bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-Reported Outcome Measures for Soft-Tissue Facial Reconstruction: A Systematic Review and Evaluation of the Quality of Their Measurement Properties
Authors: Dobbs Thomas D. , Gibson John A. G. , Hughes Sarah , Thind Arron , Patel Benjamin , Hutchings Hayley A. , Whitaker Iain S. 
Published: October 2018

Background:
A patient’s health-related quality of life can be significantly impacted by facial scarring and disfigurement. Facial soft-tissue reconstruction should aim to improve this, with outcomes measured from the patient’s perspective using patient-reported outcome measures. This systematic review identifies patient-reported outcome measures for soft-tissue facial reconstruction and appraises their methodologic and psychometric properties using up-to-date methods.

Methods:
A systematic search of the MEDLINE, Embase, PsychINFO, and Cochrane databases was performed. Identified patient-reported outcome measures were assessed using the updated Consensus-Based Standards for the Selection of Health Measurement Instruments checklist. Psychometric properties were also assessed and a modified Grading of Recommendation Assessment, Development and Evaluation analysis was performed to aid in recommendations for future questionnaire use.

Results:
Thirty-four studies covering nine patient-reported outcome measures were included. Methodologic quality and psychometric evidence were variable. FACE-Q, Skin Cancer Index, Patient Outcome of Surgery–Head/Neck, and the Derriford Appearance Scale 59/24 all demonstrated high enough evidence to be recommended as having potential for inclusion in future studies.

Conclusions:
This is the first systematic review to identify and critically appraise patient-reported outcome measures for soft-tissue facial reconstruction using internationally accepted criteria. Four questionnaires were deemed to have adequate levels of methodologic and psychometric evidence, although further studies should be conducted before they are used routinely in patients undergoing facial reconstruction. Through the use of psychometrically well-validated questionnaires, it is hoped that patients’ concerns can be truly appreciated, the level of care improved, and the quality of reconstructive options offered advanced.
Synovial Chondromatosis and Calcium Pyrophosphate Deposition of the Temporomandibular Joint: Challenging Diagnosis
Authors: Vellone Valentino , Bracciolini Valeria , Ramieri Valerio , Pernazza Angelina , Della Rocca Carlo , Cascone Piero 
Published: October 2018

Background:
The association between the synovial chondromatosis (SC) and the calcium pyrophosphate deposition (pseudogotta) in temporomandibular joint (TMJ) is very rare and has been described just 1 patient in the literature.

Clinical Presentation:
A 64-year-old woman was referred to Dipartimento di Scienze Odontostomatologiche e Maxillo-Facciali, Sapienza Università di Roma after complaining about right temporomandibular pain, limitation in mandibular movements, and tumefaction in the right preauricular region. The patient was hospitalized for the surgery. The microscopic examination of the excised material revealed calcium pyrophosphate dihydrate (CPPD) deposits crystals associated with cartilaginous proliferation.

Conclusion:
The association between the SC and the calcium pyrophosphate deposition (pseudogotta) is a challenging diagnosis among TMJ neoplasms.
Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications
Authors: Ward Carl C. , Kleinman Jordan I. , Brittain Scott M. , Lee Patrick S. , Chung Clive Yik Sham , Kim Kenneth , Petri Yana , Thomas Jason R. , Tallarico John A. , McKenna Jeffrey M. , Schirle Markus , Nomura Daniel K. 
Published: October 2018

AbstractTargeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications.
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
Authors: Reynolds Regina H , Botía Juan , Nalls Mike A ,   International Parkinson’s Disease Genomics Consortium (IPDGC),   System Genomics of Parkinson’s Disease (SGPD), Hardy John , Gagliano Sarah A , Ryten Mina 
Published: October 2018

AbstractParkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set specifically expressed in astrocytic and microglial subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes to which cell types may have varying vulnerability.
How face perception unfolds over time
Authors: Dobs Katharina , Isik Leyla , Pantazis Dimitrios , Kanwisher Nancy 
Published: October 2018

AbstractWithin a fraction of a second of viewing a face, we have already determined its gender, age and identity. A full understanding of this remarkable feat will require a characterization of the computational steps it entails, along with the representations extracted at each. To this end, we used magnetoencephalography to measure the time course of neural responses to faces, thereby addressing two fundamental questions about how face processing unfolds over time. First, using representational similarity analysis, we found that facial gender and age information emerged before identity information, suggesting a coarse-to-fine processing of face dimensions. Second, identity and gender representations of familiar faces were enhanced very early on, indicating that the previously-reported behavioral benefit for familiar faces results from tuning of early feed-forward processing mechanisms. These findings start to reveal the time course of face perception in humans, and provide powerful new constraints on computational theories of face perception.
Unbiased Atomistic Insight in the Mechanisms and Solvent Role for Globular Protein Dimer Dissociation
Authors: Brotzakis Faidon Z. , Bolhuis Peter G. 
Published: October 2018

Association and dissociation of proteins are fundamental processes in nature. While this process is simple to understand conceptually, the details of the underlying mechanism and role of the solvent are poorly understood. Here we investigate the mechanism and solvent role for the dissociation of the hydrophilic β-lactoglobulin dimer by employing transition path sampling. Analysis of the sampled path ensembles indicates that dissociation (and association) occurs via a variety of mechanisms: 1) a direct aligned dissociation 2) a hopping and rebinding transition followed by unbinding 3) a sliding transition before unbinding. Reaction coordinate and transition state analysis predicts that, besides native contact and vicinity salt-bridge interactions, solvent degrees of freedom play an important role in the dissociation process. Analysis of the structure and dynamics of the solvent molecules reveals that the dry native interface induces enhanced populations of both disordered hydration water and hydration water with higher tetrahedrality, mainly nearby hydrophobic residues. Bridging waters, hydrogen bonded to both proteins, support contacts, and exhibit a faster decay and reorientation dynamics in the transition state than in the native state interface, which renders the proteins more mobile and assists in rebinding. While not exhaustive, our sampling of rare un-biased reactive molecular dynamics trajectories shows in full detail how proteins can dissociate via complex pathways including (multiple) rebinding events. The atomistic insight obtained assists in further understanding and control of the dynamics of protein-protein interaction including the role of solvent.PACS numbers:
Deficient FGF signaling in the developing peripheral retina disrupts ciliary margin development and causes aniridia
Authors: Balasubramanian Revathi , Tao Chenqi , Polanco Karina , Zhong Jian , Wang Fen , Ma Liang , Zhang Xin 
Published: October 2018

ABSTRACTThe mammalian ciliary margin is a part of the developing peripheral neural retina that differentiates into the ciliary body and the iris. Canonical WNT signaling plays a critical role in the specification of the ciliary margin at the peripheral retina in the presence of strong FGF signaling in the central retina. The mechanism of how the boundary between the central retina and the ciliary margin is created has not been previously elucidated. Using genetic ablation and epistasis experiments, we show that loss of FGF signaling gradient in the peripheral retina causes expansion of WNT signaling towards the central retina thereby disrupting the neurogenic boundary and compartmentalization of the ciliary margin. Loss of WNT signaling displays a complimentary effect with expansion of FGF signaling into the ciliary marginal space. Usingin vivoexperiments, we elucidate the FGF signaling cascade involved in development of the ciliary margin. We also identify the surface ectoderm as the source of WNT ligands in eliciting WNT response at the ciliary margin. We show that an interaction between FGF and WNT signaling is required for generation of the ciliary marginal cells. Taken together, our results reveal that a gradient intersection of FGF and WNT signaling is required for specification of the ciliary margin.
Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma
Authors: Ferguson Blake , Handoko Herlina Y. , Mukhopadhyay Pamela , Chitsazan Arash , Balmer Lois , Morahan Grant , Walker Graeme J. 
Published: October 2018

AbstractGenetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset toPrkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit geneRrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure, Mechanistically, variation in the “usual suspects” by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.
Perceptual phenotypes: Perceptual gains and losses in synesthesia and schizophrenia
Authors: van Leeuwen Tessa M. , Sauer Andreas , Jurjut Anna-Maria , Wibral Michael , Uhlhaas Peter J. , Singer Wolf , Melloni Lucia 
Published: October 2018

AbstractIndividual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in e.g. perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Different perceptual phenotypes may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients, synesthetes, and controls. Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors – introduced during the hysteresis experiment – lowered thresholds but did not normalize perception. Our results imply that distinct perceptual phenotypes might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Proteotoxic stress-induced Nrf1 transcriptional program requires a functional TIP60 complex
Authors: Vangala Janakiram R. , Radhakrishnan Senthil K. 
Published: October 2018

ABSTRACTIn response to inhibition of the cellular proteasome, the transcription factor Nrf1 (also called NFE2L1) induces transcription of proteasome subunit genes resulting in the restoration of proteasome activity and thus enabling the cells to mitigate the proteotoxic stress. To identify novel regulators of Nrf1, we performed an RNA interference screen and discovered that the AAA+ ATPase RUVBL1 is necessary for its transcriptional activity. Given that RUVBL1 is part of different multi-subunit complexes that play key roles in transcription, we dissected this phenomenon further and found that the TIP60 chromatin regulatory complex is essential for Nrf1-dependent transcription of proteasome genes. Consistent with these observations, Nrf1, RUVBL1, and TIP60 proteins were co-recruited to the promoter regions of proteasome genes after proteasome inhibitor treatments. More importantly, depletion of RUVBL1 or TIP60 in various cancer cells sensitized them to cell death induced by proteasome inhibition. Our study provides a framework for manipulating the Nrf1-TIP60 axis to alter proteasome function in various human diseases including cancer.
Evolution of protein kinase substrate recognition at the active site
Authors: Bradley David , Beltrao Pedro 
Published: October 2018

AbstractProtein kinases catalyse the phosphorylation of target proteins, controlling most cellular processes. The specificity of serine/threonine kinases is partly determined by interactions with a few residues near the phospho-acceptor residue, forming the so-called kinase substrate motif. Kinases have been extensively duplicated throughout evolution but little is known about when in time new target motifs have arisen. Here we show that sequence variation occurring early in the evolution of kinases is dominated by changes in specificity determining residues. We then analysed kinase specificity models, based on known target sites, observing that specificity has remained mostly unchanged for recent kinase duplications. Finally, analysis of phosphorylation data from a taxonomically broad set of 48 eukaryotic species indicates that most phosphorylation motifs are broadly distributed in eukaryotes but not present in prokaryotes. Overall, our results suggest that the set of eukaryotes kinase motifs present today was acquired soon after the eukaryotic last common ancestor and that early expansions of the protein kinase fold rapidly explored the space of possible target motifs.
Diverse chemical compounds target Plasmodium falciparum plasma membrane lipid homeostasis
Authors: Bhatnagar Suyash , Nicklas Sezin , Morrisey Joanne M. , Goldberg Daniel E. , Vaidya Akhil B. 
Published: October 2018

AbstractLipid homeostasis is essential for the maintenance of life. We previously reported that disruptions of the parasite Na+ homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na+ homeostasis. We therefore screened the same collection of 800 compounds to identify chemotypes that disrupted the parasite plasma membrane lipid homeostasis. Here, we show that the compounds disrupting parasite Na+ homeostasis also induced saponin sensitivity, an indication of parasite lipid homeostasis disruption. Remarkably, 13 compounds were identified that altered plasma membrane lipid composition independent of Na+ homeostasis disruption. Further studies suggest that these compounds target the Plasmodium falciparum Niemann-Pick Type C1-Related (PfNCR1) protein, which is hypothesized to be involved in maintaining plasma membrane lipid composition. PfNCR1, like PfATP4, appears to be targeted by multiple chemotypes with potential for drug discovery.
Biology and Bias in Cell Type-Specific RNAseq of Nucleus Accumbens Medium Spiny Neurons
Authors: Kronman Hope , Richter Felix , Labonté Benoit , Chandra Ramesh , Zhao Shan , Hoffman Gabriel , Lobo Mary Kay , Schadt Eric E. , Nestler Eric J. 
Published: October 2018

AbstractIsolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.
A Simple Approximation To The Bias Of Gene-Envinornment Interactions In Case/Control Studies With Silent Disease
Authors: Lobach Iryna , Sampson Joshua , Lobach Siarhei , Alekseyenko Alexander , Pryatinska Alexandra , He Tao , Zhang Li 
Published: October 2018

AbstractOne of the most important research areas in case-control Genome-Wide Association Studies is to determine how the effect of a genotype varies across the environment or to measure the gene-environment interaction (GxE). We consider the scenario when some of the “healthy” controls actually have the disease and when the frequency of these latent cases varies by the environmental variable of interest. In this scenario, performing logistic regression of clinically defined case status on the genetic variant, environmental variable, and their interaction will result in biased estimates of GxE interaction. Here, we derive a general theoretical approximation to the bias in the estimates of the GxE interaction and show, through extensive simulation, that this approximation is accurate in finite samples. Moreover, we apply this approximation to evaluate the bias in the effect estimates of the genetic variants related to mitochondrial proteins a large-scale Prostate Cancer study.
Using experimental data and information criteria to guide model selection for reaction–diffusion problems in mathematical biology
Authors: Warne David J. , Baker Ruth E. , Simpson Matthew J. 
Published: October 2018

AbstractReaction–diffusion models describing the movement, reproduction and death of individuals within a population are key mathematical modelling tools with widespread applications in mathematical biology. A diverse range of such continuum models have been applied in various biological contexts by choosing different flux and source terms in the reaction–diffusion framework. For example, to describe collective spreading of cell populations, the flux term may be chosen to reflect various movement mechanisms, such as random motion (diffusion), adhesion, haptotaxis, chemokinesis and chemotaxis. The choice of flux terms in specific applications, such as wound healing, is usually made heuristically, and rarely is it tested quantitatively against detailed cell density data. More generally, in mathematical biology, the questions of model validation and model selection have not received the same attention as the questions of model development and model analysis. Many studies do not consider model validation or model selection, and those that do often base the selection of the model on residual error criteria after model calibration is performed using nonlinear regression techniques. In this work, we present a model selection case study, in the context of cell invasion, with a very detailed experimental data set. Using Bayesian analysis and information criteria, we demonstrate that model selection and model validation should account for both residual errors and model complexity. These considerations are often overlooked in the mathematical biology literature. The results we present here provide a clear methodology that can be used to guide model selection across a range of applications. Furthermore, the case study we present provides a clear example where neglecting the role of model complexity can give rise to misleading outcomes.