bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering the role ofLeptospirasurface protein LigA in modulating the host innate immune response
Authors: Kumar Ajay , Varma Vivek P. , Sridhar Kavela , Abdullah Mohd , Vyas Pallavi , Muhammed Ashiq T , Chang Yung-Fu , Faisal Syed M.
Published: October 2020

Leptospira, a zoonotic pathogen, is known to infect various hosts and can establish persistent infection. This remarkable ability of bacteria is attributed to its potential to modulate the host immune response by exploiting its surface proteins. We have identified and characterized the domain of the variable region ofLeptospiraimmunoglobulin-like protein A (LAV) involved in immune modulation. The 11thdomain (A11) of the variable region of LigA (LAV) induces a strong TLR4 dependent innate response leading to subsequent induction of humoral and cellular immune responses in mice. A11is also involved in acquiring complement regulator FH and binds to host protease Plasminogen (PLG), there by mediating functional activity to escape from complement-mediated killing. The deletion of A11domain significantly impaired TLR4 signaling and subsequent reduction in the innate and adaptive immune response. It also inhibited the binding of FH and PLG thereby mediating killing of bacteria. Our study discovered an unprecedented role of LAV as a nuclease capable of degrading Neutrophil Extracellular Traps (NETs). This nuclease activity was primarily mediated by A11. These results highlighted the moonlighting function of LigA and demonstrated that a single domain of a surface protein is involved in evading a myriad of host innate immune defenses, which might allow the persistence ofLeptospirain different hosts for a long term without clearance.
Vulnerability of ARID1A deficient cancer cells to pyrimidine synthesis blockade
Authors: Li Zhigui , Mi Shijun , Osagie Oloruntoba I. , Ji Jing , Yang Chia-Ping H. , Schwartz Melissa , Hui Pei , Huang Gloria S.
Published: October 2020

Here we report the discovery and preclinical validation of a novel precision medicine strategy forARID1A-mutated cancer. Unbiased proteomics reveals for the first time that ARID1A protein (BAF250a) binds aspartate transcarbamoylase (ATCase), a key regulatory enzyme of thede novopyrimidine synthesis pathway. Using isogenic paired ARID1A proficient/deficient cancer cell lines, we show that ARID1A protein deficiency (as occurs inARID1Amutant cancers) leads to metabolic reprogramming and pyrimidine synthesis dependency. Pyrimidine synthesis blockade using the FDA-approved drug teriflunomide (a DHODH inhibitor) suppresses tumor growth and selectively induces DNA damage in ARID1A-deficient tumor models. Combining pyrimidine synthesis inhibition with DNA damage repair blockade, using teriflunomide and AZD6738 (an ATR inhibitor), achieves potent synergy and induces sustained tumor regression inARID1A-mutant ovarian cancer patient-derived xenografts (PDX). These compelling preclinical data support the evaluation of this novel combination treatment in patients withARID1A-mutated cancers.

SIGNIFICANCE

We identified that ARID1A-deficient cells are selectively vulnerable to pyrimidine synthesis blockade. Preclinical studies demonstrate thein vivoefficacy of a synergistic drug combination that concurrently inhibits the de novo pyrimidine synthesis pathway and DNA damage repair to induce regression in patient-derived xenograft models of ARID1A-mutated cancer.
SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells
Authors: Suzuki Yuichiro J. , Nikolaienko Sofia I. , Dibrova Vyacheslav A. , Dibrova Yulia V. , Vasylyk Volodymyr M. , Novikov Mykhailo Y. , Shults Nataliia V. , Gychka Sergiy G.
Published: October 2020

Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. So far, 30 million people have been infected with SARS-CoV-2, and nearly 1 million people have died because of COVID-19 worldwide, causing serious health, economical, and sociological problems. However, the mechanism of the effect of SARS-CoV-2 on human host cells has not been defined. The present study reports that the SARS-CoV-2 spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in lung vascular cells. The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 – Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of SARS-CoV-2 spike protein S1 subunit (Arg319 – Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients. Thus, SARS-CoV-2 spike protein-mediated cell growth signaling may participate in adverse cardiovascular/pulmonary outcomes, and this mechanism may provide new therapeutic targets to combat COVID-19.
Evidence integration and decision-confidence are modulated by stimulus consistency
Authors: Glickman Moshe , Moran Rani , Usher Marius
Published: October 2020

Evidence-integration is a normative algorithm for choosing between alternatives with noisy evidence, which has been successful in accounting for a vast amount of behavioral and neural data. However, this mechanism has been challenged as tracking integration boundaries sub-serving choice has proven elusive. Here we first show that the decision boundary can be monitored using a novel, model-free behavioral method, termedDecision-Classification Boundary. This method allowed us to both provide direct support for evidence-integration contributions and to identify a novel integration-bias, whereby incoming evidence is modulated based on its consistency with evidence from preceding time-frames. This consistency bias was supported in three cross-domain experiments, involving decisions with perceptual and numerical evidence, which showed that choice-accuracy and decision confidence are modulated by stimulus consistency. Strikingly, despite its seeming sub-optimality, this bias fosters performance by enhancing robustness to integration noise. We argue this bias constitutes a new form of micro-level, within-trial, confirmation bias and discuss implications to broad aspects of decision making.
Replication intermediate architecture reveals the chronology of DNA damage tolerance pathways at UV-stalled replication forks in human cells
Authors: Benureau Yann , Pouvelle Caroline , Tavares Eliana Moreira , Dupaigne Pauline , Despras Emmanuelle , Cam Eric Le , Kannouche Patricia
Published: October 2020

DNA lesions in S phase threaten genome stability. The DNA damage tolerance (DDT) pathways overcome these obstacles and allow completion of DNA synthesis by the use of specialised translesion (TLS) DNA polymerases or through recombination-related processes. However, how these mechanisms coordinate with each other and with bulk replication remain elusive. To address these issues, we monitored the variation of replication intermediate architecture in response to ultraviolet irradiation using transmission electron microscopy. We show that the TLS polymeraseη, able to accurately bypass the major UV lesion and mutated in the skin cancer-prone xeroderma pigmentosum variant (XPV) syndrome, acts at the replication fork to resolve uncoupling and prevent post-replicative gap accumulation. Repriming occurs as a compensatory mechanism when this on-the-fly mechanism cannot operate, and is therefore predominant in XPV cells. Interestingly, our data support a recombination-independent function of RAD51 at the replication fork to sustain repriming. Finally, we provide evidence for the post-replicative commitment of recombination in gap repair and for pioneering observations ofin vivorecombination intermediates. Altogether, we propose a chronology of UV damage tolerance in human cells that highlights the key role of polηin shaping this response and ensuring the continuity of DNA synthesis.
In situhigh-temperature X-ray diffraction study of Sc-doped titanium oxide nanocrystallites
Authors: Zenou Victor Y. , Bertolotti Federica , Guagliardi Antonietta , Toby Brian H. , Von Dreele Robert B. , Bakardjieva Snejana
Published: October 2020

Titanium dioxide is an inexpensive wide-gap highly ionic semiconductor with striking photocatalytic capabilities in several heterogeneous photoredox reactions. A small crystal size is desirable to maximize the surface area, since photocatalytic reactions occur at the surface of a photocatalyst. Presented here are the synthesis and microstructural characterization of 4 at.% Sc-doped TiO2(4SDT) prepared by water-based co-precipitation. The crystal structure of 4SDT was examined viain situhigh-temperature powder X-ray diffraction experiments from 25 to 1200°C. Rietveld analysis revealed single-phase anatase up to 875°C, while at 900°C the anatase-to-rutile phase transformation occurred and at higher temperatures additional reflections of Sc-rich phases (Sc2TiO5from 975°C and Ti3Sc4O12or Sc2O3at 1200°C) were observed. Debye function analysis (DFA) was applied to model the total scattering pattern directly in reciprocal space, allowing the reconstruction of Ti vacancies. Both Rietveld and DFA methods were applied to estimate the nanocrystallite size and shape with consistent growth in crystallite size with temperature: an ellipsoid shape with equatorial ∼4.7 nm / axial (001) ∼6.9 nm at 25°C to equatorial ∼27.9 nm / axial (001) ∼39.6 nm at 900°C refined by Rietveld analysis,versusa cylinder shape withDa,b= 4.3 nm and size dispersion σab= 1.5 nm,Lc= 4.9 nm and σc= 2.3 nm at 25°C toDa,b= 21.4 nm, σab= 8.3 nm,Lc= 23.9 and σc= 10.9 nm at 900°C estimated by DFA. The microstructural changes obtained by Rietveld and DFA methods were supported by high-resolution transmission electron microscopy image analysis, as well as by the less direct nitrogen sorption techniques that provide information on the size of non-agglomerated and dense particles. The Ti site-occupancy factor showed a linear increase from 0.6–0.8 at 25°C to unity at 900°C for anatase, and from ∼0.7 at 900°C to unity at 1200°C for rutile, via Rietveld analysis and DFA.
Analysis of the duration of abstinence after treatment for alcohol dependence in a therapeutic community: differences between the sexes
Authors: Riera-Oliver Núria , Jiménez Carmen , Rey Joan , Calvo Ana Belén , Sanchez-Gutierrez Teresa
Published: October 2020

Purpose

The use and abuse of alcohol is problematic for a person’s social and individual development. Maintenance of abstinence after detoxification programs is difficult for patients who experience a craving, and relapses during the course of the disorder are common. The purpose of this paper is to describe the socio-demographic and clinical features of alcohol-dependent patients by sex and alcohol use status and to analyze the percentage of patients who remained abstinent after 10 months of psychological treatment.

Design/methodology/approach

In total, 50 alcohol-dependent patients were enrolled (34 men and 16 women). The patients attended a psychological treatment program at a therapeutic community, Projecte Home Balears, Spain. This paper used the European Addiction Severity Index to collect socio-demographic data and data on alcohol and other drugs and the Trait Meta-Mood Scale-24 to measure emotional management.

Findings

Significant differences were observed in occupation (χ²= 9.9; p = 0.007) and duration of alcohol use (U = 137.000; p = 0.005) by sex and hospitalizations during the previous months (χ²= 15.477; p = 0.009) and type of chronic disorder (χ²= 7.6; p = 0.022) and duration (in months) of the longest period of abstinence after treatment in facilities (U = 219.500; p = 0.097) by alcohol use status. The survival analysis showed that 25% of relapses happened after 4.5 months of treatment; at 7.3 months, 50% of the sample remained abstinent.

Originality/value

Women had used alcohol for longer since age at onset than men. Furthermore, after 7.3 months of intensive therapy, 50% of alcohol-dependent patients were abstinent.
Order‐controlled closed‐loop focal beams and resolution comparison of primary and multiple reflections for seismic acquisition geometries
Authors: Wei Wei , Blacquière Gerrit
Published: October 2020

Focal beam analysis has built a bridge between the acquisition parameters on the surface and the image quality of underground targets. However, as a practical matter, it is still difficult to answer how to choose a proper acquisition geometry according to the complexity of medium, especially considering the contradictory effects of multiple reflections on spatial resolution as they can be considered to be either potential signal or additional noise, depending on the envisioned imaging technology. We introduce an order‐controlled, closed‐loop focal beam method in which the migration operator and the resolution function can be analysed in the process of the closed‐loop migration with full control over the order of the surface and internal multiples considered. This method highlights the effects of primary and different‐order multiple wavefields on the imaging resolution for different acquisition geometries and various overburden strata. We apply the method to analyse the predicted resolution of seismic acquisition geometries considering multiples as either noise or signal. Results show, in the acquisition geometry design, that when the primaries cannot provide a complete spatial illumination for the subsurface target, e.g. because of the limited‐aperture acquisition geometries or the complicated overburden, we should use the closed‐loop focal beam analysis to assess the contradictory effects of multiples as both signal and noise, in which the maximum order of multiples ought to be chosen according to the core aim of the acquisition analysis. We can apply the second‐order closed‐loop focal beam analysis to quantify the effects of acquisition geometries on multiple‐wave suppression and can also perform the high‐order closed‐loop focal beam analysis to quantify the effects of acquisition geometries on high‐resolution imaging (migration). This method can also be used to choose the optimal order of multiples in the closed‐loop migration.
Surplus men and scarce women: The impact of mating competition on the desire for sons in China*
Authors: Dong Zhiqiang , Alhaj‐Yaseen Yaseen , Jiao Yang , Zhong Yuejun
Published: October 2020

We conducted this research to explore the possible factors shaping son preference, with a view to understanding the persistently high male/female sex ratio. Using data from the Chinese General Social Survey (CGSS) and the Population Census of China, we find a significant impact of regional sex ratio on people's preferences for the sex of their future children. Specifically, the extent of son preference decreases with the increase in the male/female sex imbalance in the local area. We also find that sex imbalance has a positive impact on a wide range of outcomes that capture the pressure on males to enter marriage markets, such as regional housing prices, the number of houses owned, and family economic status. This result is consistent with the view that greater sex imbalance exerts larger pressure on men in the marriage market, leading to changes in son preference. Omitted variable bias is addressed by using climate changes in the month preceding the fertilization period as an instrument for sex ratio. Instrumental sex ratio negatively impacts son preference, offering strong support for our hypothesis.
Review of thermal and non‐thermal based endovenous treatment: Our local experience
Authors: Au‐Yeung Chung Ling Karen , Tse On Ho Ronald , Pang Yin Chun Skyi , Tang Chung Ngai
Published: October 2020

Background

Endovenous treatment for varicose veins has become increasingly popular over the last decade. Compared to conventional surgery, endovenous options promise lower wound infection rates, less pain and quicker return to normal activities. Treatment modalities can be divided into thermal (EVLT / RFA) or non‐thermal based (Cyanoacrylate glue / MOCA). Literature review has not shown much difference between the two branches of treatment, and there remains a paucity of local data, hence we decided to conduct our own study to investigate the question.

Methods

A retrospective single centre study was performed by pooling data from the Hong Kong Health Authorities electronic patient database between March 2012 and July 2018. Patients who had the procedure done under local anaesthetics were then contacted by phone and interviewed regarding their peri‐operative pain.

Results

The study included 223 patients, 155 patients underwent radiofrequency ablation (RFA) thermal treatment and 68 patients underwent VenaSeal (Cyanoacrylate glue) non‐thermal treatment. Patients were demographically similar in terms of age, comorbidities, severity of varicose vein disease. More patients with thermal treatments had their procedure performed under general anaesthesia (GA) or monitored anaesthetic care (MAC) as compared to non‐thermal treatments. Patients were followed up for an average of 2.4 years in the thermal group and 1.3 years in the non‐thermal group. Patients in the non‐thermal group reported less perioperative pain, but overall, there were minimal complications and recurrence in both treatment modalities.

Conclusion

Both types of endovenous treatment seem equally effective with few complications. Future prospective studies can be performed to reduce study bias.
UK after Brexit – a Massive Field Experiment for CAP Reform?
Authors: Hill Berkeley
Published: October 2020

As a consequence of the UK leaving the EU (‘Brexit’) and after almost five decades of sharing the Common Agricultural Policy, its objectives and instruments, the UK is about to embark on a set of four national agricultural policies, one for each constituent country. Legislation for England, which accounts for more than 70 per cent of UK aggregate farm income, will provide for some continuity, such as agri‐environmental schemes and multi‐annual programming. However, there will be a radical reform of the income support system as direct payments are progressively scaled down over seven years, a move that has been widely advocated inside and outside government. Similar change within the CAP has been rejected by the EU as a whole. The diverging paths will provide a valuable and rare opportunity to compare policy approaches in what is really a massive field experiment. Careful monitoring should be capable of casting light on the impact that removing direct income payments has on issues such as production levels, farm household incomes, innovation and investment, structural change, succession and the social contributions made by the farm sector. This information could be of great relevance to the EU‐27 if in the future it chooses to follow a similar path of reform.
Age‐induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge
Authors: Moore Timothy M. , Zhou Zhenqi , Strumwasser Alexander R. , Cohn Whitaker , Lin Amanda J. , Cory Kevin , Whitney Kate , Ho Theodore , Ho Timothy , Lee Joseph L. , Rucker Daniel H. , Hoang Austin N. , Widjaja Kevin , Abrishami Aaron D. , Charugundla Sarada , Stiles Linsey , Whitelegge Julian P. , Turcotte Lorraine P. , Wanagat Jonathan , Hevener Andrea L.
Published: October 2020

Mitochondrial dysfunction is frequently associated with impairment in metabolic homeostasis and insulin action, and is thought to underlie cellular aging. However, it is unclear whether mitochondrial dysfunction is a cause or consequence of insulin resistance in humans. To determine the impact of intrinsic mitochondrial dysfunction on metabolism and insulin action, we performed comprehensive metabolic phenotyping of the polymerase gamma (PolG) D257A “mutator” mouse, a model known to accumulate supraphysiological mitochondrial DNA (mtDNA) point mutations. We utilized the heterozygous PolG mutator mouse (PolG+/mut) because it accumulates mtDNA point mutations ~ 500‐fold > wild‐type mice (WT), but fails to develop an overt progeria phenotype, unlike PolGmut/mut animals. To determine whether mtDNA point mutations induce metabolic dysfunction, we examined male PolG+/mut mice at 6 and 12 months of age during normal chow feeding, after 24‐hr starvation, and following high‐fat diet (HFD) feeding. No marked differences were observed in glucose homeostasis, adiposity, protein/gene markers of metabolism, or oxygen consumption in muscle between WT and PolG+/mut mice during any of the conditions or ages studied. However, proteomic analyses performed on isolated mitochondria from 12‐month‐old PolG+/mut mouse muscle revealed alterations in the expression of mitochondrial ribosomal proteins, electron transport chain components, and oxidative stress‐related factors compared with WT. These findings suggest that mtDNA point mutations at levels observed in mammalian aging are insufficient to disrupt metabolic homeostasis and insulin action in male mice.
Maximum information per time unit designs for continuous online item calibration
Authors: He Yinhong , Chen Ping , Li Yong
Published: October 2020

Previous designs for online calibration have only considered examinees’ responses to items. However, the use of response time, a useful metric that can easily be collected by a computer, has not yet been embedded in calibration designs. In this article we utilize response time to optimize the assignment of new items online, and accordingly propose two new adaptive designs. These are the D‐optimal per expectation time unit design (D‐ET) and the D‐optimal per time unit design (D‐T). The former method uses the conditional maximum likelihood estimation (CMLE) method to estimate the expected response times, while the latter employs the nonparametric k‐nearest‐neighbour method to predict the response times. Simulations were conducted to compare the two new designs with the D‐optimal online calibration design (D design) in the context of continuous online calibration. In addition, a preliminary study was carried out to evaluate the performance of CMLE prior to its application in D‐ET. The results showed that, compared to the D design, the D‐ET and D‐T designs saved response time and accrued larger calibration information per time unit, without sacrificing item calibration precision.
Debate: The impact of school closures and lockdown on mental health in young people
Authors: Townsend Ellen
Published: October 2020

The COVID‐19 pandemic lockdown response has had a disproportionate and damaging effect on the lives, mental health and well‐being of young people globally. They have been neglected in policy‐making and their needs have been subjugated to those of adults which contravenes the UN Convention on the Rights of the Child. Here, I argue that the needs and rights of young people must come first to protect their health, mental health and futures. If we do not do this, we will let down a generation of children who will bear the brunt of the fallout of the economic burden of the global COVID‐19 crisis.
Repair Avoidance: When Faithful Informational Exchanges Don't Matter That Much
Authors: Galantucci Bruno , Langstein Benjamin , Spivack Eliyahu , Paley Nathaniel
Published: October 2020

Common‐sense intuition suggests that, when people are engaged in informational exchanges, they communicate so as to be reasonably sure that they perform the exchanges faithfully. Over the years, we have found evidence suggesting that this intuition, which is woven into several influential theories of human communication, may be misleading. We first summarize this evidence and discuss its potential limitations. Then, we present a new study that addresses the potential limitations. A confederate instructed participants to “pick up the skask” from a tray containing six objects and move it to a specific location. Since skask is a non‐word invented by us, participants had to ask for clarification to perform the instruction faithfully. In contradiction with the intuition that people pursue faithfulness when engaged in informational exchanges, 29 of the 48 participants we tested performed the instruction without asking for clarification. We identified a possible cause for this behavior, which occurred more frequently when avoiding the clarification was unlikely to result in an overt consequence (an error in the execution of the instruction that could be noticed by the confederate or the experimenter). Other factors such as individual differences and the specific interpersonal dynamics of the experimental settings, if they played a role at all, did it to an extent that is unlikely to be comparable to that of the role played by overt consequences. Considered together, our various assessments of the extent to which people engage in faithful informational exchanges converge on a simple conclusion: Communicating faithfully is a substantially demanding task, and people often fail at it. We discuss the implications of this conclusion and speculate on its relevance for understanding the evolutionary past of human communication.
Long‐lasting cluster of nosocomial pneumonia with a single Pneumocystis jirovecii genotype involving different organ allograft recipients
Authors: Hosseini‐Moghaddam Seyed M. , Dufresne Philippe J. , Hunter Gutierrez Elaine , Dufresne Simon F. , House Andrew A. , Humar Atul , Kumar Deepali , Jevnikar Anthony M.
Published: October 2020

Pneumocystis pneumonia (PCP) outbreaks may occur in solid organ transplant (SOT) patients. Transmissibility of Pneumocystis jirovecii among SOT and non‐SOT patients has not been investigated. Ten SOT (ie, 4 heart, 4 kidney, 2 liver allograft recipients) and 11 non‐SOT (ie, 7 HIV‐infected, 3 hematologic malignancies, and 1 stem cell transplant) patients with PCP were admitted to London Health Sciences Center (LHSC) from October 2014 to August 2016. We investigated the course of illness and outcome of PCP in SOT and non‐SOT patients. Post‐transplant PCP was frequently an acute‐onset disease (90% vs. 18.2%, p = .01) requiring ICU admission (70% vs. 20%, p = .03) and hemodialysis (60% vs. 0, p = .003). Mortality was more frequent in SOT patients (40% vs. 18.1%, p = .36). Multilocus sequence typing (MLST) demonstrated circulation of a single genotype of P. jirovecii among SOT patients. However, 8 different genotypes were detected from non‐SOT patients. Reinstitution of prophylaxis successfully controlled post‐transplant cluster until end of observation period in October 2019. No transmission was detected from non‐SOT patients to SOT recipients. Detection of a single P. jirovecii genotype from all SOT recipients highlights the likelihood of nosocomial transmission. No source control method is recommended by current guidelines. Improvement of preventive strategies is required.
Correlation Analysis Among the Level of IL‐35, Microvessel Density, Lymphatic Vessel Density, and Prognosis in Non‐Small Cell Lung Cancer
Authors: Zhang Tenglong , Nie Jing , Liu Xiaojiang , Han Zenglei , Ding Ning , Gai Kai , Liu Yang , Chen Ling , Guo Chengye
Published: October 2020

The aim of this study was to determine the expression of IL‐35 and the lymphatic vessel density (LVD) and microvessel density (MVD) in the pathological tissues from patients with non‐small cell lung cancer (NSCLC) and to analyze their correlation with other common clinical prognostic factors, as well as patients’ overall survival and progression‐free survival. We analyzed the pathological characteristics of 130 patients with NSCLC and determined the IL‐35 expression, MVD, and LVD changes in the pathological tissues by immunohistochemistry. The results showed that IL‐35 expression was significantly correlated with tumor differentiation, lymph node metastasis, T staging, LVD, and MVD (P < 0.05) but was not associated with age, sex, smoking, and other factors. Univariate analysis of risk models showed that age, lymph node metastasis, T stage, and high IL‐35 expression, LVD, and MVD were significantly associated with NSCLC prognosis (P < 0.05), whereas sex, smoking, and high differentiation were not correlated with prognosis. Multivariate analysis of the proportional risk model showed that the IL‐35 expression, lymph node metastasis, high LVD, and high MVD were significantly correlated with NSCLC prognosis (P < 0.05). In conclusion, IL‐35, MVD, and LVD may be independent prognostic markers. In addition, IL‐35 might represent a promising clinical drug target for the treatment of NSCLC.
Retrospective Review of Pharmacogenetic Testing at an Academic Children’s Hospital
Authors: Roberts Timothy A. , Wagner Jennifer A. , Sandritter Tracy , Black Benjamin T. , Gaedigk Andrea , Stancil Stephani L.
Published: October 2020

There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children’s hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene‐drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene‐drug‐diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene‐drug‐diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene‐drug‐diagnosis groups with matching diagnoses and prescriptions. The most common gene‐drug‐diagnosis groups with matching diagnoses and prescriptions were CYP2C19‐citalopram‐escitalopram‐depression 3.3% of patients tested; CYP2C19‐dexlansoprazole‐gastritis‐esophagitis 3.1%; CYP2C19‐omeprazole‐gastritis‐esophagitis 2.4%; CYP2D6‐atomoxetine‐attention deficit hyperactivity disorder 2.2%; and CYP2C19‐citalopram‐escitalopram‐obsessive‐compulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene‐drug pairs in the pediatric population.
Preservation of biomarkers immunoreactivity on cytospins protected with polyethylene glycol
Authors: Srebotnik Kirbis Irena , Praça Maria José , Roque Ruben Rodrigues , Košuta Tina , Saudade André , Strojan Flezar Margareta
Published: October 2020

Introduction

The aim of this retrospective study was to evaluate the preservation of biomarkers immunoreactivity on cytospins protected with polyethylene glycol (PEG).

Methods

In two independent cytopathology laboratories, immunocytochemical reactions were retrospectively evaluated on methanol‐fixed and PEG‐protected cytospins stored at room temperature (RT) for different time periods and compared with immunocytochemical reactions on corresponding baseline methanol‐fixed cytospins. Semi‐quantitatively assessed immunoreactivity, using scores from 0 to 3, was considered reduced if two sequential scores were lowered by at least one point.

Results

Immunocytochemical reactions for 40 biomarkers with membrane (10), cytoplasmic (22) and nuclear (8) localisation were performed on 921 slides prepared from 183 cytological samples. For the majority of biomarkers (29/37, 78%), immunoreactivity on PEG‐protected cytospins stored at RT remained unchanged in the first 12 months. Immunoreactivity for GFAP, p40 and hepatocyte antigen was monitored and remained unchanged for 1, 8 and 7 months, respectively. Partial or complete loss of immunoreactivity on PEG‐protected cytospins stored for less than 12 months was found on a single sample out of the total evaluated for CD3 (1/7), CD30 (1/4), CD45 (1/10), CK5/6 (1/7), MelanA (1/7) and vimentin (1/7), while more frequent changes of immunoreactivity were found for Ki67 (4/7) and p63 (2/7).

Conclusion

Immunoreactivity on cytospins protected with PEG and stored at RT is well‐preserved for at least 12 months for the majority of biomarkers.
Discrete sampling in perception via neuronal oscillations—Evidence from rhythmic, non‐invasive brain stimulation
Authors: Kasten Florian H. , Herrmann Christoph S.
Published: October 2020

A variety of perceptual phenomena suggest that, in contrast to our everyday experience, our perception may be discrete rather than continuous. The possibility of such discrete sampling processes inevitably prompts the question of how such discretization is implemented in the brain. Evidence from neurophysiological measurements suggest that neural oscillations, particularly in the lower frequencies, may provide a mechanism by which such discretization can be implemented. It is hypothesized that cortical excitability is rhythmically enhanced or reduced along the positive and negative half‐cycle of such oscillations. In recent years, rhythmic non‐invasive brain stimulation approaches such as rhythmic transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) are increasingly used to test this hypothesis. Both methods are thought to entrain endogenous brain oscillations, allowing them to alter their power, frequency, and phase in order to study their roles in perception. After a brief introduction to the core mechanisms of both methods, we will provide an overview of rTMS and tACS studies probing the role of brain oscillations for discretized perception in different domains and will contrast these results with unsuccessful attempts. Further, we will discuss methodological pitfalls and challenges associated with the methods.
Elements of disease in a changing world: modelling feedbacks between infectious disease and ecosystems
Authors: Borer Elizabeth T. , Asik Lale , Everett Rebecca A. , Frenken Thijs , Gonzalez Angelica L. , Paseka Rachel E. , Peace Angela , Seabloom Eric W. , Strauss Alexander T. , Van de Waal Dedmer B. , White Lauren A.
Published: October 2020

An overlooked effect of ecosystem eutrophication is the potential to alter disease dynamics in primary producers, inducing disease‐mediated feedbacks that alter net primary productivity and elemental recycling. Models in disease ecology rarely track organisms past death, yet death from infection can alter important ecosystem processes including elemental recycling rates and nutrient supply to living hosts. In contrast, models in ecosystem ecology rarely track disease dynamics, yet elemental nutrient pools (e.g. nitrogen, phosphorus) can regulate important disease processes including pathogen reproduction and transmission. Thus, both disease and ecosystem ecology stand to grow as fields by exploring questions that arise at their intersection. However, we currently lack a framework explicitly linking these disciplines. We developed a stoichiometric model using elemental currencies to track primary producer biomass (carbon) in vegetation and soil pools, and to track prevalence and the basic reproduction number (R0) of a directly transmitted pathogen. This model, parameterised for a deciduous forest, demonstrates that anthropogenic nutrient supply can interact with disease to qualitatively alter both ecosystem and disease dynamics. Using this element‐focused approach, we identify knowledge gaps and generate predictions about the impact of anthropogenic nutrient supply rates on infectious disease and feedbacks to ecosystem carbon and nutrient cycling.
Spatial co‐localisation of extreme weather events: a clear and present danger
Authors: Dodd Rosalind J. , Chadwick David R. , Harris Ian M. , Hines Adrian , Hollis Dan , Economou Theodoros , Gwynn‐Jones Dylan , Scullion John , Robinson David A. , Jones David L.
Published: October 2020

Extreme weather events have become a dominant feature of the narrative surrounding changes in global climate with large impacts on ecosystem stability, functioning and resilience; however, understanding of their risk of co‐occurrence at the regional scale is lacking. Based on the UK Met Office’s long‐term temperature and rainfall records, we present the first evidence demonstrating significant increases in the magnitude, direction of change and spatial co‐localisation of extreme weather events since 1961. Combining this new understanding with land‐use data sets allowed us to assess the likely consequences on future agricultural production and conservation priority areas. All land‐uses are impacted by the increasing risk of at least one extreme event and conservation areas were identified as the hotspots of risk for the co‐occurrence of multiple event types. Our findings provide a basis to regionally guide land‐use optimisation, land management practices and regulatory actions preserving ecosystem services against multiple climate threats.
An Examination of Classification Accuracy in the Continuous Testing Framework
Authors: Coggeshall Whitney Smiley
Published: October 2020

The continuous testing framework, where both successful and unsuccessful examinees have to demonstrate continued proficiency at frequent prespecified intervals, is a framework that is used in noncognitive assessment and is gaining in popularity in cognitive assessment. Despite the rigorous advantages of this framework, this paper demonstrates that there is significant inflation in false negatives as both passers and failers continually take a test, especially for examinees closer to the passing score. Several passing policies are investigated to control the inflation of false negatives while maintaining low false‐positive rates for fixed‐length tests. Lastly, recommendations are made for testing professionals who wish to utilize the rigorous nature of the continuous testing framework while also avoiding the inflation of qualified examinees failing.
The economic benefit of timely, adequate, and adherence to Parkinson's disease treatment: the Value of Treatment Project 2
Authors: Dodel R. , Tinelli M. , Deuschl G. , Petersen G. , Oertel W. , Ahmerkamp‐Böhme J.
Published: October 2020

Background

Parkinson's disease (PD) is a chronic progressive neurological disorder with a high psychosocial and economic burden. As part of the European Brain Council (EBC)‐led Value of Treatment project, this study aimed to capture the economic benefit of timely, adequate, and adherence to PD treatment.

Methods

The EBC Value of Treatment Initiative combined different stakeholders to identify unmet needs in the patients’ journey according to Rotterdam methodology. The economic evaluation focused on three major topics identified as major gaps: start of treatment; best treatment for advanced disease; and adherence to treatment. Two separate healthcare systems (Germany and the UK) were chosen. Cost‐effectiveness was determined by using decision‐analytical modelling approaches. Effectiveness was expressed as quality‐adjusted life‐years (QALYs) gained and incremental cost‐effectiveness ratio (ICER).

Results

Treatment intervention in PD was found to be cost‐effective regardless of the initial health state of the patient receiving the treatment. Cost savings were between ‐€1000 and −€5400 with 0.10 QALY gain and ‐€1800 and ‐€7600 with 0.10 QALY gain for Germany and the UK, respectively. Treatment remains cost‐effective within the National Institute for Health and Care Excellence thresholds. Availability of adequate treatment to more patients was also found to be cost‐effective, with an ICER of €15,000–€32,600 across country settings. Achieving the target adherence to treatment would generate cost‐savings of €239,000–€576,000 (Germany) and €917,000–€2,980.000 (UK) for every 1,000 patients treated adequately.

Conclusions

The analyses confirmed that timely, adequate, and adherence to PD treatment will not only improve care of the patients but is also cost‐effective across healthcare systems. Further studies with a distinct identification of gaps in care are necessary to develop better and affordable care.
Diversification benefits of cat bonds: An in‐depth examination
Authors: Demers‐Bélanger Karl , Lai Van Son
Published: October 2020

We investigate whether the inclusion of Cat Bonds in portfolios composed of traditional assets and common factors is beneficial to investors. Various mean‐variance spanning tests performed for the period of 2002 to 2017 show that under different market conditions, the addition of Cat Bonds gives rise to previously unattainable portfolios. Using the Engle (2002) Dynamic Conditional Correlation (DCC) model, we find that including Cat bonds increases significantly the time‐varying Sharpe ratio and the Choueifaty and Coignard (2008) maximum diversification ratio. Cat Bonds provide needed diversification during critical times particularly during episodes of crisis and of high volatility. Under the second‐order stochastic dominance efficiency (SDE) tests, the null hypothesis that portfolios without Cat Bonds are efficient cannot be rejected. Out‐of‐sample analyses indicate that the performance of portfolios with Cat Bonds included varies depending on the performance measures employed, the portfolio construction techniques used and the assets or factors considered.
‘TIEF / IN DER ZEITENSCHRUNDE’: READING TIME IN PAUL CELAN'S POETICS
Authors: Olschner Leonard
Published: October 2020

Concepts of time play a crucial role at the centre of Paul Celan's poetics and poetry, though not in any formal, systematic, or schematic sense, even when they appear to be informed by the philosophy of, for example, Martin Heidegger or Edmund Husserl. Celan expands this notion beyond any mere idea of time as one theme among others, or time as a mere measurable quantity, to include and integrate historical time, especially with reference to the Shoah and the so‐called ‘Goll‐Affäre’. In Celan's work, time becomes a structure upon and around which he explores the limits of the sayable or the ineffable. Examples of this can be seen in his early to late poetry, in his various writings on poetics, and not least in the extensive notes he made when writing Der Meridian, his acceptance speech for the Georg Büchner Prize. This article looks at three poems: ‘Regenflieder’ (1943), ‘Köln, Am Hof’ (1957), and ‘Rebleute’ (1970), all of which approach notions of time differently, along with two translations (Guillaume Apollinaire, Jean Daive). The consistency inherent in Celan's poetic vision is suggested by the simultaneity of his images and poetic insights.
TALKING BACK: SHARON DODUA OTOO'S HERR GRÖTTRUP SETZT SICH HIN AND THE EPISTEMOLOGY OF RESISTANCE
Authors: Colvin Sarah
Published: October 2020

Sharon Dodua Otoo has called the artistic production of Black and of Colour writers in contemporary Germany ‘eine Praxis des Widerstands’. Here I read her Bachmann‐prizewinning story Herr Gröttrup setzt sich hin through the lens of Jamika Ajalon's conception of a fugitive archetype of resistance, which is, I argue, simultaneously a working definition of a literary work of art. I also read the story as a literary investigation of the phenomenon Miranda Fricker has called epistemic injustice (‘a wrong done to someone specifically in their capacity as a knower’). Fricker's articulation of epistemic injustice has helped spark an ‘epistemic turn’ across disciplines. I refer particularly to José Medina's development of her work in his Epistemology of Resistance (2013). Subaltern subjects, argues Medina, can gain an epistemic advantage because they have to work harder cognitively, maintaining ‘two cognitive perspectives simultaneously’. Theorists of epistemic injustice strikingly often rely for their arguments on literary fiction, which has long been alerting its readers to epistemic injustice and its painful or lethal consequences. Otoo, I argue, uses storytelling and humour to offer both the epistemically privileged Gröttrups and her epistemically privileged readers opportunities to understand and transcend their cognitive limitations.
Comparisons of three‐dimensional urban forms in different urban expansion types: 58 sample cities in China
Authors: Rao Yingxue , Zhou Jiang , Zhou Min , He Qingsong , Wu Jiayu
Published: October 2020

Traditional studies of urban spatial expansion typically focus on a single vertical or horizontal dimension and rarely consider the two together. Using 58 cities in China as examples, this paper first identifies the urban growth pattern (UGP) of newly built‐up land patches in each city from 1995 to 2015 horizontally. It then compares and analyses the distribution patterns of three‐dimensional buildings in different UGP patches vertically. There were two important findings: (a) Building patterns in the outlying patches were characterized by low density, high floor numbers, and smooth changes. The infilling patches represented compact development and had the lowest average building height. Edge patches had the highest average number of floors, the most dramatic floor variability, and the lowest utilization rate of three‐dimensional space. (b) In western cities, building distribution characteristics in outlying patches were similar and formed clusters. The distribution characteristics of buildings in the Beijing‐Tianjin‐Hebei urban agglomeration edge patches, as well as those in the northeast urban agglomeration infilling patches, were similar, forming clusters of different types. The results of this paper will contribute to an understanding of both sprawl and the compact development of Chinese cities and will provide international comparative examples.
Enhanced retinoid response by a combination of the vitamin A ester retinyl propionate with niacinamide and a flavonoid containing Ceratoniasiliqua extract in retinoid responsive invitro models
Authors: Lam E.C.S. , Li R. , Rodrigues M.R. , Vires L. , Adams R.L. , Sherrill J.D. , Oblong J.E.
Published: October 2020

Objectives

Retinoids have been used for decades as efficacious topical agents to treat photoaged skin. The purpose of our present research is to evaluate whether the activity of the vitamin A ester retinyl propionate (RP) can be enhanced by niacinamide (Nam) and a flavonoid containing Ceratonia siliqua (CS) fruit extract in retinoid responsive in vitro models.

Methods

Retinyl propionate was tested alone and in combination with Nam and CS in an RARα reporter cell line for promoter activation and compared to trans‐retinoic acid (tRA) activation. These treatments were also tested in keratinocytes for gene expression profiling by qPCR using a panel of 40 retinoid responsive genes.

Results

tRA or RP elicited RARα reporter activation in a dose‐dependent manner. The combination of 0.5 μM or 2 μM RP with 10 mM Nam had a 56% and 95% signal increase compared to RP, respectively. The addition of 1% CS to 0.5 μM or 2 μM RP with 10 mM Nam elicited a further increase of 114% and 156%, respectively, over RP and Nam combinations. All retinoids elicited an increase in expression of 40 retinoid sensitive genes over control levels. Of the 40 genes, 27 were enhanced by either 0.1 μM RP or 0.5 μM RP with 10 mM Nam and 1% CS. Nam or CS had very modest activity in both models.

Conclusion

The combination of RP with Nam and CS showed a higher retinoid response than RP in two separate retinoid responsive in vitro models. We hypothesize Nam and CS enhances RP activity by modulating metabolism to tRA via increasing NAD+ pools and inhibiting reduction of retinal (RAL) back to retinol, respectively. The findings provide evidence that this combination may have enhanced efficacy for treating the appearance of photoaged skin.