bluuebunny/crossref_metadata_2025 huggingface dataset:
The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients
Authors: Giannuzzi Giuliana , Schmidt Paul J. , Porcu Eleonora , Willemin Gilles , Munson Katherine M. , Nuttle Xander , Earl Rachel , Chrast Jacqueline , Hoekzema Kendra , Risso Davide , Männik Katrin , De Nittis Pasquelena , Baratz Ethan D. ,   16p11.2 Consortium, Herault Yann , Gao Xiang , Philpott Caroline C. , Bernier Raphael A. , Kutalik Zoltan , Fleming Mark D. , Eichler Evan E. , Reymond Alexandre
Published: July 2019

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes of autism. These copy number polymorphic duplications are under positive selection and include 3–8 copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, P=4e-7, OR=5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, with 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, P=1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The deletion and Bola2-deficient mice showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc protoporphyrin to heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo and its expansion has a potential adaptive role in protecting against iron deficiency.
Empirical Performance of Tree-based Inference of Phylogenetic Networks
Authors: Cao Zhen , Nakhleh Luay
Published: July 2019

Phylogenetic networks extend the phylogenetic tree structure and allow for modeling vertical and horizontal evolution in a single framework. Statistical inference of phylogenetic networks is prohibitive and currently limited to small networks. An approach that could significantly improve phylogenetic network space exploration is based on first inferring an evolutionary tree of the species under consideration, and then augmenting the tree into a network by adding a set of “horizontal” edges to better fit the data.

In this paper, we study the performance of such an approach on networks generated under a birth-hybridization model and explore its feasibility as an alternative to approaches that search the phylogenetic network space directly (without relying on a fixed underlying tree). We find that the concatenation method does poorly at obtaining a “backbone” tree that could be augmented into the correct network, whereas the popular species tree inference method ASTRAL does significantly better at such a task. We then evaluated the tree-to-network augmentation phase under the minimizing deep coalescence and pseudo-likelihood criteria. We find that even though this is a much faster approach than the direct search of the network space, the accuracy is much poorer, even when the backbone tree is a good starting tree.

Our results show that tree-based inference of phylogenetic networks could yield very poor results. As exploration of the network space directly in search of maximum likelihood estimates or a representative sample of the posterior is very expensive, significant improvements to the computational complexity of phylogenetic network inference are imperative if analyses of large data sets are to be performed. We show that a recently developed divide-and-conquer approach significantly outperforms tree-based inference in terms of accuracy, albeit still at a higher computational cost.
Three-dimensional total-internal reflection fluorescence nanoscopy with nanometric axial resolution by photometric localization of single molecules
Authors: Szalai Alan M. , Siarry Bruno , Lukin Jerónimo , Williamson David J. , Unsain Nicolás , Refojo Damián , Cáceres Alfredo , Pilo-Pais Mauricio , Acuna Guillermo , Owen Dylan M. , Simoncelli Sabrina , Stefani Fernando D.
Published: July 2019

Single-molecule localization microscopy (SMLM) enables far-field imaging with lateral resolution in the range of 10 to 20 nanometres, exploiting the fact that the centre position of a single molecule’s image can be determined with much higher accuracy than the size of that image itself. However, attaining the same level of resolution in the axial (third) dimension remains challenging. Here, we present SIMPLER, a photometric method to decode the axial position of single molecules in a total internal reflection fluorescence (TIRF) microscope. SIMPLER requires no hardware modification whatsoever to a conventional TIRF microscope, and complements any 2D SMLM method to deliver 3D images with nearly isotropic nanometric resolution. Examples of the performance of SIMPLER include the visualization of the nuclear pore complex through dSTORM with sub-20 nm resolution and of microtubule cross-sections resolved with sub-10 nm through DNA-PAINT.
Scaling of organ masses in mammals and birds: phylogenetic signal and implications for metabolic rate scaling
Authors: Antoł Andrzej , Kozłowski Jan
Published: July 2019

The persistent enigma of why the whole-body metabolic rate increases hypoallometrically with body mass should be solved on both the ultimate and proximate levels. The proximate mechanism may involve hyperallometric scaling of metabolically relatively inert tissue/organ masses, hypoallometric scaling of metabolically expensive organ masses, a decrease in mass-specific metabolic rates of organs or, more likely, a combination of these three factors. Although there are in data in the literature on the scaling of tissue/organ masses, they do not take phylogenetic information into account. Here, we analyse the scaling of tissue/organ masses in a sample of 100 mammalian species and 22 bird species with a phylogenetically informed method (PGLS) to address two questions: the role of phylogenetic signal in organ/tissue size scaling and the potential role of organ/tissue mass scaling in interspecific metabolic rate scaling. Strong phylogenetic signal was found for the brain, kidney, spleen and stomach mass in mammals but only for the brain and leg muscle in birds. Metabolically relatively inert adipose tissue scales isometrically in both groups. The masses of energetically expensive visceral organs scale hypoallometrically in mammals, with the exception of lungs, with the lowest exponent occurring for the brain. In contrast, only brain mass scales hypoallometrically in birds, whereas other tissues and organs scale isometrically or almost isometrically. Taking into account that the whole-body metabolic rate scales more steeply in mammals than in birds, the mass-specific metabolic rate of visceral organs must decrease with body mass at a much faster rate in birds than in mammals. To explain this striking difference, there is an urgent need to study the metabolic rates of tissues and organs to supplement measurements of the whole-body metabolic rate.
Molecular and cellular phenotypic differences distinguish murine syngeneic models from human tumors
Authors: Zhong Wenyan , Myers Jeremy S. , Wang Fang , Wang Kai , Lucas Justin , Rosfjord Edward , Lucas Judy , Hooper Andrea T. , Yang Sharon , Lemon LuAnna , Guffroy Magali , May Chad , Bienkowska Jadwiga R. , Rejto Paul A.
Published: July 2019

Abstract

The clinical success of immune checkpoint inhibitors that target cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. The combination of multiple immunotherapies as well as the combination of immunotherapy with targeted therapy is being pursued vigorously to increase the rate and extend the duration of response. Preclinical in vivo models for immuno-oncology (IO) typically require immunocompetent mice bearing murine syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of mouse tumor cell lines grown in vitro culture as well as in vivo tumor samples. Our studies identified many genetic and cellular phenotypic differences that distinguish murine syngeneic models from human cancers. For example, only a small fraction of the somatic single nucleotide variants (SNVs) in mouse cell lines directly match SNVs from human actionable cancer genes. At the cellular level, some epithelial tumor models have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. Furthermore, in contrast to what has been reported for human tumors, we did not observe a correlation between neoantigen load and cytolytic activity in syngeneic models. Finally, the relative immunogenicity of syngeneic tumors does not typically resemble that of human tumors of the same tissue origin. CT26, a colon tumor model, had the highest immunogenicity and was the most responsive model to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers. These differences highlight limitations of syngeneic models for evaluating novel immune therapies and rationalize some of the challenges associated with translating preclinical findings to clinical studies.
Spatial Ecology of Territorial Populations
Authors: Weiner Benjamin G. , Posfai Anna , Wingreen Ned S.
Published: July 2019

Many ecosystems, from vegetation to biofilms, are composed of territorial populations that compete for both nutrients and physical space. What are the implications of such spatial organization for biodiversity? To address this question, we developed and analyzed a model of territorial resource competition. In the model, all species obey trade-offs inspired by biophysical constraints on metabolism; the species occupy non-overlapping territories while nutrients diffuse in space. We find that the nutrient diffusion time is an important control parameter for both biodiversity and the timescale of population dynamics. Interestingly, fast nutrient diffusion allows the populations of some species to fluctuate to zero, leading to extinctions. Moreover, territorial competition spontaneously gives rise to both multistability and the Allee effect (in which a minimum population is required for survival), so that small perturbations can have major ecological effects. While the assumption of trade-offs allows for the coexistence of more species than the number of nutrients – thus violating the principle of competitive exclusion – overall biodiversity is curbed by the domination of “oligotroph” species. Importantly, in contrast to well-mixed models, spatial structure renders diversity robust to inequalities in metabolic trade-offs. Our results suggest that territorial ecosystems can display high biodiversity and rich dynamics simply due to competition for resources in a spatial community.
Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms
Authors: Novikova Gloriia , Kapoor Manav , TCW Julia , Abud Edsel M. , Efthymiou Anastasia G. , Cheng Haoxiang , Fullard John F. , Bendl Jaroslav , Roussos Panos , Poon Wayne W. , Hao Ke , Marcora Edoardo , Goate Alison M.
Published: July 2019

Genome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD.
Genotypic variation in morphological source and sink traits affects the response of rice photosynthesis and growth to elevated atmospheric CO2
Authors: Fabre Denis , Dingkuhn Michael , Yin Xinyou , Clément-Vidal Anne , Roques Sandrine , Soutiras Armelle , Luquet Delphine
Published: July 2019

This study aimed to understand the response of photosynthesis and growth to e-CO2conditions (800 vs. 400 μmol mol-1) of rice genotypes differing in source-sink relationships. A proxy trait called local C source-sink ratio was defined as the ratio of flag leaf area over the number of spikelets on the corresponding panicle, and five genotypes differing in this ratio were grown in a controlled greenhouse. Differential CO2resources were applied either during the two weeks following heading (EXP1) or during the whole growth cycle (EXP2). Under e-CO2, low source-sink ratio cultivars (LSS) had greater gains in photosynthesis, and they accumulated less nonstructural carbohydrate in the flag leaf than high source-sink ratio cultivars (HSS). In EXP2, grain yield and biomass gain was also greater in LSS probably caused by their strong sink. Photosynthetic capacity response to e-CO2was negatively correlated across genotypes with local C source-sink ratio, a trait highly conserved across environments. HSS were sink-limited under e-CO2, probably associated with low triose phosphate utilization (TPU) capacity. We suggest that the local C source-sink ratio is a potential target for selecting more CO2-responsive cultivars, pending validation for a broader genotypic spectrum and for field conditions.

Highlight

Rice local carbon source-sink ratio and sink plasticity can drive genotypic responses of leaf photosynthesis and plant production in a CO2elevation context.
Daytime Colour Preference in Drosophila Depends on the Circadian Clock and TRP Channels
Authors: Lazopulo Stanislav , Lazopulo Andrey , Baker James , Syed Sheyum
Published: July 2019

By guiding animals towards food and shelter and repelling them from potentially harmful situations, light discrimination according to colour can confer survival advantages1,2. Such colour-dependent behaviour may be experiential or innate. Data on innate colour preference remain controversial in mammals3and limited in simpler organisms4–7. Here we show that when given a choice among blue, green and dim light, fruit flies exhibit an unexpectedly complex pattern of colour preference that changes with the time of day. Flies show a strong preference for green in the early morning and late afternoon, a reduced green preference at midday and a robust avoidance of blue throughout the day. Genetic manipulations reveal that the peaks in green preference require rhodopsin-based photoreceptors, and are controlled by the circadian clock. The midday reduction in green preference in favour of dim light depends on the Transient Receptor Potential (TRP) channels dTRPA1 and Pyrexia (Pyx), and is also timed by the clock. In contrast, blue avoidance is primarily mediated by class IV multidendritic neurons, requires the TRP channel Painless (Pain) and is independent of the clock. With unexpected roles for several TRP channels inDrosophilacolour-specific phototransduction, our results reveal distinct pathways of innate colour preference that coordinate the fly’s behavioural dynamics in ambient light.
cAMP signalling is required for the actions of IP3on Ca2+-transients in cardiac atria and beating rate in sino-atrial node
Authors: Capel Rebecca A , Collins Thomas P , Bose Samuel J , Rajasundaram Skanda , Ayagama Thamali , Zaccolo Manuela , Burton Rebecca AB , Terrar Derek A
Published: July 2019

Inositol trisphosphate (IP3) is a major Ca2+-mobilising second messenger and atrial IP3receptor (IP3R) expression is greatly increased in atrial fibrillation (AF). Cardiac atrial and sino-atrial node (SAN) myocytes also express Ca2+-stimulated adenylyl cyclases (AC1 and AC8); however the pathways underlying atrial AC1 and AC8 activation are unknown. We investigated whether IP3signalling in cardiac atria and SAN utilises ACs. Immunocytochemistry in isolated guinea pig atrial myocytes identified co-localisation of type 2 IP3Rs with AC8, while AC1 was located in close vicinity. UV photorelease of IP3significantly enhanced Ca2+transient amplitudes following stimulation of atrial myocytes (31 ± 6 % increase 60 s post photorelease, n=16), an effect abolished by inhibitors of ACs (MDL-12,330) or PKA (H89). The maximum rate change observed in spontaneously-beating murine right atrial preparations exposed to phenylephrine (14.7 ± 0.5 %, n=10) was significantly reduced by 2.5 μmol/L 2-APB and abolished by a low dose of MDL-12,330. These observations are consistent with a functional interaction between IP3and cAMP signalling involving Ca2+stimulation of ACs in cardiac atria and the SAN. Structural evidence supports AC8 as the most likely effector. This signal transduction mechanism is important for future study in atrial physiology and pathophysiology, particularly AF.
Unique Cancer Motility Behaviors in Confined Spaces of Microgroove Topography with Acute Wall Angles
Authors: Yaginuma T. , Kushiro K. , Takai M.
Published: July 2019

In recent years, many types of micro-engineered platform have been fabricated to investigate the influences of surrounding microenvironments on cell migration. Previous researches demonstrate that microgroove-based topographies can influence cell motilities of normal and cancerous cells differently. In this paper, the microgroove wall angle is altered from obtuse to acute angles and the resulting differences in the responses of normal and cancer cells are investigated to explore the geometrical characteristics that can efficiently distinguish normal and cancer cells. Interestingly, trends in cell motilities of normal and cancer cells as the wall angles are varied between 60-120° were different, and in particular, invasive cancer cells exhibit a unique, oscillatory migratory behavior. Results from the immunostaining of cell mechanotransduction components suggest that this difference stems from directional extension and adhesion behaviors of each cell type. In addition, the specific behaviors of invasive cancer cells are found to be dependent on the myosin II activity, and modulating the activity can revert cancerous behaviors to normal ones. These novel findings on the interactions of acute angle walls and cancer cell migration provide a new perspective on cancer metastasis and additional strategies via microstructure geometries for the manipulations of cell behaviors in microscale biodevices.

Statement of Significance

Cancer metastasis is the leading cause of cancer patient deaths, and yet how the microstructures within the body affect this cell migration phenomenon is not well understood. In this paper, microdevices containing microgroove structures of varying geometries, in particular obtuse and acute angles, were utilized to monitor cell motilities of various cancer cells to understand the influences of the geometrical features of microstructures on cancer metastasis. Surprisingly, it was found that the acute angle geometries lowered the persistence of migration for cancer cells, which was a totally different response from non-cancerous cells. These new findings would enable the next-generation biodevices to analyze, separate and capture cancer cells, as well as shed light onto the underlying mechanisms of cancer metastasis.
Crosstalk between eIF2α and eEF2 phosphorylation pathways optimizes translational arrest in response to oxidative stress
Authors: Sanchez Marisa , Lin Yingying , Yang Chih-Cheng , McQuary Philip , Campos Alexandre Rosa , Blanc Pedro Aza , Wolf Dieter A.
Published: July 2019

The cellular stress response triggers a cascade of events leading to transcriptional reprogramming and a transient inhibition of global protein synthesis, which is thought to be mediated by phosphorylation of eukaryotic initiation factor-2α (eIF2α). Using mouse embryonic fibroblasts (MEFs) and the fission yeast S. pombe, we report here that rapid translational arrest and cell survival in response to hydrogen peroxide-induced oxidative stress do not rely on eIF2α kinases and eIF2α phosphorylation. Rather H2O2 induces a block in elongation through phosphorylation of eukaryotic elongation factor 2 (eEF2). Kinetic and dose-response analyses uncovered crosstalk between the eIF2α and eEF2 phosphorylation pathways, indicating that, in MEFs, eEF2 phosphorylation initiates the acute shutdown in translation, which is then maintained by eIF2α phosphorylation. Our results challenge the common conception that eIF2α phosphorylation is the primary trigger of translational arrest in response to oxidative stress and point to integrated control that may facilitate the survival of cancer cells.

HIGHLIGHTS

Oxidative stress-induced translation arrest is independent of eIF2α phosphorylation

Oxidative stress blocks translation elongation

Oxidative stress triggers eEF2 kinase activation

eEF2K KO cells are hypersensitive to oxidative stress
Acquisition design for direct reflectivity and velocity estimation from blended and irregularly sampled data
Authors: Nakayama Shotaro , Blacquière Gerrit , Ishiyama Tomohide
Published: July 2019

Blended acquisition along with efficient spatial sampling is capable of providing high‐quality seismic data in a cost‐effective and productive manner. While deblending and data reconstruction conventionally accompany this way of data acquisition, the recorded data can be processed directly to estimate subsurface properties. We establish a workflow to design survey parameters that account for the source blending as well as the spatial sampling of sources and detectors. The proposed method involves an iterative scheme to derive the survey design leading to optimum reflectivity and velocity estimation via joint migration inversion. In the workflow, we extend the standard implementation of joint migration inversion to cope with the data acquired in a blended fashion along with irregular detector and source geometries. This makes a direct estimation of reflectivity and velocity models feasible without the need of deblending or data reconstruction. During the iterations, the errors in reflectivity and velocity estimates are used to update the survey parameters by integrating a genetic algorithm and a convolutional neural network. Bio‐inspired operators enable the simultaneous update of the blending and sampling operators. To relate the choice of survey parameters to the performance of joint migration inversion, we utilize a convolutional neural network. The applied network architecture discards suboptimal solutions among newly generated ones. Conversely, it carries optimal ones to the subsequent step, which improves the efficiency of the proposed approach. The resultant acquisition scenario yields a notable enhancement in both reflectivity and velocity estimation attributable to the choice of survey parameters.
Biophysical and biological characterization of PEGylated recombinant human endostatin
Authors: Guo Lifang , Xu Benshan , Zhou Daifu , Chang Guodong , Fu Yan , Liu Lihong , Luo Yongzhang
Published: July 2019

Recombinant human endostatin (MES), showing potent inhibition on angiogenesis and tumour growth, has great potential as a therapeutic agent for tumours. The aim of this study was to evaluate the biophysical and biological characterization of PEGylated recombinant human endostatin (M2ES). Recombinant human endostatin was mono‐PEGylated by conjugation with methoxy polyethylene glycol aldehyde (mPEG‐ALD), and the modification site was identified by digested peptide mapping and matrix assisted laser desorption/ionization–time of flight–mass spectrometry (MALDI–TOF–MS). The purity was assessed by SDS‐PAGE, high‐performance liquid chromatography (HPLC), and capillary zone electrophoresis. The physicochemical property was analyzed through fluorescence spectroscopy, and circular dichroism. The bioactivity and anti‐tumour efficacy of M2ES were evaluated using an in vitro endothelial cell migration model and a null‐mouse xenograft model of a prostatic cancer, respectively. M2ES molecules contain a single 20 kDa mPEG‐ALD molecule conjugated at the N‐terminal portion of MES. The purity of M2ES was greater than 98%. The physicochemical analysis demonstrated that PEGylation does not change the secondary and tertiary structure of MES. Notably, M2ES retards endothelial cell migration and tumour growth when compared to control group. These biophysical and biological characterization study data contribute to the initiation of the ongoing clinical study.
Validation of a universal set of primers to study animal‐associated microeukaryotic communities
Authors: del Campo Javier , Pons Maria J. , Herranz Maria , Wakeman Kevin C. , del Valle Juana , Vermeij Mark J. A. , Leander Brian S. , Keeling Patrick J.
Published: July 2019

The application of metabarcoding to study animal‐associated microeukaryotes has been restricted because the universal barcode used to study microeukaryotic ecology and distribution in the environment, the Small Subunit of the Ribosomal RNA gene (18S rRNA), is also present in the host. As a result, when host‐associated microbial eukaryotes are analysed by metabarcoding, the reads tend to be dominated by host sequences. We have done an in silico validation against the SILVA 18S rRNA database of a non‐metazoan primer set (primers that are biased against the metazoan 18S rRNA) that recovers only 2.6% of all the metazoan sequences, while recovering most of the other eukaryotes (80.4%). Among metazoans, the non‐metazoan primers are predicted to amplify 74% of Porifera sequences, 4% of Ctenophora, and 15% of Cnidaria, while amplifying almost no sequences within Bilateria. In vivo, these non‐metazoan primers reduce significantly the animal signal from coral and human samples, and when compared against universal primers provide at worst a 2‐fold decrease in the number of metazoan reads and at best a 2800‐fold decrease. This easy, inexpensive, and near‐universal method for the study of animal‐associated microeukaryotes diversity will contribute to a better understanding of the microbiome.
High incidence and morbidity of Clostridium difficile infection among hospitalized patients with inflammatory bowel disease: A prospective observational cohort study
Authors: Chen Xiao Li , Deng Jing , Chen Xin , Wan Shan Shan , Wang Yu , Cao Qian
Published: July 2019

Objective

To investigate the clinical features of Clostridium difficile infection (CDI) in hospitalized patients with inflammatory bowel disease (IBD) and to analyze the impact of CDI on IBD.

Methods

A prospective study on patients newly diagnosed with IBD was conducted at the IBD center at Sir Run Run Shaw Hospital from March 2015 to May 2016. Stool samples for anaerobic culture and polymerase chain reaction were used to test CDI and to detect the different toxins in the groups. The patients were followed up for 2 years.

Results

Altogether 230 patients with IBD were enrolled, including 77 with ulcerative colitis (UC) and 153 with Crohn's disease (CD). The incidence rate of CDI was 13.9% (32/230). Patients with UC were more susceptible to CDI than those with CD (24.7% vs 8.5%, P < 0.01). Among UC patients, a long disease course, prior hospitalization, proton pump inhibitor use, and disease severity were associated with an increased risk of CDI (all P < 0.05). CDI prolonged hospital stay and increased the rate of long‐term surgery rate in UC (both P < 0.05). Among patients with CD, CDI increased both short‐ and long‐term surgery rates during the 2‐year follow‐up (P < 0.05) and increased repeated hospitalization in the follow‐up study (odds ratio 2.41, P = 0.02).

Conclusions

A high incidence rate of CDI in patients hospitalized with IBD was related with longer hospital stay and higher surgery rates in our center. Patients with UC are more vulnerable to CDI than those with CD.
Does Other Comprehensive Income Volatility Influence Credit Risk and the Cost of Debt?
Authors: Bao May Xiaoyan , Billett Matthew T. , Smith David B. , Unlu Emre
Published: July 2019

We examine the usefulness of other comprehensive income (OCI) to debt investors in nonfinancial companies. Motivated by Merton's (1974) real options framework, we construct a measure of incremental OCI volatility, designed to capture the effect of OCI on overall firm asset volatility, which is a primary driver of credit risk in Merton's (1974) model. We find that the volatility of incremental OCI influences the likelihood of default, credit ratings, and the cost of debt. Overall, our evidence suggests that creditors use information from OCI in their assessment of firm credit risk and in pricing debt contracts.
Circumstances of death of opioid users being treated with naltrexone
Authors: Darke Shane , Farrell Michael , Duflou Johan , Larance Briony , Lappin Julia
Published: July 2019

Background and aims

Naltrexone is an opioid antagonist used as a maintenance drug for the treatment of opioid dependence and in opioid withdrawal regimens. The current study aimed to: (1) determine the clinical characteristics and circumstances of death of people undergoing naltrexone treatment for opioid dependence; and (2) determine the blood toxicology of cases including naltrexone concentrations, the presence of other drugs and a comparison of morphine concentrations in the presence and absence of naltrexone.

Design

Retrospective study of all deaths among people undergoing naltrexone treatment for opioid dependence retrieved from the National Coronial Information System, 2000–17.

Setting

Australia‐wide.

Cases

Seventy‐four cases, with a mean age of 32.5 years; 81.1% male.

Measurements

Information was collected on demographics, manner of death, naltrexone treatment history, toxicology and major organ pathology.

Findings

Death was attributed to opioid toxicity in 86.5% of cases: accidental (79.7%), deliberate (6.8%). In 55.4% of all cases the decedent was maintained on oral naltrexone and 32.4% had a recent naltrexone implant. In five cases the decedent was undergoing opioid detoxification. Among those screened for naltrexone, naltrexone was present in the blood or urine of 52.5% (15.8% of oral maintenance cases, 85.7% of implant cases). Fourteen cases were known to have died from opioid toxicity with naltrexone present in their blood or urine. The median blood naltrexone concentrations were within the reported therapeutic range.

Conclusions

The primary cause of death among people undergoing naltrexone treatment for opioid dependence in Australia from 2000 to 2017 was opioid toxicity, the majority of cases having been maintained on oral naltrexone. Cases in which naltrexone was not detected indicate the importance of treatment compliance. Deaths due to opioid toxicity where naltrexone was present indicates the possibility of overdose while naltrexone medication is maintained.
Adipocyte‐derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus
Authors: Gao Jie , Li Xinyu , Wang You , Cao Yan , Yao Dengju , Sun Lijie , Qin Lv , Qiu Hui , Zhan Xiaorong
Published: July 2019

Aim

Type 2 diabetes and obesity are diseases related to surplus energy in the body. Abnormal interaction between the hypothalamus and adipose tissues is a key trigger of energy metabolism dysfunction. Extracellular vesicles (EVs) regulate intercellular communication by transporting intracellular cargo to recipient cells thereby altering the function of recipient cells. This study aimed to evaluate whether adipocyte‐derived EVs can act on hypothalamic neurons to modulate energy intake and to identify the EV‐associated non‐coding RNAs.

Methods

Confocal imaging was used to trace the uptake of labelled adipocyte‐derived exosomes by hypothalamic anorexigenic POMC neurons. The effects of adipocyte‐derived EVs on the mammalian target of rapamycin (mTOR) signalling pathway in POMC neurons were evaluated based on mRNA and protein expression in vitro using quantitative real‐time PCR and western blotting. In addition, adipocyte‐derived EVs were injected into recipient mice, and changes in mice body weight and daily food intake were monitored. The biological effects of the EV‐associated MALAT1 on POMC neurons were explored.

Results

Adipocyte‐derived EVs were successfully transferred into POMC neurons in vitro. Results showed that adipocytes of obese mice secreted MALAT1‐containing EVs, which increased appetite and weight when administered to lean mice. Conversely, adipocyte‐derived EVs from lean mice decreased food intake and weight when administered to obese mice.

Conclusion

Adipocyte‐derived EVs play important roles in mediating the interaction between adipocytes and hypothalamic neurons. Adipocyte‐derived EVs can regulate POMC expression through the hypothalamic mTOR signalling in vivo and in vitro, thereby affecting body energy intake.
Neuronal loss without amyloid‐β deposits in the thalamus and hippocampus in the late period after middle cerebral artery occlusion in cynomolgus monkeys
Authors: Ouyang Fubing , Chen Xinran , Chen Yonghong , Liang Jiahui , Chen Yicong , Lu Tao , Huang Weixian , Zeng Jinsheng
Published: July 2019

Conflicting evidence exists regarding whether focal cerebral infarction contributes to cerebral amyloid‐β (Aβ) deposition, as observed in Alzheimer's disease. In this study, we aimed to evaluate the presence of Aβ deposits in the ipsilateral thalamus and hippocampus 12 months post‐stroke in non‐human primates, whose brains are structurally and functionally similar to that of humans. Four young male cynomolgus monkeys were subjected to unilateral permanent middle cerebral artery occlusion (MCAO), and another four sham‐operated monkeys served as controls. All monkeys underwent magnetic resonance imaging examination on post‐operative day 7 to assess the location and size of the infarction. The numbers of neurons, astrocytes, microglia and the Aβ load in the non‐affected thalamus and hippocampus ipsilaterally remote from infarct foci were examined immunohistochemically at sacrifice 12 months after operation. Thioflavin S and Congo Red stainings were used to identify amyloid deposits. Multiple Aβ antibodies recognizing both the N‐terminal and C‐terminal epitopes of Aβ peptides were used to avoid antibody cross‐reactivity. Aβ levels in cerebrospinal fluid (CSF) and plasma were examined using enzyme‐linked immunosorbent assay. The initial infarct was restricted to the left temporal, parietal, insular cortex and the subcortical white matter, while the thalamus and hippocampus remained intact. Of note, there were fewer neurons and more glia in the ipsilateral thalamus and hippocampus in the MCAO group at 12 months post‐stroke compared to the control group (all P < 0.05). However, there was no sign of extracellular Aβ plaques in the thalamus or hippocampus. No statistically significant difference was found in CSF or plasma levels of Aβ40, Aβ42 or the Aβ40/Aβ42 ratio between the two groups (P > 0.05). These results suggest that significant secondary neuronal loss and reactive gliosis occur in the non‐affected thalamus and hippocampus without Aβ deposits in the late period after MCAO in non‐human primates.
Effects of metformin and phenformin on apoptosis and epithelial‐mesenchymal transition in chemoresistant rectal cancer
Authors: Park Ji‐Hye , Kim Young‐heon , Park Eun Hyeh , Lee Sun‐Joo , Kim Hyewon , Kim Areumnuri , Lee Seung Bum , Shim Sehwan , Jang Hyosun , Myung Jae Kyung , Park Sunhoo , Lee Su‐Jae , Kim Min Jung
Published: July 2019

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling.
Uridine‐cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer
Authors: Wu Yingjie , Jamal Muhammad , Xie Tian , Sun Jiaxing , Song Tianbao , Yin Qian , Li Jingyuan , Pan Shan , Zeng Xingruo , Xie Songping , Zhang Qiuping
Published: July 2019

Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine‐cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor‐associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.
Childhood adiposity and adolescent sex steroids in the Exploring Perinatal Outcomes among Children study
Authors: Kim Catherine , Harrall Kylie K. , Glueck Deborah H. , Shumer Daniel , Dabelea Dana
Published: July 2019

Objective

It is unclear how childhood adipose tissue deposition influences sex hormone profiles in later adolescence.

Design

Prospective cohort study.

Participants

Children (n = 418) with a mean age of 10.5 (1.5) years at visit 1 and 16.7 (1.2) at visit 2 in the Exploring Perinatal Outcomes among Children (EPOCH) Study.

Measurements

We used reverse‐scale Cox proportional hazard models to assess associations between pubertal dehydroepiandrosterone (DHEA), testosterone (T), and oestradiol (E2) and childhood‐to‐puberty rate of change in visceral (VAT) and subcutaneous adipose tissue (SAT). Models stratified by sex and adjusted for childhood adiposity, maternal factors, birthweight and pubertal onset, and then further adjusted for insulin, luteinizing hormone (LH), leptin and hepatic fat fraction.

Results

Among boys, more rapid accumulation of either VAT or SAT was associated with lower testosterone at visit 2 (HR 0.86, and .96, respectively, both P < .0001), independently of race/ethnicity, LH, leptin and hepatic fat fraction. Among boys, more childhood VAT was associated with lower testosterone in adolescence (HR 0.98, P = .003), but this association did not persist after adjustment for leptin or insulin. No associations were observed between either fat measure and oestradiol or DHEA in boys. In girls, no associations between childhood fat or fat accumulation and sex hormones were observed.

Conclusions

More rapid accumulation of fat is associated with lower testosterone in boys. These associations suggest that fat growth influences androgen profiles in adolescent boys. Since fat accumulation is a modifiable risk factor, the study results provide a possible intervention target and time period for improving adult health.
Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition
Authors: Gambale Antonella , Russo Roberta , Andolfo Immacolata , Quaglietta Lucia , De Rosa Gianluca , Contestabile Valentina , De Martino Lucia , Genesio Rita , Pignataro Piero , Giglio Sabrina , Capasso Mario , Parasole Rosanna , Pasini Barbara , Iolascon Achille
Published: July 2019

Cancer predisposition syndromes (CPS) result from germline pathogenic variants, and they are increasingly recognized in the etiology of many pediatric cancers. Herein, we report the genetic/genomic analysis of 40 pediatric patients enrolled from 2016 to 2018. Our diagnostic workflow was successful in 50% of screened cases. Overall, the proportion of CPS in our case series is 10.9% (20/184) of enrolled patients. Interestingly, 12.5% of patients achieved a conclusive diagnosis through the analysis of chromosomal imbalance. Indeed, we observed germline microdeletions/duplications of regions encompassing cancer‐related genes in 50% of patients undergoing array‐CGH: EIF3H duplication in a patient with infantile desmoplastic astrocytoma and low‐grade Glioma; SLFN11 deletion, SOX4 duplication, and PARK2 partial deletion in three neuroblastoma patients; a PTPRD partial deletion in a child diagnosed with glioblastoma multiforme. Finally, we identified two cases due to DICER1 germline mutations.
Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype
Authors: Sha Yanwei , Liu Wensheng , Wei Xiaoli , Zhu Xingshen , Luo Xiangmin , Liang Lei , Guo Tonghang
Published: July 2019

Male patients with multiple morphological abnormalities of the sperm flagella (MMAF) are infertile and exhibit absent, short, coiled, bent and/or irregular sperm flagella. Mutations in the SPEF2 gene reduce sperm motility and cause sperm tail defects in animal models and humans. In the present study, we performed a genetic analysis on an MMAF patient and identified novel biallelic mutations in the SPEF2 gene. The biallelic mutations were confirmed by Sanger sequencing and in silico analysis revealed that, these variations were deleterious. The expression of truncated SPEF2 protein was reduced significantly in the patient's spermatozoa. The spermatozoa harbored biallelic mutations and showed severe ultrastructural defects in the axoneme and mitochondrial sheath. Our data suggest that biallelic mutations in SPEF2 can cause severe sperm flagellum defects, thus providing a novel candidate genetic pathogen for the human MMAF phenotype.
Immediate versus early loading protocols of titanium—zirconium narrow‐diameter implants for mandibular overdentures in edentulous patients: 1‐year results from a randomized controlled trial
Authors: Reis Rita , Nicolau Pedro , Calha Nuno , Messias Ana , Guerra Fernando
Published: July 2019

Objectives

The purpose of this randomized clinical trial was to compare immediate and early loading protocols for mandibular overdentures with two‐splinted narrow‐diameter implants in thin, non‐augmented residual ridge situations.

Material and methods

Each edentulous patient received two implants in the interforaminal region. If primary stability after implant placement was achieved, patients were randomized either to the immediate (48 hr post‐surgery) or the early (2 weeks after surgery) loading group. In prosthetic rehabilitation, a bar prosthetic system with a titanium bar was used. Implant survival, success rates, and radiographic changes at the crestal bone level were evaluated after 1 year, and patient satisfaction was recorded at 1 and 6 months post‐surgery.

Results

Twenty‐four patients with a mean age of 67 ± 9 years were included. One patient passed away after 11 months due to treatment‐independent reasons. In the 24 implants of the immediate loading group, the mean bone level change from surgery/loading to the first‐year evaluation was 0.32 ± 0.80 mm (p = .066). Regarding the early group (22 implants), the mean bone level change from loading to 1 year was 0.34 ± 0.69 mm (p = .048). After 1 year, no differences could be detected between groups (p = .91) with a mean difference of 0.02 mm (95% CI: [−0.42, 0.47]). The mean implant survival and success rates were 100% for both groups.

Patient satisfaction was high; however, at 6 months, there was a difference between groups regarding the ability to chew.

Conclusions

Both loading protocols for mandibular overdentures supported by two‐splinted narrow‐diameter implants were successful at the 1‐year follow‐up.