bluuebunny/crossref_metadata_2025 huggingface dataset:
Is type 2 diabetes an adiposity-based metabolic disease? From the origin of insulin resistance to the concept of dysfunctional adipose tissue
Authors: Sbraccia Paolo , D’Adamo Monica , Guglielmi Valeria
Published: February 2021

In the last decades of the past century, a remarkable amount of research efforts, money and hopes was generated to unveil the basis of insulin resistance that was believed to be the primary etiological factor in the development of type 2 diabetes. From the Reaven’s insulin resistance syndrome to the DeFronzo’s triumvirate (skeletal muscle, liver and beta-cell) and to Kahn’s discovery (among many others) of insulin receptor downregulation and autophosphorylation, an enthusiastic age of metabolic in vivo and in vitro research took place, making the promise of a resolutory ending. However, from many published data (those of insulin receptoropathies and lipodystrophies, the genome-wide association studies results, the data on reversibility of type 2 diabetes after bariatric surgery or very-low-calorie diets, and many others) it appears that insulin resistance is not a primary defect but it develops secondarily to increased fat mass. In particular, it develops from a mismatch between the surplus caloric intake and the storage capacity of adipose tissue. On this basis, we propose to change the today’s definition of type 2 diabetes in adiposity-based diabetes.

Level of Evidence as a narrative review a vast array of studies have been included in the analysis, ranging from properly designed randomized controlled trials to case studies; however, the overall conclusion may be regarded as level IV.
Influence of graphene nanoplatelets on mechanical properties and adhesive wear performance of epoxy-based composites
Authors: Eayal Awwad K. Y. , Yousif B. F. , Fallahnezhad Khosro , Saleh Khalid , Zeng Xuesen
Published: February 2021

Epoxy resin is one of the most widely used thermoset polymers in high-performance composite materials for lightweight applications. However, epoxy has a high coefficient of friction, which limits its tribological applications. In this study, the effect was investigated of different weight fractions of solid lubricant graphene nanoplatelets (GNPs), ranging from 0 to 4.5 wt%, on mechanical and adhesive wear performance of epoxy. Adhesive wear tests covered mild and severe wear regimes. The correlation of tribological and mechanical properties was studied as well. Scanning electron microscopy (SEM) was used to observe the failure mechanisms for both tribological and mechanical samples after each test. The results revealed that the addition of GNPs to the epoxy improved its stiffness and hardness but reduced its fracture strength and toughness. Adhesive wear performance exhibited high efficiency with GNP additions and showed reductions in the specific wear rate, the coefficient of friction, and the induced interface temperature by 76%, 37%, and 22%, respectively. A fatigue wear mechanism was predominant as the applied load increased. Most importantly, severe wear signs occurred when the interface temperature reached the heat distortion temperature of the epoxy. The tribological, and mechanical properties showed only a weak correlation to each other. The addition of GNPs to epoxy by less than 4.5 wt% was highly efficient to improve the wear performance while maintaining the fracture strength and toughness. Fourier transform infrared spectroscopy (FTIR) analysis shows no chemical interaction between the epoxy matrix with GNPs, which implies its physical interaction.
Overlapping International Instruments for Enforcement of Insolvency Judgments: Undermining or Strengthening Universalism?
Authors: Mevorach Irit
Published: February 2021

In recent years modified universalism has emerged as the normative framework for governing international insolvency. Yet, divergences from the norm, specifically regarding the enforcement of insolvency judgments, have also been apparent when the main global instrument for cross-border insolvency has been interpreted too narrowly as not providing the grounds for enforcing judgments emanating from main insolvency proceedings. This drawback cannot be overcome using general private international law instruments as they exclude insolvency from their scope. Thus, a new instrument—a model law on insolvency judgments—has been developed. The article analyses the model law on insolvency judgments against the backdrop of the existing cross-border insolvency regime. Specifically, the article asks whether overlaps and inconsistencies between the international instruments can undermine universalism. The finding is mixed. It is shown that the model law on insolvency judgments does add vigour to the cross-border insolvency system where the requirement to enforce and the way to seek enforcement of insolvency judgments is explicit and clear. The instrument should, therefore, be adopted widely. At the same time, ambiguities concerning refusal grounds based on proper jurisdiction and inconsistencies with the wider regime could undermine the system. Consequently, the article considers different ways of implementing the model law and using it in future cases, with the aim of maximizing its potential, including in view of further developments concerning enterprise groups and choice of law.
Defect and Doping Co-Engineered Non-Metal Nanocarbon ORR Electrocatalyst
Authors: Zhang Jian , Zhang Jingjing , He Feng , Chen Yijun , Zhu Jiawei , Wang Deli , Mu Shichun , Yang Hui Ying
Published: February 2021

Exploring low-cost and earth-abundant oxygen reduction reaction (ORR) electrocatalyst is essential for fuel cells and metal–air batteries. Among them, non-metal nanocarbon with multiple advantages of low cost, abundance, high conductivity, good durability, and competitive activity has attracted intense interest in recent years. The enhanced ORR activities of the nanocarbons are normally thought to originate from heteroatom (e.g., N, B, P, or S) doping or various induced defects. However, in practice, carbon-based materials usually contain both dopants and defects. In this regard, in terms of the co-engineering of heteroatom doping and defect inducing, we present an overview of recent advances in developing non-metal carbon-based electrocatalysts for the ORR. The characteristics, ORR performance, and the related mechanism of these functionalized nanocarbons by heteroatom doping, defect inducing, and in particular their synergistic promotion effect are emphatically analyzed and discussed. Finally, the current issues and perspectives in developing carbon-based electrocatalysts from both of heteroatom doping and defect engineering are proposed. This review will be beneficial for the rational design and manufacturing of highly efficient carbon-based materials for electrocatalysis.
Rational Dissenters in Late Eighteenth-Century England
Authors: Smith Valerie
Published: February 2021

Rational Dissent was a branch of Protestant religious nonconformity which emerged to prominence in England between c. 1770 and c. 1800. While small, the movement provoked fierce opposition from both Anglicans and Orthodox Dissenters.
Metaheuristic data fitting methods to estimate Weibull parameters for wind speed data: a case study of Hasan Polatkan Airport
Authors: Kaba A. , Suzer A. E.
Published: February 2021

Flight delays may be decreased in a predictable way if the Weibull wind speed parameters of a runway, which are an important aspect of safety during the take-off and landing phases of aircraft, can be determined. One aim of this work is to determine the wind profile of Hasan Polatkan Airport (HPA) as a case study. Numerical methods for Weibull parameter determination perform better when the average wind speed estimation is the main objective. In this paper, a novel objective function that minimises the root-mean-square error by employing the cumulative distribution function is proposed based on the genetic algorithm and particle swarm optimisation. The results are compared with well-known numerical methods, such as maximum-likelihood estimation, the empirical method, the graphical method and the equivalent energy method, as well as the available objective function. Various statistical tests in the literature are applied, such asR2, Root-Mean-Square Error (RMSE) and$\chi$2. In addition, the Mean Absolute Error (MAE) and total elapsed time calculated using the algorithms are compared. According to the results of the statistical tests, the proposed methods outperform others, achieving scores as high as 0.9789 and 0.9996 for theR2test, as low as 0.0058 and 0.0057 for the RMSE test, 0.0036 and 0.0045 for the MAE test and 3.53 × 10−5and 3.50 × 10−5for the$\chi$2test. In addition, the determination of the wind speed characteristics at HPA show that low wind speed characteristics and regimes throughout the year offer safer take-off and landing schedules for target aircraft. The principle aim of this paper is to help establish the correct orientation of new runways at HPA and maximise the capacity of the airport by minimising flight delays, which represent a significant impediment to air traffic flow.
The procedural syntax of fake modification constructions in Chinese
Authors: Li Wenshan
Published: February 2021

The clitic morphemedein Mandarin Chinese has various uses. Typically, it is cliticized to a phrase whether the phrase is nominal or adjectival; it can also occur between two noun phrases when there is no relation of semantic modification. The constructions that involve the latter use ofde, known as fake modification constructions, have been theoretically characterized many a time. In the existing characterizations, the morpheme is treated either as a mysteriously inserted lexical item, a modification marker, or a genitive morpheme. The existing accounts suffer from a variety of theoretical and empirical problems. Evidence is presented that in some other constructions and in fake modification constructions,de, while having no lexical semantic content of its own, occupies a position that is otherwise occupied by a two-place predicate. Based on this observation, a partially unitary theoretical account of fake modification constructions is formulated from a parsing perspective in the framework of Dynamic Syntax. In this account, fourde-morphemes in fake modification constructions are recognized with different syntactic distributions; however, they all contribute a semantically underspecified predicate that is updated by syntactically constrained or context-based inference.
Norwegian Emergency Medicine Systems’ Training and Equipment for Penetrating Injuries: A National Survey-Based Study
Authors: Blix Sigurd W. , Melau Jørgen , Thorvaldsen Nina , Lund-Kordahl Inger
Published: February 2021

Objective:

Recent terror attacks led the Norwegian government to develop a procedure for emergency and law enforcement services cooperation during Active Violent Incidents (AVI, abbreviated PLIVO in Norwegian). To address further national initiatives to improve preparedness for mass casualty events and penetrating injuries among emergency medical services (EMS) in Norway, training and equipment status were mapped.

Methods:

All EMS regions in Norway were invited to participate in an electronic nation-wide survey about practical medical training in PLIVO scenario training and specific training in hemorrhage control and penetrating injuries.

Results:

Ninety percent (842/938) had attended at least 1 PLIVO training scenario. Of these, 76% (642/938) reported only evacuation training during the exercise, while only 20% (168/938) had practiced hemorrhage control. Eighty-one percent (760/938) respondents reported that they were equipped with tourniquets and 91% (853/938) were equipped with gauze to pack wounds. However, only 52% (487/938) and 48% (450/938) reported practical training in tourniquet application and wound packing, respectively, while 30% (280/938) reported that they had no training or only theoretical education in tourniquet application. Supervised practical training on penetrating thoracic injuries was reported by <20%, and <50% reported practical training in needle decompression of a tension pneumothorax.

Conclusions:

Enhanced focus on training in hemorrhage control and penetrating injuries is needed. This supports the recent decision from the Norwegian government to strengthen the training for EMS in AVI (PLIVO) exercises, by focusing on medical procedures in addition to evacuation training. Although the estimated response rate is 17%, we believe the large number of respondents still make the results valuable.
Soft Law Governance in Times of Coronavirus in Spain
Authors: UTRILLA FERNÁNDEZ-BERMEJO Dolores
Published: February 2021

Early in the COVID-19 pandemic, between March and July 2020, Spanish national and regional authorities made extensive use of soft law mechanisms to fight the spread of the virus and to tackle the consequences of the crisis. Soft law was used either as an instrument in and of itself, or as a justification for hard law instruments, with more than 200 non-binding measures being enacted by the state and by the Autonomous Communities. Spanish courts also used soft law as a tool to interpret existing hard law instruments, Such uses give rise to concerns about the transparency of administrative action and the principle of legal certainty. Moreover, the widespread use of soft law to justify the adoption of binding measures restricting fundamental rights might have consequences for democratic accountability and judicial control of executive action. This article indicates the need to reconsider the current system of constitutional and legal constraints attached to this form of regulation, by introducing some binding procedural rules relating to its adoption and its publication, and by clarifying its legal effects and the mechanism through which it can be enforced by courts.
Interaction between Apo A-II -265T>C polymorphism and dietary total antioxidant capacity on some anthropometric indices and serum lipid profile in patients with type 2 diabetes mellitus
Authors: Jafari Azad Banafsheh , Yaseri Mehdi , Daneshzad Elnaz , Koohdani Fariba
Published: February 2021

The present study aimed to investigate the interaction of Apo A-II polymorphism and dietary total antioxidant capacity (DTAC) with lipid profile and anthropometric markers in patients with type 2 diabetes (T2DM) that are at risk for atherosclerosis. This cross-sectional study was conducted on 778 patients with T2DM (35–65 years). Dietary intakes were assessed by a 147-item food frequency questionnaire. DTAC was computed using international databases. Participants were categorised into two groups based on rs5082 genotypes. The gene–diet interaction was analysed by an ANCOVA multivariate interaction model. Total cholesterol, TC; triacylglycerol, TG; high- and low-density lipoprotein, HDL and LDL; TC–HDL ratio; waist circumference, WC and body mass index, BMI were obtained according to standard protocols. Overall, the frequency of CC homozygous was 12⋅1 % among study participants. We found that a significant interaction between rs5082 variants and DTAC on mean WC (PTEAC = 0⋅044), TC concentration (PFRAP = 0⋅049 and PTEAC = 0⋅031) and TC/HDL (PFRAP = 0⋅031 and PTRAP = 0⋅040). Among patients whose DTAC was higher than the median intake, the mean of weight, WC and TC/HDL were significantly higher only in individuals with CC genotype. Also, the high DTAC was associated with a lower TC concentration only in T-allele carriers (PFRAP = 0⋅042). We found that adherence to a diet with high total antioxidant capacity can improve the complications of diabetes and atherosclerosis in the T carrier genotype more effectively than the CC genotype. These results could indicate the anti-atherogenic properties of Apo A-II. However, further studies are needed to shed light on this issue.
The Emergence of New Paramilitary Organizations in Bulgaria and Yugoslavia after the First World War
Authors: Tasić Dmitar
Published: February 2021

As elsewhere in Europe after the First World War, the Balkans went through a process of “paramilitarization.” Unlike the rest of Europe, there existed a strong indigenous paramilitary culture originating from the time of Ottoman rule. In the interconnected, harsh political realities of victorious Yugoslavia and vanquished Bulgaria, both states and their political elites resolved to create new paramilitary formations. While in the case of Yugoslavia and its Organization Against Bulgarian Bandits there was a resurgence of an older style paramilitary formation, in Bulgaria leading figures of the ruling Bulgarian Agrarian National Union decided to create the Orange Guards—a completely new paramilitary formation based on the existing structure of their party. The common denominator for both formations was the threat posed by the Internal Macedonian Revolutionary Organization for security, territorial integrity, and the normal development of both states. As in most cases of paramilitary formation, their existence and actions were followed by violence, often marked by extreme brutality. Both the agrarian regime and Orange Guards perished in the violent summer of 1923, when a carefully planned and executed coup d’état ended the agrarian revolutionary attempt to transform Bulgarian society. The Organization Against Bulgarian Bandits, under the new name of Peoples Self-Defense, continued to function throughout the existence of the Yugoslav kingdom.
Remnant radio galaxies discovered in a multi-frequency survey
Authors: Quici Benjamin , Hurley-Walker Natasha , Seymour Nicholas , Turner Ross J. , Shabala Stanislav S. , Huynh Minh , Andernach H. , Kapińska Anna D. , Collier Jordan D. , Johnston-Hollitt Melanie , White Sarah V. , Prandoni Isabella , Galvin Timothy J. , Franzen Thomas , Ishwara-Chandra C. H. , Bellstedt Sabine , Tingay Steven J. , Gaensler Bryan M. , O’Brien Andrew , Rogers Johnathan , Chow Kate , Driver Simon , Robotham Aaron
Published: February 2021

The remnant phase of a radio galaxy begins when the jets launched from an active galactic nucleus are switched off. To study the fraction of radio galaxies in a remnant phase, we take advantage of a$8.31$deg$^2$subregion of the GAMA 23 field which comprises of surveys covering the frequency range 0.1–9 GHz. We present a sample of 104 radio galaxies compiled from observations conducted by the Murchison Widefield Array (216 MHz), the Australia Square Kilometer Array Pathfinder (887 MHz), and the Australia Telescope Compact Array (5.5 GHz). We adopt an ‘absent radio core’ criterion to identify 10 radio galaxies showing no evidence for an active nucleus. We classify these as new candidate remnant radio galaxies. Seven of these objects still display compact emitting regions within the lobes at 5.5 GHz; at this frequency the emission is short-lived, implying a recent jet switch off. On the other hand, only three show evidence of aged lobe plasma by the presence of an ultra-steep-spectrum ($\alpha<-1.2$) and a diffuse, low surface brightness radio morphology. The predominant fraction of young remnants is consistent with a rapid fading during the remnant phase. Within our sample of radio galaxies, our observations constrain the remnant fraction to$4\%\lesssim f_{\mathrm{rem}} \lesssim 10\%$; the lower limit comes from the limiting case in which all remnant candidates with hotspots are simply active radio galaxies with faint, undetected radio cores. Finally, we model the synchrotron spectrum arising from a hotspot to show they can persist for 5–10 Myr at 5.5 GHz after the jets switch of—radio emission arising from such hotspots can therefore be expected in an appreciable fraction of genuine remnants.
Domestic Politics, China's Rise, and the Future of the Liberal International Order
Authors: Weiss Jessica Chen , Wallace Jeremy L.
Published: February 2021

With the future of liberal internationalism in question, how will China's growing power and influence reshape world politics? We argue that views of the Liberal International Order (LIO) as integrative and resilient have been too optimistic for two reasons. First, China's ability to profit from within the system has shaken the domestic consensus in the United States on preserving the existing LIO. Second, features of Chinese Communist Party rule chafe against many of the fundamental principles of the LIO, but could coexist with a return to Westphalian principles and markets that are embedded in domestic systems of control. How, then, do authoritarian states like China pick and choose how to engage with key institutions and norms within the LIO? We propose a framework that highlights two domestic variables—centrality and heterogeneity—and their implications for China's international behavior. We illustrate the framework with examples from China's approach to climate change, trade and exchange rates, Internet governance, territorial sovereignty, arms control, and humanitarian intervention. Finally, we conclude by considering what alternative versions of international order might emerge as China's influence grows.
The Liquidation of the Greek Catholic Church in Communist Czechoslovakia, 1948–50
Authors: CORANIČ JAROSLAV
Published: February 2021

This article examines the liquidation of the Greek Catholic Church in Czechoslovakia following the Communist takeover in February 1948. The Greek Catholic Church was to be separated from the mother Catholic Church and incorporated into the Orthodox Church. The process culminated at the irregular Sobor (synod) of Prešov held on 28 April 1950. The synod was orchestrated and headed by the ruling Communist party, which enforced its conclusions. Greek Catholics were either outlawed or compelled to become Orthodox, although their situation slightly brightened during the Prague Spring of 1968 when their Church became legal again.
Crystal structure of (E)-doxepin hydrochloride, C19H22NOCl
Authors: Hong Jerry , Golab Joseph T. , Kaduk James A. , Gindhart Amy M. , Blanton Thomas N.
Published: February 2021

The crystal structure of (E)-doxepin hydrochloride has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. (E)-doxepin hydrochloride crystallizes in space group P21/a (#14) with a = 13.78488(7), b = 8.96141(7), c = 14.30886(9) Å, β = 96.5409(5)°, V = 1756.097(12) Å3, and Z = 4. There is a strong discrete hydrogen bond between the protonated nitrogen atom and the chloride anion. There are six C–H⋯Cl hydrogen bonds between the methyl groups and the chloride, as well as additional hydrogen bonds from methylene groups and the vinyl proton. The hydrogen bonds are important in determining the solid-state conformation of the cation. The compound is essentially isostructural to amitriptyline hydrochloride. The powder pattern is included in the Powder Diffraction File™ as entry 00-066-1613.
Depression and anxiety in healthcare professionals during the COVID-19 pandemic
Authors: Weibelzahl S. , Reiter J. , Duden G.
Published: February 2021

Healthcare staff have been at the centre of the fight against the COVID-19 pandemic, facing diverse work-related stressors. Building upon studies from various countries, we aimed to investigate (1) the prevalence of various work-related stressors among healthcare professionals in Germany specific to the COVID-19 pandemic, (2) the psychological effects of these stressors in terms of clinical symptoms, and (3) the healthcare professionals' help-seeking behaviour. To this end, N = 300 healthcare professionals completed an online survey including the ICD-10 Symptom Rating checklist (ISR), event-sampling questions on pandemic-related stressors and self-formulated questions on help-seeking behaviour. Participants were recruited between 22 May and 22 July 2020. Findings were analysed using t tests, regressions and comparisons to large clinical and non-clinical samples assessed before and during the pandemic. Results show that healthcare professionals were most affected by protective measures at their workplace and changes in work procedures. Psychological symptoms, particularly anxiety and depression, were significantly more severe than in a non-clinical pre-pandemic sample and in the general population during the pandemic. At the same time, most professionals indicated that they would not seek help for psychological concerns. These findings indicate that healthcare employers need to pay greater attention to the mental health of their staff.
Tending the ‘Contested’ Castle Garden: Sowing Seeds of Feminist Thought
Authors: Dempsey Karen
Published: February 2021

Medieval women are typically portrayed as secluded, passive agents within castle studies. Although the garden is regarded as associated with women there has been little exploration of this space within medieval archaeology. In this paper, a new methodological framework is used to demonstrate how female agency can be explored in the context of the lived experience of the medieval garden. In particular, this study adopts a novel approach by focusing on relict plants at some medieval castles in Britain and Ireland. Questions are asked about the curation of these plants and the associated social practices of elite women, including their expressions of material piety, during the later medieval period. This provides a way of questioning the ‘sacrality’ of medieval gardening which noblewomen arguably used as a devotional practice and as a means to further their own bodily agency through sympathetic medicine.
Carbon-reducing innovation as the essential policy frontier – towards finding the ways that work
Authors: Convery Frank J.
Published: February 2021

Finding the ways that work to deliver the innovation needed should be given parity of esteem with getting the prices right as a focus of the economics profession and policy systems. Learn from experience as regards carbon pricing and carbon-reducing innovation; insights from the latter coming mainly from the US, China and Europe; demographically relatively small countries – Denmark (wind) and Australia (solar PV) – can make outsize contributions. A carbon price ceiling is too low to drive innovation; generating carbon-reducing innovation requires that it be explicitly recognized as a priority, and nurtured accordingly: identify the priority area(s) where innovation at scale will be necessary to make progress; baseline the elements of the innovation ecosystem which are already in place, and the gaps that need to be filled. Key elements include institutions and incentives that promote innovation, a research and enterprise community that make it happen, and a supportive public.
Colorectal cancer incidence in Australia before and after mandatory fortification of bread flour with folic acid
Authors: van der Pols Jolieke C , Baade Peter , Spencer Lauren B
Published: February 2021

Objective:

Mandatory fortification of bread flour with folic acid has helped to reduce the incidence of neural tube defects in several countries. However, it has been suggested that folic acid may have potential adenoma-promoting effects, and reports from some countries have suggested that mandatory folic acid food fortification programmes have increased the incidence of colorectal cancer. The objective of this study was to evaluate colorectal cancer incidence patterns before and after introduction of mandatory folic acid fortification of bread flour in Australia in 2009.

Design:

Data from the Australian Cancer Database were used to plot age-standardised incidence of colorectal cancer. We calculated age-adjusted rate ratios with 95 % CIs.

Setting:

Australia.

Participants:

We used population-level aggregate data obtained from cancer registries.

Results:

Age-standardised colorectal cancer incidence generally decreased between 1999 and 2016. Although there was a slight increase in rates in 2010 compared with 2009 (62·8 v. 61·6 cases per 100 000, age-adjusted rate ratio 1·02 (95 % CI 0·99, 1·04), joinpoint regression indicated decreases of –0·4 % (95 % CI –0·7, 0·0) per year from 1999 to 2010 and –2·2 % (95 % CI –3·1, –1·3) per year from 2010 to 2016.

Conclusions:

While causation cannot be assessed from these population-level data, our observations indicate that there is no evidence that introduction of mandatory folic acid fortification of bread flour has influenced colorectal cancer incidence in Australia.
Hot Jupiters: Origins, Structure, Atmospheres
Authors: Fortney Jonathan J. , Dawson Rebekah I. , Komacek Thaddeus D.
Published: February 2021

We provide a brief review of many aspects of the planetary physics of hot Jupiters. Our aim is to cover most of the major areas of current study while providing the reader with additional references for more detailed follow‐up. We first discuss giant planet formation and subsequent orbital evolution via disk‐driven torques or dynamical interactions. More than one formation pathway is needed to understand the population. Next, we examine our current understanding of the evolutionary history and current interior structure of the planets, where we focus on bulk composition as well as viable models to explain the inflated radii of the population. Finally, we discuss aspects of their atmospheres in the context of observations and 1D and 3D models, including atmospheric structure and escape, spectroscopic signatures, and complex atmospheric circulation. The major opacity sources in these atmospheres, including alkali metals, water vapor, and others, are discussed. We discuss physics that control the 3D atmospheric circulation and day‐to‐night temperature structures. We conclude by suggesting important future work for still‐open questions.
Parsing Routes to Aquifer Recharge Along Mountain Fronts
Authors: Cook Terri
Published: February 2021

Research from the Tucson Basin indicates that tracers can be used to distinguish surface and subsurface recharge, providing crucial data to support sustainable water management in arid environments.
Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZβ
Authors: Ye Zuodong , Wang Dawei , Lu Yingying , He Yunjiao , Yu Jingting , Wei Wenjie , Chen Chang , Wang Rui , Zhang Liang , Zhang Liangren , Le Minh T. N. , Cho William C. , Yang Mengsu , Zhang Hongmin , Yue Jianbo
Published: February 2021

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZβ to inhibit endosomal trafficking and metastasis.
Long-term biopsy outcomes in prostate cancer patients treated with external beam radiotherapy: a systematic review and meta-analysis
Authors: Singh Saurabh , Moore Caroline M. , Punwani Shonit , Mitra Anita V. , Bandula Steve
Published: February 2021

Background

Biopsy after external beam radiotherapy (EBRT) for localised prostate cancer (PCa) is an infrequently used but potentially valuable technique to evaluate local recurrence and predict long-term outcomes.

Methods

We performed a meta-analysis of studies until March 2020 where a post-EBRT biopsy was performed on patients with low-to intermediate risk PCa, according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The primary outcome was the aggregate post-EBRT positive biopsy rate (≥2 years after EBRT) and the associated odds ratio (OR) of a positive biopsy on biochemical failure (BCF), distant metastasis-free survival (DMFS) and prostate cancer-specific mortality (PCSM). A sensitivity analysis was performed which examined biopsy rate as a function of post-EBRT biopsy protocol, PCa risk, ADT usage and radiation dose.

Results

A total of 22 studies were included, of which 10 were randomised controlled trials and 12 were cohort studies. Nine out of the 22 studies used dosing regimens consistent with the 2020 NCCN radiotherapy guidelines. The weighted-average positive biopsy rate across all 22 studies was 32% (95%-CI: 25–39%, n = 3017). In studies where post-treatment biopsy was part of the study protocol, the rate was 35% (95%-CI: 21–38%, n = 2450). In the subgroup of studies that conformed to the 2020 NCCN radiotherapy guidelines, this rate was 22% (95% CI: 19–41%, n = 832). Patients with positive biopsy had a 10-fold higher odds of developing BCF (OR of 10.3, 95%-CI: 3.7–28.7, p < 0.00001), 3-fold higher odds of developing distant metastasis (OR 3.1, 95%-CI: 2.1–4.7, p < 0.00001) and 5-fold higher odds of dying from their PCa (OR 5.1, 95%-CI: 2.6–10, p < 0.00001).

Conclusion

A positive biopsy after EBRT is associated with a poor prognosis compared to a negative biopsy. The post-EBRT positive biopsy rate is an important measure which provides additional insight when comparing EBRT to other treatment modalities for PCa.
Psychological distress in men with prostate cancer undertaking androgen deprivation therapy: modifying effects of exercise from a year-long randomized controlled trial
Authors: Galvão Daniel A. , Newton Robert U. , Chambers Suzanne K. , Spry Nigel , Joseph David , Gardiner Robert A. , Fairman Ciaran M. , Taaffe Dennis R.
Published: February 2021

Objectives

To assess the long-term effects of various exercise modes on psychological distress in men with prostate cancer on androgen deprivation therapy (ADT).

Patients and methods

135 prostate cancer patients aged 43–90 years on ADT were randomized to twice weekly supervised impact loading and resistance exercise (ImpRes), supervised aerobic and resistance exercise (AerRes), and usual care/delayed supervised aerobic exercise (DelAer) for 12 months, and completed measures of psychological distress using the Brief Symptom Inventory-18 (BSI-18). BSI-18 provides three subscales for anxiety, depression, and somatisation, as well as the global severity index (GSI) where higher scores indicate higher distress.

Results

Following the intervention, somatization was not different to baseline, however, there were significant interactions (p < 0.01) for depression, anxiety, and the GSI. In ImpRes, depression was reduced at 12 months compared to baseline and 6 months (0.78 ± 1.39 vs. 1.88 ± 3.24 and 1.48 ± 2.65, p < 0.001), as was the GSI (3.67 ± 4.34 vs. 5.94 ± 7.46 and 4.64 ± 4.73, p < 0.001) with anxiety reduced compared to baseline (1.08 ± 1.54 vs. 1.98 ± 2.56). Depression and the GSI decreased (p < 0.05) in AerRes at 6 months but increased by 12 months, while in DelAer the GSI was reduced at 12 months compared to 6 months (3.78 ± 3.94 vs. 5.25 ± 4.22, p = 0.031). Men with the highest level of anxiety, depression, somatization, and the GSI improved the most with exercise (ptrend < 0.001).

Conclusion

Various supervised exercise modes (aerobic, resistance and impact loading) are effective in reducing psychological distress in men with prostate cancer on ADT. Those with the highest level of psychological distress improved the most. Supervised exercise should be prescribed to improve psychological health in prostate cancer patients on ADT.
Exploring the contextual transition from spinal cord injury rehabilitation to the home environment: a qualitative study
Authors: Weber Lene , Voldsgaard Nanna Hoffgaard , Holm Nicolaj Jersild , Schou Lone Helle , Biering-Sørensen Fin , Møller Tom
Published: February 2021

Study design

Explorative qualitative study based on an interpretative phenomenological approach.

Objectives

This study explored the possibility of transferring knowledge and skills from a spinal cord injury (SCI) unit to the home environment; the individual and structural factors that potentially influenced this transfer; and its compatibility with a meaningful everyday life.

Setting

Hospital-based rehabilitation unit and community in Denmark.

Methods

Fourteen individuals with SCI were selected with maximum variation according to age, sex, marital status, and level of injury. In-depth, semi-structured interviews were conducted in the participants’ homes, 2–10 months after discharge from an SCI unit. Data analysis involved taking an interpretative phenomenological approach combined with a template analysis and applying the transfer of training theory to the discussion.

Results

Transitioning from the SCI unit to the home environment involved a multidimensional change of context in which most of the participants’ previous life roles had changed. This overarching theme had a decisive influence on: balancing loss and acceptance, facing external structural barriers, and the strength of social relationships when the knowledge and skills acquired at the unit were applied in a meaningful everyday life.

Conclusions

Transition from the SCI unit to the home environment is influenced by a multidimensional change of context that may restrict the use of acquired skills post-discharge, provide distant prospects for tertiary health promotion, and aggravate the experience of loss in people with SCI. Maintaining relationships is a strong mediator for transferring skills and re-establishing a meaningful everyday life.
Priority effects dictate community structure and alter virulence of fungal-bacterial biofilms
Authors: Cheong J Z Alex , Johnson Chad J , Wan Hanxiao , Liu Aiping , Kernien John F , Gibson Angela L F , Nett Jeniel E , Kalan Lindsay R
Published: February 2021

Polymicrobial biofilms are a hallmark of chronic wound infection. The forces governing assembly and maturation of these microbial ecosystems are largely unexplored but the consequences on host response and clinical outcome can be significant. In the context of wound healing, formation of a biofilm and a stable microbial community structure is associated with impaired tissue repair resulting in a non-healing chronic wound. These types of wounds can persist for years simmering below the threshold of classically defined clinical infection (which includes heat, pain, redness, and swelling) and cycling through phases of recurrent infection. In the most severe outcome, amputation of lower extremities may occur if spreading infection ensues. Here we take an ecological perspective to study priority effects and competitive exclusion on overall biofilm community structure in a three-membered community comprised of strains of Staphylococcus aureus, Citrobacter freundii, and Candida albicans derived from a chronic wound. We show that both priority effects and inter-bacterial competition for binding to C. albicans biofilms significantly shape community structure on both abiotic and biotic substrates, such as ex vivo human skin wounds. We further show attachment of C. freundii to C. albicans is mediated by mannose-binding lectins. Co-cultures of C. freundii and C. albicans trigger the yeast-to-hyphae transition, resulting in a significant increase in neutrophil death and inflammation compared to either species alone. Collectively, the results presented here facilitate our understanding of fungal-bacterial interactions and their effects on host-microbe interactions, pathogenesis, and ultimately, wound healing.
Soil microbial diversity–biomass relationships are driven by soil carbon content across global biomes
Authors: Bastida Felipe , Eldridge David J , García Carlos , Kenny Png G , Bardgett Richard D , Delgado-Baquerizo Manuel
Published: February 2021

The relationship between biodiversity and biomass has been a long standing debate in ecology. Soil biodiversity and biomass are essential drivers of ecosystem functions. However, unlike plant communities, little is known about how the diversity and biomass of soil microbial communities are interlinked across globally distributed biomes, and how variations in this relationship influence ecosystem function. To fill this knowledge gap, we conducted a field survey across global biomes, with contrasting vegetation and climate types. We show that soil carbon (C) content is associated to the microbial diversity–biomass relationship and ratio in soils across global biomes. This ratio provides an integrative index to identify those locations on Earth wherein diversity is much higher compared with biomass and vice versa. The soil microbial diversity-to-biomass ratio peaks in arid environments with low C content, and is very low in C-rich cold environments. Our study further advances that the reductions in soil C content associated with land use intensification and climate change could cause dramatic shifts in the microbial diversity-biomass ratio, with potential consequences for broad soil processes.
Urological cancer patients receiving treatment during COVID-19: a single-centre perspective
Authors: Williams Sophie Therese , El Badri Salma , Hussain Syed Anwer
Published: February 2021

Background

Active cancer, immunosuppressive treatments and immunotherapies have been reported to increase cancer patients’ risk of developing severe COVID-19 infection. For patients and clinicians, treatment risk must be weighed against disease progression.

Methods

This retrospective case series surveys urological cancer patients who made informed decisions to continue anticancer treatment (ACT) at one centre from March to June 2020.

Results

Sixty-one patients (44 bladder, 10 prostate, 7 upper urinary tract cancers) received 195 cycles of ACT (99 chemotherapy, 59 immunotherapy, 37 as part of ongoing clinical trials), with a range of indications: 43 palliative, 10 neoadjuvant, 8 adjuvant. One patient tested positive for COVID-19 but experienced only mild symptoms. Fourteen patients interrupted treatment outside of their schedule, seven of these due to potential COVID-19 associated risk. ACT supportive steroids were not associated with higher rates of COVID-19.

Conclusions

This single-centre series reports that ACT administration did not result in an apparent excess in symptomatic COVID-19 infections.
Recovery strategies following COVID-19 disruption to cervical cancer screening and their impact on excess diagnoses
Authors: Castanon Alejandra , Rebolj Matejka , Pesola Francesca , Sasieni Peter
Published: February 2021

Background

The COVID-19 pandemic has disrupted cervical cancer screening services. Assuming increases to screening capacity are unrealistic, we propose two recovery strategies: one extends the screening interval by 6 months for all and the other extends the interval by 36/60 months, but only for women who have already missed being screened.

Methods

Using routine statistics from England we estimate the number of women affected by delays to screening. We used published research to estimate the proportion of screening age women with high-grade cervical intraepithelial neoplasia and progression rates to cancer. Under two recovery scenarios, we estimate the impact of COVID-19 on cervical cancer over one screening cycle (3 years at ages 25–49 and 5 years at ages 50–64 years). The duration of disruption in both scenarios is 6 months. In the first scenario, 10.7 million women have their screening interval extended by 6 months. In the second, 1.5 million women (those due to be screened during the disruption) miss one screening cycle, but most women have no delay.

Results

Both scenarios result in similar numbers of excess cervical cancers: 630 vs. 632 (both 4.3 per 100,000 women in the population). However, the scenario in which some women miss one screening cycle creates inequalities—they would have much higher rates of excess cancer: 41.5 per 100,000 delayed for screened women compared to those with a 6-month delay (5.9 per 100,000).

Conclusion

To ensure equity for those affected by COVID-19 related screening delays additional screening capacity will need to be paired with prioritising the screening of overdue women.
Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data
Authors: Joussen Antonia M. , Ricci Federico , Paris Liliana P. , Korn Claudia , Quezada-Ruiz Carlos , Zarbin Marco
Published: February 2021

The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.
Ethnic-specific association of amylase gene copy number with adiposity traits in a large Middle Eastern biobank
Authors: Rossi Niccolo’ , Aliyev Elbay , Visconti Alessia , Akil Ammira S. A. , Syed Najeeb , Aamer Waleed , Padmajeya Sujitha S. , Falchi Mario , Fakhro Khalid A.
Published: February 2021

Studies assessing the impact of amylase genes copy number (CN) on adiposity report conflicting findings in different global populations, likely reflecting the impact of ancestral and ethnic-specific environment and lifestyle on selection at the amylase loci. Here, we leverage population size and detailed adiposity measures from a large population biobank to resolve confounding effects and determine the relationship between salivary (AMY1) and pancreatic (AMY2A) amylase genes CN and adiposity in 2935 Qatari individuals who underwent whole-genome sequencing (WGS) as part of the Qatar Genome Programme. We observe a negative association between AMY1 CNs and trunk fat percentage in the Qatari population (P = 7.50 × 10−3) and show that Qataris of Arab descent have significantly lower CN at AMY1 (P = 1.32 × 10−10) as well as less favorable adiposity and metabolic profiles (P < 1.34 × 10−8) than Qataris with Persian ancestry. Indeed, lower AMY1 CN was associated with increased total and trunk fat percentages in Arabs (P < 4.60 × 10−3) but not in Persians. Notably, overweight and obese Persians reported a significant trend towards dietary restraint following weight gain compared to Arabs (P = 4.29 × 10−5), with AMY1 CN showing negative association with dietary self-restraint (P = 3.22 × 10−3). This study reports an association between amylase gene CN and adiposity traits in a large Middle Eastern population. Importantly, we leverage rich biobank data to demonstrate that the strength of this association varies with ethnicity, and may be influenced by population-specific behaviors that also contribute to adiposity traits.