bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertebrates are poor umbrellas for invertebrates: cross‐taxon congruence in an Australian tropical savanna
Authors: Oberprieler Stefanie K. , Andersen Alan N. , Gillespie Graeme R. , Einoder Luke D.
Published: June 2019

Invertebrates are commonly ignored in conservation planning due to their vast diversity, difficulties with species identification, a poor understanding of their spatial patterns, and the impracticability of carrying out comprehensive sampling. Conservation planning for fauna is therefore often based on patterns of diversity and distribution of vertebrates, under the assumption that these are representative of animal diversity more generally. Here, we evaluate how well vertebrates act as umbrellas for invertebrate diversity and distribution in a highly diverse tropical savanna landscape, and we investigate the effect of vertebrate sampling intensity (i.e., number of surveys) on congruence results. We assessed congruence between each of the four classes of terrestrial vertebrates (amphibians, reptiles, birds, and mammals) and twelve invertebrate families (representing four dominant invertebrate taxa: ants, beetles, flies, and spiders) by applying a range of modeling approaches to analyze patterns of cross‐taxon congruence in species richness and composition across sampling sites. To investigate drivers of congruence, we applied generalized and distance‐based linear models to identify environmental associations of richness and composition for each taxon, then examined variation in environmental associations across taxa. Vertebrate and invertebrate richness was weakly (<30%) associated, and ~60% of the significant associations were negative. Correlations in species composition between vertebrate and invertebrate taxa were also weak, with a maximum of 13% congruence. In most cases, pairwise correlation scores using data from single surveys of vertebrates were only marginally lower than those from multiple surveys. Poor among‐site congruence between vertebrates and invertebrates was reflected by marked variation among taxa in their environmental associations. Our findings show that vertebrates are poor umbrellas for invertebrates in the tropical savannas of northern Australia in terms of geographic patterns of diversity and distribution and that this is not just an artifact of low vertebrate sampling intensity. Our study is one of the most comprehensive regional analyses of the congruence of vertebrate and invertebrate diversity, and it significantly adds to the growing evidence that empirical data on invertebrate diversity and distribution are required for conservation planning that effectively protects all faunal diversity.
Cortical morphometry in anorexia nervosa: An out‐of‐sample replication study
Authors: Leppanen Jenni , Sedgewick Felicity , Cardi Valentina , Treasure Janet , Tchanturia Kate
Published: June 2019

Background

Acute anorexia nervosa (AN) is frequently accompanied by reduced global cortical volume. Investigations of local cortical alterations in AN have revealed widespread reduction in cortical thickness, gyrification, and curvature. The aim of the present study was to combine data from two previous studies to replicate previous findings.

Methodology

Magnetic resonance imaging (MRI) images from 46 adult women with AN and 54 age‐matched healthy comparison (HC) women were analysed using FreeSurfer. Group differences in cortical volume and local cortical measures, including gyrification, curvature, thickness, and area, were examined controlling for dataset and age.

Results

The AN group had reduced global cortical volume relative to the HC group. The AN group also had reduction in local cortical gyrification, small localised clusters of reduced cortical thickness, in the occipital and parietal cortices, and surface area in the frontal and temporal cortices. The AN group also had increased cortical thickness in the ACC relative to the HC participants.

Conclusions

The present findings replicate and validate previous findings of reduced global cortical volume and local gyrification in acute AN. The findings highlight the need for further investigation of local cortical folding, thickness, and surface area in AN to gain further insight into the biological underpinnings of AN.
Der Untertagebau im Baulos Prutz/Ried des Gemeinschaftskraftwerks Inn (GKI)
Authors: Wachter Robert , Bonapace Paul , Bilak Andreas
Published: June 2019

Even in the 1920s were already the plans for hydropower exploitation of the upper River Inn. Since the resumption of design work, the Gemeinschaftskraftwerk Inn (GKI) project has been optimised and adapted to the latest state of the technology as well as ecological requirements. After a collaborative process involving the authorities from both countries, the start of construction could be approved in 2014. The project will build a diversion hydropower station with an annual generation of about 414 GWh in the border area of Switzerland and Austria.
Untere Tuxbachüberleitung – Ein Überleitungsstollen als Hochdruckstollen: Vortrieb und Auskleidungskonzept für Innendrücke über 20 bar
Authors: Blauhut Andreas , Steyrer Peter , Eichiner Hans , Fiegl Marco , Gasser Oliver , Riediger Christian
Published: June 2019

The ”Lower Tuxbach diversion“ project includes an 8.5 km headrace tunnel to the Stillupp reservoir. Nearly in the middle, the tunnel has to pass under the Zemm valley, which is more than 200 m deeper than the weir and the reservoir. With the shallow gradient of the TBM excavation, long sections of the tunnel will then have a high internal pressure during operation (pressure > 20 bar). The TBM excavation was carried out mainly in the Ahorn gneiss of the ”Tauernfenster“, which strikes perpendicular to the tunnel axis. The stability of the rock mass was regular, but in the tunnel section to the weir, many joints and smaller fault zones with non‐water‐resistant infilling were encountered. Considering the high internal pressure, it was decided to retain most of the originally foreseen concrete lining. In the tunnel section to the reservoir, the decision about a possible optimisation of the lining design will be made after the completion of excavation.
Geologische Grundlagen, geotechnische Planung und Auskleidung des neuen Kraftabstiegs Rodundwerk I
Authors: Gerstner Reinhold , Dich Christopher , Tschuchnigg Franz , Bickel Lukas
Published: June 2019

In Memoriam Reinhold Gerstner

The Vorarlberger Illwerke AG is currently working on redesigning the headrace system to the existing Rodundwerk I. The old power water way consists of an upper pressure tunnel, a penstock, a lower pressure tunnel along with the distribution pipeline to the four turbines and a pump. The same headwater sections are being constructed with an optimized route in the immediate vicinity of the existing structure. For the optimized layout of the new headrace, system options were isolated by means of 2D analyses. The variant for construction was investigated by means of a 3D analysis and the obtained results are the basis of the definition of the lining areas and thus the dimensioning of the individual types of lining. The present contribution deals with the geological boundary conditions, the findings from the old headrace, the assumptions and the resulting layout of the redesign. Finally, the basics of the lining concept and the design results are presented.
Potentially inappropriate prescribing in people with dementia: An Australian population‐based study
Authors: Eshetie Tesfahun C. , Nguyen Tuan A. , Gillam Marianne H. , Kalisch Ellett Lisa M.
Published: June 2019

Objective

To investigate the prevalence of potentially inappropriate prescribing (PIP) using the Screening Tool of Older Person's Prescriptions (STOPP) criteria in people with dementia compared with people without dementia.

Methods

A retrospective cohort study was conducted using the Pharmaceutical Benefits Scheme 10% sample of pharmacy claims. People with dementia were defined as those dispensed a medicine for dementia (cholinesterase inhibitors, memantine, or risperidone for behavioural and psychological symptoms of dementia) between 1 January 2005 and 31 December 2015, aged 65 years or older at 1 January 2016 and alive at the end of 2016. An age‐ and gender‐matched comparison cohort of people not dispensed medicines for dementia was identified. PIP prevalence was determined between 1 January 2016 and 31 December 2016.

Results

In total, 8280 people dispensed medicines for dementia and 41 400 comparisons not dispensed medicines for dementia were included: 63% were female and the median age was 82 years. PIP prevalence was 79% among people with dementia compared with 70% among the comparison group (P < .0001). Use of anticholinergics, long‐term use of high‐dose proton pump inhibitors, and use of benzodiazepines were the most common instances of PIP in people with dementia. After adjustments for age, gender, comorbidity, and number of prescribers, people with dementia were more likely to be exposed to PIP than comparisons (adjusted OR 1.44, 95% CI, 1.35‐1.53, P < .0001).

Conclusions

PIP was more common in people dispensed medicines for dementia than comparisons. These results highlight the need for effective interventions to optimize prescribing in people with dementia.
Effects of exercise dose and type during breast cancer chemotherapy on longer‐term patient‐reported outcomes and health‐related fitness: A randomized controlled trial
Authors: An Ki‐Yong , Morielli Andria R. , Kang Dong‐Woo , Friedenreich Christine M. , McKenzie Donald C. , Gelmon Karen , Mackey John R. , Reid Robert D. , Courneya Kerry S.
Published: June 2019

The Combined Aerobic and Resistance Exercise (CARE) Trial compared different types and doses of exercise performed during breast cancer chemotherapy. Here, we report the longer‐term follow‐up of patient‐reported outcomes, health‐related fitness and exercise behavior at 6, 12 and 24 months postintervention. A multicenter trial in Canada randomized 301 breast cancer patients initiating chemotherapy to thrice weekly, supervised exercise consisting of a standard dose of 25–30 min of aerobic exercise (STAN; n = 96), a higher dose of 50–60 min of aerobic exercise (HIGH; n = 101) or a combined dose of 50–60 min of aerobic and resistance exercise (COMB; n = 104) performed for the duration of chemotherapy (median of 17 weeks). Primary outcomes were patient‐reported outcomes including quality of life, cancer‐related symptoms and psychosocial outcomes. Secondary outcomes were objective health‐related fitness (assessed at 12 months only) and self‐reported exercise behavior. A total of 269 (89.4%) participants completed patient‐reported outcomes at all three follow‐up time points and 263 (87.4%) completed the health‐related fitness assessment at 12‐month follow‐up. COMB was significantly superior to (i) STAN for sleep quality at 6‐month follow‐up (p = 0.027); (ii) HIGH for upper body muscular endurance at 12‐month follow‐up (p = 0.020); and (iii) HIGH for meeting the resistance exercise guideline at 6‐month follow‐up (p = 0.006). Moreover, self‐reported meeting of the combined exercise guideline during follow‐up was significantly associated with better patient‐reported outcomes and health‐related fitness. Performing combined exercise during and after breast cancer chemotherapy may result in better longer‐term patient‐reported outcomes and health‐related fitness compared to performing aerobic exercise alone.
Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis
Authors: Beshara Amani , Ahoroni Maya , Comanester Doron , Vilkin Alex , Boltin Doron , Dotan Iris , Niv Yaron , Cohen Arnon D. , Levi Zohar
Published: June 2019

We evaluated time to colonoscopy after a positive guaiac‐based fecal occult blood test (gFOBT) result and its association with the risk of overall colorectal cancer (CRC) and advanced‐stage disease at diagnosis. We conducted a retrospective cohort study (2011–2013) within the Clalit Health Services, Israel. Participants were patients between 50 and 74 years old with a positive gFOBT result who had follow‐up colonoscopies within 24 months. The exposure was time to colonoscopy, and the main outcome measure was a risk for overall and advanced CRC (defined as Stages III–IV). Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for patient demographics and baseline risk factors. Of the 17,958 patients with positive gFOBT results (median age, 61 years [interquartile range, 56–67 years]; women, 52.2%), there were 685 cases of CRC and 156 cases of an advanced‐stage disease diagnosed. The rate of cancer diagnosis at 0–3, 4–6, 7–9, 10–12 and 13–24 months was 3.9%, 2.5%, 3.5%, 4.2% and 7.3%, respectively (p < 0.001). Compared to colonoscopy follow‐up within 0–3 months, risks for any CRC and advanced stage disease were higher for a follow‐up of 12–24 months: OR, 1.97 (95% CI, 1.51–2.56) and 1.88 (95% CI, 1.43–2.46), respectively. For right‐sided cancer (n = 194), an increased risk starts at 10 months, OR, 1.91 (95% CI 1.03–3.56). A result of 3–6 positive fields was significantly associated diagnosis of cancer (OR, 5.52; 95% CI, 4.71–6.46) and advanced stage disease (OR, 8.07; 95% CI, 5.74–11.36). Encouraging an early uptake of colonoscopy and targeting those with 10–24 months delay and a 3–6 positive fields is warranted.
Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria
Authors: Wang Shengfeng , Pitt Jason J. , Zheng Yonglan , Yoshimatsu Toshio F. , Gao Guimin , Sanni Ayodele , Oluwasola Olayiwola , Ajani Mustapha , Fitzgerald Dominic , Odetunde Abayomi , Khramtsova Galina , Hurley Ian , Popoola Abiodun , Falusi Adeyinka , Ogundiran Temidayo , Obafunwa John , Ojengbede Oladosu , Ibrahim Nasiru , Barretina Jordi , White Kevin P. , Huo Dezheng , Olopade Olufunmilayo I.
Published: June 2019

Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole‐genome or whole‐exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60–85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21–0.45) of APOBEC signature contribution at genome‐wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10−6). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.
LncRNA TTN‐AS1 drives invasion and migration of lung adenocarcinoma cells via modulation of miR‐4677‐3p/ZEB1 axis
Authors: Zhong Yuanbo , Wang Jin , Lv Wen , Xu Jianzhong , Mei Shanshan , Shan Aijun
Published: June 2019

Lung adenocarcinoma is the most prevalent type of lung cancer with a high incidence and mortality worldwide. Metastasis is the major cause of high death rate in lung cancer and the potential mechanism of lung adenocarcinoma metastasis remains indistinct. Emerging investigations have demonstrated that long noncoding RNA is a kind of non–protein coding RNA and plays a critical role in cancer progression and metastasis. TTN antisense RNA 1 (TTN‐AS1) has been reported to promote cell growth and metastasis in cancer. However, the function of TTN‐AS1 in lung adenocarcinoma is still to be illustrated. In this study, we observed that TTN‐AS1 was upregulated in tissues and cells of lung adenocarcinoma and associated with poor overall survival. TTN‐AS1 promoted cell proliferation, migration, invasion, and epithelial‐mesenchymal transition in lung cancer. TTN‐AS1 directly bound with miR‐4677‐3p and negatively regulated miR‐4677‐3p. MiR‐4677‐3p rescued the inhibitive impacts of TTN‐AS1 knockdown on lung adenocarcinoma. Furthermore, zinc finger E‐box binding homeobox 1 (ZEB1) was the target of miR‐4677‐3p, and TTN‐AS1 modulated ZEB1 by competing for miR‐4677‐3p. TTN‐AS1 drove the invasion and migration of lung adenocarcinoma cells by targeting the miR‐4677‐3p/ZEB1 axis. To sum up, our study offers insights into the mechanism of TTN‐AS1 in lung adenocarcinoma metastasis and targeting the TTN‐AS1/miR‐4677‐3p/ZEB1 axis may be the potential innovate therapeutic strategy for the patients with lung adenocarcinoma.
Binding and uptake of single and dual‐opsonized targets by macrophages
Authors: Naik Urja , Nguyen Quynh Phuong Hai , Harrison Rene E.
Published: June 2019

Our current understanding of phagocytosis is largely derived from studies of individual receptor‐ligand interactions and their downstream signaling pathways. Because phagocytes are exposed to a variety of ligands on heterogeneous target particles in vivo, it is important to observe the engagement of multiple receptors simultaneously and the triggered involvement of downstream signaling pathways. Potential crosstalk between the two well‐characterized opsonic receptors, FcγR and CR3, was briefly explored in the early 1970s, where macrophages were challenged with dual‐opsonized targets. However, subsequent studies on receptor crosstalk were primarily restricted to using single opsonins on different targets, typically at saturating opsonin conditions. Beyond validating these initial explorations on receptor crosstalk, we identify the early signaling mechanisms that underlie the binding and phagocytosis during the simultaneous activation of both opsonic receptors, through the presence of a dual‐opsonized target (immunoglobulin G [IgG] and C3bi), compared with single receptor activation. For this purpose, we used signaling protein inhibitor studies as well as live cell brightfield and fluorescent imaging to fully understand the role of tyrosine kinases, F‐actin dynamics and internalization kinetics for FcγR and CR3. Importantly, opsonic receptors were studied together and in isolation, in the context of sparsely opsonized targets. We observed enhanced particle binding and a synergistic effect on particle internalization during the simultaneous activation of FcγR and CR3 engaged with sparsely opsonized targets. Inhibition of early signaling and cytoskeletal molecules revealed a differential involvement of Src kinase for FcγR‐ vs CR3‐ and dual receptor‐mediated phagocytosis. Src activity recruits Syk kinase and we observed intermediate levels of Syk phosphorylation in dual‐opsonized particles compared with those opsonized with IgG or C3bi alone. These results likely explain the intermediate levels of F‐actin that is recruited to sites of dual‐opsonized particle uptake and the notoriously delayed internalization of C3bi‐opsonized targets by macrophages.
Brain‐derived neurotrophic factor downregulation in gastric cancer
Authors: Esfandi Farbod , Bouraghi Hamid , Glassy Mark C , Taheri Mohammad , Kahaei Mir Salar , Kholghi Oskooei Vahid , Ghafouri‐Fard Soudeh
Published: June 2019

The brain‐derived neurotrophic factor (BDNF) is a certain type of growth factor that participates in the correct construction of the brain. Moreover, some reports have shown its participation in the tumorigenesis process. A long noncoding RNA known as BDNF‐antisense (BDNF‐AS) is shown to be transcribed from the antisense direction of the BDNF gene and control its expression. In the current study, we compared expression levels of BDNF and its antisense in gastric cancer tissues and adjacent noncancerous tissues (ANCTs) using quantitative real‐time polymerase chain reaction. Expression of both genes tended to decrease in gastric cancer tissues in comparison with ANCTs (expression ratio = 0.4 and P = .06 for BDNF; expression ratio = 0.35 and P = .05 for BDNF‐AS, respectively). Relative transcript levels of both genes were remarkably associated with the site of primary tumor in a way that all cardia tumors had low levels of both BDNF and BDNF‐AS in comparison with their paired ANCTs (P = .002 and P = <.001). We also found higher amounts of both genes in malignant samples obtained from older patients (P = .01 and P = .03 for BDNF and BDNF‐AS, respectively). Besides, BDNF expression was higher in tumors with lymphatic/vascular invasion (P = .01). There was also a trend toward upregulation of BDNF‐AS in tumors with lymphatic/vascular invasion (P = .05). The current study underscores the role of BDNF and BDNF‐AS in the pathogenic process leading to gastric cancer.
Cell‐penetrable nanobodies (transbodies) that inhibit the tyrosine kinase activity of EGFR leading to the impediment of human lung adenocarcinoma cell motility and survival
Authors: Tabtimmai Lueacha , Suphakun Praphasri , Srisook Pimonwan , Kiriwan Duangnapa , Phanthong Siratcha , Kiatwuthinon Pichamon , Chaicumpa Wanpen , Choowongkomon Kiattawee
Published: June 2019

Most patients suffering from non–small cell lung cancer (NSCLC) have epidermal growth factor receptor (EGFR) overexpression. Currently, EGFR tyrosine kinase inhibitors (TKIs) that act as the ATP‐analogs and monoclonal antibodies (MAbs) to EGFR‐ectodomain that block intracellular signaling are used for the treatment of advanced NSCLC. Unfortunately, adverse effects due to the TKI off‐target and drug resistance occur in a significant number of the treated patients while some NSCLC genotypes do not respond to the therapeutic MAbs. Thus, a more effective remedy for the treatment of EGFR‐overexpressed cancers is deemed necessary. In this study, VH/VHH displayed‐phage clones that are bound to recombinant EGFR‐TK were fished‐out from a humanized‐camel VH/VHH phage display library. VH/VHH of three phage‐infected Escherichia coli clones (VH18, VHH35, and VH36) were linked molecularly to nonaarginine (R9) for making them cell penetrable. R9‐VH18, R9‐VHH35, and R9‐VH36 were cytotoxic to human adenocarcinomic alveolar basal epithelial cells (A549) at the fifty percent inhibitory concentration (IC50) 0.181 ± 0.132, 0.00961 ± 0.00516, and 0.00996 ± 0.00752 μM, respectively, which were approximately 1000‐fold more effective than small molecular TKIs. R9‐VH18 and R9‐VH36 also delayed cancer cell migration in a scratch‐wound assay. Computerized homology modeling and intermolecular docking revealed that VH18 and VHH35 used CDR3 to interact with EGFR‐TK residues close to the catalytic site, which might sterically hinder the ATP‐binding of the TK; VH36 used CDR2 to bind at the asymmetric dimerization surface, which might disrupt EGFR dimerization leading to inhibition of intracellular signaling. The humanized‐cell penetrable nanobodies have a high potential for developing further towards a clinical application.
Stimulating DDX3 expression by serotonin 5‐HT receptor 7 through phosphorylation of p53 via the AC‐PKA‐ERK signaling pathway
Authors: Kang Li‐Jung , Nguyen Khoa V.A. , Eom Sanung , Choi Yeo‐Jin , Nguyen Cam Ngoc , Lee Jaeeun , Kim Chaelin , Lee Shinhui , Lee Seong‐Gene , Lee Jun‐Ho
Published: June 2019

DDX3 is a host viral factor that can inhibit the hepatitis B virus‐induced innate immune responses. In this study, the 20 bioactive compounds have screened the effects on DDX3 and we found that 5‐HT upregulated DDX3 promoter activity via the 5‐HT7 receptor on liver hepatocellular cells (HepG2 cells) by using a luciferase assay, reverse transcription‐polymerase chain reaction analysis, and Western blot analysis. Furthermore, we are trying to elucidate the pathways involved in the stimulating effect of 5‐HT on DDX3 expression to induce innate immune responses against hepatitis B virus infection. A knockdown of the 5‐HT7 receptor by transfection si‐5‐HT7 receptors or si‐control into HepG2 cells treated by 5‐HT (or 5‐HT plus agonist) confirmed the role of the 5‐HT7 receptor in DDX3 expression. The IFN‐β‐Luc expression and level of hepatitis B virus surface Antigen (HBsAg) showed that DDX3 mediated by the 5‐HT7 agonist (AS‐19) increased IFN‐β expression and inhibited HBV replication. Luciferase assays showed the involvement of 5‐HT7 receptors in DDX3 expression via cAMP/AC/PKA pathways by using protein kinase A (PKA) and adenylyl cyclase inhibitor (MDL 12330A). AS‐19 mediated DDX3 promoter activated PKA extracellular signal‐regulated kinase ERK signaling the p53 phosphorylation (‐1080/‐1070) resulted in upregulation of DDX3 promoter transactivation via the 5‐HT7 receptors agonist. Overall, 5‐HT7 was found to be a new potential target to inhibit hepatitis B infection by activating AC/PKA/ERK pathways by phosphorylating p53 via the 5‐HT7 agonist response by mediating DDX3 expression.
Vitamin D receptor gene polymorphism is associated with multiple myeloma
Authors: Rui Hongbing , Liu Ying , Lin Meiying , Zheng Xiaoqiang
Published: June 2019

Objectives

The aim of this study was to explore the Vitamin D receptor (VDR) gene polymorphism and its association with multiple myeloma (MM) development.

Methods

The peripheral blood of 40 MM cases and 84 healthy controls were collected. Polymerase chain reaction (PCR) and DNA sequencing were applied to detect VDR gene polymorphism (including: FokI, BsmI, ApaI, and TaqI). SHESIS biological information software was used to analyze genotypes, alleles, linkage disequilibrium (LD), haplotype distribution, and their association with MM.

Results

Compared with controls, the MM group had a significantly higher frequency of the A allele in BsmI site (8.7% vs 2.4%) and C allele in the TaqI site (10.5% vs 3.6%). These two alleles were closely associated with an increased risk of MM (P = .025; P = .030). The highly rare genotypes (BsmI‐AA and TaqI‐CC) were found in one patient with MM.

Conclusion

VDR gene polymorphisms may be a molecular marker of MM risk.
autoCAS: A Program for Fully Automated Multiconfigurational Calculations
Authors: Stein Christopher J. , Reiher Markus
Published: June 2019

We present our implementation autoCAS for fully automated multiconfigurational calculations, which we also make available free of charge on our webpages. The graphical user interface of autoCAS connects a general electronic structure program with a density‐matrix renormalization group program to carry out our recently introduced automated active space selection protocol for multiconfigurational calculations (Stein and Reiher, J. Chem. Theory Comput., 2016, 12, 1760). Next to this active space selection, autoCAS carries out several steps of multiconfigurational calculations so that only a minimal input is required to start them, comparable to that of a standard Kohn–Sham density‐functional theory calculation, so that black‐box multiconfigurational calculations become feasible. Furthermore, we introduce a new extension to the selection algorithm that facilitates automated selections for molecules with large valence orbital spaces consisting of several hundred orbitals. © 2019 Wiley Periodicals, Inc.
NEAT1 promotes colon cancer progression through sponging miR‐495‐3p and activating CDK6 in vitro and in vivo
Authors: He Zhiyun , Dang Jie , Song Ailin , Cui Xiang , Ma Zhijun , Zhang Zhongtao
Published: June 2019

Recently, increasing evidence has indicated lncRNAs are powerful regulators in the progression of multiple tumors. Dysregulation of lncRNA NEAT1 has been recognized in many cancer types. Meanwhile, the studies on NEAT1 function have suggested that NEAT1 can serve as a crucial oncogene. Nevertheless, the investigation of NEAT1 in colon cancer is still few. In our study, the function of NEAT1 was studied in colon cancer. As we observed, NEAT1 level was obviously elevated in colon cancer cells. Then, HCT‐116 and SW620 cells were stably infected with shRNA‐NEAT1 for 48 hr. As exhibited, silence of NEAT1 could greatly repress colon cancer cell progression. Apoptosis of colon cancer cells was triggered and the cell cycle progression was remarkably inhibited by downregulation of NEAT1. Interestingly, as exhibited, miR‐495‐3p was obviously decreased in colon cancer cells and it significantly suppressed colon cancer progression. Subsequently, miR‐495‐3p was predicted as a target of NEAT1. CDK6 was speculated as the target of miR‐495‐3p and miR‐495‐3p modulated its expression negatively. Finally, it was indicated that NEAT1 promoted colon cancer development through modulating miR‐495‐3p and CDK6 in vivo. Taken these together, we reported that NEAT1 could sponge miR‐495‐3p to contribute to colon cancer progression through activating CDK6.
Zinc ions increase GH signaling ability through regulation of available plasma membrane‐localized GHR
Authors: Li Ruonan , Hui Junnan , Luo Gan , Hong Pan , Li Lingqian , Yang Yu , Zheng Xin , Lan Hainan
Published: June 2019

It is well known that zinc ion (Zn2+) can regulate the biological activity of growth hormone (GH). However, until now, the mechanism by which Zn2+ regulates GH biological activity remains unclear. In the current study, we first performed molecular docking between Zn2+ and porcine GH (pGH) using computational biology. We then explored the effect of Zn2+ on the GH signaling ability in the cell model expressing porcine growth hormone receptor (GHR). It was found that the phosphorylation levels of Janus kinase 2, signal transducers and activators of transcription 5/3/1, and GHR increased significantly under Zn2+ treatment, indicating that Zn2+ can enhance the signaling ability of GH/GHR. On this basis, we further explored how Zn2+ regulates the biological activity of GH/GHR. The results showed that downregulation and turnover of GHR changed under Zn2+/pGH treatment. Zn2+ enhanced the membrane residence time of pGH/GHR and delayed GHR downregulation. Further investigation showed that the internalization dynamic of pGH/GHR was changed by Zn2+, which prolonged the residence time of pGH/GHR in the cell membrane. These factors acted together to upregulate the signaling of GH/GHR. This study lays a foundation for further exploration of the biological effects of Zn2+ on GH.

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Retracted: Long noncoding RNA BCAR4 promotes glioma cell proliferation via EGFR/PI3K/AKT signaling pathway
Authors: Wei Lian , Yi Zhao , Guo Kongyan , Long Xu
Published: June 2019

Long noncoding RNA Breast Cancer Antiestrogen Resistance 4 (BCAR4) has been identified to be oncogenic in several cancers. In our study, we demonstrated that BCAR4 expression was significantly upregulated in glioma tissues compared with paired nontumor tissues. In addition, higher BCAR4 level was associated with poor overall survival in patients with glioma. Besides, we also discovered that knockdown of BCAR4 inhibited cell proliferation, whereas BCAR4 overexpression promoted this process. Intriguingly, we proved a cellular transformation of normal human astrocyte cells (NHAs) in response to enforced expression of BCAR4. In addition, we revealed that BCAR4 affected cell proliferation in glioma cells by promoting cell cycle progression and inhibiting cell apoptosis. Mechanistically, we uncovered that BCAR4 activated PI3K/AKT signaling pathway in glioma through upregulating EGFR and interacting with it. Moreover, activating PI3K/AKT pathway could reverse the repressive effects caused by BCAR4 silence on the biological behaviors of glioma cells, whereas inhibition of this pathway rescued the impact of BACR4 upregulation in NHAs. These findings disclosed that BCAR4 contributes to glioma progression by enhancing cell growth via activating EGFR/PI3K/AKT pathway, providing potent evidence that BCAR4 could be an effective new target for treatment and prognosis of glioma patients.
Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
Authors: Ogasawara Ken , MacGorman Kimberly , Liu Liangang , Chen Jian , Carayannopoulos Leonidas N. , Zhou Simon , Palmisano Maria , Li Yan
Published: June 2019

Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.
Soluble adenylyl cyclase‐mediated cAMP signaling and the putative role of PKA and EPAC in cerebral mitochondrial function
Authors: Jakobsen Emil , Lange Sofie C. , Bak Lasse K.
Published: June 2019

Mitochondria produce the bulk of the ATP in most cells, including brain cells. Regulating this complex machinery to match the energetic needs of the cell is a complicated process that we have yet to understand in its entirety. In this context, 3′,5′‐cyclic AMP (cAMP) has been suggested to play a seminal role in signaling‐metabolism coupling and regulation of mitochondrial ATP production. In cells, cAMP signals may affect mitochondria from the cytosolic side but more recently, a cAMP signal produced within the matrix of mitochondria by soluble adenylyl cyclase (sAC) has been suggested to regulate respiration and thus ATP production. However, little is known about these processes in brain mitochondria, and the effectors of the cAMP signal generated within the matrix are not completely clear since both protein kinase A (PKA) and exchange protein activated by cAMP 1 (EPAC1) have been suggested to be involved. Here, we review the current knowledge and relate it to brain mitochondria. Further, based on measurements of respiration, membrane potential, and ATP production in isolated mouse brain cortical mitochondria we show that inhibitors of sAC, PKA, or EPAC affect mitochondrial function in distinct ways. In conclusion, we suggest that brain mitochondria do regulate their function via sAC‐mediated cAMP signals and that both PKA and EPAC could be involved downstream of sAC. Finally, due to the role of faulty mitochondrial function in a range of neurological diseases, we expect that the function of sAC‐cAMP‐PKA/EPAC signaling in brain mitochondria will likely attract further attention.
Association of PROtein and CAloric Intake and Clinical Outcomes in Adult SEPTic and Non‐Septic ICU Patients on Prolonged Mechanical Ventilation: The PROCASEPT Retrospective Study
Authors: de Koning Marie‐Sophie Louise Yvonne , Koekkoek Wilhelmina Aria Christina (Kristine) , Kars Johannes Cornelis Nicolaas (Hans) , van Zanten Arthur Raymond Hubert
Published: June 2019

Background

The optimal nutritional support for critically ill septic patients remains unknown. This study evaluates the associations of macronutrient intake during the first week of intensive care unit (ICU) admission and long‐term clinical outcomes in septic and non‐septic patients.

Methods

Prolonged mechanically ventilated patients were retrospectively studied. The association of protein (low: <0.8 g/kg/d, medium: 0.8–1.2 g/kg/d, high >1.2 g/kg/d) and energy intake (<80%, 80%–110%, 110% of target) during days 1–3 and 4–7 after ICU admission and 6‐month mortality was analyzed for septic and non‐septic patients separately.

Results

A total of 423 patients were investigated. Of these, 297 had sepsis. In the sepsis group, medium protein
intake at days 4–7 was associated with lower 6‐month mortality (hazard ratio [HR]: 0.646, 95% confidence interval [CI]: 0.418‐0.996, P=0.048) compared with high intake. In the non‐sepsis group, early high and late low protein intake were associated with higher 6‐month mortality (HR: 3.902, 95% CI: 1.505‐10.115, P=0.005; HR: 2.642, 95% CI: 1.128‐6.189, P=0.025) compared with low and high protein intake, respectively. For energy intake, late energy intake of >110% was associated with decreased mortality in septic patients (HR: 0.400, 95% CI: 0.222‐0.721, P=0.002), whereas in non‐septic patients, late medium energy intake (80%–110%) was associated with better survival (HR: 0.379, 95% CI: 0.175‐0.820, P=0.014), both compared with low energy intake.

Conclusion

Divergent associations of macronutrient intake were found; early high protein intake in non‐septic patients, but not in septic patients, was found to be associated with higher 6‐month mortality.
The role of radiation therapy and margin width in localized soft‐tissue sarcoma: Analysis from the US Sarcoma Collaborative
Authors: Gannon Nicholas P. , King David M. , Ethun Cecilia G. , Charlson John , Tran Thuy B. , Poultsides George , Grignol Valerie , Howard J. Harrison , Tseng Jennifer , Roggin Kevin K. , Votanopoulos Konstantinos , Krasnick Bradley , Fields Ryan C. , Cardona Kenneth , Bedi Meena
Published: June 2019

Background and Objectives

Soft‐tissue sarcomas (STSs) are often treated with resection and radiation (RT)±chemotherapy. The role of RT in decreasing resection width to achieve local control is unclear. We evaluated RT on margin width to achieve local control and local recurrence (LR).

Methods

From 2000 to 2016, 514 patients with localized STS were identified from the US Sarcoma Collaborative database. Patients were stratified by a margin and local control was compared amongst treatment groups.

Results

LR was 9% with positive, 4.2% with ≤1 mm, and 9.3% with >1 mm margins (P = .315). In the ≤1 mm group, LR was 5.7% without RT, 0% with preoperative RT, and 0% with postoperative RT (P < .0001). In the >1 mm group, LR was 10.2%, 0%, and 3.7% in the no preoperative and postoperative RT groups, respectively (P = .005). RT did not influence LR in patients with positive margins. In stage I‐III and II‐III patients, local recurrence‐free survival was higher following RT (P = .008 and P = .05, respectively).

Conclusions

RT may play a larger role in minimizing LR than margin status. In patients with positive margins, RT may decrease LR to similar rates as a negative margin without RT and may be considered to decrease the risk of LR with anticipated close/positive margins.
Commentary on the Special Issue on Moral Injury: Unpacking Two Models for Understanding Moral Injury
Authors: Nash William P.
Published: June 2019

The most robust finding of moral injury (MI) research thus far—that past exposure to potentially morally injurious events predicts current symptoms of posttraumatic stress disorder (PTSD)—challenges conceptions that trauma is exclusively the result of fear‐evoking brushes with death or sexual assault. It also calls into question the applicability to MI of treatments for PTSD grounded in the fear model of trauma. In the current article, two divergent theoretical models that have been applied to the understanding and treatment of moral injury are compared: the stress–appraisal–coping model and the stress injury model. Attention is drawn to the differences between how these models conceptualize stress and distress, including psychological trauma, and to their potential implications for the sustainment of mental health stigma, especially in military and veteran populations.
Optical Information Multiplexing with Nonlinear Coding Metasurfaces
Authors: Ma Menglin , Li Zhi , Liu Wenwei , Tang Chengchun , Li Zhancheng , Cheng Hua , Li Junjie , Chen Shuqi , Tian Jianguo
Published: June 2019

Coding metasurfaces, as a new type of design concept, have provided many attractive functionalities for manipulating the wave fronts of light. Previous research only focused on linear coding metasurfaces; however, with the increasing demand for highly integrated and compact multifunctional chips, the drawbacks of linear coding metasurfaces, the constraints on information capacity and operating frequency are becoming more and more obvious. Here, Pancharatnam–Berry‐phase‐based nonlinear coding metasurfaces are proposed, in which convenient digital signal processing is employed to design multidimensional information channels in nonlinear optical processes to achieve optical information multiplexing. In order to confirm the feasibility of this methodology, by encoding various focusing functionalities and image information into nonlinear metasurfaces, a multifocal metalens and a multifunctional metasurface are theoretically designed, and their excellent performances are experimentally demonstrated. The proposed nonlinear coding metasurfaces may provide a promising platform for information encryption, multi‐channel optical data storage, and real space encoding imaging.
Treatment and persistence/recurrence of sleep‐disordered breathing in children with Down syndrome
Authors: Nehme Joy , LaBerge Robert , Pothos Mary , Barrowman Nicholas , Hoey Lynda , Kukko Madelaine , Monsour Andrea , Katz Sherri L.
Published: June 2019

Objective

Sleep‐disordered breathing (SDB) is common in children with Down syndrome, but the trajectory and long‐term outcomes are not well‐described. In a retrospective longitudinal cohort of children with Down syndrome, study objectives were to (1) characterize polysomnography (PSG), treatments received, and persistence/recurrence of SDB and (2) explore predictors of SDB persistence/recurrence.

Methods

A retrospective cohort study was conducted of children who underwent PSGs between 2004 and 2014. SDB was defined as obstructive sleep apnea (OSA)‐mixed (apnea‐hypopnea index [AHI] >5 events/hour), central sleep apnea or hypoventilation. PSGs, interventions, and trajectory of SDB were described. Age, body mass index (BMI) Z‐score and AHI at first SDB diagnosis were evaluated as predictors of persistent/recurrent SDB.

Results

Of 506 children, 120 had ≥1 PSG; 54 had subsequent PSGs. Children with ≥2 PSGs were more likely to have higher total AHI (P = .02) and obstructive‐mixed AHI (P = .01). Thirty‐five of fifty‐four (65%) were initially diagnosed with OSA‐mixed SDB. After first PSG, 67 of 120 had OSA‐mixed SDB, of whom 25 (37.3%) underwent adenotonsillectomy (T&A), 13 (19.4%) received positive airway pressure (PAP). Those who underwent T&A after PSG were significantly younger than those who received PAP (median age 6.2 vs 12.5 years; P = .005). OSA‐mixed SDB persisted/recurred in 33 of 54 (73.3%) with ≥2 PSGs. Persistence/recurrence was not associated with age, AHI or BMI Z‐score at first SDB.

Conclusion

Children with Down syndrome undergoing T&A for SDB were significantly younger than those treated with PAP. SDB persisted/recurred in three of four and was not predicted by age, SDB severity or BMI Z‐score. Longitudinal PSG assessment for persistence/recurrence of SDB is required in this population.
Effect of gas mixing on Xe ion currents from an ECR ion source
Authors: Mandal Anuvab , Thulasiram K.V. , Fernandes W. , Tribedi Lokesh C.
Published: June 2019

Gas mixing technique has been used in order to increase the current of highly charged ions of Xe at the TIFR‐ECRIA. The He, N2, O2, Ne, and Ar are used as support gases, and their effect on output currents of Xe ions is studied. The effective ion charge and the total loss rate of ions are calculated from the measured currents. It is found that molecular gases, such as N2 and O2, exhibit better mixing effect in the enhancement of output of highly charged Xe ions. Furthermore, we describe this 14.5‐GHz ECR ion source mounted on a high voltage (400 kV) deck, with its four beamlines, as well as the control system for the remote operation.
Characterization and correlations of behavioral and adrenocortical activities of zoo‐housed lesser anteaters (Tamandua tetradactyla)
Authors: Eguizábal Gabina V. , Palme Rupert , Superina Mariella , Asencio Camila J. , García Capocasa María C. , Busso Juan M.
Published: June 2019

We characterized behavioral and adrenocortical activities ofTamandua tetradactylaunder human care driven by the hypothesis that they vary between males and females. We also assessed the potential association between natural or abnormal behaviors and adrenocortical activity. We kept females and malesT. tetradactylain individual, contiguous enclosures at Córdoba Zoo (Argentina), under natural photoperiod and temperature. During 29 consecutive days we monitored the animals’ behavior by recording their activity pattern every 5 min using infrared cameras (8352 records/individual). We collected all feces and measured fecal glucocorticoid metabolites (FGM) with an 11‐oxoaetiocholanolone enzyme immunoassay. We found individual differences in all behavioral variables. We detected that females exhibited lower total activity than males (23.8 ± 0.2% and 32.3 ± 0.3%, respectively;p = .005). Females were more active at night and males during the day (p < .05) and exhibited less abnormal behaviors than males (p = .05). Although we did not find sex‐related differences for average FGM, we detected individual differences (p < .0001). We found that daily FGM showed negative (−0.39) and positive (0.38) correlations with natural and abnormal behaviors, respectively (p < .0001). Thus, we consider that individual input and sex are factors to be considered in stress responses of the species in captivity. Natural and abnormal behaviors may demand different levels of adrenocortical activity. Our findings may prove useful as normative data for ex situ management of conservation programs.