of acute under-nutrition. In order to enhance insight into nutritional surveillance, a community-based sentinel sites approach, known as the Listening Posts (LP) Project, was piloted in Burkina Faso by Action Contre la Faim (ACF). This paper presents ACF’s experience with the LP approach and investigates potential selection and observational biases.

Methods

Six primary sampling units (PSUs) were selected in each livelihood zone using the centric systematic area sampling methodology. In each PSU, 22 children aged between 6 and 24 months were selected by proximity sampling. The prevalence of GAM for each month from January 2011 to December 2013 was estimated using a Bayesian normal–normal conjugate analysis followed by PROBIT estimation. To validate the LP approach in detecting changes over time, the time trends of MUAC from LP and from five cross-sectional surveys were modelled using polynomial regression and compared by using a Wald test. The differences between prevalence estimates from the two data sources were used to assess selection and observational biases.

Results

The 95 % credible interval around GAM prevalence estimates using LP approach ranged between +6.5 %/−6.0 % on a prevalence of 36.1 % and +3.5 %/−2.9 % on a prevalence of 10.8 %. LP and cross-sectional surveys time trend models were well correlated (p = 0.6337). Although LP showed a slight but significant trend for GAM to decrease over time at a rate of −0.26 %/visit, the prevalence estimates from the two data sources showed good agreement over a 3-year period.

Conclusions

The LP methodology has proved to be valid in following trends of GAM prevalence for a period of 3 years without selection bias. However, a slight observational bias was observed, requiring a periodical reselection of the sentinel sites. This kind of surveillance project is suited to use in areas with high burden of acute under-nutrition where early warning systems are strongly needed. Advocacy is necessary to develop sustainable nutrition surveillance system and to support the use of surveillance data in guiding nutritional programs.
Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer’s disease: post-hoc analysis of a randomized placebo-controlled study
Authors: Hager Klaus , Baseman Alan S. , Nye Jeffrey S. , Brashear H. Robert , Han John , Sano Mary , Davis Bonnie , Richards Henry M.
Published: November 2016

Background

A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer’s disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome.

Methods

Randomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints.

Results

Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores.

Conclusion

This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation.

Trial registration

ClinicalTrials.gov NCT00679627. Registered 15 May 2008.
Microvesicles secreted from equine amniotic-derived cells and their potential role in reducing inflammation in endometrial cells in an in-vitro model
Authors: Perrini Claudia , Strillacci Maria Giuseppina , Bagnato Alessandro , Esposti Paola , Marini Maria Giovanna , Corradetti Bruna , Bizzaro Davide , Idda Antonella , Ledda Sergio , Capra Emanuele , Pizzi Flavia , Lange-Consiglio Anna , Cremonesi Fausto
Published: November 2016

Background

It is known that a paracrine mechanism exists between mesenchymal stem cells and target cells. This process may involve microvesicles (MVs) as an integral component of cell-to-cell communication.

Methods

In this context, this study aims to understand the efficacy of MVs in in-vitro endometrial stressed cells in view of potential healing in in-vivo studies. For this purpose, the presence and type of MVs secreted by amniotic mesenchymal stem cells (AMCs) were investigated and the response of endometrial cells to MVs was studied using a dose-response curve at different concentrations and times. Moreover, the ability of MVs to counteract the in vitro stress in endometrial cells induced by lipopolysaccharide was studied by measuring the rate of apoptosis and cell proliferation, the expression of some pro-inflammatory genes such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin 1β (IL-1β), and metalloproteinases (MMP) 1 and 13, and the release of some pro- or anti-inflammatory cytokines.

Results

MVs secreted by the AMCs ranged in size from 100 to 200 nm. The incorporation of MVs was gradual over time and peaked at 72 h. MVs reduced the apoptosis rate, increased cell proliferation values, downregulated pro-inflammatory gene expression, and decreased the secretion of pro-inflammatory cytokines.

Conclusion

Our data suggest that some microRNAs could contribute to counteracting in-vivo inflammation of endometrial tissue.
Phenotypic correction of Fanconi anemia cells in the murine bone marrow after carrier cell mediated delivery of lentiviral vector
Authors: Chakkaramakkil Verghese Santhosh , Goloviznina Natalya A. , Kurre Peter
Published: November 2016

Fanconi anemia (FA) is an autosomal-recessive disorder associated with hematopoietic failure and it is a candidate for hematopoietic stem cell (HSC)-directed gene therapy. However, the characteristically reduced HSC numbers found in FA patients, their ineffective mobilization from the marrow, and re-oxygenation damage during ex vivo manipulation have precluded clinical success using conventional in vitro approaches. We previously demonstrated that lentiviral vector (LV) particles reversibly attach to the cell surface where they gain protection from serum complement neutralization. We reasoned that cellular delivery of LV to the bone marrow niche could avoid detrimental losses during FA HSC mobilization and in vitro modification. Here, we demonstrate that a VSV-G pseudotyped lentivector, carrying the FANCC transgene, can be transmitted from carrier to bystander cells. In cell culture and transplantation models of FA, we further demonstrate that LV carrier cells migrate along SDF-1α gradients and transfer vector particles that stably integrate and phenotypically correct the characteristic DNA alkylator sensitivity in murine and human FA-deficient target bystander cells. Altogether, we demonstrate that cellular homing mechanisms can be harnessed for the functional phenotype correction in murine FA hematopoietic cells.
From classical reflectivity-to-velocity inversion to full-waveform inversion using phase-modified and deconvolved reverse time migration images
Authors: Tang Chen , McMechan George A.
Published: November 2016

To obtain a physical understanding of gradient-based descent methods in full-waveform inversion (FWI), we find a connection between the FWI gradient and the image provided by reverse time migration (RTM). The gradient uses the residual data as a virtual source, and RTM uses the observed data directly as the boundary condition, so the FWI gradient is similar to a time integration of the RTM image using the residual data, which physically converts the phase of the reflectivity to the phase of the velocity. Therefore, gradient-based FWI can be connected to the classical reflectivity-to-velocity/impedance inversion (RVI). We have developed a new FWI scheme that provides a self-contained and physically intuitive derivation, which naturally establishes a connection among the amplitude-preserved RTM, the Zoeppritz equations (amplitude variation with angle inversion), and RVI, and combines them into a single framework to produce a preconditioned inversion formula. In this scheme, the relative velocity update is a phase-modified and deconvolved RTM image obtained with the residual data. Consistent with the deconvolution, the multiscale approach applies a gradually widening low-pass frequency filter to the deconvolved wavelet at early iterations, and then it uses the unfiltered deconvolved wavelet for the final iterations. Our numerical testing determined that the new method makes a significant improvement to the quality of the inversion result.
MarvelD3 regulates the c-Jun N-terminal kinase pathway during eye development in Xenopus
Authors: Vacca Barbara , Sanchez-Heras Elena , Steed Emily , Balda Maria S. , Ohnuma Shin-Ichi , Sasai Noriaki , Mayor Roberto , Matter Karl
Published: November 2016

Ocular morphogenesis requires several signalling pathways controlling the expression of transcription factors and cell-cycle regulators. However, despite a well-known mechanism, the dialogue between those signals and factors remains to be unveiled. Here, we identify a requirement for MarvelD3, a tight junction transmembrane protein, in eye morphogenesis in Xenopus. MarvelD3 depletion led to an abnormally pigmented eye or even an eye-less phenotype, which was rescued by ectopic MarvelD3 expression. Altering MarvelD3 expression led to deregulated expression of cell-cycle regulators and transcription factors required for eye development. The eye phenotype was rescued by increased c-Jun terminal Kinase activation. Thus, MarvelD3 links tight junctions and modulation of the JNK pathway to eye morphogenesis.
Alternative exon usage creates novel transcript variants of tumor suppressor SHREW-1 gene with differential tissue expression profile
Authors: Klemmt Petra A. B. , Resch Eduard , Smyrek Isabell , Engels Knut , Stelzer Ernst H. K. , Starzinski-Powitz Anna
Published: November 2016

Shrew-1, also called AJAP1, is a transmembrane protein associated with E-cadherin-mediated adherence junctions and a putative tumor suppressor. Apart from its interaction with β-catenin and involvement in E-cadherin internalization, little structure or function information exists. Here we explored shrew-1 expression during postnatal differentiation of mammary gland as a model system. Immunohistological analyses with antibodies against either the extracellular or the cytoplasmic domains of shrew-1 consistently revealed the expression of full-length shrew-1 in myoepithelial cells, but only part of it in luminal cells. While shrew-1 localization remained unaltered in myoepithelial cells, nuclear localization occurred in luminal cells during lactation. Based on these observations, we identified two unknown shrew-1 transcript variants encoding N-terminally truncated proteins. The smallest shrew-1 protein lacks the extracellular domain and is most likely the only variant present in luminal cells. RNA analyses of human tissues confirmed that the novel transcript variants of shrew-1 exist in vivo and exhibit a differential tissue expression profile. We conclude that our findings are essential for the understanding and interpretation of future functional and interactome analyses of shrew-1 variants.
Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine
Authors: Guo Jiu-qing , Deng Hui-hui , Bo Xiao , Yang Xiao-su
Published: November 2016

Migraine is a highly prevalent headache disorder especially in women. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinases (TrkB), as well as extracellular signal-regulated kinase (ERK) and its downstream target c-AMP-responsive element binding protein (CREB) are strongly associated with the transmission of nociceptive information. However, the involvement of these substances in migraine has rarely been examined. In the present study, intraperitoneal injection of nitroglycerin (NTC) successfully induced rat migraine attack, as evidenced by the behavioral testing. The location and abundance of these substances in the migraine model were determined by Immunohistochemistry, Real-time polymerase chain reaction, Western blot and Enzyme-linked immunosorbant assays. Results showed that BDNF, TrkB, phosphor(p)-ERK and p-CREB were up-regulated in the brain neurons of both male and female rats with NTG-induced migraine compared to non-migraine control, whereas their expression levels were decreased in headache-free intervals of the migraine compared to migraine attacks. Estrogen is an important contributor to migraine. Female rats with ovariectomy showed significant reduction in the expression of BDNF, TrkB, p-CREB and p-ERK in both attacks and intervals of NTG-induced migraine, relative to rats that have their ovaries. But, intraperitoneal administration of exogenous estrogen recovered their expression in ovariectomized rats. Collectively, this study unveiled positive correlation of BDNF/TrkB and ERK/CREB axes in NTG-induced migraine and promoting effects of estrogen on their signals in the migraine. These findings contribute to further understanding the pathogenesis of migraine in the molecular basis.
REV-ERBα regulates Fgf21 expression in the liver via hepatic nuclear factor 6
Authors: Chavan Rohit , Preitner Nadia , Okabe Takashi , Strittmatter Laureen Mansencal , Xu Cheng , Ripperger Jürgen A. , Pitteloud Nelly , Albrecht Urs
Published: November 2016

The circadian clock contributes to the timing of many body functions including metabolism and reproduction. The hepatokine fibroblast growth factor 21 (FGF21) is a critical metabolic regulator involved in regulation of fertility. Here we show that lack of the clock component REV-ERBα elevates FGF21 levels in liver and plasma. At the molecular level REV-ERBα modulates the expression of FGF21 via the liver specific hepatic nuclear factor 6 (HNF6). We conclude, that REV-ERBα regulates metabolism and reproduction at least in part via regulation of Fgf21.
Quantitative stem cell biology: the threat and the glory
Authors: Pollard Steven M.
Published: November 2016

Major technological innovations over the past decade have transformed our ability to extract quantitative data from biological systems at an unprecedented scale and resolution. These quantitative methods and associated large datasets should lead to an exciting new phase of discovery across many areas of biology. However, there is a clear threat: will we drown in these rivers of data? On 18th July 2016, stem cell biologists gathered in Cambridge for the 5th annual Cambridge Stem Cell Symposium to discuss ‘Quantitative stem cell biology: from molecules to models’. This Meeting Review provides a summary of the data presented by each speaker, with a focus on quantitative techniques and the new biological insights that are emerging.
An interview with Kathryn Anderson
Authors: Maartens Aidan
Published: November 2016

Kathryn Anderson is Professor and Chair of the Developmental Biology Program at the Sloan Kettering Institute in New York. Her lab investigates the genetic networks underlying the patterning and morphogenesis of the early mouse embryo. We caught up with Kathryn at the 2016 Society for Developmental Biology – International Society of Differentiation joint meeting in Boston, where she was awarded the Edwin G. Conklin medal.
RNA-dependent disassembly of nuclear bodies
Authors: Musinova Yana R. , Lisitsyna Olga M. , Sorokin Dmitry V. , Arifulin Eugene A. , Smirnova Tatiana A. , Zinovkin Roman A. , Potashnikova Daria M. , Vassetzky Yegor S. , Sheval Eugene V.
Published: November 2016

Nuclear bodies are membraneless organelles that play important roles in genome functioning. A specific type of nuclear bodies known as interphase prenucleolar bodies (iPNBs) are formed in the nucleoplasm after hypotonic stress from partially disassembled nucleoli. iPNBs are then disassembled, and the nucleoli are reformed simultaneously. Here, we show that diffusion of B23 molecules (also known as nucleophosmin, NPM1) from iPNBs, but not fusion of iPNBs with the nucleoli, contributes to the transfer of B23 from iPNBs to the nucleoli. Maturation of pre-ribosomal RNAs (rRNAs) and the subsequent outflow of mature rRNAs from iPNBs led to the disassembly of iPNBs. We found that B23 transfer was dependent on the synthesis of pre-rRNA molecules in nucleoli; these pre-rRNA molecules interacted with B23 and led to its accumulation within nucleoli. The transfer of B23 between iPNBs and nucleoli was accomplished through a nucleoplasmic pool of B23, and increased nucleoplasmic B23 content retarded disassembly, whereas B23 depletion accelerated disassembly. Our results suggest that iPNB disassembly and nucleolus assembly might be coupled through RNA-dependent exchange of nucleolar proteins, creating a highly dynamic system with long-distance correlations between spatially distinct processes.
SIRT2 regulates nuclear envelope reassembly through ANKLE2 deacetylation
Authors: Kaufmann Tanja , Kukolj Eva , Brachner Andreas , Beltzung Etienne , Bruno Melania , Kostrhon Sebastian , Opravil Susanne , Hudecz Otto , Mechtler Karl , Warren Graham , Slade Dea
Published: November 2016

Sirtuin 2 (SIRT2) is an NAD-dependent deacetylase known to regulate microtubule dynamics and cell cycle progression. SIRT2 has also been implicated in the pathology of cancer, neurodegenerative diseases and progeria. Here, we show that SIRT2 depletion or overexpression causes nuclear envelope reassembly defects. We link this phenotype to the recently identified regulator of nuclear envelope reassembly ANKLE2. ANKLE2 acetylation at K302 and phosphorylation at S662 are dynamically regulated throughout the cell cycle by SIRT2 and are essential for normal nuclear envelope reassembly. The function of SIRT2 therefore extends beyond the regulation of microtubules to include the regulation of nuclear envelope dynamics.
Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts
Authors: Syed Khaja Mohieddin , Joseph Sunu , Mukherjee Ananda , Majumder Aditi , Teixeira Jose M. , Dutta Debasree , Pillai Madhavan Radhakrishna
Published: November 2016

Induction of pluripotency in differentiated cells through the exogenous expression of the transcription factors Oct4, Sox2, Klf4 and cellular Myc involves reprogramming at the epigenetic level. Histones and their metabolism governed by histone chaperones constitute an important regulator of epigenetic control. We hypothesized that histone chaperones facilitate or inhibit the course of reprogramming. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)–MET–histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis.
A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants: Trial protocol
Authors: Slater Rebeccah , Hartley Caroline , Moultrie Fiona , Adams Eleri , Juszczak Ed , Rogers Richard , Norman Jane E. , Patel Chetan , Stanbury Kayleigh , Hoskin Amy , Green Gabrielle ,   Poppi Trial Team
Published: November 2016

Infant pain has both immediate and long-term negative consequences, yet in clinical practice it is often undertreated. To date, few pain-relieving drugs have been tested in infants. Morphine is a potent analgesic that provides effective pain relief in adults, but there is inconclusive evidence for its effectiveness in infants. The purpose of this study is to establish whether oral morphine provides effective analgesia for procedural pain in infants.

A blinded, placebo-controlled, parallel-group randomized, phase II, clinical trial will be undertaken to determine whether morphine sulphate administered orally prior to clinically-required retinopathy of prematurity (ROP) screening and heel lancing provides effective analgesia.  156 infants between 34 and 42 weeks’ gestational age who require a clinical heel lance and ROP screening on the same test occasion will be included in the trial. Infants will be randomised to receive either a single dose of morphine sulphate (100 μg/kg) or placebo. Each infant will be monitored for 48 hours and safety data will be collected during the 24 hours following drug administration.

The primary outcome will be the Premature Infant Pain Profile–revised (PIPP-R) score 30 seconds after ROP screening. The co-primary outcome will be the magnitude of nociceptive-specific brain activity evoked by a clinically-required heel lance. Infant clinical stability will be assessed by comparing the number of episodes of bradycardia, tachycardia, desaturation and apnoea, and changes in respiratory support requirements in the 24-hour periods before and after the clinical intervention. In addition, drug safety will be assessed by considering the occurrence of apnoeic and hypotensive episodes requiring intervention in the 24-hour period following drug administration. This study has been published as an Accepted Protocol Summary by The Lancet.
Efficient and versatile CRISPR engineering of human neurons in culture to model neurological disorders
Authors: Shah Ruth R. , Cholewa-Waclaw Justyna , Davies Faith C.J. , Paton Katie M. , Chaligne Ronan , Heard Edith , Abbott Catherine M. , Bird Adrian P.
Published: November 2016

The recent identification of multiple new genetic causes of neurological disorders highlights the need for model systems that give experimental access to the underlying biology. In particular, the ability to couple disease-causing mutations with human neuronal differentiation systems would be beneficial. Gene targeting is a well-known approach for dissecting gene function, but low rates of homologous recombination in somatic cells (including neuronal cells) have traditionally impeded the development of robust cellular models of neurological disorders. Recently, however, CRISPR/Cas9 gene editing technologies have expanded the number of systems within which gene targeting is possible. Here we adopt as a model system LUHMES cells, a commercially available diploid human female mesencephalic cell line that differentiates into homogeneous mature neurons in 1-2 weeks. We describe optimised methods for transfection and selection of neuronal progenitor cells carrying targeted genomic alterations using CRISPR/Cas9 technology. By targeting the endogenous X-linked MECP2 locus, we introduced four independent missense mutations that cause the autism spectrum disorder Rett syndrome and observed the desired genetic structure in 3-26% of selected clones, including gene targeting of the inactive X chromosome. Similar efficiencies were achieved by introducing neurodevelopmental disorder-causing mutations at the autosomal EEF1A2 locus on chromosome 20. Our results indicate that efficiency of genetic “knock-in” is determined by the location of the mutation within the donor DNA molecule. Furthermore, we successfully introduced an mCherry tag at the MECP2 locus to yield a fusion protein, demonstrating that larger insertions are also straightforward in this system. We suggest that our optimised methods for altering the genome of LUHMES cells make them an attractive model for the study of neurogenetic disorders.
Cerebral lateralisation of first and second languages in bilinguals assessed using functional transcranial Doppler ultrasound
Authors: Grabitz Clara R. , Watkins Kate E. , Bishop Dorothy V. M.
Published: November 2016

Background: Lateralised representation of language in monolinguals is a well-established finding, but the situation is much less clear when there is more than one language. Studies to date have identified a number of factors that might influence the brain organisation of language in bilinguals. These include proficiency, age of acquisition and exposure to the second language. The question as to whether the cerebral lateralisation of first and second languages are the same or different is as yet unresolved.

Methods: We used functional transcranial Doppler sonography (FTCD) to measure cerebral lateralisation in the first and second languages in 26 high proficiency bilinguals with German or French as their first language (L1) and English as their second language (L2). FTCD was used to measure task-dependent blood flow velocity changes in the left and right middle cerebral arteries during word generation cued by single letters. Language history measures and handedness were assessed through self-report questionnaires.

Results:The majority of participants were significantly left lateralised for both L1 and L2, with no significant difference in the size of asymmetry indices between L1 and L2. Asymmetry indices for L1 and L2 were not related to language history, such as proficiency of the L2.

Conclusion: In highly proficient bilinguals, there is strong concordance for cerebral lateralisation of first and second languages.
COMPASS: Continuous Open Mouse Phenotyping of Activity and Sleep Status
Authors: Brown Laurence A. , Hasan Sibah , Foster Russell G. , Peirson Stuart N.
Published: November 2016

Background: Disruption of rhythms in activity and rest occur in many diseases, and provide an important indicator of healthy physiology and behaviour. However, outside the field of sleep and circadian rhythm research, these rhythmic processes are rarely measured due to the requirement for specialised resources and expertise. Until recently, the primary approach to measuring activity in laboratory rodents has been based on voluntary running wheel activity. By contrast, measuring sleep requires the use of electroencephalography (EEG), which involves invasive surgical procedures and time-consuming data analysis.

Methods: Here we describe a simple, non-invasive system to measure home cage activity in mice based upon passive infrared (PIR) motion sensors. Careful calibration of this system will allow users to simultaneously assess sleep status in mice. The use of open-source tools and simple sensors keeps the cost and the size of data-files down, in order to increase ease of use and uptake.

Results: In addition to providing accurate data on circadian activity parameters, here we show that extended immobility of >40 seconds provides a reliable indicator of sleep, correlating well with EEG-defined sleep (Pearson’s r >0.95, 4 mice). 

Conclusions: Whilst any detailed analysis of sleep patterns in mice will require EEG, behaviourally-defined sleep provides a valuable non-invasive means of simultaneously phenotyping both circadian rhythms and sleep. Whilst previous approaches have relied upon analysis of video data, here we show that simple motion sensors provide a cheap and effective alternative, enabling real-time analysis and longitudinal studies extending over weeks or even months. The data files produced are small, enabling easy deposition and sharing. We have named this system COMPASS - Continuous Open Mouse Phenotyping of Activity and Sleep Status. This simple approach is of particular value in phenotyping screens as well as providing an ideal tool to assess activity and rest cycles for non-specialists.
Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice
Authors: Wilson Robert , Geyer Stefan H. , Reissig Lukas , Rose Julia , Szumska Dorota , Hardman Emily , Prin Fabrice , McGuire Christina , Ramirez-Solis Ramiro , White Jacqui , Galli Antonella , Tudor Catherine , Tuck Elizabeth , Mazzeo Cecilia Icoresi , Smith James C. , Robertson Elizabeth , Adams David J. , Mohun Timothy , Weninger Wolfgang J.
Published: November 2016

Background: Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities.

Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant embryos from 42 lethal and subviable lines, analysed at E14.5.

Results: Virtually all embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve.

Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates.
The LonDownS adult cognitive assessment to study cognitive abilities and decline in Down syndrome
Authors: Startin Carla M. , Hamburg Sarah , Hithersay Rosalyn , Davies Amy , Rodger Erin , Aggarwal Nidhi , Al-Janabi Tamara , Strydom André
Published: November 2016

Background:Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with an ultra-high risk of developing Alzheimer’s disease. However, there is individual variability in the onset of clinical dementia and in baseline cognitive abilities prior to decline, particularly in memory, executive functioning, and motor coordination. The LonDownS Consortium aims to determine risk and protective factors for the development of dementia and factors relating to cognitive abilities in people with DS. Here we describe our cognitive test battery and related informant measures along with reporting data from our baseline cognitive and informant assessments.

Methods:We developed a cognitive test battery to assess general abilities, memory, executive function, and motor coordination abilities in adults with DS, with informant ratings of similar domains also collected, designed to allow for data on a broad range of participants. Participants (n=305) had a range of ages and abilities, and included adults with and without a clinical diagnosis of dementia.

Results:Results suggest the battery is suitable for the majority of adults with DS, although approximately half the adults with dementia were unable to undertake any cognitive task. Many test outcomes showed a range of scores with low floor and ceiling effects. Non-verbal age-adjusted IQ scores had lower floor effects than verbal IQ scores. Before the onset of any cognitive decline, females aged 16-35 showed better verbal abilities compared to males. We also identified clusters of cognitive test scores within our battery related to visuospatial memory, motor coordination, language abilities, and processing speed / sustained attention.

Conclusions:Our further studies will use baseline and longitudinal assessments to explore factors influencing cognitive abilities and cognitive decline related to ageing and onset of dementia in adults with DS.
Relação entre intangibilidade, desempenho econômico e social das empresas listadas na BM&Fbovespa
Authors: Vogt Mara , Kreuzberg Fernanda , Degenhart Larissa , Rodrigues Junior Moacir Manoel , Biavatti Vania Tanira
Published: November 2016

Este estudo objetiva verificar a relação entre o nível de intangibilidade e o desempenho econômico e social das empresaslistadas na BM&FBovespa. Realizou-se uma pesquisa descritiva, documental e com uma abordagem quantitativa dos dadosdurante o período de 2009 a 2012, por meio de uma correlação canônica. A amostra da pesquisa é composta por 131empresas pertencentes ao Índice de Governança Corporativa (IGC). Os resultados indicam que o desempenho econômicoe o desempenho social não apresentaram relação significativa e relevante com o grau de intangibilidade das empresas brasileiras.Em relação à comparação do desempenho econômico foram utilizados indicadores tradicionais e o desempenhosocial de indicadores provenientes da DVA (Demonstração do Valor Adicionado). Os resultados evidenciaram que há umaforte relação entre as duas categorias de desempenho. Além disso, a intangibilidade não possui relação com o desempenhoda empresa no âmbito social e econômico, porém esses são fortemente relacionados entre si.