bluuebunny/crossref_metadata_2025 huggingface dataset:
Mavacamten stabilizes the auto-inhibited state of two-headed cardiac myosin
Authors: Rohde John A. , Thomas David D. , Muretta Joseph M.
Published: March 2018

We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an auto-inhibited state of two-headed cardiac myosin, not found in the isolated S1 myosin motor fragment. We determined this by measuring cardiac myosin actin-activated and actin-independent ATPase and single ATP turnover kinetics. A two-headed myosin fragment exhibits distinct auto-inhibited ATP turnover kinetics compared to a single-headed fragment. Mavacamten enhanced this auto-inhibition. It also enhanced auto-inhibition of ADP release. Furthermore, actin changes the structure of the auto-inhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state.

Significance Statement

Small-molecule allosteric effectors designed to target and modulate striated and smooth myosin isoforms for the treatment of disease show promise in preclinical and clinical trials. Beta-cardiac myosin is an especially important target, as heart disease remains a primary cause of death in the U.S. One prevalent type of heart disease is hypertrophic cardiomyopathy (HCM), which is hypothesized to result from dysregulated force generation by cardiac myosin. Mavacamten is a potent cardiac myosin ATPase activity inhibitor that improves cardiac output in HCM animal models. Our results show that mavacamten selectively stabilizes a two-head dependent, auto-inhibited state of cardiac myosin in solution. The kinetics and energetics of this state are consistent with the auto-inhibited super-relaxed state, previously only observed in intact sarcomeres.
Early identity recognition of familiar faces is not dependent on holistic processing
Authors: Mohr Sarah , Wang Anxu , Engell Andrew D.
Published: March 2018

It is widely accepted that holistic processing is critical for early face recognition, but recent work has suggested a larger role for feature-based processing. The earliest step in familiar face recognition is thought to be matching a perceptual representation of a familiar face to a stored representation of that face, which is thought to be indexed by the N250r event-related potential (ERP). In the current face priming studies, we investigated whether this perceptual representation can be effectively activated by feature-based processing. In the first experiment, prime images were familiar whole faces, isolated eyes, or isolated mouths. Whole faces and isolated eyes, but not isolated mouths, effectively modulated the N250r. In the second experiment, prime images were familiar whole faces presented either upright or inverted. Inverted face primes were no less effective than upright face primes in modulating the N250r. Together, the results of these studies indicate that activation of the earliest face recognition processes is not dependent on holistic processing of a typically configured face. Rather, feature-based processing can effectively activate the perceptual memory of a familiar face. However, not all features are effective primes as we found eyes, but not mouths, were effective in activating early face recognition.

Highlights

Holistic processing is not necessary for early identity recognition of familiar faces.

Inverted faces and isolated features can effectively activate the perceptual memory of a familiar face.

This effectiveness was observed for eyes, but not mouths.
Reproductive interference hampers species coexistence despite conspecific sperm precedence
Authors: Iritani Ryosuke , Noriyuki Suzuki
Published: March 2018

Negative interspecific mating interactions, known as reproductive interference, can hamper species coexistence in a local patch and promote niche partitioning or geographical segregation of closely related species. Conspecific sperm precedence (CSP), which occurs when females that have mated with both conspecific and heterospecific males preferentially use conspecific sperm for fertilization, might contribute to species coexistence by mitigating the costs of interspecific mating and hybridization. We examined whether two closely related species exhibiting CSP can coexist in a local environment in the presence of reproductive interference. First, using a behaviourally explicit mathematical model, we demonstrated that two species characterized by negative mating interactions are unlikely to coexist because the costs of reproductive interference, such as loss of mating opportunity with conspecific partners, are inevitably incurred when individuals of both species are present. Second, we experimentally demonstrated differences in mating activity and preference in twoHarmonialadybird species known to exhibit CSP. According to the developed mathematical model of reproductive interference, these behavioural differences should lead to local extinction ofH. yedoensisbecause of reproductive interference byH. axyridis. This prediction is consistent with field observations thatH. axyridisuses various food sources and habitats whereasH. yedoensisis confined to a less preferred prey item and a pine tree habitat. Finally, by a comparative approach, we showed that niche partitioning or parapatric distribution, but not sympatric coexistence in the same habitat, is maintained between species with CSP belonging to a wide range of taxa, including vertebrates and invertebrates living in aquatic or terrestrial environments. Taken together, these results lead us to conclude that reproductive interference generally destabilizes local coexistence even in closely related species that exhibit CSP.
Cell type-specific interchromosomal interactions as a mechanism for transcriptional diversity
Authors: Horta A. , Monahan K. , Bashkirova E. , Lomvardas S.
Published: March 2018

The eukaryotic genome is partitioned into topologically associated domains (TADs) that assemble into compartments of shared chromatin valance. This architecture is influenced by the physical constraints imposed by the DNA polymer, which restricts DNA interactions predominantly to genomic segments from the same chromosome. Here, we report a dramatic divergence from this pattern of nuclear organization that occurs during the differentiation and specification of mouse olfactory sensory neurons (OSNs). In situ HiC on FAC-sorted OSNs shows that olfactory receptor (OR) genes from numerous chromosomes make frequent, extensive, and highly specific interchromosomal contacts that strengthen with differentiation. Moreover, in terminally differentiated OSNs, >30 intergenic enhancers generate a multi-chromosomal hub that associates only with the single active OR from a pool of ∼1400 genes. Our data reveal that interchromosomal interactions can form with remarkable stereotypy between like neurons, generating a regulatory landscape for stochastic, monogenic, and monoallelic gene expression.
Dynamic functional connectivity markers of objective trait mindfulness
Authors: Lim Julian , Teng James , Patanaik Amiya , Tandi Jesisca , Massar Stijn A. A.
Published: March 2018

While mindfulness is commonly viewed as a skill to be cultivated through practice, untrained individuals can also vary widely in dispositional mindfulness. Prior research has identified static neural connectivity correlates of this trait. Here, we use dynamic functional connectivity (DFC) analysis of resting-state fMRI to study time-varying connectivity patterns associated with naturally varying and objectively measured trait mindfulness. Participants were selected from the top and bottom tertiles of performers on a breath-counting task to form high trait mindfulness (HTM; N = 21) and low trait mindfulness (LTM; N = 18) groups. DFC analysis of resting state fMRI data revealed that the HTM group spent significantly more time in a brain state associated with task-readiness – a state characterized by high within-network connectivity and greater anti-correlations between task-positive networks and the default-mode network (DMN). The HTM group transitioned between brain states more frequently, but the dwell time in each episode of the task-ready state was equivalent between groups. These results persisted even after controlling for vigilance. Across individuals, certain connectivity metrics were weakly correlated with self-reported mindfulness as measured by the Five Facet Mindfulness Questionnaire, though these did not survive multiple comparisons correction. In the static connectivity maps, HTM individuals had greater within-network connectivity in the DMN and the salience network, and greater anti-correlations between the DMN and task-positive networks. In sum, DFC features robustly distinguish HTM and LTM individuals, and may be useful biological markers for the measurement of dispositional mindfulness.
PromoterPredict: sequence-based modelling of Escherichia coli σ70 promoter strength yields logarithmic dependence between promoter strength and sequence
Authors: Bharanikumar Ramit , Premkumar Keshav Aditya R. , Palaniappan Ashok
Published: March 2018

We present PromoterPredict, a dynamic multiple regression approach to predict the strength of Escherichia coli promoters binding the σ70 factor of RNA polymerase. σ70 promoters are ubiquitously used in recombinant DNA technology, but characterizing their strength is demanding in terms of both time and money. Using a well-characterized set of promoters, we trained a multivariate linear regression model and found that the log of the promoter strength is significantly linearly associated with a weighted sum of the –10 and –35 sequence profile scores. It was found that the two regions contributed almost equally to the promoter strength. PromoterPredict accepts –10 and –35 hexamer sequences and returns the predicted promoter strength. It is capable of dynamic learning from user-supplied data to refine the model construction and yield more confident estimates of promoter strength.

Availability

Open source code and a standalone executable with both dynamic model-building and prediction are available (under GNU General Public License 3.0) at https://github.com/PromoterPredict, and require Python 2.7 or greater. PromoterPredict is also available as a web service at https://promoterpredict.com.

Contact

apalania@scbt.sastra.edu
Stabilising and destabilising kinesin complexes queue at plus tips to ensure microtubule catastrophe at cell ends
Authors: Meadows John C. , Messin Liam J. , Kamnev Anton , Lancaster Theresa C. , Balasubramanian Mohan K. , Cross Robert A. , Millar Jonathan B.A.
Published: March 2018

In fission yeast, the length of interphase microtubule (iMT) arrays are adapted to cell length so as to maintain cell polarity and to help centre the nucleus and cell division ring. Here we show that length regulation of iMTs is dictated by spatially-regulated competition between MT-stabilising Tea2/Tip1/Mal3 (Kinesin-7) and MT-destabilising Klp5/Klp6/Mcp1 (Kinesin-8) complexes at iMT plus tips. During MT growth, the Tea2/Tip1/Mal3 complex remains bound to the plus tips of iMT bundles and restricts access to the plus tips by Klp5/Klp6/Mcp1, which accumulates behind it. At cell ends, Klp5/Klp6/Mcp1 invades the space occupied by the Tea2/Tip1/Tea1 kinesin complex triggering its displacement from iMT plus tips and MT catastrophe. These data show that in vivo, whilst the “antenna model” for iMT length- and age-dependent catastrophase accumulation has validity, length control is an emergent property reflecting spatially-regulated competition between multiple complexes at the MT plus tip.
Direct estimation of mutations in great apes reveals significant recent human slowdown in the yearly mutation rate
Authors: Besenbacher Søren , Hvilsom Christina , Marques-Bonet Tomas , Mailund Thomas , Schierup Mikkel Heide
Published: March 2018

The human mutation rate per generation estimated from trio sequencing has revealed an almost linear relationship with the age of the father and the age of the mother. The yearly trio-based mutation rate estimate of ~0.43×10−9 is markedly lower than prior indirect estimates of ~1×10−9 per year from phylogenetic comparisons of the great apes. This suggests either a slowdown over the past 10 million years or an inaccurate interpretation of the fossil record. Here we use sequencing of chimpanzee, gorilla and orangutan trios and find that each species has higher estimated mutation rates per year by factors of 1.67+/− 0.22, 1.54+/− 0.2 and 1.84+/− 0.19, respectively. These estimates suggest a very recent and appreciable slowdown in human mutation rate, and, if extrapolated over the great apes phylogeny, yields divergence estimates much more in line with the fossil record and the biogeography.
Anisotropic Crb accumulation, modulated by Src42A, orients epithelial tube growth in Drosophila
Authors: Olivares-Castiñeira Ivette , Llimargas Marta
Published: March 2018

Size control of internal tubular organs, such as the lungs or vascular system, is critical for proper physiological activity and to prevent disease or malformations. This control incorporates the intrinsic physical anisotropy of tubes to generate proportionate organs that match their function. The exact mechanisms underlying tube size control and how tubular anisotropy is translated at the cellular level are still not fully understood. Here we investigate these mechanisms using the Drosophila tracheal system. We show that the apical polarity protein Crumbs transiently accumulates anisotropically at longitudinal cell junctions during tube elongation. We provide evidence indicating that the accumulation of Crumbs in specific apical domains correlates with apical surface growth. Hence, we propose that the anisotropic accumulation of Crb at the cellular level promotes a bias towards longitudinal membrane growth, orienting cell elongation and, as a consequence, longitudinal growth at the tissue level. We find that Src42A promotes Crb anisotropic accumulation, thereby identifying the first polarised cell behaviour downstream of Src42A. Our results indicate that Src42A activity favours a higher turnover of Crb protein at longitudinal junctions, possibly through a mechanism regulating protein trafficking and/or recycling. We propose a model where Src42A would sense the inherent anisotropic mechanical tension of the tube and translate it into a polarised Crumbs-mediated membrane growth, orienting longitudinal tube growth. This work provides new insights into the key question of how organ growth is controlled and polarised and unveils the function of two conserved proteins, Crumbs and Src42A, with important roles in development and homeostasis as well as in disease, in this biological process.
A taxonomically-restricted Uric Acid transporter provides insight into antioxidant equilibrium
Authors: Oliveira Diogo , Machado André , Cardoso Tiago , Lopes-Marques Mónica , Castro L. Filipe C. , Ruivo Raquel
Published: March 2018

Nucleobase-Ascorbate Transporter (NAT) family includes ascorbic acid, nucleobases and uric acid transporters, with a broad evolutionary distribution. In vertebrates, four members have been previously recognized, the ascorbate transporters Slc23a1 and Slc3a2, the nucleobase transporter Slc23a4 and an orphan transporter SLC23A3. Here we identify a fifth member of the vertebrateslc23complement (slc23a5), expressed in neopterygians (gars and teleosts) and amphibians, and clarify the evolutionary relationships between the novel gene and knownslc23genes. Further comparative analysis puts forward uric acid as the preferred substrate for Slc23a5. Gene expression quantification suggests kidney and testis as major expression sites inXenopus tropicalis(western clawed frog) andDanio rerio(zebrafish). Additional expression in brain was detected inD. rerio, while in the NeoteleosteiOryzias latipes(medaka)slc23a5expression is restricted to brain. The biological relevance of the retention of an extra transporter in fish and amphibians is examined: with respect to the (1) antioxidant role of uric and ascorbic acid in seminal fluid and brain, (2) the ability to endogenously synthesize ascorbic acid and (3) the morphological adaptations of the male urogenital system.
A polygenicpfactor for major psychiatric disorders
Authors: Selzam Saskia , Coleman Jonathan R. I. , Caspi Avshalom , Moffitt Terrie E. , Plomin Robert
Published: March 2018

It has recently been proposed that a single dimension, called thepfactor, can capture a person’s liability to mental disorder. Relevant to thephypothesis, recent genetic research has found surprisingly high genetic correlations between pairs of psychiatric disorders. Here, for the first time we compare genetic correlations from different methods and examine their support for a geneticpfactor. We tested the hypothesis of a geneticpfactor by using principal component analysis on matrices of genetic correlations between major psychiatric disorders estimated by three methods – family study, Genome-wide Complex Trait Analysis, and Linkage-Disequilibrium Score Regression – and on a matrix of polygenic score correlations constructed for each individual in a UK-representative sample of 7,026 unrelated individuals. All disorders loaded on a first unrotated principal component, which accounted for 57%, 43%, 34% and 19% of the variance respectively for each method. Our results showed that all four methods provided strong support for a geneticpfactor that represents the pinnacle of the hierarchical genetic architecture of psychopathology.
Dynamic temperature-sensitive A-to-I RNA editing in the brain of a heterothermic mammal during hibernation
Authors: Riemondy Kent A. , Gillen Austin E. , White Emily A. , Bogren Lori K. , Hesselberth Jay R. , Martin Sandra L.
Published: March 2018

RNA editing diversifies genomically encoded information to expand the complexity of the transcriptome. In ectothermic organisms, including Drosophila and Cephalopoda, where body temperature mirrors ambient temperature, decreases in environmental temperature lead to increases in A-to-I RNA editing and cause amino acid recoding events that are thought to be adaptive responses to temperature fluctuations. In contrast, endothermic mammals, including humans and mice, typically maintain a constant body temperature despite environmental changes. Here, A-to-I editing primarily targets repeat elements, rarely results in the recoding of amino acids and plays a critical role in innate immune tolerance. Hibernating ground squirrels provide a unique opportunity to examine RNA editing in a heterothermic mammal whose body temperature varies over 30°C and can be maintained at 5°C for many days during torpor. We profiled the transcriptome in three brain regions at six physiological states to quantify RNA editing and determine whether cold-induced RNA editing modifies the transcriptome as a potential mechanism for neuroprotection at low temperature during hibernation. We identified 5,165 A-to-I editing sites in 1,205 genes with dynamically increased editing after prolonged cold exposure. The majority (99.6%) of the cold-increased editing sites are outside of previously annotated coding regions, 82.7% lie in SINE-derived repeats, and 12 sites are predicted to recode amino acids. Additionally, A-to-I editing frequencies increase with increasing cold-exposure demonstrating that ADAR remains active during torpor. Our findings suggest that dynamic A-to-I editing at low body temperature may provide a neuroprotective mechanism to limit aberrant dsRNA accumulation during torpor in the mammalian hibernator.
The [4 + 4] thermocyclization of 9-anthraldehyde: synthesis, crystal structure, experimental and theoretical UV spectra, natural bonding orbital analysis and prediction of third-order nonlinear optical properties
Authors: Zarei Seyed Amir , Akhtari Keivan , Piltan Mohammad , Kamel Shaaban M. , Mague Joel T.
Published: March 2018

The dimer of 9-anthraldehyde, namely heptacyclo[8.6.6.62,9.03,8.011,16.017,22.023,28]octacosa-3,5,7,11,13,15,17(22),18,20,23(28),24,26-dodecaene-1,9-carbaldehyde, C30H20O2, has been synthesized by refluxing an ethanol solution in the presence of M(ClO4)2 and 1,3-diaminopropan-2-ol (M = Co2+ or Cu2+). Its structure has been determined by single-crystal X-ray diffraction, showing it to be a new polymorph, referred to as polymorph II, in the monoclinic space group P21/n. It is compared with the previously reported triclinic modification [Ehrenberg (1968). Acta Cryst. B24, 1123–1125], which is referred to as polymorph I. The asymmetric unit of polymorph II contains two half molecules located on crystallographic centres, while the asymmetric unit of polymorph I includes one half molecule, also located on a crystallographic centre. Time-dependent density functional theory (TD-DFT) at the RB3LYP level using the 6-31G(d,p) basis set was applied. The predicted electronic absorption spectrum is in good agreement with the experimental one. The analysis of the calculated electronic absorption spectrum of polymorph II was carried out in order to assign the observed electronic transitions and to determine their character. A natural bonding orbital (NBO) analysis was executed at the same level to evaluate charge-transfer, intramolecular hydrogen-bonding interactions and hyperconjugative interactions. The third-order nonlinear optical (NLO) properties of the compound were appraised by the ZINDO/sum-over-states method in both static and dynamic states. The orientationally averaged (isotropic) value of γ for the compound is greater than the corresponding value of 4-nitroaniline (pNA).
The putative compatible solute-binding protein ProX fromMycobacterium tuberculosisH37Rv: biochemical characterization and crystallographic data
Authors: Zhao Jian-Hong , Chen Jiang-Huai , Wang Yong , Wang Zhi-Ping , He Yong-Xing
Published: March 2018

InMycobacterium tuberculosis, theproXgene encodes a putative compatible solute-binding protein (MtProX). However, it was found through sequence alignment that the MtProX protein has very different ligand-binding residues compared with other compatible solute-binding proteins, implying that MtProX may bind to ligands that are as yet uncharacterized. In this work, it was demonstrated that MtProX binds to polyphenols such as phloretin, monoacetylphloroglucinol and 2,4-dihydroxyacetophloroglucinol with dissociation constants between 20 and 70 µM. Crystals of MtProX were obtained using a precipitant consisting of 0.2 MNaCl, 0.1 MTris pH 8.5, 25%(w/v) polyethylene glycol 3350. The crystals diffracted to 2.10 Å resolution and belonged to space groupP43212, with unit-cell parametersa=b= 90.17,c= 161.92 Å, α = β = γ = 90.0°. Assuming the presence of two MtProX molecules in the asymmetric unit, the Matthews coefficient was calculated to be 2.74 Å3 Da−1, which corresponds to a solvent content of 55%.
Tris[2,2,6,6-tetramethyl-8-(trimethylsilyl)benzo[1,2-d;4,5-d′]bis(1,3-dithiol)-4-yl]methanol diethyl ether monosolvate
Authors: Fleck Nico , Schnakenburg Gregor , Filippou Alexander C. , Schiemann Olav
Published: March 2018

The title compound, a triarylmethanol, C46H64OS12Si31, was synthesizedvialithiation of tris-2,2,6,6-tetramethylbenzo[1,2-d;4,5-d′]bis[1,3]dithiol-4-yl-methanol,2, and electrophilic quenching with trimethylsilyl chloride. The current crystal structure reveals information about the reactivity of this compound and compares well with the structure reported for the unsubstituted parent compound2[Driesschaertet al.(2012).Eur. J. Org. Chem.33, 6517–6525]. The title compound1forms molecular propellers and crystallizes inP-1, featuring an unusually long Si—Carbond of 1.910 (3) Å. Moreover, the geometry at the central quaternary carbon is rather trigonal-pyramidal than tetrahedral due to vast intramolecular stress. One trimethylsilyl group is disordered over two positions in a 0.504 (4):0.496 (4) ratio and one S atom is disordered over two positions in a 0.509 (7):0.491 (7) ratio. The contribution of disordered diethyl ether solvent molecule(s) was removed using thePLATONSQUEEZE (Spek, 2015) solvent masking procedure. These solvent molecules are not considered in the given chemical formula and other crystal data.
Crystal structure and catalytic activity of tetrakis(μ2-ethyl 2,6-di-tert-butyl-4-methylphenyl phosphato-κ2
O:O′)bis(ethyl 2,6-di-tert-butyl-4-methylphenyl phosphato-κ2
O,O′)dilutetium n-heptane disolvate
Authors: Minyaev Mikhail E. , Tavtorkin Alexander N. , Korchagina Sof'ya A. , Nifant'ev Ilya E. , Churakov Andrei V.
Published: March 2018

The title complex, [Lu2(C17H28O4P)6]·2C7H16, was formed in the reaction between potassium 2,6-di-tert-butyl-4-methylphenyl ethyl phosphate, [K(2,6-
t
Bu2-4-MeC6H2-O)(EtO)PO2], and LuCl3(H2O)6 in water, followed by vacuum drying and recrystallization from heptane. Its crystal structure has triclinic (P-1) symmetry at 120 K. The lutetium tris(phosphate) complex has a binuclear [Lu2(μ-OPO)4] core and the organophosphate ligand exhibits κ2
O,O′ terminal and μ2-κ1
O:κ1
O′ bridging coordination modes with the LuIII ion being sixfold coordinated. The complex is of interest as a precatalyst in the acrylonitrile polymerization process and displays good catalytic activity under mild conditions.
The key technology toward the self-driving car
Authors: Zhao Jianfeng , Liang Bodong , Chen Qiuxia
Published: March 2018

Purpose

The successful and commercial use of self-driving/driverless/unmanned/automated car will make human life easier. The paper aims to discuss this issue.

Design/methodology/approach

This paper reviews the key technology of a self-driving car. In this paper, the four key technologies in self-driving car, namely, car navigation system, path planning, environment perception and car control, are addressed and surveyed. The main research institutions and groups in different countries are summarized. Finally, the debates of self-driving car are discussed and the development trend of self-driving car is predicted.

Findings

This paper analyzes the key technology of self-driving car and illuminates the state-of-art of the self-driving car.

Originality/value

The main research contents and key technology have been introduced. The research progress as well as the research institution has been summarized.
Inside out, outside in: “supporting members” in multi-stakeholder cooperatives
Authors: Michaud Myriam , Audebrand Luc K.
Published: March 2018

Purpose

The purpose of this paper is to examine multi-stakeholder cooperatives (MSCs), a relatively new and understudied type of cooperative, by focusing on the impact of a new member status: the “supporting member.” Supporting members are included in the ownership structure, participate in the decision-making process and contribute to the share capital without being formally defined as users of the cooperative’s services, an important disruption to the traditional cooperative venture.

Design/methodology/approach

This paper is based on a qualitative study using in-depth interviews with 30 members (i.e. founders, managers, board members and employees) of 14 MSCs located in the Canadian province of Québec.

Findings

This study suggests that including supporting members in the cooperative venture impacts the three core features of cooperatives, which are traditionally user-owned, user-controlled and user-benefiting. Despite supporting members’ positive contributions to an MSC’s development and success, the inclusion of such members generates management challenges and organizational paradoxes.

Social implications

The inclusion of supporting members allows MSCs to become an experiment in “stakeholder democracy” and a space of negotiation between organizations, citizens and institutions, as MSCs represent and embody some of the community’s needs and desires.

Originality/value

This study constitutes an original contribution to paradox literature, as it describes the specific upward and downward spirals related to the inclusion of supporting members, highlights innovative responses to these paradoxes and extends understandings of cooperatives as hybrid organizations entangled in bundles of paradoxes.
Case of lamotrigine‐induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug‐induced hypersensitivity syndrome
Authors: Iriki Hisato , Ouchi Takeshi , Ito Hiromi , Sawada Miho , Mukai Miho , Nomura Hisashi , Baba Yuko , Adachi Takeya , Funakoshi Takeru , Amagai Masayuki , Takahashi Hayato
Published: March 2018

The pathological mechanisms and immunological kinetics of drug‐induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)‐6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti‐IL‐6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL‐6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.
Hyperuricaemia and type 2 diabetes mellitus
Authors: Kawada Tomoyuki
Published: March 2018

Choi et al reported the effect of hyperuricaemia on the new‐onset type 2 diabetes mellitus (T2DM). I present three queries. (i) Insulin is considered to stimulate uric acid reabsorption via specific transporter and the effect of hyperuricaemia on the new‐onset T2DM should be evaluated by considering insulin resistance. (ii) There is a limitation in the number of events for stable estimates. (iii) Obesity and sex should be considered for the analysis.
Influence of diabetes on tissue healing in orthopaedic injuries
Authors: Stolarczyk Artur , Sarzyńska Sylwia , Gondek Agata , Cudnoch‐Jędrzejewska Agnieszka
Published: March 2018

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from the defective action or secretion of insulin. Chronic hyperglycaemia can lead to the damage, dysfunction and failure of various organs. In the context of complications of healing and orthopaedic rehabilitation, vascular (microangiopathy) and nerve (neuropathy) disorders deserve particular attention. About 12% of the patients admitted to orthopaedic departments have diabetes. Studies indicate that there is an indisputable link between diabetes and: an increased risk of fractures, the difficult healing of injuries of bones, ligaments and musculotendinous. It appears that one of the main reasons for this is non‐enzymatic glycosylation (glycation) of collagen molecules, a phenomenon observed in the elderly and diabetic populations, as it leads to the formation of advanced glycation end products (AGEs). Collagen is one of the major connective tissue components, and is therefore part of ligaments, tendons and bones. AGEs affect the weakening of its structure and biomechanical properties, and thus also affects the weakening of the structure and properties of the above‐mentioned tissues. The aim of the study is to undertake an overview of the current knowledge of the impact of diabetes on the risk of some injuries and subsequent healing and rehabilitation of patients following orthopaedic injuries.
Down‐regulation of microRNA‐375 regulates adipokines and inhibits inflammatory cytokines by targeting AdipoR2 in non‐alcoholic fatty liver disease
Authors: Lei Lei , Zhou Chao , Yang Xue , Li Liangping
Published: March 2018

Non‐alcoholic fatty liver disease (NAFLD) has been considered as a multi‐factorial metabolic syndrome. MicroRNA‐375 (MiR‐375) was significantly up‐regulated in serum of NAFLD patients and the role of miR‐375 was addressed as a putative biomarker of NAFLD progression. However, the specific function of miR‐375 in the progression of NAFLD is still unclear and the molecular mechanisms underlying NAFLD have yet to be elucidated. Our study aimed at investigating the regulatory role of miR‐375 in the molecular mechanisms of the pathogenic progression of NAFLD and to find out whether miR‐375 regulates the expression level of adipokines and inflammatory cytokines in NAFLD. We found that miR‐375 expression was increased in the serum of high fat diet (HFD)‐feeding mice comparing to that in healthy controls, whereas the expression of Adiponectin receptor 2 (AdipoR2) was decreased in mice fed with HFD. Moreover, inhibiton of miR‐375 up‐regulated the expression of Adiponectin, inhibited the lipid accumulation and down‐regulated both the level of Leptin and inflammatory cytokines including tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 in palmiticacid (PA)‐induced human hepatocellular carcinoma HepG2 cells. In addition, we also found that AdipoR2 was a target of miR‐375 by binding directly to the 3′UTR of it. Of note, the reduced level of TNF‐α, IL‐6 as well as Leptin and the production of Adiponectin by miR‐375 inhibitors was significantly reversed by silencing of AdipoR2 in PA‐induced HepG2 cells. Our findings bring new insight into understanding the complex mechanisms underlying the pathogenesis of NAFLD and provide evidence that miR‐375 might represent a novel therapeutic target for NAFLD.
Between recognition and redistribution: disability, (human) rights, and struggles over welfare in Serbia
Authors: Mikuš Marek
Published: March 2018

This article analyses the discourse surrounding, implementation of, and struggles over the new disability policy in Serbia to show how its founding principles of human rights became partially co‐opted by neoliberal welfare restructuring. As a result, it sought to make disabled people not only equal but also economically ‘independent’ in the sense of relying on wage labour instead of welfare. Owing to its inadequate assumptions and instruments, the policy has largely failed to deliver on these objectives. Disabled people mobilized against neoliberalization by defending material welfare entitlements inherited from Yugoslav socialism. At the same time, they appropriated the register of human rights to demand a substantive political and civic equality. This points to the possibility of rights‐based projects that fuse rather than oppose the politics of recognition and redistribution.
A systematic review of drug treatment of vulvodynia: evidence of a strong placebo effect
Authors: Miranda Varella Pereira G , Soriano Marcolino M , Silveira Nogueira Reis Z , Vale de Castro Monteiro M
Published: March 2018

Background

Vulvodynia is the most common type of chronic pelvic pain and dyspareunia in premenopausal women. The effect of drugs for the treatment of vulvodynia remains poorly discussed.

Objectives

To conduct a systematic review of randomised controlled studies which assess medications used to treat vulvar pain in vulvodynia.

Search strategy

Web of Science, Cochrane Library, EBSCO Academic, LILACS and MEDLINE were searched from 1985 to September 2016.

Selection criteria

Randomised controlled trials comparing any kind of medication for vulvodynia treatment with placebo or with another medication in adult patients were included.

Data collection and analysis

The two investigators independently conducted data extraction. The synthesis was provided by the pain reduction index. Study quality assessment was performed using the Cochrane Handbook for Systematic Reviews of Intervention and analysis of publication bias was conducted.

Main results

Five studies were included in qualitative synthesis. Number of participants varied from 30 to 133 participants among the eligible studies, resulting in a total of 297 patients. The pain reduction rates of patients with vulvodynia assessed by Q‐tipped cotton test and visual analogue scale varied between studies. Placebo was shown to be as effective as any medication.

Conclusions

There is a need for further studies evaluating topical monotherapy for the treatment of vulvodynia, as they are the main drugs used in clinical practice.

Tweetable abstract

No medication has shown impact on vulvar pain in vulvodynia. There is evidence of a placebo effect.
NAV Premiums & REIT Property Transactions
Authors: Kim Dongshin , Wiley Jonathan A.
Published: March 2018

This study explores the outcome for REIT investment in response to NAV premiums considering (1) the volume of acquisition activity, and (2) relative prices paid for individual assets. Regarding the first, we provide evidence that REIT managers increase real estate investment following positive changes in NAV premiums. Regarding the second, we use a large sample of transactions for retail, office and multifamily property and find that REITs appear to pay significantly higher prices relative to other investors. Transaction prices paid by REIT managers for all three property types are positively and significantly affected by market‐wide NAV premiums.
Why do ‘fast track’ patients stay more than four hours in the emergency department? An investigation of factors that predict length of stay
Authors: Gill Stephen D , Lane Stephen E , Sheridan Michael , Ellis Elizabeth , Smith Darren , Stella Julian
Published: March 2018

Objective

Low‐acuity ‘fast track’ patients represent a large portion of Australian EDs’ workload and must be managed efficiently to meet the National Emergency Access Target. The current study determined the relative importance and estimated marginal effects of patient and system‐related variables in predicting ED fast track patients who stayed longer than 4 h in the ED.

Methods

Data for ED presentations between 1 July 2014 and 30 June 2015 were collected from a large regional Australian public hospital. Only ‘fast track’ patients were included in the analysis. A gradient boosting machine was used to predict which patients would have an ED length of stay greater or less than 4 h. The performance of the final model was tested using a validation data set that was withheld from the initial analysis. A total of 27 variables were analysed.

Results

The model’s performance was very good (area under receiver operating characteristic curve 0.89, where 1.0 is perfect prediction). The five most important variables for predicting length of stay were time‐dependent and system‐related (not patient‐related); these were the amount of time taken from when the patient arrived at the ED to: (i) order imaging; (ii) order pathology; (iii) request admission to hospital; (iv) allocate a clinician to care for the patient; and (v) handover a patient between ED clinicians.

Conclusions

We identified the most important variables for predicting length of stay greater than 4 h for fast track patients in our ED. Identifying factors that influence length of stay is a necessary step towards understanding ED patient flow and identifying improvement opportunities.
Effect of fruit host on wing morphology in Drosophila suzukii (Diptera: Drosophilidae): A first view using geometric morphometrics
Authors: Pajač Živković Ivana , Lemic Darija , Mešić Aleksandar , Barić Božena , Órdenes Rodrigo , Benítez Hugo A.
Published: March 2018

The invasive alien fruit pest Drosophila suzukii, (Matsumura 1931) causes economic loss in soft‐skinned fruit production across Europe. After its first detection in 2008, the species has successfully expanded to a wide geographic area and invaded new host plants in a relatively short period of time. The aim of the present study was to analyze the connection between food preferences as host specialization and the morphology of D. suzukii. Population morphological variation in wings was investigated in two different host fruits (grape and strawberry) in which economic damage has been recorded. The geometric morphometric results revealed two noticeable wing shape morphotypes in D. suzukii (i.e. vein configuration) between the grape and strawberry fruits. Flies reared in grapes had wider wings, whereas flies grown in strawberries had more narrow wings. These differences in morphotype could be explained by the effects of wing aerodynamics, which affect the strength of the wings in flight. This, in turn, can lead to better dispersion within the associated fruit host. These results confirm that this extremely invasive species, found worldwide, is successful at spreading in part because of its potential to adapt rapidly under different rearing conditions. Therefore, adaptive variations in the wing shape of D. suzukii can be used to differentiate populations based on food preference (e.g. soft fruits) and can serve as an additional tool for detecting different bioecological types of D. suzukii.
Impact of upper respiratory tract infections on perioperative outcomes of children undergoing therapeutic cardiac catheterisation
Authors: Zhang S. , Ding S. , Cai M. , Bai J. , Zhang M. , Huang Y. , Zheng J.
Published: March 2018

Background

Recent upper respiratory tract infection (URI) is associated with increased incidence of perioperative complications in children undergoing open heart surgery. As a result, surgery is often postponed. However, the effect of recent URI on the incidence of perioperative complications in children undergoing therapeutic cardiac catheterisation is unknown. We investigated the perioperative outcomes of congenital heart disease (CHD) children with recent URI who underwent elective therapeutic catheterisation.

Methods

We prospectively included children treated for CHD. Before surgery, parents or legal guardians were interviewed to complete a questionnaire on the child's demographics, history of asthma and passive smoking, and URI symptoms. Recorded perioperative respiratory adverse events (PRAEs) included laryngospasm, bronchospasm, breath holding, oxygen desaturation, and severe cough. Information on postoperative dysphoria, fever, copious sputum, and vomiting was obtained by telephone 24 h after surgery.

Results

Of 363 included children, 169 had recently (within 2 weeks) had a URI. The URI did not affect the incidence of laryngospasm, bronchospasm, breath holding, fever, or vomiting. The incidence of desaturation, severe cough, dysphoria, and copious sputum were significantly increased. Independent risk factors for PRAEs in children with a recent URI included age, passive smoking, and presence of rhinorrhoea or moist cough. The lengths of stay in the hospital and intensive care unit were not significantly different between groups.

Conclusion

Although recent URI increased the incidence of PRAEs in children undergoing therapeutic cardiac catheterisation, most CHD patients with recent URI can undergo elective therapeutic cardiac catheterisation without serious adverse events or prolonged hospitalisation.
Out of sight, out of mind? Testing the effects of overwinter habitat alterations on breeding territories of a migratory endangered species
Authors: Morant J. , Zabala J. , Martínez J. E. , Zuberogoitia I.
Published: March 2018

Anthropogenic activities are one of the main threats to species living in human‐dominated landscapes and can promote behavioral changes in birds. This paper presents a novel approach to test how a migratory species responds to habitat alterations occurring in nesting territories during winter, when the species is absent. From 2000 to 2016, we collated territory and nest monitoring data for the endangered Egyptian vulture Neophron percnopterus in the north of Spain, to test the effects of overwinter habitat alterations (OHA) around breeding territories on the species reproductive output. We monitored 70 different nest sites and observed OHA around the nesting area in 39 cases. Probability of switching to another nesting site almost tripled after OHA. Pairs that switched experienced substantially decreased breeding success and avoided reusing the nest for 4.8 ± 4.64 years. The presence of determinate landscape elements that provide screening, such as forest patches, increased nest reoccupancy probability after OHA by more than 0.3, to 0. 55 (compared to 0.24 when no screening was present). We also found that the distance and the situation of the OHA were critical factors explaining reproduction probabilities at nest sites. Our results demonstrate how OHA can strongly impact the breeding behavior of long‐lived species. This highlights the need to examine the long‐term impact of OHA rather than focusing only on disturbances during sensitive periods, as is often the case with habitual mitigation measures.
Antibiotic resistance in severe odontogenic infections of the South Australian population: a 9‐year retrospective audit
Authors: Liau I , Han J , Bayetto K , May B , Goss A , Sambrook P , Cheng A
Published: March 2018

Background

The aims of this study were to evaluate the microbiological trends in severe odontogenic infections requiring hospital admission in the South Australian Oral and Maxillofacial Surgery Unit. Rates of antibiotic resistance to empirical antibiotic regimens were determined to quantify the clinical implications of antibiotic‐resistant odontogenic infections.

Methods

A retrospective case audit was performed on all odontogenic infections admitted to the Royal Adelaide Hospital over a 9‐year period. Data was collected regarding demographics, microbiological culture and sensitivity results, and clinical outcome variables.

Results

Of a total of 672 patients, microbiology data was available for 447 cases. Penicillin‐resistant organisms were identified in 10.8% of patients, who required a significantly longer length of hospital admission (mean, 9.93 days) and higher rates of non‐response to initial surgical therapy (40%).

Conclusions

There were moderate rates of antibiotic‐resistant odontogenic infections within the South Australian population. Patients within this subgroup demonstrate markedly poorer clinical outcomes. Effective treatment of odontogenic infections involves early operative intervention, with adjunctive use of appropriate antibiotic therapy that involves close monitoring of response to removal of the cause and use of first‐line antibiotic agents. Cases that fail to respond require urgent specialist review in order to reduce morbidity and mortality outcomes.
Substance‐use initiation moderates the effect of stress on white‐matter microstructure in adolescents
Authors: Zhai Zu Wei , Yip Sarah W. , Morie Kristen P. , Sinha Rajita , Mayes Linda C. , Potenza Marc N.
Published: March 2018

Background

While childhood stress may contribute risk to substance‐use initiation and differences in brain white‐matter development, understanding of the potential impact of substance‐use initiation on the relationship between experienced stress and white‐matter microstructure remains limited.

Objectives

This study examined whether substance‐use initiation moderated the effect of perceived stress on white‐matter differences using measures of primary white‐matter fiber anisotropy.

Methods

Forty adolescents (age 14.75 ± .87 years) were assessed on the Perceived Stress Scale, and 50% were determined to have presence of substance‐use initiation. White‐matter microstructure was examined using primary‐fiber orientations anisotropy, which may reflect white‐matter integrity, modeled separately from other fiber orientations in the same voxels. Analyses were conducted on regions of interest previously associated with childhood stress and substance use.

Results

Lower perceived stress and presence of substance‐use initiation were related to greater right cingulum primary‐fiber measures. Substance‐use‐initiation status moderated the association between perceived stress and right cingulum primary‐fiber measures, such that higher perceived stress was associated with lower right cingulum primary‐fiber anisotropy in adolescents without substance‐use initiation, but not in those with substance‐use initiation.

Conclusions and Scientific Significance

Findings in primary‐fiber anisotropy suggest differences in right cingulum white‐matter integrity is associated with substance‐use initiation in higher‐stress adolescents. This reflects a possible pre‐existing risk factor, an impact of early substance use, or a combination thereof. Examination of potential markers associated with substance‐use initiation in white‐matter microstructure among stress‐exposed youth warrant additional investigation as such biomarkers may inform efforts relating to tailored interventions. (Am J Addict 2018;27:217–224)