bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential mutational evaluation of CALR ‐mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression
Authors: Cottin Laurane , Riou Jérémie , Orvain Corentin , Ianotto Jean Christophe , Boyer Françoise , Renard Maxime , Truchan‐Graczyk Matgorzata , Murati Anne , Jouanneau‐Courville Rébecca , Allangba Olivier , Mansier Olivier , Burroni Barbara , Rousselet Marie-Christine , Quintin‐Roué Isabelle , Martin Antoine , Sadot‐Lebouvier Sophie , Delneste Yves , Chrétien Jean‐Marie , Hunault‐Berger Mathilde , Blanchet Odile , Lippert Eric , Ugo Valérie , Luque Paz Damien
Published: November 2019

In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR‐mutated cases. Additional mutations found by next‐generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR‐mutated patients. We performed a molecular evaluation combining next‐generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow‐up in a cohort of 45 patients with CALR‐mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1‐like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow‐up, independently of additional mutations and WHO2016‐reviewed diagnosis. Patients with disease progression at the time of follow‐up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.
THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors
Authors: Alexander Stephen P H , Christopoulos Arthur , Davenport Anthony P , Kelly Eamonn , Mathie Alistair , Peters John A , Veale Emma L , Armstrong Jane F , Faccenda Elena , Harding Simon D , Pawson Adam J , Sharman Joanna L , Southan Christopher , Davies Jamie A ,   CGTP Collaborators
Published: November 2019

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Guanidine modifications enhance the anti‐herpes simplex virus activity of (E,E)‐4,6‐bis(styryl)‐pyrimidine derivatives in vitro and in vivo
Authors: Wang Wei , Xu Cuijing , Zhang Jianqiang , Wang Jinpeng , Yu Rilei , Wang Dongping , Yin Ruijuan , Li Wenmiao , Jiang Tao
Published: November 2019

Background and Purpose

The worldwide prevalence of herpes simplex virus (HSV) and shortage of efficient therapeutic strategies to counteract it are global concerns. In terms of treatment, the widely utilized anti‐HSV drugs such as acyclovir have serious limitations, for example, drug resistance and side effects. Here, we have identified the guanidine‐modified (E,E)‐4,6‐bis(styryl)‐pyrimidine (BS‐pyrimidine) derivative compound 5d as an inhibitor of HSV and further elucidated the anti‐HSV mechanisms of compound 5d both in vitro and in vivo.

Experimental Approach

Cytopathic effect inhibition assay, plaque assay, and immunofluorescence assay were used to evaluate the anti‐HSV effects of compound 5d in vitro. Membrane fusion assays, immunofluorescence assays, Western blotting assays, and pull‐down assays were used to explore the anti‐HSV mechanisms of compound 5d. HSV‐1‐infected mice, combined with haematoxylin–eosin staining and quantitative RT‐PCR, were used to study the anti‐HSV effects of compound 5d in vivo.

Key Results

The guanidine‐modified compound 5d rather than the un‐modified compound 3a effectively inhibited both HSV‐1 and HSV‐2 multiplication in different cell lines, more effectively than acyclovir. Compound 5d may block virus binding and post‐binding processes such as membrane fusion, by targeting virus gB protein. In addition, compound 5d may also down‐regulate the cellular PI3K/Akt signalling pathway to interfere with HSV replication. Treatment with compound 5d also markedly improved survival and decreased viral titres in HSV‐infected mice.

Conclusions and Implications

Thus, the guanidine‐modified BS‐pyrimidine derivatives have the potential to be developed into novel anti‐HSV agents targeting both virus gB protein and cellular PI3K/Akt signalling pathways.
Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer
Authors: Li Dongbo , Ji Hongfei , Niu Xingjian , Yin Lei , Wang Yiran , Gu Yucui , Wang Jinlu , Zhou Xiaoping , Zhang Han , Zhang Qingyuan
Published: November 2019

Breast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor‐associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine‐resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen‐sensitive (MCF7‐S) or ‐resistant (MCF7‐R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC‐chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor‐positive breast cancer. We found that macrophages cultured in the CM of MCF7‐S and MCF7‐R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression‐free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrine‐resistant breast cancer.
Conditional survival and recurrence of remnant gastric cancer after surgical resection: A multi‐institutional study
Authors: Chen Qi‐Yue , Zhong Qing , Zhou Jun‐Feng , Qiu Xian‐Tu , Dang Xue‐Yi , Cai Li‐Sheng , Su Guo‐Qiang , Xu Dong‐Bo , Lin Guang‐Tan , Guo Kai‐Qing , Liu Zhi‐Yu , Chen Qiu‐Xian , Li Ping , Li Teng‐Wen , Xie Jian‐Wei , Lin Shuang‐Ming , Wang Jia‐Bin , Lin Jian‐Xian , Lu Jun , Cao Long‐Long , Lin Mi , Zheng Chao‐Hui , Lin Wei , He Qing‐Liang , Huang Chang‐Ming
Published: November 2019

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow‐up strategies. A total of 298 patients were analyzed for their 3‐year conditional overall survival (COS3), 3‐year conditional disease‐specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5‐year overall survival (OS) and the 5‐year disease‐specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%‐83.0%, Δ36.6% vs ≤T2: 82.4%‐85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time‐dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time‐dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow‐up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages, which may affect the design of future clinical trials.
High expression of COPB2 predicts adverse outcomes: A potential therapeutic target for glioma
Authors: Zhou Yan , Wang Xuan , Huang Xing , Li Xu‐Dong , Cheng Kai , Yu Hao , Zhou Yu‐Jie , Lv Peng , Jiang Xiao‐Bing
Published: November 2019

Aims

To evaluate the clinical significance of coatomer protein complex subunit beta 2 (COPB2) in patients with glioma using a bioinformatics analysis.

Methods

Oncomine, GEO, and The Cancer Genome Atlas databases were used to examine the COPB2 transcript levels in glioma tissues. Gene expression profiles with clinical information from low‐grade glioma and glioblastoma (GBM) projects were analyzed for associations between COPB2 expression and clinicopathologic characteristics. Kaplan‐Meier survival and Cox regression analyses were used for survival analysis. Gene set enrichment analysis (GSEA) was conducted to screen the pathways involved in COPB2 expression. Gene set variation analysis (GSVA) and correlograms were performed to verify the correlations between COPB2 and inflammatory responses. Canonical correlation analyses examined whether COPB2‐high patients have more infiltrating inflammatory and immune cells.

Results

COPB2 was highly expressed in gliomas and high COPB2 expression correlated with shorter overall survival time and several poor clinical prognostic variables. GSEA indicated that some immune‐related pathways and other signaling pathways in cancer were associated with the COPB2‐high phenotype. The GSVA and canonical correlation analysis demonstrated that COPB2 expression was closely linked to inflammatory and immune responses, and higher immune cell infiltration.

Conclusions

COPB2 may be a potential prognostic biomarker and an immunotherapeutic target for glioma.
Management of pouch‐vaginal fistulas – experience from our institution
Authors: Sivathondan P. C. , Bloemendaal A. , Travis S. , Mortensen N. , George B. D.
Published: November 2019

Aim

Pouch–vaginal fistula (PVF) is an uncommon but serious complication of ileo‐anal pouch reconstruction. This study aimed to review the recent management of PVF, in particular the role of anti‐tumour necrosis factor (anti‐TNF) drugs.

Method

All patients presenting for management of PVF to our surgical service between 2007 and 2016 were studied. The median duration of follow‐up from diagnosis of PVF was 6 years. Details of the original pouch surgery, timing of presentation of PVF, management and final outcome were recorded. Primary outcome was gastrointestinal (GI) continuity (as defined by the presence or absence of a stoma).

Results

A total of 23 patients were identified (median age 45 years) of whom nine had pelvic sepsis at the time of original pouch surgery. Management included local surgical repair, defunctioning ileostomy, pouch excision and anti‐TNF therapy. GI continuity was achieved in 12 patients (52%). Healing of the PVF was achieved in 12 patients (52%). Pelvic sepsis was significantly associated with the need for a long‐term ileostomy (P = 0.009). Biological therapy was used in 12 patients, of whom seven maintained GI continuity. Patients with late presentation PVF (60 months or longer postsurgery) and those with clinical features of Crohn’s disease appeared to benefit from anti‐TNF treatment.

Conclusion

PVF remains a challenging problem with overall healing rates and GI continuity rates of just over 50%. Anti‐TNF therapy may have a role in patients with late presentation PVF and those with features suggestive of Crohn’s disease.
The value of flexible bronchoscopy in pulmonary infections of immunosuppressed children
Authors: Eroglu‐Ertugrul Nesibe Gevher , Yalcin Ebru , Oguz Berna , Ocal Turgay , Kuskonmaz Baris , Emiralioglu Nagehan , Dogru‐Ersoz Deniz , Ozcelik Ugur , Tezcan Ilhan , Kiper Nural
Published: November 2019

Objectives

To demonstrate the value of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) when determining causes of lung infection in immunocompromised children; to investigate differences in causes and radiological features of lung infections following bone marrow transplantation (BMT) compared to other immunosuppressive conditions; to evaluate the reliability of radiological findings when predicting the pathogen.

Methods

We retrospectively evaluated 132 immunosuppressed children who underwent FB and BAL because pulmonary complications between January 1999 and May 2014 at the Hacettepe University Hospital Pediatric Pulmonology Unit. Two groups, Group I (n = 106) and Group II (n = 26), consisted of patients who had primary or secondary immunodeficiency and those who were immunosuppressed because BMT, respectively. Radiological findings before FB and macroscopic and microscopic findings of the procedure were evaluated.

Results

FB and BAL were diagnostic in 86/132 patients (65.1%) and the antimicrobial treatment changed for 75/132 patients (56.8%). The most common pathogen was bacteria (Streptococcus pneumoniae was the leading one). Bacteria were more frequent in Group I than Group II (P = .008). No significant difference in radiological findings between Groups I and II was found. Considering all patients, a significant association was detected between viral pathogens and radiologically interstitial infiltration and a ground‐glass appearance (P = .003). However, no significant association was detected between bacterial and fungal pathogens and the radiological findings.

Conclusion

In immunosuppressed patients, FB and BAL should be evaluated early for clarifying the causative agents. Then, appropriate treatments can be utilised and the side effects and high cost of unnecessary treatment may be mitigated.
The presence of two reduced function variants in CYP2C9 influences the acute response to glipizide
Authors: Chen L. , Li J. H. , Kaur V. , Muhammad A. , Fernandez M. , Hudson M. S. , Goldfine A. B. , Florez J. C.
Published: November 2019

Aims

To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naïve to diabetes medications.

Methods

In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR‐MGH), 786 individuals genotyped for rs1799853/rs41291560 (*2) and rs1057910/rs9332214 (*3) were treated with 5 mg glipizide in the fasting state. Glucose and insulin levels were measured at baseline, 30, 60, 90, 120, 180 and 240 min for calculation of phenotypic endpoints of glipizide response. The challenge was aborted as a result of hypoglycaemia, defined as glucose <2.8 mmol/l or hypoglycaemia‐related symptoms.

Results

Carriers with two reduced function alleles had a 50% larger insulin area under the curve than carriers with zero or one copy (P=0.037), although this finding was primarily driven by an individual with a robust insulin response. In adjusted analyses, the risk of aborting the glipizide challenge was doubled in two‐copy carriers (P=0.034). No significant findings were observed in glucose‐based endpoints.

Conclusions

Carriers of two reduced function alleles in CYP2C9 may experience an increased insulin response to glipizide and be predisposed to a higher risk of hypoglycaemia, although no effect of genotype was seen in glucose‐based measurements. Further studies are needed to clarify the utility of CYP2C9 genotyping to guide sulfonylurea treatment.
Increased proportion of time in hybrid closed‐loop “Auto Mode” is associated with improved glycaemic control for adolescent and young patients with adult type 1 diabetes using the MiniMed 670G insulin pump
Authors: Duffus Sara H. , Ta'ani Zain Al , Slaughter James C. , Niswender Kevin D. , Gregory Justin M
Published: November 2019

The Medtronic MiniMed 670G system delivers insulin to patients with type 1 diabetes mellitus (T1DM) using either its hybrid closed‐loop (HCL) “Auto Mode” feature or an open‐loop mode. In this retrospective, cross‐sectional analysis, we quantified the association between time in Auto Mode and both haemoglobin A1c (HbA1c) and time in range (TIR, sensor glucose 70–180 mg/dL) among 96 paediatric and young adult patients with T1DM. The median percentage time in Auto Mode was 38.5% (interquartile range 0%–64%). The percentage time in Auto Mode significantly correlated with HbA1c after adjustment for covariables (β = −0.008, P = 0.014). Each daily 3.4‐h increase in Auto Mode time was associated with a 0.1% decrease in HbA1c. Auto Mode time was also correlated with TIR after adjustment for covariables (β = 0.14, P = 0.02): for each daily 8.6‐h increase in Auto Mode time, TIR increased by 5%. While Auto Mode use was low, increased time in Auto Mode was associated with a significantly lower HbA1c and increased TIR. These findings emphasize the importance of identifying strategies to improve the ease of use of HCL systems.
A food‐based, low‐energy, low‐carbohydrate diet for people with type 2 diabetes in primary care: A randomized controlled feasibility trial
Authors: Morris Elizabeth , Aveyard Paul , Dyson Pamela , Noreik Michaela , Bailey Clare , Fox Robin , Jerome Derek , Tan Garry D , Jebb Susan A
Published: November 2019

Aim

To examine the feasibility of a food‐based, low‐energy, low‐carbohydrate diet with behavioural support delivered by practice nurses for patients with type 2 diabetes.

Materials and Methods

People with type 2 diabetes and a body mass index (BMI) of ≥30 kg/m2 were randomized 2:1 to intervention or control (usual care) and assessed at 12 weeks. The intervention comprised an 800–1000 kcal/day, food‐based, low‐carbohydrate (<26% energy) diet for 8 weeks, followed by a 4‐week weight maintenance period and four 15‐20‐minute appointments with a nurse. Primary outcomes were feasibility of recruitment, fidelity of intervention delivery and retention of participants at 12 weeks. Secondary outcomes included change in weight and HbA1c. Focus groups explored the intervention experience.

Results

Forty‐eight people were screened, 33 enrolled and 32 followed‐up. Mean (±SD) weight loss in the intervention group was 9.5 kg (± 5.4 kg) compared with 2 kg (± 2.5 kg) in the control group (adjusted difference − 7.5 kg [−11.0 to −4.0, P < 0.001]). Mean reduction in HbA1c in the intervention group was 16.3 mmol/mol (± 13.3 mmol/mol) compared with 0.7 mmol/mol (±4.5 mmol/mol) in the control group (difference − 15.7 mmol/mol [−24.1 to −7.3, P < 0.001]).

Conclusions

It is feasible to recruit participants to a food‐based, low‐energy, low‐carbohydrate intervention, for practice nurses to deliver the programme in primary care, and to retain participants in both groups. There is evidence of clinically significant short‐term improvements in weight and glycaemic control.
Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis
Authors: Ferraro D. , Trovati A. , Bedin R. , Natali P. , Franciotta D. , Santangelo M. , Camera V. , Vitetta F. , Varani M. , Trenti T. , Gastaldi M. , De Biasi S. , Nasi M. , Pinti M. , Meletti S. , Sola P.
Published: November 2019

Background and purpose

Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB‐negative patients with suspected MS.

Methods

The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB‐negative patients with suspected/possible MS and in 54 OCB‐positive patients with MS.

Results

The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut‐off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB‐negative MS (23/92) and in 98% of OCB‐positive patients with MS. Using a qualitative approach and a kappa index cut‐off of 5.9, based on literature data, we likewise found that 24% of OCB‐negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB‐negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples.

Conclusions

The kappa index could contribute to the identification of OCB‐negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index.
Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms
Authors: Mayneris‐Perxachs Jordi , Fernández‐Real José‐Manuel
Published: November 2019

Thanks to the emergence and recent advances in high‐throughput sequencing technologies, it is becoming more evident every day that changes in the microbiome composition are linked to a myriad of health conditions. Despite this, the mechanisms of host–microbiota signalling remain largely unknown. The microbiome has an extensive metabolic activity that leads to the generation of a large number of compounds that are likely to influence host health. Therefore, the microbiome–host cross‐talk is in part mediated by microbial‐derived metabolites. Unlike metagenomics, which only provides information about microbial genes and thus the microbiome functional potential, metabolic phenotyping is well suited to capture their actual metabolic activity. Here, we provide an overview of these approaches and propose an integration of metagenomics, as a microbiome compositional readout, with faecal and plasma/urine metabolomics, as a functional readout, to unravel novel mechanisms linking the microbiome to host health and disease.
Fast and slow cancellations and trader behavior
Authors: McInish Thomas H. , Nikolsko‐Rzhevska Olena , Nikolsko‐Rzhevskyy Alex , Panovska Irina
Published: November 2019

We investigate how short‐lived liquidity supply due to order cancellations affects the order‐placement behavior of slow traders. When order cancellations increase, slow traders submit fewer and less aggressive orders. Both short‐ and long‐lived liquidity supply have positive effects on the market overall, reducing spreads and increasing depth. We conclude that it is not necessary to require limit orders to have a minimum lifespan. We develop econometric and machine‐learning frameworks that allow traders to predict whether a quote is likely to have a short or long life, increasing the ability of slow traders to respond strategically to changing order flow.
Temporal β diversity—A macroecological perspective
Authors: Magurran Anne E. , Dornelas Maria , Moyes Faye , Henderson Peter A.
Published: November 2019

Issue

Biodiversity change, that is how the taxonomic identities and abundances of species in ecological systems are changing over time, has two facets: temporal α diversity and temporal β diversity. To date, temporal α diversity has received most attention even though compositional shifts in assemblages exceed expectations based on ecological theory. Growing concern about the state of the world’s biodiversity highlights the need for better understanding of the extent, and consequences, of compositional reorganization in ecological systems.

Challenges

Most methods of measuring β diversity have been developed in a spatial context. We discuss the additional challenges involved in the assessment of temporal change, summarize existing methodological approaches, highlight the importance of establishing relevant baselines, and identify the need for appropriate null models of temporal β diversity. Given considerable potential for research on the macroecology of temporal β diversity we suggest future directions and challenges.

Conclusions

Although data availability remains the main impediment to improved quantification of temporal β diversity at macroecological scales, there are substantial opportunities for improved methodology and theory. Taxonomic β diversity has received most attention, but other dimensions of diversity, including functional and phylogenetic, should be part of integrated assessments of biodiversity change. Future approaches need to be ecologically meaningful and interpretable as well as statistically robust.
Obscuring Corporate Violence: Corporate Manslaughter in Action
Authors: HÉBERT JASMINE , BITTLE STEVEN , TOMBS STEVE
Published: November 2019

In April 2008, the Corporate Manslaughter and Corporate Homicide Act 2007 (CMCHAct) came into force in the UK. Since then, the Act has failed to live up to expectations, resulting in only 26 convictions in the first decade of its existence, despite thousands of work‐related fatalities during this time. This article critically analyses these CMCHAct prosecutions in order to chronicle the problems of the law in action and to demonstrate how the Act serves to downplay the seriousness of corporate killing. In so doing, we approach law as an ‘active discourse’ that is mutually constitutive of the broader social formation, so that it both creates, but is also a product of, the capitalist social order. Thus we explore the extent to which the CMCHAct ultimately privileges dominant beliefs that corporate killing is not ‘true’ crime and that corporate capitalism is an inherent good that must be defended, not disrupted.
ZrSi2–MgO as novel additives for high thermal conductivity of β‐Si3N4 ceramics
Authors: Wang Weide , Yao Dongxu , Chen Huanbei , Xia Yongfeng , Zuo Kaihui , Yin Jinwei , Liang Hanqin , Zeng Yu‐Ping
Published: November 2019

A novel ZrSi2–MgO system was used as sintering additive for fabricating high thermal conductivity silicon nitride ceramics by gas pressure sintering at 1900°C for 12 hours. By keeping the total amount of additives at 7 mol% and adjusting the amount of ZrSi2 in the range of 0‐7 mol%, the effect of ZrSi2 addition on sintering behaviors and thermal conductivity of silicon nitride were investigated. It was found that binary additives ZrSi2–MgO were effective for the densification of Si3N4 ceramics. XRD observations demonstrated that ZrSi2 reacted with native silica on the Si3N4 surface to generate ZrO2 and β‐Si3N4 grains. TEM and in situ dilatometry confirmed that the as formed ZrO2 collaborated with MgO and Si3N4 to form Si–Zr–Mg–O–N liquid phase promoting the densification of Si3N4. Abnormal grain growth was promoted by in situ generated β‐Si3N4 grains. Consequently, compared to ZrO2‐doped materials, the addition of ZrSi2 led to enlarged grains, extremely thin grain boundary film and high contiguity of Si3N4–Si3N4 grains. Ultimately, the thermal conductivity increased by 34.6% from 84.58 to 113.91 W·(m·K)−1 when ZrO2 was substituted by ZrSi2.
The Human Right to Free Internet Access
Authors: Reglitz Merten
Published: November 2019

In 2016, the United Nation's General Assembly adopted a non‐binding resolution regarding ‘The Promotion, Protection and Enjoyment of Human Rights on the Internet’. At the heart of this resolution is the UN's concern that rights that people have offline must also be protected online. While the UN thus recognises the importance of the Internet, it problematically does so selectively by focusing on protecting existing offline rights online. I argue instead that Internet access is itself a moral human right that requires that everyone has unmonitored and uncensored access to this global medium, which should be publicly provided free of charge for those unable to afford it. Rather than being a mere luxury, Internet access should be considered a universal entitlement because it is necessary for people to be able to lead minimally decent lives. Accepting this claim transforms our conception of the Internet from a technology to that of a basic right.
Use of sea ice by arctic terns Sterna paradisaea in Antarctica and impacts of climate change
Authors: Redfern Chris P. F. , Bevan Richard M.
Published: November 2019

Arctic terns spend their breeding and non‐breeding seasons in polar environments at opposite ends of the world. The sensitivity of polar regions to climate change makes it essential to understand the ecology of arctic terns but the remoteness of the Antarctic presents a considerable challenge. One solution is to use ‘biologgers’ to monitor remotely their behaviour and distribution in the Antarctic. Data from birds tagged with light‐level global location sensors (geolocators) in 2015 and 2017 showed that a third of their annual cycle was spent amongst Antarctic sea ice. After reaching the East Antarctic in the austral spring, they gradually moved west, foraging in fragmented ice zones of the Antarctic coastline, leaving in the austral autumn for their return northward migration via the Atlantic. Changes in patterns of movement between phases of 24‐h daylight and diel day/night conditions were likely linked to the annual moult, and stable isotope analyses suggest that krill (Euphausia species) was an important component of their diet. There were marked differences in movement behaviour between arctic terns tagged in 2015 compared to 2017 that may relate to unusual changes in sea‐ice extent. The arctic tern may be unique amongst seabirds that utilise the Antarctic environment in summer in being able to move widely without nesting constraints, and may present a means of characterising the effects of climate change on species dependent for foraging on Antarctic sea‐ice and krill.
Clinical significance of circulating microRNAs as diagnostic biomarkers for coronary artery disease
Authors: Zhang Lei , Zhang Yuan , Xue Sheng , Ding Han , Wang Yu , Qi Hongzhao , Wang Yin , Zhu Wenjie , Li Peifeng
Published: November 2019

Coronary artery disease (CAD) is one of the biggest threats to human life. Circulating microRNAs (miRNAs) have been reported to be linked to the pathogenesis of CAD, indicating the possible role in CAD diagnosis. The present study aimed to explore the expression profile of plasma miRNAs and estimate their value in diagnosis for CAD. 67 Non‐CAD control subjects and 88 CAD patients were enrolled. We conducted careful evaluation by RT‐PCR analysis, Spearman rank correlation coefficients analysis, Receiver Operating Characteristic (ROC) curves analysis and so on. The plasma levels of six miRNAs known to be related to CAD were measured and three of them showed obvious expression change. Circulating miR‐29a‐3p, miR‐574‐3p and miR‐574‐5p were all significantly increased. ROC analysis revealed the probability of the three miRNAs as biomarkers with AUCs (areas under the ROC curve) of 0.830, 0.792 and 0.789, respectively. They were significantly correlated with each other in CAD patients, suggesting the possibility of joint diagnosis. The combined AUC was 0.915, much higher than each single miRNA. Therefore, our study revealed three promising biomarkers for early diagnosis of CAD. The combination of these miRNAs may act more effectively than individual ones for CAD diagnosis.
Therapist self‐disclosure and the problem of shared‐decision making
Authors: Berg Henrik , Bjornestad Jone , Våpenstad Eystein Victor , Davidson Larry , Binder Per‐Einar
Published: November 2019

Therapist self‐disclosure is one of the most controversial topics in the history of psychotherapy. The controversies reflect some basic discussions regarding the nature of psychotherapy practice. In psychotherapy practice, a particular concern is the interaction between the psychotherapist and the patient. The expert‐patient interaction has been addressed in a novel framework for clinical practice called shared‐decision making. In this paper, we discuss the relationship between self‐disclosure and shared‐decision making. The chief aim is to illustrate some of the principles and practical problems with shared‐decision making by using therapist self‐disclosure as an example.
Allergic reaction from dental bonding material through nitrile gloves: Clinical case study and glove permeability testing
Authors: Sananez Andreina , Sanchez April , Davis Loretta , Vento Yosvany , Rueggeberg Frederick
Published: November 2019

Objective

This study examines monomer permeation of commercial dental adhesive through nitrile‐based gloves, and correlates findings with clinical case studies of dental students having localized skin eruptions following resin placement on a gloved hand to manipulate composite.

Methods

Three dental students self‐reported presenting itchy, red skin lesions underneath the area where they placed uncured adhesive resin on a nitrile‐gloved hand. Histories and cursory examinations were performed in the Department of Dermatology at The Medical College of Georgia. Infrared spectroscopic methods were used to determine permeation times of known monomer components of commercial adhesive material used through nitrile glove. Monomer permeation times were correlated with the time when the commercial adhesive first applied and penetrated through the glove.

Results

Assessment by the dermatologist concluded that the reporting students had occupational contact dermatitis resulting from components of the adhesive permeating through the barrier glove. Permeation times of neat monomer components of the adhesive resin varied over a wide range, with lower molecular weight showing faster pass‐through times. Spectroscopic interpretation indicated that the probable causative agent for the student's skin reaction was 2‐hydroxyethyl methacrylate (HEMA).

Conclusions

Probable correlation of the observed skin reaction sites was made with diffusion of HEMA in the uncured dental adhesive formulation through nitrile glove material.

Clinical Significance

All measures to prevent skin contact with uncured methacrylate‐based resin components should be taken, including avoidance of resin permeation through a gloved hand. Sensitization to one type of methacrylate can result in sensitization to other types of resins within this family, significantly impacting the careers of both dental auxiliaries as well as clinicians.
Factors associated with severity of naturally occurring piscirickettsiosis in netpen‐ and tank‐reared juvenile Atlantic salmon at a research aquarium in western Canada
Authors: Jones Simon R. M. , Long Amy , MacWilliams Christine , Polinski Mark , Garver Kyle
Published: November 2019

The opportunistic examination of factors associated with an outbreak of piscirickettsiosis (SRS) is described in Atlantic salmon Salmo salar post‐smolts held in an open netpen or in tanks supplied with raw sea water at a research aquarium in western Canada. During the outbreak, seawater temperature was significantly higher and salinity significantly lower in the netpen compared with the tanks. Mortality in the netpen began approximately 3 weeks prior to that in the tanks, and cumulative mortality in the netpen (34%) was significantly higher than in the tanks (12%). Piscirickettsia salmonis was confirmed by qPCR in tissues from moribund and dead fish and from colonies grown on enriched blood agar medium. Neither P. salmonis nor SRS were observed in salmon held concurrently in UV‐irradiated sea water. The elevated mortality was curtailed by treatment with oxytetracycline. These observations further indicate warmer, less saline and periodically hypoxic seawater are risk factors for SRS. UV irradiation of sea water is shown to be a tool for SRS management in fish‐holding facilities.
Vertebrate mucus stimulates biofilm development and upregulates iron acquisition genes in Flavobacterium columnare
Authors: Lange Miles D. , Farmer Bradley D. , Abernathy Jason
Published: November 2019

Columnaris disease is responsible for substantial losses throughout the production of many freshwater fish species. One of the ways in which the bacterium Flavobacterium columnare is so effective in initiating disease is through the formation of biofilms on fish skin and gills. To further explore the interaction between host factors and bacterial cells, we assayed the ability of vertebrate mucus to enhance F. columnare biofilm development. Different concentrations of catfish, tilapia and pig mucus (5–60 µg/ml) increased biofilm growth at varying degrees among F. columnare isolates. Our data suggest that vertebrate mucus acts as a signalling molecule for the development of F. columnare biofilms; however, there are clear disparities in how individual isolates respond to different mucus fractions to stimulate biofilms. The expression of iron acquisition genes among two genomovar II isolates showed that ferroxidase, TonB receptor and the siderophore synthetase gene were all significantly upregulated among F. columnare biofilms. Interestingly, the siderophore acetyltransferase gene was only shown to be significantly upregulated in one of the genomovar II isolates. This work provides insight into our understanding of the interaction between F. columnare and vertebrate mucus, which likely contributes to the growth of planktonic cells and the transition into biofilms.
Intermediary metabolic response and gene transcription modulation on the Sub‐Antarctic notothenioid Eleginops maclovinus (Valenciennes, 1930) injected with two strains of Piscirickettsia salmonis
Authors: Soto‐Dávila Manuel , Martinez Danixa , Oyarzún Ricardo , Pontigo Juan P. , Vargas‐Lagos Carolina , Morera Francisco J. , Saravia Julia , Zanuzzo Fábio , Vargas‐Chacoff Luis
Published: November 2019

Pathogen interactions with cultured fish populations are well studied, but their effects on native fishes have not been characterized. In Chile, the disease caused by bacterial species Piscirickettsia salmonis represents one of the main issues and is considered to be one of the important pathogens in the field of aquaculture. They have been found to infect native fish. Therefore, it is necessary to understand the impact of P. salmonis on native species of local commercial value, as well as the potential impact associated with the emergence of antibiotic‐resistant strains of P. salmonis. Due to this purpose, the native fish Eleginops maclovinus was used in our study. Fish were randomly distributed in tanks and intraperitoneally inoculated with two strains of P. salmonis. No mortality was recorded during the experiment. Cortisol, glucose and total α‐amino acid levels increased in fish injected with AUSTRAL‐005 strain compared to sham‐injected and LF‐89‐inoculated fish. Moreover, results showed an increase in the activity of carbohydrates and lipids metabolism in liver; and an increase in the carbohydrates, lipids and total α‐amino acid metabolism in muscle after injection with AUSTRAL‐005. Our results suggest that P. salmonis modulates the physiology of E. maclovinus and the physiological impact increase in the presence of the antibiotic‐resistant strain AUSTRAL‐005.
“Our Brazil Has Become a Mess”: Nostalgic Narratives of Disorder and Disinterest as a “Once‐Rising Poor” Family from Recife, Brazil, Anticipates the 2018 Elections
Authors: Junge Benjamin
Published: November 2019

Este artigo apresenta um relato etnográfico de uma família extensa da cidade de Recife, nos meses que antecederam as eleições de 2018, nas quais o político de direita Jair Bolsonaro foi eleito para a presidência do Brasil. A família exemplifica o setor contenciosamente chamado de “nova classe média” ‐ os estimados 35 milhões que subiram acima da linha da pobreza durante 14 anos de governo do Partido dos Trabalhadores, mas cujas perspectivas se tornaram precárias desde então. A partir de um extenso trabalho de campo etnográfico, apresento uma série de momentos etnográficos, cada um ilustrando como as conversas informais sobre as próximas eleições refletiram e influenciaram a dinâmica familiar. Surgem nesses momentos narrativas de desintegração moral, aparente nostalgia da ditadura militar brasileira de 1964–85, a perda de masculinidades, sexualidades ameaçadoras e a regeneração de “zumbis” políticos. Adianto uma série de afirmações teóricas sobre as dimensões das afinidades políticas dos "previamente pobres” que merecem uma investigação etnográfica mais profunda.
Decreased levels of constitutive proteasomes in experimental autoimmune encephalomyelitis may be caused by a combination of subunit displacement and reduced Nfe2l1 expression
Authors: Shanley Kara L. , Hu Che‐Lin , Bizzozero Oscar A.
Published: November 2019

The goal of this study was to determine if subunit displacement and/or alterations in proteasome biosynthesis could explain the changes observed in the levels of constitutive proteasomes (c‐20S) and immunoproteasomes (i‐20S) in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE). To this end, EAE was induced in C57BL/6 mice by immunization with MOG35–55 peptide. Spinal cords were collected at different times during the disease course and used for western blotting, RNA analysis, and immunohistochemistry. The results show that, as expression of i‐20S and the activator PA28 rise in EAE, there is a concomitant decline in that of c‐20S at the mRNA and protein level. These changes are observed in neurons and astrocytes but not in oligodendrocytes. The increased amounts of the i‐20S‐specific subunit β5i and PA28α/β in EAE correlate with the levels of interferon‐γ and its downstream effectors p‐signal transducer and activator of transcription 1 and interferon regulatory factor‐1, but not with those of nuclear factor kappa‐light‐chain‐enhancer of activated B cells. This suggests that the signal transducer and activator of transcription 1/interferon regulatory factor‐1 pathway is solely responsible for the induction of these subunits. The decrease in the mRNA and protein levels corresponding to the c‐20S‐specific subunit β5 may also be due to reduced expression of the nuclear factor (erythroid‐derived 2)‐like‐1 (Nrf1 or Nfe2l1), specifically Nrf1α and Nrf1β. Low Nfe2l1 mRNA expression is unlikely caused by reduced mammalian target of rapamycin signaling but could be the result of diminished pre‐B‐cell leukemia homeobox‐1 transcription factor levels. Together, these findings suggest that a combination of subunit displacement and reduced Nrf1 expression may be responsible for c‐20S impairment in EAE. The present work provides insights into the dynamics of proteasome expression in the CNS of EAE mice and is the first to explore Nrf1 signaling in an inflammatory demyelinating disorder.

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Blood flow rate and wall shear stress in seven major cephalic arteries of humans
Authors: Seymour Roger S. , Hu Qiaohui , Snelling Edward P.
Published: November 2019

Blood flow rate () in relation to arterial lumen radius (ri) is commonly modelled according to theoretical equations and paradigms, including Murray’s Law ( ∝ ) and da Vinci’s Rule ( ∝ ). Wall shear stress (τ) is independent of ri with Murray’s Law (τ ∝ ) and decreases with da Vinci’s Rule (τ ∝ ). These paradigms are tested empirically with a meta‐analysis of the relationships between and ri in seven major arteries of the human cephalic circulation from 19 imaging studies in which both variables were presented. The analysis shows that ∝ and τ ∝ , more consistent with da Vinci’s Rule than Murray’s Law. This meta‐analysis provides standard values for , ri and τ in the human cephalic arteries that may be a useful baseline in future investigations. On average, the paired internal carotid arteries supply 75%, and the vertebral arteries supply 25%, of total brain blood flow. The internal carotid arteries contribute blood entirely to the anterior and middle cerebral arteries and also partly to the posterior cerebral arteries via the posterior communicating arteries of the circle of Willis. On average, the internal carotid arteries provide 88% of the blood flow to the cerebrum and the vertebral arteries only 12%.
Trust, ability‐to‐pay, and charitable giving
Authors: Ferrara Ida , Missios Paul
Published: November 2019

In the literature on privately provided public goods, altruism has been motivated by what contributions can accomplish (public goods philanthropy), by the pleasure of giving (warm‐glow philanthropy), or by the desire to personally make a difference (impact philanthropy). Underlying these motives is the idea that individuals trust that their donations reach their goal. We revisit these models but allow for distrust in the institutional structures involved. An important result we derive is that trust considerations determine whether crowding out is less or more than complete, and we thus open up possibilities in terms of the extent of crowding out not currently available. We also model socially motivated philanthropy when income‐heterogeneous donors take trust and ability‐to‐pay into account. With ability‐to‐pay in social motivation, an important result we obtain is that low‐income donors may contribute more than high‐income donors (in both absolute and percentage‐of‐income terms), giving a potential theoretical foundation to the frequently observed “U‐shaped” pattern of giving.