bluuebunny/crossref_metadata_2025 huggingface dataset:
Homologous Banked Bone Grafts for the Reconstruction of Large Cranial Defects in Pediatric Patients
Authors: Canzi Gabriele , Talamonti Giuseppe , Mazzoleni Fabio , Bozzetti Alberto , Sozzi Davide
Published: June 2018

Purpose:

Autogenous bone represents the best material in pediatric reconstructive cranioplasty because of its compatibility with growth; however, its availability is limited. Alternative use of alloplastic materials would have the advantage of unlimited amount, but shows an increased risk of complications and incompatibility with growth. Fresh frozen banked cadaveric bones could be ideal for the reconstruction of large cranial defects in growing patients, because it offers unlimited amount of structural grafts with biomechanics properties quite similar to the autologous bones.

Results:

The authors report 2 cases of growing patients (13 months female and 9 years old male) undergoing the reconstruction of large (about 70 cm2 and 50 cm2 respectively) cranial vault defects, by using structural homologous banked bone grafts.

Analytic main reconstruction materials risks/benefits evaluation, literature review of few previously reported pediatric cranioplasty with homologous bone, and both clinical cases satisfactory radiologic long-term results (beyond 4 years of F.U.) are reported.

Conclusion:

Structural homologous banked bone grafts appear as a valid solution for pediatric canioplasty reconstruction of wide defects, entailing the advantages of available without limitations and compatibility with future growth. The risk of transmissible infections seems minimal and is totally counterbalanced by the stability of long-term results.
Effectiveness of Nasoalveolar Molding in the Unilateral Cleft Lip and Cleft Palate
Authors: Mariqueo Gabriela Edith Castillo , Arriagada Eduardo Enrique Almeida , Bustos Teresita del Pilar Iturriaga , Navarro Sergio Muñoz , Espinoza Gerardo Enrique Espinoza
Published: June 2018

Background:

Cleft lip and palate develops during embryogenesis due to an alteration in the fusion of the tissues which will form the upper lip and palate. The rate of occurrence in Chile is 1.6 per 1000 live births. The object of the present study was to determine the effectiveness of the Grayson nasoalveolar molding appliance in reducing the gap between the alveolar segments in cases of unilateral cleft lip and palate by sex, age at start of treatment, initial gap between the alveolar segments, and number of checkups.

Methods:

The study design was quasi-experimental, with measurements taken before and after surgery and no control group. The authors studied the medical records and models of a sample of 52 patients with complete unilateral cleft lip and palate who were discharged after treatment using Grayson nasoalveolar molding appliance. Treatment was considered effective when the final gap was 3 mm or less. Then the percentage of cases in which treatment was effective, applying statistical tests, including log regression, to assess the influence of other variables was calculated.

Results:

The authors observed that the Grayson nasoalveolar molding appliance was effective in 69.23% of patients. Of the variables studied, the initial gap presented statistically significant differences (initial gap of 8–12 mm, effectiveness 82.61%); in the log regression, the same variable presented a statistically significant difference in the adjusted odds of effectiveness.

Conclusion:

Grayson nasoalveolar molding appliance presents good effectiveness in reducing the gap between the alveolar segments in patients with unilateral cleft lip and palate, especially in cases with a gap of 8 to 12 mm.
Serious Complications After Le Fort III Distraction Osteogenesis in Syndromic Craniosynostosis: Evolution of Preventive and Therapeutic Strategies
Authors: Raposo-Amaral Cassio Eduardo , Denadai Rafael , Pereira-Filho João Carlos , Vieira Pedro Henrique , Ghizoni Enrico , Raposo-Amaral Cesar Augusto
Published: June 2018

Background:

There is a paucity of studies that report complication rates following a subcranial Le Fort III advancement using distraction osteogenesis. The purpose of this study was to identify and describe serious postoperative complications following Le Fort III advancement with distraction osteogenesis, and provide strategies to assist in the resolution of these complications.

Methods:

An observational retrospective study was performed on consecutive patients with Apert, Crouzon, or Pfeiffer syndromes (n = 16) who underwent Le Fort III advancement using distraction osteogenesis between 2008 and 2017. Serious complications were defined as frontal bone loss, cerebrospinal fluid leak, meningitis, seizures, or major blood loss (ie, massive transfusion within the first postoperative day).

Results:

Three (18.7%) patients presented serious complications, namely cerebrospinal fluid leak (n = 1; 6.2%), seizures (n = 1; 6.2%) due to a halo-type device trans-pin intracranial migration, and major blood loss (n = 1; 6.2%). Adopting well-delineated interventions, all of these complications were resolved without fatality.

Conclusion:

A Le Fort III advancement has a significant morbidity rate, with 3 of our patients (18.7%) in this study presenting serious complications. Appropriate management reduced this morbidity, and all complications were resolved without fatality.
Comparative Analysis of the Efficacy of Dental Plaque Removal Between Manual and Powered Toothbrushes in Individuals With Syndactyly
Authors: Kaizer Rosane de Oliveira Fortes , Alves Patrick Henry Machado , Tereza Guida Paola Genovez , Dalben Gisele da Silva , Neppelenbroek Karin Hermana , Soares Simone , Almeida Ana Lúcia Pompéia Fraga de
Published: June 2018

Objective:

To compare the efficacy of dental plaque removal between manual and powered toothbrushes in individuals with syndactyly.

Material and methods:

Seventeen patients with Apert syndrome aged 11 to 30 years. The efficacy of toothbrushing was evaluated by the O’Leary plaque index at 2 periods: initial (before toothbrushing) and final (immediately after toothbrushing), using manual toothbrush (Colgate Twister) and powered toothbrush (Colgate Actibrush). Means were compared by the ANOVA test at a significance level of 5%.

Results:

The reduction in the plaque index was different for each type of toothbrush (interaction factor between manual and powered toothbrushes and initial and final periods, P = 0.026). The powered toothbrush provided greater reduction of dental plaque than the manual toothbrush.

Conclusion:

In individuals with syndactyly, both manual and powered toothbrushes allowed significant plaque reduction on tooth surfaces; however, the powered toothbrush exhibited greater efficacy of plaque removal compared with the manual toothbrush.
MRI-based neuroimaging: atypical parkinsonisms and other movement disorders
Authors: Kassubek Jan
Published: June 2018

Purpose of review

MRI has become a well established technical tool for parkinsonism both in the diagnostic work-up to differentiate between causes and to serve as a neurobiological marker. This review summarizes current developments in the advanced MRI-based assessment of brain structure and function in atypical parkinsonian syndromes and explores their potential in a clinical and neuroscientific setting.

Recent findings

Computer-based unbiased quantitative MRI analyses were demonstrated to guide in the discrimination of parkinsonian syndromes at single-patient level, with major contributions when combined with machine-learning techniques/support vector machine classification. These techniques have shown their potential in tracking the disease progression, perhaps also as a read-out in clinical trials. The characterization of different brain compartments at various levels of structural and functional alterations can be provided by multiparametric MRI, including a growing variety of diffusion-weighted imaging approaches and potentially iron-sensitive and functional MRI.

In case that the recent advances in the MRI-based assessment of atypical parkinsonism will lead to standardized protocols for image acquisition and analysis after the confirmation in large-scale multicenter studies, these approaches may constitute a great achievement in the (operator-independent) detection, discrimination and characterization of degenerative parkinsonian disorders at an individual basis.
Dermatomal Versus Mixed Somatosensory Evoked Potentials in the Diagnosis of Lumbosacral Spinal Canal Stenosis
Authors: Essa Zainab M. , AL-Hashimi Ali F. , Nema Ihssan S.
Published: June 2018

Purpose:

The existing literature on the use of dermatomal somatosensory evoked potentials in lumbosacral spinal canal stenosis is limited. The goal of this study was to evaluate the role of dermatomal against mixed tibial somatosensory evoked potential (SEP) as a complementary procedure to imaging studies in the diagnosis of lumbosacral stenosis.

Methods:

Thirty patients with clinically and radiologically diagnosed lumbosacral stenosis and 20 normal individuals were enrolled in the study. The study was ethically approved, and informed consent for participation was provided. All participants underwent bilateral mixed tibial and dermatomal SEP study of the third (L3), fourth (L4), fifth lumbar (L5), and first sacral (S1) dermatomes. N45, N25, N20, and N10 tibial SEP waves were measured from four channels, whereas dermatomal waves were measured from cortical recording. Peak latency and amplitude of each wave were calculated.

Results:

The cutoff value of the dermatomal S1 latency showed the highest sensitivity and specificity percentages (81.7 and 82.5, respectively), followed by L5 and N25. N25-N45 interpeak latency showed the lowest sensitivity and specificity. All L5, S1, L4, and N25 latency cutoff values presented highly significant differences between affected sides and controls (P < 0.0001), followed by N45 and N20. The amplitude cutoff values of SEP waves showed equivocal sensitivity and specificity percentages.

Conclusions:

Somatosensory evoked potential studies can be used as a supplementary test for the diagnosis of lumbosacral stenosis, with the dermatomal studies being more valuable expressing multiple root abnormalities. S1 dermatomal wave latency has the highest diagnostic value, followed by L5, N25, and then L4 latencies.
The Psychiatric Neuromodulation Unit
Authors: Sauvaget Anne , Poulet Emmanuel , Mantovani Antonio , Bulteau Samuel , Damier Philippe , Moutaud Baptiste , Paternoster Mariano , de Bartolomeis Andrea , D'Urso Giordano
Published: June 2018

The proven effectiveness of neuromodulation and stimulation techniques for the management of psychiatric disorders has brought strongly needed innovation in psychiatry, given the high prevalence and high costs of treatment resistance. Although evidence-based guidelines in neuromodulation have been implemented to improve the clinical efficacy, safety, and research procedures, practical suggestions on how to design a psychiatric neuromodulation unit (PNU) are not available in the scientific literature. In this contribution, we have combined the results of a literature search with the suggestions of clinical psychiatrists, managers, and bioethicists who have had firsthand experience in building a PNU. Eleven key issues concerning the implementation and management of a PNU were identified: general context, team composition, environment, basic technical equipment, clinical versus research activities, target clinical population, education and training, interdisciplinarity, ethical aspects, regulatory and reimbursement issues, fund-raising, and partnership development. Moreover, a business plan comprising pragmatic solutions and recommendations for designing an efficient PNU was laid out.
Translational regulation of Syngap1 by FMRP modulates NMDAR mediated signalling
Authors: Paul Abhik , Nawalpuri Bharti , Sateesh Shruthi , Muddashetty Ravi S , Clement James P
Published: June 2018

SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in SYNGAP1 (SYNGAP1+/-) has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of Syngap1+/-. However, the molecular mechanisms behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in Syngap1+/- mice. Our results demonstrated that FMRP interacts with and regulates the translation of Syngap1 mRNA. We further show that, during development, reduced translation of FMRP and this decrease in FMRP leads to a compensatory increase of Syngap1 translation in Syngap1+/-. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA receptor signalling. We propose a cross-talk between FMRP and SYNGAP1 mediated signalling which can also explain the compensatory effect of impaired signalling observed in Syngap1+/- mice.
Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining
Authors: Liu Qi , Ma Lin , Jones Trevor , Palomero Luis , Pujana Miquel A. , Martinez-Ruiz Haydeliz , Ha Patrick , Murnane John , Cuartas Isabel , Seoane Joan , Baumann Michael , Linge Annett , Barcellos-Hoff Mary Helen
Published: June 2018

Purpose:Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV) positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared to 30% of those with similar HPV-negative cancer, which is thought to be due to dysregulation of DNA repair. Loss of transforming growth factor β (TGFβ) signaling is a poorly studied consequence of HPV that could contribute to this phenotype.

Experimental Design:Human HNSCC cell lines (n=9), patient-derived xenografts (n=9), tissue microarray (n=194), TCGA expression data and primary tumor specimens (n=10) were used to define the relationship between TGFβ competency, response to DNA damage, and type of DNA repair.

Results:Analysis of HNSCC specimensin situandin vitroshowed that HPV associates with loss of TGFβ signaling that increases the response to radiation or cisplatin. TGFβ suppressed miR-182 that inhibited both BRCA1, necessary for homologous recombination repair, and FOXO3, which is required for ATM kinase activity. TGFβ signaling blockade by either HPV or inhibitors released this control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the homologous recombination deficit in HPV+ cells. Loss of TGFβ signaling unexpectedly increased error-prone, alternative end-joining repair.

Conclusions: HPV-positive HNSCC cells are unresponsive to TGFβ. Abrogated TGFβ signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGFβ’s role in DNA repair proficiency and further raises the translational potential of TGFβ inhibitors in cancer therapy.
Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis
Authors: Brumshtein Boris , Esswein Shannon R. , Sawaya Michael R. , Ly Alan T. , Landau Meytal , Eisenberg David S.
Published: June 2018

Systemic light chain amyloidosis (AL) is a disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into β-sheets that pair forming a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, we identify segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate there are at least two such segments. Each one can drive amyloid fibril assembly independently of the other. Thus these two segments are therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach to identify segments that drive fibril formation in other amyloid diseases.
Bacteria-to-human protein networks reveal origins of endogenous DNA damage
Authors: Xia Jun , Chiu Li-Ya , Nehring Ralf B. , Bravo Núñez María Angélica , Mei Qian , Perez Mercedes , Zhai Yin , Fitzgerald Devon M. , Pribis John P. , Wang Yumeng , Hu Chenyue W. , Powell Reid T. , LaBonte Sandra A. , Jalali Ali , Matadamas Guzmán Meztli L. , Lentzsch Alfred M. , Szafran Adam T. , Joshi Mohan C. , Richters Megan , Gibson Janet L. , Frisch Ryan L. , Hastings P.J. , Bates David , Queitsch Christine , Hilsenbeck Susan G. , Coarfa Cristian , Hu James C. , Siegele Deborah A. , Scott Kenneth L. , Liang Han , Mancini Michael A. , Herman Christophe , Miller Kyle M. , Rosenberg Susan M.
Published: June 2018

DNA damage provokes mutations and cancer, and results from external carcinogens or endogenous cellular processes. Yet, the intrinsic instigators of DNA damage are poorly understood. Here we identify proteins that promote endogenous DNA damage when overproduced: the DNA-damaging proteins (DDPs). We discover a large network of DDPs inEscherichia coliand deconvolute them into six DNA-damage-causing function clusters, demonstrating DDP mechanisms in three: reactive-oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their expression in tumors predicts heavy mutagenesis and poor prognosis. Half of tested human homologs, when overproduced in human cells, promote DNA damage and mutation, with DNA-damaging mechanisms like those inE. coli. Together, our work reveals DDP networks that provoke endogenous DNA damage and may indicate functions of many human known and newly implicated cancer-promoting proteins.
The Impact of Grant Funding on the Publication Activity of Awarded Applicants: A Systematic Review of Comparative Studies and Meta-analytical Estimates
Authors: Saygitov Ruslan T.
Published: June 2018

The connection between grant funding and research productivity has not been well established.

Objective

to examine the impact of grant funding on the publication activity of awarded applicants.

Methods

a systematic review of results from comparative studies on the publication activity of applicants (awarded vs rejected) both prior to and after the award process. All pool estimates (weighted mean difference) were based on random-effects models.

Results

revealed 16 relevant publications (grant funding from 14 funds, 1980 to 2007 years), all with results from quasi-experimental studies. 45 paired values (ex ante – ex post) for the number of articles published by awarded and rejected applicants were used in the quantitative synthesis. The median average publication activity of awarded applicants before the award process was 2.4 (1.3; 3.4) and after the award process 3.1 (1.7; 4.3) publications per year, for rejected applicants was 1.8 (1.0; 2.9) and 2.4 (1.1; 3.8) respectively. The summation of the results from these studies using the difference-in-differences approach showed that awarded applicants published 0.14 articles per year (95% Cl 0.07 to 0.21) more than rejected applicants (adjusted for publication bias). A meta-regression analysis made it possible to tie together the revealed small difference with the difference-in-differences approach bias − the subsequent differences in the groups are determined by the scale of the initial differences in their publication activity.

Conclusion

awarded applicants published slightly more often than their rejected opposites. However, this effect may be the result of a bias caused by the shortcomings of the difference-in-differences approach.
Mutation rate variability as a driving force in adaptive evolution
Authors: Engelhardt Dalit , Shakhnovich Eugene I.
Published: June 2018

Mutation rate is a key determinant of the pace as well as outcome of evolution, and variability in this rate has been shown in different scenarios to play a key role in evolutionary adaptation and resistance evolution under stress. Here we investigate the dynamics of resistance fixation in a bacterial population with variable mutation rates and show that evolutionary outcomes are most sensitive to mutation rate variations when the population is subject to environmental and demographic conditions that suppress the evolutionary advantage of high-fitness subpopulations. By directly mapping a molecular-level biophysical fitness function to the system-level dynamics of the population we show that both low and very high, but not intermediate, levels of stress result in a disproportionate effect of hypermutation on resistance fixation and that traditional definitions of the selection coefficient are insufficient to account for this effect. We demonstrate how this behavior is directly tied to the extent of genetic hitchhiking in the system, the propagation of high-mutation rate cells through association with high-fitness mutations. Our results indicate a substantial role for mutation rate flexibility in the evolution of antibiotic resistance under conditions that present a weak advantage over wildtype to resistant cells.
DNA-uptake pilus ofVibrio choleraecapable of kin-discriminated auto-aggregation
Authors: Adams David. W. , Stutzmann Sandrine , Stoudmann Candice , Blokesch Melanie
Published: June 2018

Natural competence for transformation is a widely used and key mode of horizontal gene transfer that can foster rapid bacterial evolution. Competent bacteria take-up DNA from their environment using Type IV pili, a widespread and multi-purpose class of cell surface polymers. However, how pili facilitate DNA-uptake has remained unclear. Here, using direct labelling, we show that in the Gram-negative pathogenVibrio choleraeDNA-uptake pili are highly dynamic and that they retract prior to DNA-uptake. Unexpectedly, these pili can self-interact to mediate auto-aggregation of cells into macroscopic structures. This phenotype is conserved in disease causing pandemic strains. However, extensive strain-to-strain variability in the major pilin subunit PilA, present in environmental isolates, controls the ability of pili to interact without affecting transformation. We go on to show that interactions between pili are highly specific, enabling cells producing pili composed of different PilA subunits to discriminate between one another. On chitin surfaces, a natural habitat ofV. cholerae, pili connect cells within dense networks, suggesting a model whereby DNA-uptake pili function to promote inter-bacterial interactions during surface colonisation. Moreover, our results provide evidence that type IV pili could provide a simple and potentially widespread mechanism for bacterial kin recognition.
Robustness of local control strategies under modelling uncertainties: the 2004 avian influenza H5N1 outbreak in Thailand
Authors: Retkute Renata , Jewell Chris P. , Van Boeckel Thomas P. , Zhang Geli , Xiao Xiangming , Thanapongtharm Weerapong , Keeling Matt , Gilbert Marius , Tildesley Michael J.
Published: June 2018

The Highly Pathogenic Avian Influenza (HPAI) subtype H5N1 virus persists in many countries and has been circulating in poultry, wild birds. In addition, the virus has emerged in other species and frequent zoonotic spillover events indicate that there remains a significant risk to human health. It is crucial to understand the dynamics of the disease in the poultry industry to develop a more comprehensive knowledge of the risks of transmission and to establish a better distribution of resources when implementing control. In this paper, we develop a set of mathematical models that simulate the spread of HPAI H5N1 in the poultry industry in Thailand, utilising data from the 2004 epidemic. The model that incorporates the intensity of duck farming when assessing transmision risk provides the best fit to the spatiotemporal characteristics of the observed outbreak, implying that intensive duck farming drives transmission of HPAI in Thailand. We also extend our models using a sequential model fitting approach to explore the ability of the models to be used in “real time” during novel disease outbreaks. We conclude that, whilst predictions of epidemic size are estimated poorly in the early stages of disease outbreaks, the model accurately predicts the preferred control policy that should be deployed to minimise the impact of the disease.
Orchestration ofDrosophilapost-feeding physiology and behavior by the neuropeptide leucokinin
Authors: Zandawala Meet , Yurgel Maria E. , Liao Sifang , Texada Michael J. , Rewitz Kim F. , Keene Alex C. , Nässel Dick R.
Published: June 2018

Behavior and physiology are orchestrated by neuropeptides acting as neuromodulators and/or circulating hormones. A central question is how these neuropeptides function to coordinate complex and competing behaviors. The neuropeptide leucokinin (LK) modulates diverse functions, including circadian rhythms, feeding, water homeostasis, and sleep, but the mechanisms underlying these complex interactions remain poorly understood. Here, we delineate the LK circuitry that governs homeostatic functions that are critical for survival. We found that impaired LK signaling affects diverse but coordinated processes, including regulation of stress, water homeostasis, locomotor activity, and metabolic rate. There are three different sets of LK neurons, which contribute to different aspects of this physiology. We show that the calcium activity of abdominal ganglia LK neurons (ABLKs) increases specifically following water consumption, but not under other conditions, suggesting that these neurons regulate water homeostasis and its associated physiology. To identify targets of LK peptide, we mapped the distribution of the LK receptor (Lkr), mined brain single-cell transcriptome dataset for genes coexpressed withLkr, and utilized trans-synaptic labeling to identify synaptic partners of LK neurons.Lkrexpression in the brain insulin-producing cells (IPCs), gut, renal tubules and sensory cells, and the post-synaptic signal in sensory neurons, correlates well with regulatory roles detected in theLkandLkrmutants. Furthermore, these mutants and flies with targeted knockdown ofLkrin IPCs displayed altered expression of insulin-like peptides (DILPs) in IPCs and modulated stress responses. Thus, some effects of LK signaling appear to occur via DILP action. Collectively, our data suggest that the three sets of LK neurons orchestrate the establishment of post-prandial homeostasis by regulating distinct physiological processes and behaviors such as diuresis, metabolism, organismal activity and insulin signaling. These findings provide a platform for investigating neuroendocrine regulation of behavior and brain-to-periphery communication.
Critical transitions in malaria transmission models are consistently generated by superinfection
Authors: Alonso David , Dobson Andy , Pascual Mercedes
Published: June 2018

The history of infectious disease modelling essentially begins with the papers by Ross on malaria [1–5]. These models assume that the dynamics of malaria can most simply be characterized by two equations that describe the prevalence of malaria in the human and mosquito hosts. This structure has formed the central core of models for malaria and most other vector-borne diseases for the last century with occasional additions acknowledging important aetiological details. We partially add to this tradition by describing a malaria model that provides for vital dynamics in the vector and the possibility of super-infection in the human host; reinfection of asymptomatic hosts before they have cleared a prior infection. These key features of malaria aetiology create the potential for break points in the prevalence of infected hosts, sudden transitions that seem to characterize malaria’s response to control in different locations. We show that this potential for critical transitions is a general and underappreciated feature of any model for vector borne diseases with incomplete immunity and asymptomatic patients, including the canonical Ross-McDonald model. Ignoring these details of the host’s immune response to infection can potentially lead to serious misunderstanding in the interpretation of malaria distribution patterns and the design of control schemes for other vector-borne diseases.
Meta-analysis of 1,200 transcriptomic profiles identifies a prognostic model for pancreatic ductal adenocarcinoma
Authors: Sandhu Vandana , Labori Knut Jorgen , Borgida Ayelet , Lungu Ilinca , Bartlett John , Hafezi-Bakhtiari Sara , Denroche Rob , Jang Gun Ho , Pasternack Danielle , Mbaabali Faridah , Watson Matthew , Wilson Julie , Kure Elin H. , Gallinger Steven , Haibe-Kains Benjamin
Published: June 2018

Background

With a dismal 8% median 5-year overall survival (OS), pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Only 10-20% of patients are eligible for surgery, and over 50% of these will die within a year of surgery. Identify molecular predictors of early death would enable the selection of PDAC patients at high risk.

Methods

We developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors where gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework based on the binary gene pair method to create gene expression barcodes robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic datasets to date, we show that PCOSP is a robust single-sample predictor of early death (≤1 yr) after surgery in a subset of 823 samples with available transcriptomics and survival data.

Results

The PCOSP model was strongly and significantly prognostic with a meta-estimate of the area under the receiver operating curve (AUROC) of 0.70 (P=1.9e-18) and hazard ratio (HR) of 1.95(1.6-2.3) (P=2.6e-16) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathological parameters and molecular subtypes. Over-representation analysis of the PCOSP 2619 gene-pairs (1070 unique genes) unveiled pathways associated with Hedgehog signalling, epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) signalling.

Conclusion

PCOSP could improve treatment decision by identifying patients who will not benefit from standard surgery/chemotherapy and may benefit from alternate approaches.

Abbreviations

AUROC

Area under the receiver operating curve

GO

Gene annotation

OS

Overall survival

PCOSP

Pancreatic cancer overall survival predictor

PDAC

Pancreatic ductal adenocarcinoma

TSP

Top scoring pairs.
Gene-regulatory independent functions for insect DNA methylation
Authors: Bewick Adam J. , Sanchez Zachary , Mckinney Elizabeth C. , Moore Allen J. , Moore Patricia J. , Schmitz Robert J.
Published: June 2018

The function of cytosine (DNA) methylation in insects remains unknown. Here we provide evidence for the functional role of the maintenance DNA methyltransferase 1 (Dnmt1) in an insect using experimental manipulation. Through RNA interference (RNAi) we successfully post-transcriptionally knocked downDnmt1in ovarian tissue of the hemipteranOncopeltus fasciatus(the large milkweed bug). Individuals depleted forDnmt1, and subsequently DNA methylation, failed to reproduce. Eggs were inviable and declined in number, and nuclei structure of follicular epithelium was aberrant. Depletion of DNA methylation did not result in changes in gene or transposable element expression revealing an important function of DNA methylation seemingly not contingent on gene expression. Our work provides direct experimental evidence for a functional role ofDnmt1and DNA methylation independent of gene expression in insects.
CellSpecks: A Software for Automated Detection and Analysis of Calcium Channels in Live Cells
Authors: Shah S I , Smith M , Swaminathan D , Parker I , Ullah G , Demuro A
Published: June 2018

To couple the fidelity of patch-clamp recording with a more high-throughput screening capability, we pioneered a novel approach to single channel recording that we named “optical patch clamp”. By using highly-sensitive fluorescent Ca2+ indicator dyes in conjunction with total internal fluorescence microscopy techniques, we monitor Ca2+ flux through individual Ca2+-permeable channels. This approach provides information about channel gating analogous to patch-clamp recording at time resolution of ~ 2 ms, with the additional advantage of being massively parallel, providing simultaneous and independent recording from thousands of channels in native environment. However, manual analysis of the data generated by this technique presents severe challenges as a video recording can include many thousands of frames. To overcome this bottleneck, we developed an image processing and analysis framework called CellSpecks, capable of detecting and fully analyzing the kinetics of ion channels within a video sequence. By using a randomly generated synthetic data, we tested the ability of CellSpecks to rapidly and efficiently detect and analyze the activity of thousands of ion channels, including openings for a few milliseconds. Here, we report the use of CellSpecks for the analysis of experimental data acquired by imaging muscle nicotinic acetylcholine receptors and the Alzheimer’s disease-associated amyloid beta pores with multiconductance levels in the plasma membrane of Xenopus laevis oocytes. We show that CellSpecks can accurately and efficiently generate location maps, create raw and processed fluorescence time-traces, histograms of mean open times, mean close times, open probabilities, durations, and maximum amplitudes, and a ‘channel chip’ showing the activity of all channels as a function of time. Although we specifically illustrate the application of CellSpecks for analyzing data from Ca2+ channels, it can be easily customized to analyze other spatially and temporally localized signals.
Canonical Wnt signaling regulates patterning, differentiation and nucleogenesis in mouse hypothalamus and prethalamus
Authors: Newman Elizabeth A. , Wu Dan , Taketo Makoto Mark , Zhang Jiangyang , Blackshaw Seth
Published: June 2018

The hypothalamus is a small, but anatomically and functionally complex, region of the brain whose development is poorly understood. In this study, we have explored its development by studying the canonical Wntsignalling pathway, generating gain and loss of function mutations of betacaten in(Ctnnb1) in both hypothalamic and prethalamic neuroepithelium. Deletion ofCtnnb1resulted in an anteriorized and hypoplastic hypothalamus. Posterior structures were lost or reduced, and anterior structures were expanded. In contrast, over expression of a constitutively active mutant form ofCtnnb1resulted in severe hyperplasia of prethalamus and hypothalamus, and expanded expression of a subset of posterior and premamillary hypothalamic markers. Moderate defects in differentiation ofArx-positive GABAergic neural precursors were observed in both prethalamus and hypothalamus ofCtnnb1loss of function mutants, while in gain of function mutants, their differentiation was completely suppressed, although markers of prethalamic progenitors were preserved. Multiple other region-specific markers, including several specific posterior hypothalamic structures, were also suppressed inCtnnb1gain of function mutations. Severe, region-specific defects in hypothalamic nucleogenesis were also observed in both gain and loss of function mutations ofCtnnb1. Finally, both gain and loss of function ofCtnnb1also produced severe, cell nonautonomous disruptions of pituitary development. These findings demonstrate acentral and multifaceted role for canonical Wnt signalling in regulating growth, patterning, differentiation and nucleogenesis in multiple diencephalic regions.

Highlights

Canonical Wnt signalling regulates anteroposterior patterning in the hypothalamus.

Canonical Wnt signalling regulates differentiation of GABAergic neurons in both prethalamus and hypothalamus.

Canonical Wnt signalling regulates differentiation and nucleogenesis of multiple hypothalamic neuronal subtypes.

Canonical Wnt signalling in hypothalamic neuroepithelium regulates pituitary morphogenesis and differentiation.
Temporal ordering of input modulates connectivity formation in a developmental neuronal network model of the cortex
Authors: Hartley Caroline , Farmer Simon , Berthouze Luc
Published: June 2018

Preterm infant brain activity is discontinuous; bursts of activity recorded using EEG (electroencephalography), thought to be driven by subcortical regions, display scale free properties and exhibit a complex temporal ordering known as long-range temporal correlations (LRTCs). During brain development, activity-dependent mechanisms are essential for synaptic connectivity formation, and abolishing burst activity in animal models leads to weak disorganised synaptic connectivity. Moreover, synaptic pruning shares similar mechanisms to spike-timing dependent plasticity (STDP), suggesting that the timing of activity may play a critical role in connectivity formation. We investigated, in a computational model of leaky integrate-and-fire neurones, whether the temporal ordering of burst activity within an external driving input could modulate connectivity formation in the network. Connectivity evolved across the course of simulations using an approach analogous to STDP, from networks with initial random connectivity. Small-world connectivity and hub neurones emerged in the network structure - characteristic properties of mature brain networks. Notably, driving the network with an external input which exhibited LRTCs in the temporal ordering of burst activity facilitated the emergence of these network properties, increasing the speed with which they emerged compared with when the network was driven by the same input with the bursts randomly ordered in time. Moreover, the emergence of small-world properties was dependent on the strength of the LRTCs. These results suggest that the temporal ordering of burst activity could play an important role in synaptic connectivity formation and the emergence of small-world topology in the developing brain.
A regulatory-sequence classifier with a neural network for genomic information processing
Authors: Onimaru Koh , Nishimura Osamu , Kuraku Shigehiro
Published: June 2018

Genotype-phenotype mapping is one of the fundamental challenges in biology. The difficulties stem in part from the large amount of sequence information and the puzzling genomic code, particularly of non-protein-coding regions such as gene regulatory sequences. However, recently deep learning–based methods were shown to have the ability to decipher the gene regulatory code of genomes. Still, prediction accuracy needs improvement. Here, we report the design of convolution layers that efficiently process genomic sequence information and developed a software, DeepGMAP, to train and compare different deep learning-based models (https://github.com/koonimaru/DeepGMAP). First, we demonstrate that our convolution layers, termed forward- and reverse-sequence scan (FRSS) layers, enhance the power to predict gene regulatory sequences. Second, we assessed previous studies and identified problems associated with data structures that caused overfitting. Finally, we introduce several visualization methods that provide insights into the syntax of gene regulatory sequences.
Experimental infection characteristics ofBordetellapertussis via aerosol challenge on rhesus macaques
Authors: Mou Dachao , Luo Peng , Liang Jiangli , Ji Qiuyan , Wang Lichan , Gao Na , Gu Qin , Wei Chen , Ma Yan , Li Jingyan , Liu Shuyuan , Shi Li , Sun Mingbo
Published: June 2018

The effect of aerosol challenge of rhesus macaques withBordetella pertussisand the feasibility of using rhesus monkeys as an animal model for pertussis infection were evaluated in this study. Four 1-year old rhesus macaques were aerosol challenged withB. pertussisat the concentration of 105CFU/mL for 30 min (group 1) or 60 min (group 2). Rectal temperature was found slightly increased at days 3 and 5 and returned to baseline levels at day 21 after challenge. White blood cell counts peaked at day 7, with a 4.7~6.1-fold increase and returned to baseline levels at day 45. Bacteria colonization of nasopharyngeal swabs was observed, and the number of colonies was gradually increased and peaked at day 14, reaching 5.4-8.1 × 106/mL. The seroconversion rate of anti-pertussis toxin (PT), pertactin (PRN), and filamentous hemagglutinin(FHA) antibodies was 100%, with an increase in geometric mean titers after challenge. Analysis of cytokines revealed that the levels of cytokines including IL-2, IL-6, IL-8, IL-10, IL-17A, IL-13, IL-12, and IL-18 were significantly increased at days 5 to 14 in group 2. These results demonstrate that the characteristic of pertussis infection in infant rhesus macaque was similar as in human beings, which provide a clue to using infant rhesus macaque as a candidate model for pertussis infection in the future studies
Two point mutations in the Hantaan virus glycoproteins afford the generation of a highly infectious recombinant vesicular stomatitis virus vector
Authors: Slough Megan M. , Chandran Kartik , Jangra Rohit K.
Published: June 2018

Rodent-to-human transmission of hantaviruses is associated with severe disease. Currently, no FDA-approved, specific antivirals or vaccines are available, and the requirement for high biocontainment (BSL3) laboratories limits hantavirus research. To study hantavirus entry in a BSL-2 laboratory, we set out to generate replication-competent, recombinant vesicular stomatitis viruses (rVSVs) bearing the Gn/Gc entry glycoproteins. As previously reported, rVSVs bearing New World hantavirus Gn/Gc were readily rescued from cDNAs, but their counterparts bearing Gn/Gc from the Old World hantavirus, Hantaan virus (HTNV), were refractory to rescue and only grew to low titers. However, serial passage of the rescued rVSV-HTNV Gn/Gc virus markedly increased its infectivity and capacity for cell-to-cell spread. This gain in viral fitness was associated with the acquisition of two point mutations; I532K in the cytoplasmic tail of Gn, and S1094L in the membrane-proximal stem of Gc. Follow-up experiments with rVSVs and single-cycle VSV pseudotypes confirmed these results. Mechanistic studies revealed that both mutations were determinative and contributed to viral infectivity in a synergistic manner. Our findings indicate that the primary mode of action of these mutations is to relocalize HTNV Gn/Gc from the Golgi complex to the cell surface, thereby affording significantly enhanced Gn/Gc incorporation into budding VSV particles. Our results suggest that enhancements in cell-surface expression of hantaviral glycoprotein(s) through incorporation of cognate mutations could afford the generation of rVSVs that are otherwise challenging to rescue. The robust replication-competent rVSV-HTNV Gn/Gc reported herein may also have utility as a vaccine.

Importance

Human hantavirus infections cause pulmonary syndrome in the Americas and hemorrhagic fever with renal syndrome (HFRS) in Eurasia. No FDA-approved vaccines and therapeutics exist for these deadly viruses, and their development is limited by the requirement for high biocontainment. In this study, we identified and characterized key amino acid changes in the surface glycoproteins of HFRS-causing Hantaan virus that enhance their incorporation into recombinant vesicular stomatitis virus (rVSV) particles. The replication-competent rVSV genetically encoding Hantaan virus glycoproteins described in this work provides a powerful and facile system to study hantavirus entry under lower biocontainment and may have utility as a hantavirus vaccine.
Single-trial characterization of neural rhythms: potential and challenges
Authors: Kosciessa Julian Q. , Grandy Thomas H. , Garrett Douglas D. , Werkle-Bergner Markus
Published: June 2018

The average power of rhythmic neural responses as captured by MEG/EEG/LFP recordings is a prevalent index of human brain function. Increasing evidence questions the utility of trial-/group averaged power estimates, as seemingly sustained activity patterns may be brought about by time-varying transient signals in each single trial. Hence, it is crucial to accurately describe the duration and power of rhythmic and arrhythmic neural responses on the single trial-level. However, it is less clear how well this can be achieved in empirical MEG/EEG/LFP recordings. Here, we extend an existing rhythm detection algorithm (extended Better OSCillation detection: “eBOSC”; cf. Whitten et al., 2011) to systematically investigate boundary conditions for estimating neural rhythms at the single-trial level. Using simulations as well as resting and task-based EEG recordings from a micro-longitudinal assessment, we show that alpha rhythms can be successfully captured in single trials with high specificity, but that the quality of single-trial estimates varies greatly between subjects. Importantly, our analyses suggest that rhythmic estimates are reliable within-subject markers, but may not be consistently valid descriptors of the individual rhythmic process. Finally, we highlight the utility and potential of rhythm detection with multiple proof-of-concept examples, and discuss various implications for single-trial analyses of neural rhythms in electrophysiological recordings.

Highlights

Traditional narrow-band rhythm metrics conflate the power and duration of rhythmic and arrhythmic periods.

We extend a state-of-the-art rhythm detection method (eBOSC) to derive rhythmic episodes in single trials that can disambiguate rhythmic and arrhythmic periods.

Simulations indicate that this can be done with high specificity given sufficient rhythmic power, but with strongly impaired sensitivity when rhythmic power is low.

Empirically, surface EEG recordings exhibit stable inter-individual differences in α-rhythmicity in ranges where simulations suggest a gradual bias, leading to high collinearity between narrow-band and rhythm-specific estimates.

Beyond these limitations, we highlight multiple empirical proof-of-concept benefits of characterizing rhythmic episodes in single trials.
Efficient whole genome haplotyping and high-throughput single molecule phasing with barcode-linked reads
Authors: Redin David , Frick Tobias , Aghelpasand Hooman , Theland Jennifer , Käller Max , Borgström Erik , Olsen Remi-Andre , Ahmadian Afshin
Published: June 2018

The future of human genomics is one that seeks to resolve the entirety of genetic variation through sequencing. The prospect of utilizing genomics for medical purposes require cost-efficient and accurate base calling, long-range haplotyping capability, and reliable calling of structural variants. Short read sequencing has lead the development towards such a future but has struggled to meet the latter two of these needs1. To address this limitation, we developed a technology that preserves the molecular origin of short sequencing reads, with an insignificant increase to sequencing costs. We demonstrate a novel library preparation method which enables whole genome haplotyping, long-range phasing of single DNA molecules, and de novo genome assembly through barcode-linked reads (BLR). Millions of random barcodes are used to reconstruct megabase-scale phase blocks and call structural variants. We also highlight the versatility of our technology by generating libraries from different organisms using only picograms to nanograms of input material.