bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cul3 ubiquitin ligase engages Insomniac as an adaptor to impact sleep and synaptic homeostasis
Authors: Li Qiuling , Lim Kayla Y. , Altawell Raad , Verderose Faith , Li Xiling , Dong Wanying , Martinez Joshua , Dickman Dion , Stavropoulos Nicholas
Published: July 2019

Mutations of the Cullin-3 (Cul3) E3 ubiquitin ligase are associated with autism and schizophrenia, neurological disorders characterized by sleep disturbances and altered synaptic function. Cul3 engages dozens of adaptor proteins to recruit hundreds of substrates for ubiquitination, but the adaptors that impact sleep and synapses remain ill-defined. Here we implicate Insomniac (Inc), a conserved protein required for normal sleep and synaptic homeostasis inDrosophila, as a Cul3 adaptor. Inc binds Cul3 in vivo, and mutations within the N-terminal BTB domain of Inc that weaken Inc-Cul3 associations impair Inc activity, indicating that Inc function requires binding to the Cul3 complex. Deletion of the conserved C-terminus of Inc does not alter Cul3 binding but abolishes Inc activity in the context of sleep and synaptic homeostasis, suggesting that the C-terminal domain of Inc is a substrate recruitment domain. Mutation of a conserved, disease-associated arginine in the Inc C-terminus also abolishes Inc function, suggesting that this residue is vital for recruiting Inc targets. Inc levels are negatively regulated by Cul3 in neurons, consistent with Inc degradation by autocatalytic ubiquitination, a hallmark of Cullin adaptors. These findings link Inc and Cul3 in vivo and indicate that Cul3-Inc complexes are essential for normal sleep and synaptic function. Furthermore, these results indicate that dysregulation of conserved substrates of Cul3-Inc complexes may contribute to altered sleep and synaptic function in autism and schizophrenia associated withCul3mutations.

Author Summary

Cul3is a highly conserved gene important for brain development and function.Cul3mutations are a risk factor for autism and schizophrenia, neurological disorders associated with disturbed sleep and changes in neuronal synapses. A key challenge in understanding howCul3impacts brain function is elucidating the downstream molecular pathways. Cul3 is a ubiquitin ligase that assembles with dozens of adaptor proteins, which in turn recruit specific protein substrates for ubiquitination. Identifying and characterizing Cul3 adaptors in the nervous system is thus a critical step in understanding Cul3 function. Because Cul3 and its adaptors are conserved through evolution, simpler organisms including the fruit flyDrosophilaprovide powerful systems for identifying and characterizing Cul3 adaptors. We found that the Insomniac (Inc) protein has the properties of a Cul3 adaptor that impacts sleep and synaptic function inDrosophila. These results suggest that human proteins related to Inc may be relevant for changes in sleep and synaptic function in autism and schizophrenia associated with reduced Cul3 activity.
A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins
Authors: Kohler Kristin M. , Kutsch Miriam , Piro Anthony S. , Wallace Graham , Coers Jörn , Barber Matthew F.
Published: July 2019

Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri. By swapping this membrane-binding motif between primate GBP orthologs, we find that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World monkeys. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense.
Asparagine deprivation causes a reversible inhibition of Human Cytomegalovirus acute virus replication
Authors: Lee Chen-Hsuin , Griffiths Samantha , Digard Paul , Pham Nhan T. , Auer Manfred , Haas Juergen , Grey Finn
Published: July 2019

As obligate intracellular pathogens, viruses rely on the host cell machinery to replicate efficiently, with the host metabolism extensively manipulated for this purpose. High throughput siRNA screens provide a systematic approach for the identification of novel host-virus interactions. Here, we report a large-scale screen for host factors important for human cytomegalovirus (HCMV), consisting of 6,881 siRNAs. We identified 47 proviral factors and 68 antiviral factors involved in a wide range of cellular processes including the mediator complex, proteasome function and mRNA splicing. Focused characterisation of one of the hits, asparagine synthetase (ASNS), demonstrated a strict requirement for asparagine for HCMV replication which leads to an early block in virus replication before the onset of DNA amplification. This effect is specific to HCMV, as knockdown of ASNS had little effect on herpes simplex virus-1 or influenza A virus replication, suggesting the restriction is not simply due to a failure in protein production. Remarkably, virus replication could be completely rescued seven days post-infection with addition of exogenous asparagine, indicating that while virus replication is restricted at an early stage, it maintains the capacity for full replication days after initial infection. This study represents the most comprehensive siRNA screen for the identification of host factors involved in HCMV replication and identifies the non-essential amino acid, asparagine as a critical factor in regulating HCMV virus replication. These results have implications for control of viral latency and the clinical treatment of HCMV in patients.

Importance

HCMV accounts for more than 60% of complications associated with solid organ transplant patients. Prophylactic or preventative treatment with antivirals, such as ganciclovir, reduces the occurrence of early onset HCMV disease. However, late onset disease remains a significant problem and prolonged treatment, especially in patients with suppressed immune systems, greatly increases the risk of antiviral resistance. Very few antivirals have been developed for use against HCMV since the licensing of ganciclovir, and of these, the same viral genes are often targeted, reducing the usefulness of these drugs against resistant strains. An alternative approach is to target host genes essential for virus replication. Here we demonstrate that HCMV replication is highly dependent on levels of the amino acid asparagine and knockdown of a critical enzyme involved in asparagine synthesis results in severe attenuation of virus replication. These results suggest that reducing asparagine levels through dietary restriction or chemotherapeutic treatment could limit HCMV replication in patients.
Deer slow down litter decomposition by reducing litter quality in a temperate forest
Authors: Simon Chollet , Morgane Maillard , Juliane Schörghuber , Sue Grayston , Jean-Louis Martin
Published: July 2019

ABSTRACT

In temperate forest ecosystems, the role of deer in litter decomposition, a key nutrient cycling process, remains debated. Deer may modify the decomposition process by affecting plant cover and thus modifying litter abundance. They can also alter litter quality through differential browsing and affect decomposer ability by changing soil abiotic properties and the nature of decomposer communities. We used two litterbag experiments in a quasi-experimental situation resulting from the introduction of Sitka black-tailed deer Odocoileus odocoileus sitkensis on forested islands of Haida Gwaii (Canada). We investigated the effects of deer on decomposition through their impacts on litter quality and on decomposer ability. After one year, the effect of deer on litter quality resulted in a lower rate of mass loss in litter from litterbags. This mass loss mainly reflected a 21 and 38 % lower rate of carbon (C) and nitrogen (N) loss, respectively. Presence of deer resulted in lower decomposer ability for the rate of carbon loss, but not for nitrogen loss. The level of C loss after one year was 5% higher for litter decomposing on an island without deer. But the change in the rate of carbon loss explained by the effect of deer on decomposer ability was outweighed by the effect deer had on litter quality. Additional effects of deer on the decomposition process through feces deposition were significant but minor. These results question the role the large increase in deer populations observed in temperate forests at continental scales may play in broad scale patterns of C and N cycling.
Model-based cell clustering and population tracking for time-series flow cytometry data
Authors: Minoura Kodai , Abe Ko , Maeda Yuka , Nishikawa Hiroyoshi , Shimamura Teppei
Published: July 2019

Motivation

Modern flow cytometry technology has enabled the simultaneous analysis of multiple cell markers at the single-cell level, and it is widely used in a broad field of research. The detection of cell populations in flow cytometry data has long been dependent on “manual gating” by visual inspection. Recently, numerous software have been developed for automatic, computationally guided detection of cell populations; however, they are not designed for time-series flow cytometry data. Time-series flow cytometry data are indispensable for investigating the dynamics of cell populations that could not be elucidated by static time-point analysis.

Therefore, there is a great need for tools to systematically analyze time-series flow cytometry data.

Results

We propose a simple and efficient statistical framework, named CYBERTRACK (CYtometry-Based Estimation and Reasoning for TRACKing cell populations), to perform clustering and cell population tracking for time-series flow cytometry data. CYBERTRACK assumes that flow cytometry data are generated from a multivariate Gaussian mixture distribution with its mixture proportion at the current time dependent on that at a previous timepoint. Using simulation data, we evaluate the performance of CYBERTRACK when estimating parameters for a multivariate Gaussian mixture distribution, tracking time-dependent transitions of mixture proportions, and detecting change-points in the overall mixture proportion. The CYBERTRACK performance is validated using two real flow cytometry datasets, which demonstrate that the population dynamics detected by CYBERTRACK are consistent with our prior knowledge of lymphocyte behavior.

Conclusions

Our results indicate that CYBERTRACK offers better understandings of time-dependent cell population dynamics to cytometry users by systematically analyzing time-series flow cytometry data.
Cyclin-dependent-like kinase 5 is required for pain signalling in both human neurons and mouse models
Authors: La Montanara Paolo , Hervera Arnau , Baltussen Lucas , Hutson Thomas , Palmisano Ilaria , De Virgiliis Francesco , Gao Yunan , Majid Qasim A. , Gorgoraptis Nikos , Wong Kingsley , Downs Jenny , Di Lazzaro Vincenzo , Pizzorusso Tommaso , Ultanir Sila , Leonard Helen , Istvan Nagy , Mazarakis Nicholas D , Di Giovanni Simone
Published: July 2019

Cyclin-dependent-like kinase 5 (Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

One Sentence Summary

Cyclin-dependent-like kinase 5 (Cdkl5) controls nociception in patients and murine models of Cdkl5 deficiency disorder via CaMKII-dependent mechanisms
Transcriptional Differences of Peanut (Arachis hypogaea L.) Seeds in the Fresh-harvest, After-ripened and Just-germinated States: insights into regulatory networks of seed dormancy-release and germination
Authors: Xu Pingli , Tang Guiying , Cui Weipei , Chen Guangxia , Ma Chang-Le , Zhu Jieqiong , Li Pengxiang , Shan Lei , Liu Zhanji , Wan Shubo
Published: July 2019

Seed dormancy and germination are the two important traits related to plant survival and reproduction, and crop yield. To understand their regulation mechanism, it is crucial to clarify which genes or which pathways participate in the regulation of these processes. However, little information is available during the procedure of seed dormancy and germination in peanut. In this study, the seeds of the variety Luhua No.14 with non-deep dormancy were selected and its transcriptional changes at three developmental stages: the fresh-harvest (FS), the after-ripened (DS) and the just-germinated seeds (GS), were investigated by comparative transcriptomics analysis. The results showed that genes with increased transcription in DS vs FS comparison were overrepresented for oxidative phosphorylation, glycolysis pathway and tricarboxylic acid cycle (TCA), suggesting that after a period of drying storage, the intermediates stored in dry seeds were rapidly mobilized by glycolysis, TCA cycle, glyoxylate cycle, etc.; the electron transport chain accompanying with respiration has been reactivated to provide ATP for mobilization of other reserves and seed germination. In GS vs DS pairwise, dozens of the up-regulated genes were related to plant hormone biosynthesis and signal transduction, including the majority of components in auxin signal pathway, and brassinosteroid biosynthesis and signal transduction, and some GA and ABA signal transduction genes. During seeds germination, the expression of some EXPANSIN and XYLOGLUCAN ENDOTRANSGLYCOSYLASE was also significantly enhanced. To investigate the effect of different hormone during the procedure of seed germination, the contents and the differential distribution of ABA, GA, BR and IAA in cotyledon, hypocotyl and radicle, and plumule of three seed sections at different developmental stages were also detected. Combining with previous data in other species, a model of regulatory network related to peanut seed germination was developed. This model will helpful to gain further understanding of the mechanisms controlling seed dormancy and germination.
FZD10 regulates cell proliferation and mediates Wnt1 induced neurogenesis in the developing spinal cord
Authors: Alrefaei Abdulmajeed Fahad , Münsterberg Andrea E. , Wheeler Grant N.
Published: July 2019

Wnt/FZD signalling activity is required for spinal cord development, including the dorsal-ventral patterning of the neural tube, where it affects proliferation and specification of neurons. Wnt ligands initiate canonical, β-catenin-dependent, signaling by binding to Frizzled receptors. However, in many developmental contexts the cognate FZD receptor for a particular Wnt ligand remains to be identified. Here, we characterized FZD10 expression in the dorsal neural tube where it overlaps with both Wnt1 and Wnt3a, as well as markers of dorsal progenitors and interneurons. We show FZD10 expression is sensitive to Wnt1, but not Wnt3a expression, and FZD10 plays a role in neural tube patterning. Knockdown approaches show that Wnt1 induced ventral expansion of dorsal neural markes, Pax6 and Pax7, requires FZD10. In contrast, Wnt3a induced dorsalization of the neural tube is not affected by FZD10 knockdown. Gain of function experiments show that FZD10 is not sufficient on its own to mediate Wnt1 activityin vivo. Indeed excess FZD10 inhibits the dorsalizing activity of Wnt1. However, addition of the Lrp6 co-receptor dramatically enhances the Wnt1/FZD10 mediated activation of dorsal markers. This suggests that the mechanism by which Wnt1 regulates proliferation and patterning in the neural tube requires both FZD10 and Lrp6.
Principles for simultaneous measurement of excitatory and inhibitory conductances of single cells in a single trial
Authors: Lampl Ilan
Published: July 2019

Neuronal activity is determined by the interplay between excitatory and inhibitory inputs of individual cells. Whether or not these inputs covary over time or between repeated stimuli remains unclear due to the lack of experimental methods for measuring both inputs at the same time. Current methods for conductance measurement are based on repeatedly stimulating neurons while holding their membrane potential at different levels so to reveal either excitation or inhibition, which can only provide the averaged relationship between the two. Here we develop a new framework for simultaneously measuring both the excitatory and inhibitory inputs of single cells in a single trial under current clamp. This method is based on theoretical analysis of passive circuits and can be practically achieved by injecting a high frequency sinusoidal current and then analysing the data using an optimization algorithm. We use simulations to demonstrate the ability of this approach to reveal the excitatory and inhibitory inputs of point neurons, in which we mimic adapting sensory inputs as well as an asynchronous balanced state.
Combination of Immunomagnetic Separation and Real‐Time Recombinase Polymerase Amplification (IMS‐qRPA) for Specific Detection of Listeria monocytogenes in Smoked Salmon Samples
Authors: Garrido‐Maestu Alejandro , Azinheiro Sarah , Carvalho Joana , Prado Marta
Published: July 2019

Nowadays, Listeria monocytogenes continues to be a major health issue. Therefore, improvements in the speed and reliability of its detection are still needed. In the present study, the combination of real‐time Recombinase Polymerase Amplification (qRPA) with immunomagnetic separation (IMS) is described. The proposed methodology was tested against a real‐time PCR method, and was successfully applied to 50 smoked salmon samples spiked at levels ranging from 2 to 9.3 × 102 cfu/25 g. L. monocytogenes was detected after a 24 hr pre‐enrichment, which represents a great improvement over other previously published RPA methods. Additionally, the evaluation of the method reported a Limit of dDetection 50 (LoD50) of 6.3 cfu/25 g, along with relative sensitivity, specificity and accuracy values higher than 90%. Finally, the index of kappa concordance was calculated to be 0.93 which is interpreted as “almost complete concordance” between the reference and alternative method. Overall, the described methodology proved to be faster, specific, and as sensitive as other methods based on RPA or real‐time PCR.

Practical Application

The methodology described in this study significantly reduces the detection time of L. monocytogenes, when compared with culture‐based methods, and it requires fewer steps than other molecular methods, making it a reliable and more convenient method for routine testing. Finally, the evaluation of the methodology in spiked food samples, confirms its reliability.
Risk Factors for Sedation‐related Events During Acute Agitation Management in the Emergency Department
Authors: Yap Celene Y. L. , Taylor David McD. , Kong David C. M. , Knott Jonathan C. , Taylor Simone E. ,   the Sedation for Acute Agitation in Emergency Department Patients: Targeting Adverse Events (SIESTA) Collaborative Study Group
Published: July 2019

Objective

The objective was to describe the incidence, nature, and risk factors for adverse events (AEs) among patients who received parenteral sedation for acute agitation in an emergency department (ED) setting.

Methods

We undertook a prospective observational study and a clinical trial of parenteral sedation for the management of acute agitation. We included agitated adult patients who required parenteral sedation from 2014 to 2017 in 12 Australian EDs, excluding those with incomplete information or aged under 18 years. The primary outcome was the number of patients who experienced at least one AE. Multivariable logistic regression was used to determine factors associated with AEs.

Results

A total of 904 patients were included in the analyses (62.3% male; median age = 34 years, range = 18 to 95 years). Of these, 144 (15.9%) patients experienced at least one AE. The most common AEs were oxygen desaturation (7.4%), airway obstruction (3.6%), bradycardia (1.9%), hypotension (1.7%), and prolonged QTc interval (1.3%). No deaths or serious AEs were reported. The following factors had an increased adjusted odds ratio (OR) for experiencing an AE: age 65 years and older (OR = 2.8, 95% confidence interval [CI] = 1.2 to 7.2), more than one type of parenteral sedation administered within 60 minutes (OR = 2.1, 95% CI = 1.4 to 3.1), and alcohol intoxication (OR = 1.8, 95% CI = 1.2 to 2.6).

Conclusions

Sedation‐related AEs are common, especially respiratory events. Elderly patients, sedation with multiple sedatives within 60 minutes, and alcohol intoxication increased the risk.
Economic policy uncertainty and corporate inventory holdings: evidence from China
Authors: Zeng Jianyu , Zhong Teng , He Fan
Published: July 2019

We investigate the impact of economic policy uncertainty (EPU) on corporate inventory holdings in China over the period 2007–2017. We find that EPU leads firms to significantly reduce inventory holdings and this effect is particularly pronounced among non‐state‐owned enterprises. The adjustment of inventory holdings enhances firms’ operating and market performance consequently. In addition, firms with greater financial constraints or stronger external governance are more affected by EPU. Further exploration shows that EPU induces high precautionary cash holdings, which crowds out inventories. Our results illustrate that firms reallocate between inventories and cash to cope with uncertainty associated with economic policy changes.
Community‐level predictors of Australian children’s dental caries and injury
Authors: Stormon N , Ford PJ , Lalloo R
Published: July 2019

Background

Social determinants of oral health are complex and have been described by conceptual frameworks. A widely embraced model of children’s oral health was published by Fisher‐Owens et al. (2007), identifying theoretical constructs influencing oral health. The current study aimed to investigate community‐level constructs described in the conceptual model.

Methods

The Longitudinal Study of Australian Children is a cross‐sequential dual cohort study, with a representative sample (n = 10090) of Australian children. Generalized estimating equations were applied to model seven waves of carer‐reported oral health and community measures.

Results

In the final model, children living in Queensland had a 1.48 (CI 1.35–1.62) increased odds of dental caries over time. Children in low socio‐economic status (SES) areas (OR 1.32 CI 1.20–1.44) had an increased odds of caries. The state of Queensland (OR 1.24 CI 1.05–1.46) and poor neighbourhood liveability (OR 1.17 CI 1.05–1.31) were predictors of dental injury.

Conclusion

By modelling available community measures, this study found SES and rurality were predictors of caries over childhood. Our results highlight the difficulty of applying conceptual models to oral health. The use of qualitative studies and realist reviews should be considered to complement statistical models to provide contextualized insights into funding, policy and service delivery on children's oral health.
Incidence of hypophosphatemia in patients with inflammatory bowel disease treated with ferric carboxymaltose or iron isomaltoside
Authors: Detlie Trond Espen , Lindstrøm Jonas Christoffer , Jahnsen Marte Eide , Finnes Elisabeth , Zoller Heinz , Moum Bjørn , Jahnsen Jørgen
Published: July 2019

Background

Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease (IBD). In patients with moderate‐to‐severe anaemia, oral iron intolerance or ineffectiveness of oral iron, ferric carboxymaltose and iron isomaltoside are widely used. Hypophosphatemia is a side effect of both preparations.

Aims

To investigate the occurrence of hypophosphatemia in IBD patients with iron deficiency/iron deficiency anaemia treated with high‐dose intravenous iron.

Methods

A prospective observational study of adult IBD patients with iron deficiency/iron deficiency anaemia was conducted at two study sites where patients received 1000 mg of ferric carboxymaltose or iron isomaltoside. At baseline, weeks 2 and 6, blood and faecal samples were collected. The primary endpoint was to determine the incidence of moderate‐to‐severe hypophosphatemia. Secondary endpoints included the total incidence of hypophosphatemia, possible risk factors for hypophosphatemia, and response to single‐dose intravenous iron.

Results

One hundred and thirty patients were included. In the per‐protocol set, 52 patients received ferric carboxymaltose and 54 patients received iron isomaltoside. Ferric carboxymaltose treatment had a significantly higher incidence of moderate‐to‐severe hypophosphatemia compared with iron isomaltoside at week 2 (56.9% vs 5.7%, P < 0.001) and a higher incidence at week 6 (13.7% vs 1.9%, P = 0.054).The overall incidence of hypophosphatemia was significantly higher with ferric carboxymaltose compared with iron isomaltoside treatment at weeks 2 (72.5% vs 11.3%, P < 0.001) and 6 (21.6% vs 3.7%, P = 0.013).

Conclusions

In IBD patients with iron deficiency/iron deficiency anaemia, ferric carboxymaltose was associated with higher incidence, severity and persistence of hypophosphatemia compared with iron isomaltoside. The presence of moderate‐to‐severe hypophosphatemia beyond 6 weeks is a clinical concern that requires further investigation.
Effects of berberine on the growth performance, antioxidative capacity and immune response to lipopolysaccharide challenge in broilers
Authors: Yang Li , Liu Gang , Liang Xiaorui , Wang Mengmeng , Zhu Xiaoqing , Luo Yan , Shang Yunxia , Yang Jing‐quan , Zhou Ping , Gu Xin‐Li
Published: July 2019

This study evaluated the effects of berberine on growth performance, immunity, haematological parameters, antioxidant capacity, and the expression of immune response‐related genes in lipopolysaccharide (LPS)‐challenged broilers. We assigned 120 one‐day‐old male broilers (Ross 308) to two treatment groups; each group included two subgroups, each of which included six replicates of five birds per replicate. The experiment used a 2 × 2 factorial arrangement with berberine treatment (0 or 60 mg/kg dietary) and challenge status [injection of saline (9 g/L w/v) or LPS (1.5 mg/kg body weight)] as the main factors. On days 14, 16, 18 and 20, broilers were intraperitoneally injected with LPS or physiological saline. Blood and liver samples were collected on day 21. Dietary berberine supplementation significantly alleviated the compromised average daily gain and average daily feed intake (p < 0.05) caused by LPS. The LPS challenge led to increased lymphocyte and white blood cell (WBC) counts, malondialdehyde (serum and liver) content, and immunoglobulin G and M, tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) expression (p < 0.05) and significantly reduced serum total superoxide dismutase (T‐SOD) activity (p < 0.05). Dietary berberine significantly mitigated the LPS‐induced decreases in the mRNA expression of nuclear factor‐kappa B (NF‐κB), TNF‐α, IL‐1β, inducible nitrite synthase and cyclooxygenase‐2 (p < 0.05) in the liver. In conclusion, berberine supplementation has a positive effect on LPS challenge, which may be related to the increase in antioxidant enzyme activity and inhibition of both NF‐κB signalling and the expression of inflammatory mediators.
The vascular protective role of oestradiol: a focus on postmenopausal oestradiol deficiency and aneurysmal subarachnoid haemorrhage
Authors: Ramesh Shruthi S. , Christopher Rita , Indira Devi Bhagavatula , Bhat Dhananjaya I.
Published: July 2019

The steroid hormone, oestradiol, has pleiotropic functions. The protective effects of oestradiol are attributed to its anti‐inflammatory, antioxidant, anti‐atherogenic, anti‐apoptotic, vasodilatory activities and regulation of micro RNA. Oestradiol upregulates endothelial nitric oxide synthase gene expression and increases the production of nitric oxide, an important vasodilator. It suppresses the renin–angiotensin system and monitors haemodynamic stress. The hormone maintains the integrity of blood vessels by reducing oxidative stress while upregulating the expression of antioxidant enzymes and prevents vascular inflammation by regulating pro‐ and anti‐inflammatory cytokines. Aneurysmal subarachnoid haemorrhage (aSAH) occurring as a consequence of the rupture of an intracranial aneurysm is a devastating cerebrovascular event, representing 5–7% of all strokes. Postmenopausal women are more susceptible to aSAH compared to men in the same age group. This gender disparity has been attributed to reduced levels of the vascular protective hormone oestradiol following menopause. This review is focused on the protective role of oestradiol on vasculature and how the drop in oestradiol levels after menopause dramatically increases the incidence of aSAH in women. During menopause, oestradiol deficiency may affect vascular integrity causing dysregulation of vascular homeostasis by affecting the renin–angiotensin–aldosterone system (RAAS) and inflammatory and apoptotic cascades, resulting in the weakening of the cerebral arterial wall and potentially to development of an aneurysm and its rupture. In view of the role of oestradiol in maintaining vascular integrity, treatments involving hormone replacement could be a promising approach in postmenopausal women who are at risk of developing or rupturing an intracranial aneurysm.
Establishment and characterization of patient‐derived organoids from a young patient with cervical clear cell carcinoma
Authors: Maru Yoshiaki , Tanaka Naotake , Ebisawa Keiko , Odaka Akiko , Sugiyama Takahiro , Itami Makiko , Hippo Yoshitaka
Published: July 2019

Cervical clear cell carcinoma (cCCC) constitutes an extremely rare subtype of cervical cancer. Consequently, its pathogenesis remains largely unknown, with no cell lines established from primary tumors. Here, we report the first establishment ofcCCCorganoids, from biopsy samples of a 23‐year‐old patient diagnosed withcCCC. By applying a protocol that we recently optimized for gynecological tumors, we were able to propagate a patient‐derived cell line (PDC) for more than 6 months as organoids. ThisPDCtolerated cryopreservation and proliferated either as spheroids or adherent cells, and developed xenografts in immunodeficient mice, ensuring robust utility as a cell line. Intriguingly, the resected tumor focally contained serous carcinoma (SC) in a tiny protruding lesion. Both organoids and derivative xenografts resembled theCCCcomponent of the original tumor in histology, immunostaining profile, and genome‐wide copy number changes, including focal gain ofMET. Genomic analysis revealed that both organoids and theCCCcomponent harbored only a few mutations, of which 2 mutations were shared in common. In contrast, theSCcomponent showed a mutator‐phenotype and prominent genome instability along with biallelic inactivation ofTP53, but none of them were found in organoids or theCCCcomponent. ThePDCproved sensitive to major chemotherapeutic agents andMETinhibitors. These observations clearly indicated that thePDC, designated asYMC7, can be used as a novelcCCCcell line and provide novel insights into the pathogenesis of mixed cervical adenocarcinoma. As a valuable resource for rare cancer, it will likely contribute to investigations in many fields.
Screening for Compositae contact sensitization with sesquiterpene lactones and Compositae mix 2.5% pet
Authors: Paulsen Evy , Andersen Klaus E.
Published: July 2019

Background

Compositae contact sensitization may be difficult to diagnose, because of a lack of reliable screening allergens.

Objectives

To assess the suitability of Compositae mix II 2.5% pet. (CM2.5) as a screening mix in the baseline series combined with sesquiterpene lactone (SL) mix and parthenolide (PTH).

Methods

CM2.5 was added to the baseline series, which included SL mix and PTH 0.1% pet., in January 2015, and PTH was included in TRUE Test Panel 3 in October 2015. All Compositae‐sensitive patients diagnosed or tested in the next 4 years were assessed.

Results

Altogether, 57 patients (2.7%) presented with Compositae allergy. On primary testing in 53 newly diagnosed patients, SL mix elicited positive reactions most frequently (53% positive), followed by CM2.5 (47% positive), and PTH (45% positive). CM2.5 and PTH pet. elicited a few irritant reactions. Three patients had late reactions. Altogether, 16 patients (28%) were not detected by any of the three screening agents.

Conclusions

SL mix is an indispensable, although insufficient, screening mixture in Denmark. It may be relatively safely supplemented with CM2.5 and PTH in the TRUE Test system for screening, but, when Compositae sensitization is suspected, further extracts should be tested on the basis of the history.
An atypical pleomorphic lipomatous tumor arising on the cheek
Authors: Boyd Alan S.
Published: July 2019

Pathologists and dermatopathologists commonly encounter tumors with adipocyte differentiation. Most are of minimal clinical significance. Those exhibiting atypical spindle cell morphology have been reported but the terminology for such neoplasms is unsettled. Tumors with both spindle cell and pleomorphic morphology are rare, with equally unsettled descriptive nomenclature. Recently, a series of such tumors, termed atypical pleomorphic lipomatous tumor, has been published. They resided in the deep soft tissue or subcutis. To date, such a tumor has not been reported with dermal involvement.
Development of a group structured education programme to support safe exercise in people with Type 1 diabetes: the EXTOD education programme
Authors: Narendran P. , Greenfield S. , Troughton J. , Doherty Y. , Quann N. , Thompson C. , Litchfield I. , Andrews R. C. ,   the EXTOD Education Programme Development Team
Published: July 2019

Aim

To develop a structured education programme for individuals with Type 1 diabetes who are engaging in regular exercise.

Method

A multidisciplinary team of experts in supporting exercise and physical activity for people with Type 1 diabetes, alongside researchers with experience of developing self‐management education, developed an exercise programme using the Medical Research Council framework. The programme was informed by a review of the evidence relating to Type 1 diabetes and exercise, the behaviour change literature (including the behaviour change taxonomy), and qualitative interviews with stakeholders. The programme and supporting resources were refined using an iterative process of testing, delivery and collecting feedback from participants and the wider development team.

Results

The outcome of the intervention development was the design of a feasible and acceptable intervention for people with Type 1 diabetes to support safe exercise. The pilot allowed refinement of the intervention prior to testing in a two‐site feasibility randomized controlled trial. Key findings from the pilot informed minor restructuring of the timetable (timings and order) and adaptation of supporting educational materials (participant handbook and teaching materials).

Conclusion

The ‘EXercise in people with Type One Diabetes’ (EXTOD) education programme has been developed using robust methodology for the generation of educational interventions. It now needs testing in a randomized controlled trial.
Incidence and variables associated with arrhythmias during dobutamine–atropine stress echocardiography among patients with Chagas disease
Authors: Carmo Rassi Daniela , Hotta Viviane Tiemi , Gomes Furtado Rogério , Campos Vieira Marcelo Luiz , Paula Turco Fabio , Henrique Melato Luciano , Godoy Nunes Colandy , Rassi Luiz , Rassi Salvador
Published: July 2019

Background

Dobutamine stress echocardiography (DSE) is an important tool in the diagnosis of coronary artery disease. However, there is hesitation in clinical practice for using it in patients with Chagas disease (CD) due to the arrhythmogenic potential of this heart condition. This study aimed to evaluate the incidence and variables associated with arrhythmias during DSE in a population of patients with CD.

Methods

A population of 205 consecutive patients with CD and suspected coronary heart disease was assessed through a retrospective database analysis. CD was confirmed in all patients by serological testing.

Results

The mean age of the patients selected was 64 years, and 65.4% of the patients were female. Significant arrhythmias occurred as follows: nonsustained ventricular tachycardia in 7.3% of patients; supraventricular tachycardia and sustained ventricular tachycardia in 1%; and atrial fibrillation in 0.5%. Nonsignificant arrhythmias occurred as follows: premature ventricular contractions in 48% of patients and bigeminy in 4.4%. Values for the wall‐motion score index at rest greater than 1.12 and 1.18 were independently correlated with the occurrence of nonsignificant arrhythmias (odds ratio [OR] = 2.90, P < 0.001) and significant arrhythmias (OR = 4.23, P = 0.044), respectively.

Conclusion

DSE should be considered a safe examination in patients with CD despite the known increased risk of arrhythmias in this group of patients. The occurrence of arrhythmias was low in this study. Abnormal wall‐motion score index values at rest were associated with the occurrence of significant and nonsignificant arrhythmias during the test.
landscapemetrics: an open‐source R tool to calculate landscape metrics
Authors: Hesselbarth Maximilian H. K. , Sciaini Marco , With Kimberly A. , Wiegand Kerstin , Nowosad Jakub
Published: July 2019

Quantifying landscape characteristics and linking them to ecological processes is one of the central goals of landscape ecology. Landscape metrics are a widely used tool for the analysis of patch‐based, discrete land‐cover classes. Existing software to calculate landscape metrics has several constraints, such as being limited to a single platform, not being open‐source or involving a complicated integration into large workflows. We present landscapemetrics, an open‐source R package that overcomes many constraints of existing landscape metric software. The package includes an extensive collection of commonly used landscape metrics in a tidy workflow. To facilitate the integration into large workflows, landscapemetrics is based on a well‐established spatial framework in R. This allows pre‐processing of land‐cover maps or further statistical analysis without importing and exporting the data from and to different software environments. Additionally, the package provides many utility functions to visualize, extract, and sample landscape metrics. Lastly, we provide building‐blocks to motivate the development and integration of new metrics in the future. We demonstrate the usage and advantages of landscapemetrics by analysing the influence of different sampling schemes on the estimation of landscape metrics. In so doing, we demonstrate the many advantages of the package, especially its easy integration into large workflows. These new developments should help with the integration of landscape analysis in ecological research, given that ecologists are increasingly using R for the statistical analysis, modelling and visualization of spatial data.
Staged treatment and acceptability guidelines in early psychosis study (STAGES): A randomized placebo controlled trial of intensive psychosocial treatment plus or minus antipsychotic medication for first‐episode psychosis with low‐risk of self‐harm or aggression. Study protocol and baseline characteristics of participants
Authors: O'Donoghue Brian , Francey Shona M. , Nelson Barnaby , Ratheesh Aswin , Allott Kelly , Graham Jessica , Baldwin Lara , Alvarez‐Jimenez Mario , Thompson Andrew , Fornito Alex , Polari Andrea , Berk Michael , Macneil Craig , Crisp Kingsley , Pantelis Christos , Yuen Hok P. , Harrigan Susy , McGorry Patrick
Published: July 2019

Aim

It is now necessary to investigate whether recovery in psychosis is possible without the use of antipsychotic medication. This study will determine (1) whether a first‐episode psychosis (FEP) group receiving intensive psychosocial interventions alone can achieve symptomatic remission and functional recovery; (2) whether prolonging the duration of untreated psychosis (DUP) in a sub‐group according to randomisation will be associated with a poorer outcome and thereby establish whether the relationship between DUP and outcome is causative; and (3) whether neurobiological changes observed in FEP are associated with the psychotic disorder or antipsychotic medication. Baseline characteristics of participants will be presented.

Methods

This study is a triple‐blind randomized placebo‐controlled non‐inferiority trial. The primary outcome is the level of functioning measured by the Social and Occupational Functioning Assessment Scale at 6 months. This study is being conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne and includes young people aged 15 to 24 years with a DSM‐IV psychotic disorder, a DUP less than 6 months and not high risk for suicide or harm to others. Strict discontinuation criteria are being applied. Participants are also undergoing three 3‐Tesla‐MRI scans.

Results

Ninety participants have been recruited and baseline characteristics are presented.

Conclusions

Staged treatment and acceptability guidelines in early psychosis will determine whether antipsychotic medications are indicated in all young people with a FEP and whether antipsychotic medication can be safely delayed. Furthermore, the relative contribution of psychotic illness and antipsychotic medication in terms of structural brain changes will also be elucidated. The findings will inform clinical practice guidelines.
Mindfulness‐based cognitive therapy for children and adolescents with anxiety disorders at‐risk for bipolar disorder: A psychoeducation waitlist controlled pilot trial
Authors: Cotton Sian , Kraemer Kristen M. , Sears Richard W. , Strawn Jeffrey R. , Wasson Rachel S. , McCune Nina , Welge Jeffrey , Blom Thomas J. , Durling Michelle , Delbello Melissa P.
Published: July 2019

Aim

Previous studies suggest that Mindfulness‐Based Cognitive Therapy for Children (MBCT‐C) is feasible and may improve anxiety and emotion regulation in youth with anxiety disorders at‐risk for bipolar disorder. However, controlled studies are warranted to replicate and extend these findings.

Methods

In the current study, 24 youth with anxiety disorders who have at least one parent with bipolar disorder participated in a MBCT‐C treatment period (n = 24; Mage = 13.6, 75% girls, 79% White) with a subset also participating in a prior psychoeducation waitlist control period (n = 19 Mage = 13.8, 68% girls, 84% White). Participants in both the waitlist and MBCT‐C periods completed independently‐rated symptom scales at each time point. Participants in the waitlist period received educational materials 12 weeks prior to the beginning of MBCT‐C.

Results

There were significantly greater improvements in overall clinical severity in the MBCT‐C period compared to the waitlist period, but not in clinician‐ and child‐rated anxiety, emotion regulation or mindfulness. However, increases in mindfulness were associated with improvements in anxiety and emotion regulation in the MBCT‐C period, but not the waitlist period.

Conclusions

Findings suggest that MBCT‐C may be effective for improving overall clinical severity in youth with anxiety disorders who are at‐risk for bipolar disorder. However, waitlist controlled designs may inflate effect sizes so interpret with caution. Larger studies utilizing prospective randomized controlled designs are warranted.
The relation of basic self‐disturbance to self‐harm, eating disorder symptomatology and other clinical features: Exploration in an early psychosis sample
Authors: Rasmussen Andreas R. , Reich Daniel , Lavoie Suzie , Li Emily , Hartmann Jessica A. , McHugh Meredith , Whitford Thomas J. , Nelson Barnaby
Published: July 2019

Background and Aims

The notion of basic self‐disturbance has been proposed as a core feature of schizophrenia‐spectrum disorders and as an indicator of future transition to psychosis in high‐risk populations. However, the relation of this notion to many clinical characteristics has not been explored. The aim of this study was: (a) to investigate the distribution of self‐disturbance and other symptoms dimensions in ultra‐high risk (UHR), first‐episode psychosis (FEP) and healthy control groups; and (b) to explore the association of self‐disturbance with a history of self‐harm, suicidal attempt, eating disorder symptomatology, school bullying victimization and sexual or physical abuse.

Methods

Patients with UHR status (n = 38) or FEP (n = 26) and healthy controls (n = 33) were assessed with the Examination of Anomalous Self‐Experience (EASE) and the Comprehensive Assessment of at Risk Mental States (CAARMS). The clinical‐historical variables were assessed through medical records.

Results

The FEP group scored significantly higher on the EASE than the UHR group, which scored significantly higher than the healthy control group, which had a very low score. Multivariate logistic regression analyses revealed that higher EASE score was significantly associated with a history of self‐harm, disordered eating and bullying victimization (but not with suicide attempts or sexual/physical abuse) after controlling for positive, negative and depressive symptoms.

Conclusion

These novel findings suggest that self‐disturbance may be related to a history of school bullying victimization, self‐harm and eating disorder symptomatology in patients with or at‐risk of psychosis. If further confirmed, these findings are potentially relevant to clinical risk assessment and therapy.
Experimental and numerical investigation of the effect of temperature on mixed‐mode fracture behaviour of AM60 Mg alloy
Authors: Es'haghi Oskui Abuzar , Soltani Nasser
Published: July 2019

The aim of present paper is to experimentally investigate mixed‐mode fracture behaviour of AM60 Mg alloy at low and elevated temperatures. For this purpose, mode I, 45° mixed‐mode, and mode II tests were conducted using a modified version of Arcan device at three different temperatures. An elastic‐plastic finite element model was used to extract necessary geometric parameters. Crack resistance curves (J‐R) and critical J‐integral of the material were extracted. The results indicated that, for all loading modes, maximum critical J‐integral value was observed at ambient temperature and decreased by either increasing or decreasing the temperature. It was observed that effect of temperature on fracture behaviour is much larger at temperatures above 0°C rather than sub‐zero temperatures. By changing the loading angle to go from mode I to mode II, a decreasing trend was observed in the values of critical fracture parameters at all temperatures. Finally, the surfaces were examined using scanning electron microscopy (SEM).