bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous visualization of differences between biological conditions in single-cell data
Authors: Burns Tyler J. , Nolan Garry P. , Samusik Nikolay
Published: June 2018

In high-dimensional single cell data, comparing changes in functional markers between conditions is typically done across manual or algorithm-derived partitions based on population-defining markers. Visualizations of these partitions is commonly done on low-dimensional embeddings (eg. t-SNE), colored by per-partition changes. Here, we provide an analysis and visualization tool that performs these comparisons across overlapping k-nearest neighbor (KNN) groupings. This allows one to color low-dimensional embeddings by marker changes without hard boundaries imposed by partitioning. We devised an objective optimization of k based on minimizing functional marker KNN imputation error. Proof-of-concept work visualized the exact location of an IL-7 responsive subset in a B cell developmental trajectory on a t-SNE map independent of clustering. Per-condition cell frequency analysis revealed that KNN is sensitive to detecting artifacts due to marker shift, and therefore can also be valuable in a quality control pipeline. Overall, we found that KNN groupings lead to useful multiple condition visualizations and efficiently extract a large amount of information from mass cytometry data. Our software is publicly available through the Bioconductor package Sconify.
Vascular bundle sheath and mesophyll regulation of leaf water balance in response to chitin
Authors: Attia Ziv , Dalal Ahan , Moshelion Menachem
Published: June 2018

Plants can detect pathogen invasion by sensing pathogen-associated molecular patterns (PAMPs). This sensing process leads to the induction of defense responses. Most PAMP mechanisms of action have been described in the guard cells. Here, we describe the effects of chitin, a PAMP found in fungal cell walls, on the cellular osmotic water permeability (Pf) of the leaf vascular bundle-sheath (BS) and mesophyll cells and its subsequent effect on leaf hydraulic conductance (Kleaf).

The BS is a parenchymatic tissue that tightly encases the vascular system. BS cells have been shown to controlKleafthrough changes in theirPf, for example, in response to ABA. It was recently reported that, in Arabidopsis, the chitin receptors chitin elicitor receptor kinase 1 (CERK1) and LYSINE MOTIF RECEPTOR KINASE 5 (LYK5) are highly expressed in the BS, as well as the neighboring mesophyll. Therefore, we studied the possible impact of chitin on these cells.

Our results revealed that both BS cells and mesophyll cells exhibit a sharp decrease inPfin response to chitin treatment. In addition, xylem-fed chitin decreasedKleafand led to stomatal closure. However, anAtlyk5mutant showed none of these responses. ComplimentingAtLYK5specifically in the BS cells (using the SCARECROW promoter) and transient expresion in mesophyll cells each resulted in a response to chitin that was similar to that observed in the wild type. These results suggest that BS and mesophyll cells each play a role in the perception of apoplastic chitin and in initiating chitin-triggered immunity.

Significance Statement

PAMP perception by plant receptors triggers various defense responses important for plant immunity. Here we provide new insights into a topic that has received a great deal of previous attention, revealing that a chitin immune response is present in additional leaf tissues other than the stomata. Chitin perception by the bundle sheath cells enwrapping the whole leaf vascular system decrease its cellular osmotic permeability and leaf hydraulic conductance. This in turn, leads to hydraulic signals being sent to the stomata and regulates whole-leaf water balance in response to chitin application and, perhaps, during fungal infection. Emphasizing the dynamic role of the BS in chitin-sensing and water balance regulation.
Quantitation of single action potential-evoked Ca2+signals in CA1 pyramidal neuron presynaptic terminals
Authors: Church Emily , Hamid Edaeni , Alford Simon
Published: June 2018

Presynaptic Ca2+evokes exocytosis, endocytosis, and short-term synaptic plasticity. However, Ca2+flux and interactions at presynaptic molecular targets are difficult to determine, because imaging has limited resolution. We measured single varicosity presynaptic Ca2+using Ca2+dyes as buffers, and constructed models of Ca2+dispersal. Action potentials evoked Ca2+transients (peak amplitude, 789±39 nM, within 2 ms of stimulation; decay times, 119±10 ms) with little variation when measured with low-affinity dye. Endogenous Ca2+buffering capacities, action potential-evoked free [Ca2+]¡ and total amounts entering terminals were determined using high-affinity Ca2+dyes to buffer Ca2+transients. These data constrained Monte Carlo (MCell) simulations of Ca2+entry, buffering, and removal. Data were well-fit with simulations of experimentally-determined Ca2+fluxes, buffered by simulated Calbindin28K. Simulations were consistent with clustered Ca2+entry followed within 2 ms by diffusion throughout the varicosity. Repetitive stimulation caused free varicosity Ca2+to sum. However, simulated in nanometer domains, its removal by pumps and buffering was negligible, while diffusion rates were high. Thus, Ca2+within tens of nanometers of entry, did not accumulate during sequential stimuli. A model of synaptotagmin1-Ca2+binding indicates that even with 10 μM free varicosity Ca2+, synaptogmin1 must be within tens of nanometers of channels to ensure occupation of all its Ca2+binding sites. Repetitive stimulation, which evokes short-term synaptic enhancement, does not modify probabilities of Ca2+fully occupying synaptotagmin1’s C2 domains, suggesting that enhancement is not mediated by Ca2+-synaptotagmin1. We conclude that at spatio-temporal scale of fusion machines, Ca2+necessary for their activation is diffusion dominated.
QstR-dependent regulation of natural competence and type VI secretion in Vibrio cholerae
Authors: Jaskólska Milena , Stutzmann Sandrine , Stoudmann Candice , Blokesch Melanie
Published: June 2018

During growth on chitinous surfaces in its natural aquatic environment Vibrio cholerae develops natural competence for transformation and kills neighboring non-immune bacteria using a type VI secretion system (T6SS). Activation of these two phenotypes requires the chitin-induced regulator TfoX, but also integrates signals from quorum sensing via the intermediate regulator QstR, which belongs to the LuxR-type family of regulators. Here, we define the QstR regulon using RNA sequencing. Moreover, by mapping QstR binding sites using chromatin immunoprecipitation coupled with deep sequencing we demonstrate that QstR is likely a dual transcription factor that binds upstream of the up- and down-regulated genes. Like other LuxR-type family transcriptional regulators we show that QstR function is dependent on dimerization. However, in contrast to the well-studied LuxR-type biofilm regulator VpsT of V. cholerae, which requires the second messenger c-di-GMP, we show that QstR dimerization and function is c-di-GMP independent. Surprisingly, although ComEA, which is a periplasmic DNA-binding protein essential for transformation, is produced in a QstR-dependent manner, QstR-binding was not detected upstream of comEA suggesting the existence of a further regulatory pathway. Overall these results provide detailed insights into the function of a key regulator of natural competence and type VI secretion in V. cholerae.
Current and future goals are represented in opposite patterns in object-selective cortex
Authors: van Loon Anouk M. , Solis Katya Olmos , Fahrenfort Johannes J. , Olivers Christian N. L.
Published: June 2018

Adaptive behavior requires the separation of current from future goals in working memory. We used fMRI of object-selective cortex to determine the representational (dis)similarities of memory representations serving current and prospective perceptual tasks. Participants remembered an object drawn from three possible categories as the target for one of two consecutive visual search tasks. A cue indicated whether the target object should be looked for first (currently relevant), second (prospectively relevant), or if it could be forgotten (irrelevant). Prior to the first search, representations of current, prospective and irrelevant objects were similar, with strongest decoding for current representations compared to prospective (Experiment 1) and irrelevant (Experiment 2). Remarkably, during the first search, prospective representations could also be decoded, but revealed anti-correlated voxel patterns compared to currently relevant representations of the same category. We propose that the brain separates current from prospective memories within the same neuronal ensembles through opposite representational patterns.
A geometric attractor mechanism for self-organization of entorhinal grid modules
Authors: Kang Louis , Balasubramanian Vijay
Published: June 2018

Grid cells in the medial entorhinal cortex (MEC) respond when an animal occupies a periodic lattice of “grid fields” in the environment. The grids are organized in modules with spatial periods, or scales, clustered around discrete values separated by ratios in the range 1.2–2.0. We propose a mechanism that produces this modular structure through dynamical self-organization in the MEC. In attractor network models of grid formation, the grid scale of a single module is set by the distance of recurrent inhibition between neurons. We show that the MEC forms a hierarchy of discrete modules if a smooth increase in inhibition distance along its dorso-ventral axis is accompanied by excitatory interactions along this axis. Moreover, constant scale ratios between successive modules arise through geometric relationships between triangular grids and have values that fall within the observed range. We discuss how interactions required by our model might be tested experimentally.
Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish
Authors: Hortle Elinor , Johnson Khelsey E. , Johansen Matt D. , Nguyen Tuong , Shavit Jordan A. , Britton Warwick J. , Tobin David M. , Oehlers Stefan H.
Published: June 2018

Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced mycobacterial burden demonstrating a detrimental role for infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to mycobacterial infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.

Key Points

Inhibition of thrombocyte activation improves control of mycobacterial infection.

Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against mycobacterial infection.
Precise prediction of antibiotic resistance in Escherichia coli from full genome sequences
Authors: Moradigaravand Danesh , Palm Martin , Farewell Anne , Mustonen Ville , Warringer Jonas , Parts Leopold
Published: June 2018

The emergence of microbial antibiotic resistance is a global health threat. In clinical settings, the key to controlling spread of resistant strains is accurate and rapid detection. As traditional culture-based methods are time consuming, genetic approaches have recently been developed for this task. The diagnosis is typically made by measuring a few known determinants previously identified from whole genome sequencing, and thus is restricted to existing information on biological mechanisms. To overcome this limitation, we employed machine learning models to predict resistance to 11 compounds across four classes of antibiotics from existing and novel whole genome sequences of 1936 E. coli strains. We considered a range of methods, and examined population structure, isolation year, gene content, and polymorphism information as predictors. Gradient boosted decision trees consistently outperformed alternative models with an average F1 score of 0.88 on held-out data (range 0.66-0.96). While the best models most frequently employed all inputs, an average F1 score of 0.73 could be obtained using population structure information alone. Single nucleotide variation data were less useful, and failed to improve prediction for ten out of 11 antibiotics. These results demonstrate that antibiotic resistance in E. coli can be accurately predicted from whole genome sequences without a priori knowledge of mechanisms, and that both genomic and epidemiological data are informative. This paves way to integrating machine learning approaches into diagnostic tools in the clinic.

One of the major health threats of 21st century is emergence of antibiotic resistance. To manage its economic impact, efforts are made to develop novel diagnostic tools that rapidly detect resistant strains in clinical settings. In our study, we employed a range machine learning tools to predict antibiotic resistance from whole genome sequencing data for E. coli. We used the presence or absence of genes, population structure and isolation year of isolates as predictors, and could attain average precision of 0.93 and recall of 0.83, without prior knowledge about the causal mechanisms. These results demonstrate the potential application of machine learning methods as a diagnostic tool in healthcare settings.
A comparative genome analysis of Rift Valley Fever virus isolates from foci of the disease outbreak in South Africa in 2008-2010
Authors: Maluleke Moabi R. , Phosiwa Maanda , Schalkwyk Antoinette van , Michuki George , Lubisi Baratang A. , Kegakilwe Phemelo S. , Kemp Steve J. , Majiwa Phelix A.O.
Published: June 2018

Rift Valley fever (RVF) is a re-emerging zoonotic disease responsible for major losses in livestock production, with negative impact on the livelihoods of both commercial and resource-poor farmers in sub-Sahara African countries. The disease remains a threat in countries where its mosquito vectors thrives. Outbreaks of RVF usually follow weather conditions which favour increase in mosquito populations. Such outbreaks are usually cyclical, occurring every 10-15 years.

Recent outbreaks of the disease in South Africa have occurred unpredictably and with increased frequency. In 2008 outbreaks were reported in Mpumalanga, Limpopo and Gauteng provinces, followed by a 2009 outbreak in KwaZulu-Natal, Mpumalanga and Northern Cape provinces and in 2010 in the Eastern Cape, Northern Cape, Western Cape, North West, Free State and Mpumalanga provinces. By August 2010, 232 confirmed infections had been reported in humans, with 26 confirmed deaths.

To investigate the evolutionary dynamics of RVF viruses (RVFVs) circulating in South Africa, we undertook complete genome sequence analysis of isolates from animals at discrete foci of the 2008-2010 outbreaks. The genome sequences of these viruses were compared with viruses from earlier outbreaks in South Africa and in other countries. The data indicates that one 2009 and all the 2008 isolates from South Africa and Madagascar (M49/08) cluster in Lineage C or Kenya-1. The remaining of the 2009 and 2010 isolates cluster within Lineage H, except isolate M259_RSA_09, a probable segment M reassortant.

Author summary

A single RVF virus serotype exists, yet differences in virulence and pathogenicity of the virus have been observed. This necessitates the need for detailed genetic characterization of various isolates of the virus. The RVF virus isolates that caused the 2008-2010 disease outbreaks in South Africa were most probably reassortants. Reassortment results from exchange of portions of the genome, particularly those of segment M. Although clear association between RVFV genotype and phenotype has not been established, various amino acid substitutions have been implicated in the phenotype. Viruses with amino acid substitutions from glycine to glutamic acid at position 277 of segment M have been shown to be more virulent in mice in comparison to viruses with glycine at the same position. Phylogenetic analysis indicated the viruses responsible for the 2008-2010 RVF outbreaks in South Africa were not introduced from outside the country, but mutated in time and caused the outbreaks when environmental conditions became favourable.
The BTB-ZF transcription factor Tramtrack69 shapes neural cell lineages by coordinating cell proliferation and cell fate
Authors: Simon Françoise , Ramat Anne , Louvet-Vallée Sophie , Lacoste Jérôme , Burg Angélique , Audibert Agnès , Gho Michel
Published: June 2018

Cell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Here, we show that Tramtrack-69 (Ttk69, a BTB-ZF transcription factor ortholog of the human PLZF factor) plays an essential role in controlling this balance. In theDrosophilabristle cell lineage, producing the external sensory organs composed by a neuron and accessory cells, we show thatttk69loss of function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell-cycle exit of newborn terminal cells by downregulatingcycE, the principal cyclin involved in S-phase entry and (2) regulates cell fate acquisition and terminal differentiation by downregulating the expression ofhamletand upregulating that ofSuppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory-cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate commitment.

Summary statement

Tramtrack-69, a transcription factor orthologous to the human tumor-suppressor PLZF, plays a central role in precursor cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate determination.
ATRAIDregulates the action of nitrogen-containing bisphosphonates on bone
Authors: Surface Lauren E. , Burrow Damon T. , Li Jinmei , Park Jiwoong , Kumar Sandeep , Lyu Cheng , Song Niki , Yu Zhou , Rajagopal Abbhirami , Bae Yangjin , Lee Brendan H. , Mumm Steven , Gu Charles C. , Baker Jonathan C. , Mohseni Mahshid , Sum Melissa , Huskey Margaret , Duan Shenghui , Bijanki Vinieth N. , Civitelli Roberto , Gardner Michael J. , McAndrew Chris M. , Ricci William M. , Gurnett Christina A. , Diemer Kathryn , Wan Fei , Costantino Christina L. , Shannon Kristen M. , Raje Noopur , Dodson Thomas B. , Haber Daniel A. , Carette Jan E. , Varadarajan Malini , Brummelkamp Thijn R. , Birsoy Kivanc , Sabatini David M. , Haller Gabe , Peterson Timothy R.
Published: June 2018

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene,ATRAID. Loss ofATRAIDfunction results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation.ATRAIDis required for alendronate inhibition of osteoclast function, andATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF.ATRAIDis one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation inATRAIDas conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.

One Sentence Summary

ATRAIDis essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates.

Overline

BONE
Actin-inspired feedback couples speed and persistence in a Cellular Potts Model of cell migration
Authors: Wortel Inge M. N. , Niculescu Ioana , Kolijn P. Martijn , Gov Nir , de Boer Rob J. , Textor Johannes
Published: June 2018

Cell migration is astoundingly diverse. Molecular signatures, cell-cell and cell-matrix interactions, and environmental structures each play their part in shaping cell motion, yielding numerous different cell morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently. Given this universal coupling between speed and persistence (UCSP), from a modelling perspective it is important to know whether computational models of cell migration capture this speed-persistence link. Here, we present an in-depth characterisation of an existing Cellular Potts Model (CPM). We first show that this model robustly reproduces the UCSP without having been designed for this task. Instead, we show that this fundamental law of migration emerges spontaneously through a crosstalk of intracellular mechanisms, cell shape, and environmental constraints, resembling the dynamic nature of cell migrationin vivo. Our model also reveals how cell shape dynamics can further constrain cell motility by limiting both the speed and persistence a cell can reach, and how a rigid environment such as the skin can restrict cell motility even further. Our results further validate the CPM as a model of cell migration, and shed new light on the speed-persistence coupling that has emerged as a fundamental property of migrating cells.

SIGNIFICANCE

The universal coupling between speed and persistence (UCSP) is the first general quantitative law describing motility patterns across the versatile spectrum of migrating cells. Here, we show – for the first time – that this migration law emerges spontaneously in an existing, highly popular computational model of cell migration. Studying the UCSP in entirely different model frameworks,notexplicitly built with this law in mind, can help uncover how intracellular dynamics, cell shape, and environment interact to produce the diverse motility patterns observed in migrating cells.
Reduced transfer of visuomotor adaptation is associated with aberrant sense of agency in Schizophrenia
Authors: Bansal Sonia , Murthy Karthik G , Fitzgerald Justin , Schwartz Barbara L. , Joiner Wilsaan M.
Published: June 2018

One deficit associated with schizophrenia (SZ) is the reduced ability to distinguish sensations resulting from self-caused actions from those due to external sources. This reduced sense of agency (SoA, awareness of ownership over self-generated actions) is hypothesized to result from a diminished utilization of internal monitoring signals of self-movement (i.e., efferent copy) which subsequently impairs forming and utilizing sensory prediction errors (differences between the predicted and actual sensory consequences resulting from movement). Here, we investigated the connections between clinical SZ symptoms and motor adaptation, a process that uses sensory prediction errors to update motor output. Schizophrenia patients (SZP, N=30) and non-psychiatric healthy control subjects (HC, N=31) adapted to altered movement visual feedback, and then applied the motor recalibration to untested contexts (i.e., the spatial generalization to untrained targets). Although adaptation was similar for SZP and controls, the extent of generalization was significantly less for SZP; movement trajectories made by patients to the furthest untrained target (135°) before and after adaptation were largely indistinguishable. Interestingly, deficits in the generalization were correlated to positive symptoms of psychosis (e.g., hallucinations), but not negative symptoms. Generalization was also associated with subjective measures of SoA across both SZP and HC, emphasizing the major role action awareness plays in motor behavior, and suggesting that tendencies to misattribute agency, even in HC, manifest in abnormal motor performance. We discuss the possible link of these findings to cerebellar circuit abnormalities that may be a common source for deficits in the utilization of sensory prediction errors and aberrant SoA.
Pathogenic mutations inNUBPLaffect complex I activity and cold tolerance in the yeast modelYarrowia lipolytica
Authors: Maclean Andrew E. , Kimonis Virginia E. , Balk Janneke
Published: June 2018

Complex I deficiency is a common cause of mitochondrial disease, resulting from mutations in genes encoding structural subunits, assembly factors or defects in mitochondrial gene expression. Advances in genetic diagnostics and sequencing have led to identification of several variants in NUBPL, an assembly factor of complex I, which are potentially pathogenic. To help assign pathogenicity and learn more about the function of NUBPL, amino acid substitutions were recreated in the homologous Ind1 protein of the yeast modelYarrowia lipolytica. L102P destabilized the Ind1 protein, leading to a null-mutant phenotype. D103Y, L191F and G285C affected complex I assembly to varying degrees, whereas the G138D variant did not impact on complex I levels or dNADH:ubiquinone activity. Blue-native PAGE and immunolabelling of the structural subunits NUBM and NUCM revealed that all Ind1 variants accumulated a Q-module intermediate of complex I. In the D103Y variant the matrix arm intermediate was virtually absent, indicating a dominant effect. Dysfunction of Ind1, but not absence of complex I, renderedY. lipolyticasensitive to cold. The Ind1 G285C variant was able to support complex I assembly at 28°C, but not at 10°C. Our results indicate that Ind1 is required for progression of assembly from the Q module to the full matrix arm. Cold sensitivity could be developed as a phenotype assay to demonstrate pathogenicity ofNUBPLmutations and other complex I defects.
Analysis of cell size homeostasis at the single-cell and population level
Authors: Thomas Philipp
Published: June 2018

Growth pervades all areas of life from single cells to cell populations to tissues. However, cell size often fluctuates significantly from cell to cell and from generation to generation. Here we present a unified framework to predict the statistics of cell size variations within a lineage tree of a proliferating population. We analytically characterise (i) the distributions of cell size snapshots, (ii) the distribution within a population tree, and (iii) the distribution of lineages across the tree. Surprisingly, these size distributions differ significantly from observing single cells in isolation. In populations, cells seemingly grow to different sizes, typically exhibit less cell-to-cell variability and often display qualitatively different sensitivities to cell cycle noise and division errors. We demonstrate the key findings using recent single-cell data and elaborate on the implications for the ability of cells to maintain a narrow size distribution and the emergence of different power laws in these distributions.
Catalytic Use of a Leader Peptide in the Biosynthesis of 3-Thiaglutamate
Authors: Funk Michael A. , Ting Chi , van der Donk Wilfred A.
Published: June 2018

Small molecule natural products are key modulators of many types of intra- and interspecies communication. The availability of genome sequences allows the discovery of pathways to previously unknown natural products. We describe here a pathway in which a ribosomally synthesized small peptide serves as a catalytic scaffold on which a small-molecule anti-metabolite is biosynthesized in Pseudomonas syringae. First, a cysteine residue is transferred from Cys-tRNA to the C-terminus of the peptide, a reaction that replaces ribosomal protein synthesis. Then, a translocation of the cysteine thiol from the β-carbon to the α-carbon is catalyzed by an oxidase that removes the β-carbon as formate. The resulting thiol is carboxymethylated and proteolysis releases 3-thiaglutamate, in the process regenerating the peptide scaffold. This pathway features three previously unknown biochemical processes.
Mechanical and Microstructural Properties of Pediatric Anterior Cruciate Ligaments and Autograft Tendons used for Reconstruction
Authors: Schmidt Elaine C , Chin Matthew , Aoyama Julien T , Ganely Theodore J , Shea Kevin G , Hast Michael W
Published: June 2018

Background

Over the last several decades there has been a steady increase in pediatric ACL tears, particularly in young female basketball and soccer players. Because allograft tissue for pediatric ACL reconstruction (ACLR) has shown high rates of failure, autograft tissue may be the best option for ACLR in this population. However, the differences in structure and mechanical behavior of these tissues are not clear.

Purpose

This study sought to characterize mechanical and microstructural properties in pediatric ACLs and autograft tissues using a rare cadaveric cohort (mean age 9.2 years).

Study Design

Descriptive laboratory study.

Methods

ACLs, patellar tendons, quadriceps tendons, semitendinosus tendons, and iliotibial bands (ITBs) were harvested from five fresh-frozen pediatric knee specimens (3M, 2F) and subjected to a tensile loading protocol. A subset of contralateral tissues were analyzed using brightfield, polarized light, and transmission electron microscopy.

Results

Patellar tendons exhibited values for ultimate stress (5.2±3.1 MPa), ultimate strain (35.3±12.5%), and Young’s Modulus (27.0±8.0 MPa) that were most similar to the ACL (5.2±2.2 MPa; 31.4±9.9%; 23.6±15.5 MPa). Semitendinosus tendons and ITBs were stronger but less compliant than the quadriceps or patellar tendons. ITBs exhibited crimp wavelengths (24.3±3.1 um) and collagen fibril diameters (67.5±19.5 nm) that were most similar to the ACL (24.4±3.2 um; 69.7±20.3 nm).

Conclusion

The mechanical properties of the patellar tendon were almost identical to that of the ACL. The ITB exhibited increased strength and similar microstructure to the native ACL. These findings are not entirely congruent to studies examining adult tissues.

Clinical Relevance

Results suggest that ITB tissue may be the preferable choice as an autograft tissue in pediatric ACL reconstructions.

Key Terms

Pediatric, ACL reconstruction, mechanical properties, microstructural properties, patella tendon grafts, quadriceps tendon grafts, hamstring grafts

What is Known about the Subject

Due to the extreme rarity of pediatric cadaveric specimens, very little is known about these tissues.

What this Study Adds to Existing Knowledge

This suite of data can be used to further optimize the design and selection of grafts for reconstruction and may provide insight into the development of constitutive musculoskeletal models.
Absolute quantification of translational regulation and burden using combined sequencing approaches
Authors: Gorochowski Thomas E. , Chelysheva Irina , Eriksen Mette , Nair Priyanka , Pedersen Steen , Ignatova Zoya
Published: June 2018

Translation of mRNAs into proteins is a key cellular process. Ribosome binding sites and stop codons provide signals to initiate and terminate translation, while stable secondary mRNA structures can induce translational recoding events. Fluorescent proteins are commonly used to characterize such elements but require the modification of a part’s natural context and allow only a few parameters to be monitored concurrently. Here, we develop an approach that combines ribosome profiling (Ribo-seq) with quantitative RNA sequencing (RNA-seq) to enable the high-throughput characterization of genetic parts controlling translation in absolute units. We simultaneously measure 743 translation initiation rates and 746 termination efficiencies across theEscherichia colitranscriptome, in addition to translational frameshifting induced at a stable RNA pseudoknot structure. By analyzing the transcriptional and translational response, we discover that sequestered ribosomes at the pseudoknot contribute to a σ32-mediated stress response, codon-specific pausing, and a drop in translation initiation rates across the cell. Our work demonstrates the power of integrating global approaches towards a comprehensive and quantitative understanding of gene regulation and burden in living cells.
Being an adult child of an elderly person living in a nursing home: a phenomenological approach to the Turkish case
Authors: Önder Erol Pelin , Gün Elif
Published: June 2018

Purpose

A long-established cultural norm of filial piety may cause ambivalent feelings for adult children who are considered the primary caregivers for their elderly parents in Turkish culture, and whose parents have been placed into nursing homes. The purpose of this paper is to provide an insight to the lived experiences of adult children of elderly people living in a nursing home in Turkey.

Design/methodology/approach

Drawing upon dramaturgical theory and phenomenological methodology, the authors conducted interviews with ten adult children whose elderly parents had been admitted to a nursing home in Izmir, Turkey. Multi-stage purposeful random sampling was used as the sampling scheme. Thematic analysis was performed to interpret the data.

Findings

Three themes emerged from the data: adult children’s coping strategies, the ways in which the adult children rationalize their decisions, and the ways in which the adult children manage the placement process. The interviews revealed that the adult children often feel like social outcasts and experience a wide range of difficulties, including social pressures, their own inner dilemmas, and negotiations with their elderly parents.

Originality/value

An exploration for the lived experiences of adult children relating to the nursing home placement of their elderly parents contributes an insight about the well-established cultural norms that produce feelings of ambivalence.
Cytochrome P450 genotype‐guided drug therapies: An update on current states
Authors: Dong Amelia Nathania , Tan Boon Hooi , Pan Yan , Ong Chin Eng
Published: June 2018

Over the past 2 decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre‐emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as the US FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well‐defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non‐genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype‐guided therapy in clinical practice a step closer to reality.
Perceived Need and Receipt of Behavioral Health Services at Drop‐In Centers among Homeless Youth
Authors: Pedersen Eric R. , Tucker Joan S. , Klein David J. , Parast Layla
Published: June 2018

Objective

Homeless youth are a population in need of housing assistance and case management, as well as services to address behavioral health problems. This study examines youth's perceived need for and receipt of services through drop‐in centers.

Data Source

Surveys of 273 homeless youth.

Study Design

Cross‐sectional.

Extraction Methods

Descriptive analyses with bivariate and multivariable regression models.

Principal Findings

About one‐third to half of the sample met criteria for behavioral health problems, yet half or less of those meeting criteria reported a need for services targeting the problems. Most youth who perceived a need for services received relevant services through a drop‐in center, with the exception of care for substance use problems. Youth with behavioral health problems were more likely to perceive a need for services related to housing and case management than those addressing behavioral health problems more directly. Multivariable regression analyses indicated that the factors most strongly associated with perceived need for services were not behavioral health problems, but rather race/ethnicity, traveler status, trouble meeting basic needs, delinquency, abuse/victimization experiences, and trading sex.

Conclusions

Findings can help to develop outreach and intervention efforts to reach homeless youth and help promote the use of behavioral health services.
Tailored Strategies to Enhance Survey Response among Proxies of Deceased Patients
Authors: Gu Qian , Hassol Andrea , Creel Alisha , Keating Nancy L.
Published: June 2018

Objective

To enhance proxy survey responses for deceased cancer patients.

Data Sources

Two waves of surveys about care experiences of cancer chemotherapy patients (used for a value‐based purchasing initiative), collected November 2016 through March 2017.

Study Design

Surveys were mailed to deceased patients (for proxy response) in the untailored first survey wave, and using a tailored strategy in the second wave. We compared proxy responses for deceased patients with and without the tailored approach.

Principal Findings

A tailored survey approach improved the proxy response rate from 17.6 percent to 39.0 percent.

Conclusions

Simple tailoring strategies can significantly enhance proxy response rates when surveying patients in a high mortality population. However, we were unable to address the impact of higher proxy response rates on response bias since we surveyed different patients in each wave.
RPASE: Individual‐based allele‐specific expression detection without prior knowledge of haplotype phase
Authors: Wang Mi , Uebbing Severin , Pawitan Yudi , Scofield Douglas G.
Published: June 2018

Variation in gene expression is believed to make a significant contribution to phenotypic diversity and divergence. The analysis of allele‐specific expression (ASE) can reveal important insights into gene expression regulation. We developed a novel method called RPASE (Read‐backed Phasing‐based ASE detection) to test for genes that show ASE. With mapped RNA‐seq data from a single individual and a list of SNPs from the same individual as the only input, RPASE is capable of aggregating information across multiple dependent SNPs and producing individual‐based gene‐level tests for ASE. RPASE performs well in simulations and comparisons. We applied RPASE to multiple bird species and found a potentially rich landscape of ASE.
Hot Off the Press: SGEM #218. Excited Delirium: A Systematic Review
Authors: Bond Christopher , Morgenstern Justin , Heitz Corey , Milne William K.
Published: June 2018

This systematic review provides an assessment of the excited delirium syndrome (ExDS), including definition, epidemiology, pathophysiology, and management. Sixty‐six relevant articles were included with significant heterogeneity of selected studies and poor overall quality. A quantitative meta‐analysis could not be performed because there remains no clear definition for ExDS, however, this study does provide useful information regarding epidemiology, pathophysiology, and treatment of ExDS.
Face validity of a pre‐clinical model of operant binge drinking: just a question of speed
Authors: Jeanblanc Jérôme , Sauton Pierre , Jeanblanc Virginie , Legastelois Rémi , Echeverry‐Alzate Victor , Lebourgeois Sophie , del Carmen Gonzalez‐Marin Maria , Naassila Mickaël
Published: June 2018

Binge drinking (BD) is often defined as a large amount of alcohol consumed in a ‘short’ period of time or ‘per occasion’. In clinical research, few researchers have included the notion of ‘speed of drinking’ in the definition of BD. Here, we aimed to describe a novel pre‐clinical model based on voluntary operant BD, which included both the quantity of alcohol and the rapidity of consumption. In adult Long–Evans male rats, we induced BD by regularly decreasing the duration of ethanol self‐administration from 1‐hour to 15‐minute sessions. We compared the behavioral consequences of BD with the behaviors of rats subjected to moderate drinking or heavy drinking (HD). We found that, despite high ethanol consumption levels (1.2 g/kg/15 minutes), the total amounts consumed were insufficient to differentiate HD from BD. However, consumption speed could distinguish between these groups. The motivation to consume was higher in BD than in HD rats. After BD, we observed alterations in locomotor coordination in rats that consumed greater than 0.8 g/kg, which was rarely observed in HD rats. Finally, chronic BD led to worse performance in a decision‐making task, and as expected, we observed a lower stimulated dopaminergic release within nucleus accumbens slices in poor decision makers. Our BD model exhibited good face validity and can now provide animals voluntarily consuming very rapidly enough alcohol to achieve intoxication levels and thus allowing the study of the complex interaction between individual and environmental factors underlying BD behavior.
Identification of irisin immunoreactivity in porcupine (Hystrix cristata) adrenal glands and kidneys
Authors: Timurkaan Sema , Gür Fatih M. , Gençer Tarakçı Berrin , Yalçın Mehmet H. , Girgin Mustafa
Published: June 2018

Irisin, a novel peptide, was initially been shown to be expressed explicitly in the muscle tissues. We studied the presence of irisin immunoreactivity in porcupine adrenal glands and kidneys. Immunocytochemistry showed that irisin was localised both in the adrenal cortex and adrenal medulla. In organs, irisin immunoreactivity was found in the tubular and collecting system of the nephron. The functional role of irisin in the adrenal gland and kidney has not been precisely yet. However, irisin might have a paracrine and autocrine function as do other locally produced peptides.
Comparison of peripheral nerve blockade characteristics between non‐diabetic patients and patients suffering from diabetic neuropathy: a prospective cohort study
Authors: Baeriswyl M. , Taffé P. , Kirkham K. R. , Bathory I. , Rancati V. , Crevoisier X. , Cherix S. , Albrecht E.
Published: June 2018

Animal data have demonstrated increased block duration after local anaesthetic injections in diabetic rat models. Whether the same is true in humans is currently undefined. We, therefore, undertook this prospective cohort study to test the hypothesis that type‐2 diabetic patients suffering from diabetic peripheral neuropathy would have increased block duration after ultrasound‐guided popliteal sciatic nerve block when compared with patients without neuropathy. Thirty‐three type‐2 diabetic patients with neuropathy and 23 non‐diabetic control patients, scheduled for fore‐foot surgery, were included prospectively. All patients received an ultrasound‐guided popliteal sciatic nerve block with a 30 ml 1:1 mixture of lidocaine 1% and bupivacaine 0.5%. The primary outcome was time to first opioid request after block procedure. Secondary outcomes included the time to onset of sensory blockade, and pain score at rest on postoperative day 1 (numeric rating scale 0–10). These outcomes were analysed using an accelerated failure time regression model. Patients in the diabetic peripheral neuropathy group had significantly prolonged median (IQR [range]) time to first opioid request (diabetic peripheral neuropathy group 1440 (IQR 1140–1440 [180–1440]) min vs. control group 710 (IQR 420–1200 [150–1440] min, p = 0.0004). Diabetic peripheral neuropathy patients had a time ratio of 1.57 (95%CI 1.10–2.23, p < 0.01), experienced a 59% shorter time to onset of sensory blockade (median time ratio 0.41 (95%CI 0.28–0.59), p < 0.0001) and had lower median (IQR [range]) pain scores at rest on postoperative day 1 (diabetic peripheral neuropathy group 0 (IQR 0–1 [0–5]) vs. control group 3 (IQR 0–5 [0–9]), p = 0.001). In conclusion, after an ultrasound‐guided popliteal sciatic nerve block, patients with diabetic peripheral neuropathy demonstrated reduced time to onset of sensory blockade, with increased time to first opioid request when compared with patients without neuropathy.
Benign prostatic hyperplasia and intraprostatic inflammation are associated with liver inflammation: it's time for prevention
Authors: Privitera S. , Russo G. I. , La Vignera S. , Condorelli R. A. , Calogero A. E. , Cantiello F. , Damiano R. , Favilla V. , Cimino S. , Morgia G.
Published: June 2018

Some evidences have supported the link between benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) and inflammation. In this study, we aimed to evaluate the association between prostatic inflammation (PI) and non‐alcoholic steatohepatitis (NASH) evaluated by a non‐invasive scores in a cohort of patients affected by BPH/LUTS. Between January 2012 and January 2016, we conducted a prospective study in a single academic outpatient clinic on 132 consecutive patients who underwent surgery for lower urinary tract symptoms (LUTS) due to bladder outlet obstruction (BOO). A non‐invasive non‐alcoholic steatohepatitis score (NASH score) was calculated, and PI was evaluated through the Irani score. Patients with a NASH score > 1.05 had an average larger prostate volume (55 vs. 45 cc, p < 0.05), a greater waist circumference (103 vs. 93.5 cm, p < 0.01), and high values of blood glucose, triglycerides, insulin, and BMI compared to patients without NASH; 36% of patients with an Irani score ≥ 4 had NASH compared to 16.1% of patients who had a NASH score < 1.05 (p < 0.05). We found that non‐alcoholic steatohepatitis (NASH ≥ 1.05) was an independent risk factor for Irani score ≥4 (OR: 3.24; p < 0.05) and of prostate volume ≥ 40 cc (OR: 13.99; p < 0.01). LUTS/BPH and NASH can be closely related, underlying common triggers of induction. In particular, inflammation seems to be associated with both conditions and with prostate gland overgrowth. Early identification of this class of patients could play a key role in preventing complications related to disease progression.