PubMed

Recent Publications

Using the Electronic Medical Record to Identify Patients at High Risk for Frequent ED Visits and High System Costs.

Related Articles

Using the Electronic Medical Record to Identify Patients at High Risk for Frequent ED Visits and High System Costs.

Am J Med. 2017 Jan 05;:

Authors: Frost DW, Vembu S, Wang J, Tu K, Morris Q, Abrams HB

Abstract
BACKGROUND: A small proportion of patients accounts for a very high proportion of healthcare utilization. Accurate pre-emptive identification may facilitate tailored intervention. We sought to determine whether Machine Learning techniques using text from a family practice Electronic Medical Record (EMR) can be used to predict future high Emergency Department (ED) use and total costs by patients who are not yet high ED users or high cost to the healthcare system.
METHODS: Text from fields of the Cumulative Patient Profile within an EMR (PS Suite) of 43,111 patients was indexed. Separate training and validation cohorts were created. After processing, 11,905 words were used to fit a logistic regression model. The primary outcomes of interest in the 12 months following prediction were 1) 3 or more ED visits and, 2) being in the top 5% in healthcare expenditures. Outcomes were assessed through linkage to administrative databases housed at the Institute for Clinical Evaluative Sciences (ICES).
RESULTS: In the model to predict frequent ED visits, after excluding patients who were high ED users in the previous year, the area under the receiver operating characteristic (AUROC) curve was 0.71. Using the same methodology, the model to predict top 5% in total system costs had an AUROC curve of 0.76 CONCLUSION: Machine learning techniques can be applied to analyze free text contained in EMRs. This dataset is more predictive of patients who will generate future high costs than future ED visits. It remains to be seen if these predictions can be used to reduce costs by early interventions in this cohort of patients.

PMID: 28065773 [PubMed - as supplied by publisher]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.

Related Articles

A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.

Mol Cell. 2016 Dec 21;:

Authors: Yao Z, Darowski K, St-Denis N, Wong V, Offensperger F, Villedieu A, Amin S, Malty R, Aoki H, Guo H, Xu Y, Iorio C, Kotlyar M, Emili A, Jurisica I, Neel BG, Babu M, Gingras AC, Stagljar I

Abstract
Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. We used two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MaMTH), to map the PPIs between human RTKs and phosphatases. The resulting RTK-phosphatase interactome reveals a considerable number of previously unidentified interactions and suggests specific roles for different phosphatase families. Additionally, the differential PPIs of some protein tyrosine phosphatases (PTPs) and their mutants suggest diverse mechanisms of these PTPs in the regulation of RTK signaling. We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. By contrast, PTPRA plays a dual role in EGFR signaling: besides facilitating EGFR dephosphorylation, it enhances downstream ERK signaling by activating SRC. This comprehensive RTK-phosphatase interactome study provides a broad and deep view of RTK signaling.

PMID: 28065597 [PubMed - as supplied by publisher]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Achieving Efficient Manufacturing and Quality Assurance through Synthetic Cell Therapy Design.

Achieving Efficient Manufacturing and Quality Assurance through Synthetic Cell Therapy Design.

Cell Stem Cell. 2017 Jan 05;20(1):13-17

Authors: Lipsitz YY, Bedford P, Davies AH, Timmins NE, Zandstra PW

Abstract
New methods to manipulate gene and cell state can be used to engineer cell functionality, simplify quality assessment, and enhance manufacturability. These strategies could help overcome unresolved cell therapy manufacturing challenges and complement frameworks to design quality into these complex cellular systems, ultimately increasing patient access to living therapeutics.

PMID: 28061350 [PubMed - in process]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Guiding principles for a successful multidisciplinary research collaboration.

Related Articles

Guiding principles for a successful multidisciplinary research collaboration.

Future Sci OA. 2015 Nov;1(3):FSO7

Authors: Lustig LC, Ponzielli R, Tang PS, Sathiamoorthy S, Inamoto I, Shin JA, Penn LZ, Chan WC

PMID: 28031882 [PubMed]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins.

Related Articles

Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins.

EMBO J. 2016 Dec 27;:

Authors: Stolz A, Putyrski M, Kutle I, Huber J, Wang C, Major V, Sidhu SS, Youle RJ, Rogov VV, Dötsch V, Ernst A, Dikic I

Abstract
Autophagy is a cellular surveillance pathway that balances metabolic and energy resources and transports specific cargos, including damaged mitochondria, other broken organelles, or pathogens for degradation to the lysosome. Central components of autophagosomal biogenesis are six members of the LC3 and GABARAP family of ubiquitin-like proteins (mATG8s). We used phage display to isolate peptides that possess bona fide LIR (LC3-interacting region) properties and are selective for individual mATG8 isoforms. Sensitivity of the developed sensors was optimized by multiplication, charge distribution, and fusion with a membrane recruitment (FYVE) or an oligomerization (PB1) domain. We demonstrate the use of the engineered peptides as intracellular sensors that recognize specifically GABARAP, GABL1, GABL2, and LC3C, as well as a bispecific sensor for LC3A and LC3B. By using an LC3C-specific sensor, we were able to monitor recruitment of endogenous LC3C to Salmonella during xenophagy, as well as to mitochondria during mitophagy. The sensors are general tools to monitor the fate of mATG8s and will be valuable in decoding the biological functions of the individual LC3/GABARAPs.

PMID: 28028054 [PubMed - as supplied by publisher]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Stereotypical Escape Behavior in Caenorhabditis elegans Allows Quantification of Effective Heat Stimulus Level.

Read Full Article on External Site Read Full Article on External Site Related Articles

Stereotypical Escape Behavior in Caenorhabditis elegans Allows Quantification of Effective Heat Stimulus Level.

PLoS Comput Biol. 2016 Dec;12(12):e1005262

Authors: Leung K, Mohammadi A, Ryu WS, Nemenman I

Abstract
A goal of many sensorimotor studies is to quantify the stimulus-behavioral response relation for specific organisms and specific sensory stimuli. This is especially important to do in the context of painful stimuli since most animals in these studies cannot easily communicate to us their perceived levels of such noxious stimuli. Thus progress on studies of nociception and pain-like responses in animal models depends crucially on our ability to quantitatively and objectively infer the sensed levels of these stimuli from animal behaviors. Here we develop a quantitative model to infer the perceived level of heat stimulus from the stereotyped escape response of individual nematodes Caenorhabditis elegans stimulated by an IR laser. The model provides a method for quantification of analgesic-like effects of chemical stimuli or genetic mutations in C. elegans. We test ibuprofen-treated worms and a TRPV (transient receptor potential) mutant, and we show that the perception of heat stimuli for the ibuprofen treated worms is lower than the wild-type. At the same time, our model shows that the mutant changes the worm's behavior beyond affecting the thermal sensory system. Finally, we determine the stimulus level that best distinguishes the analgesic-like effects and the minimum number of worms that allow for a statistically significant identification of these effects.

PMID: 28027302 [PubMed - indexed for MEDLINE]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Parkinson's disease-associated GPR37 receptor regulates cocaine-mediated synaptic depression in corticostriatal synapses.

Related Articles

Parkinson's disease-associated GPR37 receptor regulates cocaine-mediated synaptic depression in corticostriatal synapses.

Neurosci Lett. 2016 Dec 19;:

Authors: Rial D, Morató X, Real JI, Gonçalves FQ, Stagljar I, Pereira FC, Fernández-Dueñas V, Cunha RA, Ciruela F

Abstract
GPR37 is an orphan G protein-coupled receptor highly expressed in the brain. The precise function of GPR37 is still unknown, but a number of evidences indicate it modulates the dopaminergic system. Here, we aimed to determine the role of GPR37 on the control of cocaine-mediated electrophysiological effects (synaptic transmission and short-term plasticity) in corticostriatal synapses. Accordingly, we evaluated basal synaptic transmission and paired-pulse stimulation (PPS) in wild-type and GPR37KO mice slices. Regardless of the genotype, a low concentration of cocaine (2μM) did not modify basal synaptic transmission. Conversely, a higher dose of cocaine (30μM) decreased synaptic transmission in both genotypes, although with different intensities: approximately 30% in slices from wild-type mice and 45% in slices from GPR37-KO mice. On the other hand, no differences in PPS ratio were observed between wild-type and GPR37-KO cocaine-treated mice. Overall, our data suggest that GPR37 is involved in cocaine-induced modification of basal synaptic transmission without modifying cocaine effects in short-term plasticity.

PMID: 28007645 [PubMed - as supplied by publisher]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Discovery of short linear motif-mediated interactions through phage display of intrinsically disordered regions of the human proteome.

Read Full Article on External Site Related Articles

Discovery of short linear motif-mediated interactions through phage display of intrinsically disordered regions of the human proteome.

FEBS J. 2017 Feb;284(3):485-498

Authors: Davey NE, Seo MH, Yadav VK, Jeon J, Nim S, Krystkowiak I, Blikstad C, Dong D, Markova N, Kim PM, Ivarsson Y

Abstract
The intrinsically disordered regions of eukaryotic proteomes are enriched in short linear motifs (SLiMs), which are of crucial relevance for cellular signaling and protein regulation; many mediate interactions by providing binding sites for peptide-binding domains. The vast majority of SLiMs remain to be discovered highlighting the need for experimental methods for their large-scale identification. We present a novel proteomic peptide phage display (ProP-PD) library that displays peptides representing the disordered regions of the human proteome, allowing direct large-scale interrogation of most potential binding SLiMs in the proteome. The performance of the ProP-PD library was validated through selections against SLiM-binding bait domains with distinct folds and binding preferences. The vast majority of identified binding peptides contained sequences that matched the known SLiM-binding specificities of the bait proteins. For SHANK1 PDZ, we establish a novel consensus TxF motif for its non-C-terminal ligands. The binding peptides mostly represented novel target proteins, however, several previously validated protein-protein interactions (PPIs) were also discovered. We determined the affinities between the VHS domain of GGA1 and three identified ligands to 40-130 μm through isothermal titration calorimetry, and confirmed interactions through coimmunoprecipitation using full-length proteins. Taken together, we outline a general pipeline for the design and construction of ProP-PD libraries and the analysis of ProP-PD-derived, SLiM-based PPIs. We demonstrated the methods potential to identify low affinity motif-mediated interactions for modular domains with distinct binding preferences. The approach is a highly useful complement to the current toolbox of methods for PPI discovery.

PMID: 28002650 [PubMed - indexed for MEDLINE]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

A common class of transcripts with 5'-intron depletion, distinct early coding sequence features, and N1-methyladenosine modification.

Related Articles

A common class of transcripts with 5'-intron depletion, distinct early coding sequence features, and N1-methyladenosine modification.

RNA. 2016 Dec 19;:

Authors: Cenik C, Chua HN, Singh G, Akef A, Snyder MP, Palazzo AF, Moore MJ, Roth FP

Abstract
Introns are found in 5' untranslated regions (5'UTRs) for 35% of all human transcripts. These 5'UTR introns are not randomly distributed: genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5'UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5'UTR intron status, we developed a classifier that can predict 5'UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5' proximal-intron-minus-like-coding regions ("5IM" transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5' cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the Exon Junction Complex (EJC) at non-canonical 5' proximal positions. Finally, N1-methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising ~20% of human transcripts. This class is defined by depletion of 5' proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N1-methyladenosines in the early coding region, and enrichment for non-canonical binding by the Exon Junction Complex.

PMID: 27994090 [PubMed - as supplied by publisher]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Diverse mechanisms of metaeffector activity in an intracellular bacterial pathogen, Legionella pneumophila.

Read Full Article on External Site Read Full Article on External Site Related Articles

Diverse mechanisms of metaeffector activity in an intracellular bacterial pathogen, Legionella pneumophila.

Mol Syst Biol. 2016 Dec 16;12(12):893

Authors: Urbanus ML, Quaile AT, Stogios PJ, Morar M, Rao C, Di Leo R, Evdokimova E, Lam M, Oatway C, Cuff ME, Osipiuk J, Michalska K, Nocek BP, Taipale M, Savchenko A, Ensminger AW

Abstract
Pathogens deliver complex arsenals of translocated effector proteins to host cells during infection, but the extent to which these proteins are regulated once inside the eukaryotic cell remains poorly defined. Among all bacterial pathogens, Legionella pneumophila maintains the largest known set of translocated substrates, delivering over 300 proteins to the host cell via its Type IVB, Icm/Dot translocation system. Backed by a few notable examples of effector-effector regulation in L. pneumophila, we sought to define the extent of this phenomenon through a systematic analysis of effector-effector functional interaction. We used Saccharomyces cerevisiae, an established proxy for the eukaryotic host, to query > 108,000 pairwise genetic interactions between two compatible expression libraries of ~330 L. pneumophila-translocated substrates. While capturing all known examples of effector-effector suppression, we identify fourteen novel translocated substrates that suppress the activity of other bacterial effectors and one pair with synergistic activities. In at least nine instances, this regulation is direct-a hallmark of an emerging class of proteins called metaeffectors, or "effectors of effectors". Through detailed structural and functional analysis, we show that metaeffector activity derives from a diverse range of mechanisms, shapes evolution, and can be used to reveal important aspects of each cognate effector's function. Metaeffectors, along with other, indirect, forms of effector-effector modulation, may be a common feature of many intracellular pathogens-with unrealized potential to inform our understanding of how pathogens regulate their interactions with the host cell.

PMID: 27986836 [PubMed - indexed for MEDLINE]



▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄ ▄

Back to Top