bluuebunny/crossref_metadata_2025_split huggingface dataset:
Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer
Authors: Sharma Priyanka , Shimura Tadanobu , Banwait Jasjit K , Goel Ajay 
Published: August 2020

Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality in the USA. As much as 50–60% of CRC patients develop resistance to 5-fluorouracil (5FU)-based chemotherapeutic regimens, attributing the increased overall morbidity and mortality. In view of the growing evidence that active principles in various naturally occurring botanicals can facilitate chemosensitization in cancer cells, herein, we undertook a comprehensive effort in interrogating the activity of one such botanical—andrographis—by analyzing its activity in CRC cell lines [both sensitive and 5FU resistant (5FUR)], a xenograft animal model and patient-derived tumor organoids. We observed that combined treatment with andrographis was synergistic and resulted in a significant and dose-dependent increase in the efficacy of 5FU in HCT116 and SW480 5FUR cells (P &lt; 0.05), reduced clonogenic formation (P &lt; 0.01) and increased rates of caspase-9-mediated apoptosis (P &lt; 0.05). The genomewide expression analysis in cell lines led us to uncover that activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways were the key mediators for the anti-cancer and chemosensitizing effects of andrographis. Subsequently, we validated our findings in a xenograft animal model, as well as two independent CRC patient-derived organoids—which confirmed that combined treatment with andrographis was significantly more effective than 5FU and andrographis alone and that these effects were in part orchestrated through dysregulated expression of key genes (including HMOX1, GCLC, GCLM and TCF7L2) within the ferroptosis and Wnt-signaling pathways. Collectively, our data highlight that andrographis might offer a safe and inexpensive adjunctive therapeutic option in the management of CRC patients.
Contextual Fear Memory Retrieval Is Vulnerable to Hippocampal Noise
Authors: Iwasaki Satoshi , Ikegaya Yuji 
Published: August 2020

Abstract
Memory retrieval depends on reactivation of memory engram cells. Inadvertent activation of these cells is expected to cause memory-retrieval failure, but little is known about how noisy activity of memory-irrelevant neurons impacts mnemonic processes. Here, we report that optogenetic nonselective activation of only tens of hippocampal CA1 cells (∼0.01% of the total cells in the CA1 pyramidal cell layer) impairs contextual fear memory recall. Memory recall failure was associated with altered neuronal reactivation in the basolateral amygdala. These results indicate that hippocampal memory retrieval requires strictly regulated activation of a specific neuron ensemble and is easily disrupted by the introduction of noisy CA1 activity, suggesting that reactivating memory engram cells as well as silencing memory-irrelevant neurons are both crucial for memory retrieval.
Dynamic Adjustments of Midfrontal Control Signals in Adults and Adolescents
Authors: Gyurkovics Mate , Levita Liat 
Published: August 2020

Abstract
During task performance, our level of cognitive control is dynamically adjusted to task demands as reflected, for example, by the congruency sequence effect (CSE) in conflict tasks. Although brain areas related to cognitive control show protracted maturation across adolescence, previous studies found that adolescents show similar behavioral CSEs to adults. In the present study, we investigated whether there are age-related changes in the neural underpinnings of dynamic control adjustments using electroencephalography. Early adolescents (ages 12–14, N = 30) and young adults (ages 25–27, N = 29) completed a confound-minimized flanker task optimized for the detection of sequential control adjustments. The CSE was observed in midfrontal theta power thought to capture anterior cingulate cortex-mediated monitoring processes but was not modulated significantly by age. Adolescents, however, showed a smaller congruency effect in the power and cross-trial temporal consistency of midfrontal theta oscillations than adults. No age differences were observed in phase-based connectivity between midfrontal and lateral frontal regions in the theta band. These findings provide strong support for the role of midfrontal theta oscillations in conflict monitoring and reactive control and suggest that the cognitive system of early adolescents initially responds less reliably to the occurrence of conflict than that of adults.
Using Whole-genome Sequencing to Determine the Timing of Secondary Tuberculosis in British Columbia, Canada
Authors: Romanowski Kamila , Sobkowiak Benjamin , Guthrie Jennifer L , Cook Victoria J , Gardy Jennifer L , Johnston James C 
Published: August 2020

Abstract
Combined with epidemiological data, whole-genome sequencing (WGS) can help better resolve individual tuberculosis (TB) transmission events to a degree not possible with traditional genotyping. We combine WGS data with patient-level data to calculate the timing of secondary TB among contacts of people diagnosed with active TB in British Columbia, Canada.
Evaluating the Efficacy of Therapies in Patients With Coronavirus Disease 2019
Authors: Lin Dan-Yu , Zeng Donglin , Eron Joseph J 
Published: August 2020

AbstractThere is a proliferation of clinical trials worldwide to find effective therapies for patients diagnosed with coronavirus disease 2019 (COVID-19). The endpoints that are currently used to evaluate the efficacy of therapeutic agents against COVID-19 are focused on clinical status at a particular day or on time to a specific change of clinical status. To provide a full picture of the clinical course of a patient and make complete use of available data, we consider the trajectory of clinical status over the entire follow-up period. We also show how to combine the evidence of treatment effects on the occurrences of various clinical events. We compare the proposed and existing endpoints through extensive simulation studies. Finally, we provide guidelines on establishing the benefits of treatments.
Mutations in an Aquaglyceroporin as a Proven Marker of Antimony Clinical Resistance in the Parasite Leishmania donovani
Authors: Potvin Jade-Eva , Leprohon Philippe , Queffeulou Marine , Sundar Shyam , Ouellette Marc 
Published: August 2020

Abstract

Background
Antimonial drugs have long been the mainstay to treat visceral leishmaniasis. Their use has been discontinued in the Indian subcontinent because of drug resistance, but they are still clinically useful elsewhere. The goal of this study was to find markers of antimony resistance in Leishmania donovani clinical isolates and validate experimentally their role in resistance.

Methods
The genomes of sensitive and antimony-resistant clinical isolates were sequenced. The role of a specific gene in contributing to resistance was studied by CRISPR-Cas9–mediated gene editing and intracellular drug sensitivity assays.

Results
Both gene copy number variations and single nucleotide variants were associated with antimony resistance. A homozygous insertion of 2 nucleotides was found in the gene coding for the aquaglyceroporin AQP1 in both resistant isolates. Restoring the wild-type AQP1 open reading frame re-sensitized the 2 independent resistant isolates to antimonials. Alternatively, editing the genome of a sensitive isolate by incorporating the 2-nucleotide insertion in its AQP1 gene led to antimony-resistant parasites.

Conclusions
Through genomic analysis and CRISPR-Cas9–mediated genome editing we have proven the role of the AQP1 mutations in antimony clinical resistance in L. donovani.
Corruption and the Public Service Ethos in Mid-Victorian Administration: The Case of Leonard Horner and the Factory Office
Authors: Cawood Ian 
Published: August 2020

Abstract
While the problem of political corruption in mid-nineteenth century Britain has been much studied, the experience of corrupt behaviour in public bodies, both new and long established, is comparatively neglected. This article takes the example of one of the first inspectorates set up after the Great Reform Act, the Factory Office, to examine the extent of corrupt practices in the British civic state and the means whereby it was addressed. It examines the changing processes of appointment, discipline and promotion, the issues of remuneration and venality, and the relationships between inspectors, workers, factory owners, the government and the wider civil service, and the press and public opinion. The article argues that the changing attitudes of the inspectors, especially those of Leonard Horner, were indicative of a developing ‘public service ethos’ in both bureaucratic and cultural settings and that the work of such unsung administrators was one of the agencies through which corrupt behaviour in the civic structures of Victorian Britain was, with public support, challenged. The article concludes that the endogenous reform of bureaucratic practice achieved by the factory inspectorate may even be of equal significance as that which resulted from the celebrated Northcote–Trevelyan Report of 1854.
Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia
Authors: Gaudet Daniel , Karwatowska-Prokopczuk Ewa , Baum Seth J , Hurh Eunju , Kingsbury Joyce , Bartlett Victoria J , Figueroa Amparo L , Piscitelli Philip , Singleton Walter , Witztum Joseph L , Geary Richard S , Tsimikas Sotirios , O'Dea Louis St. L ,   the Vupanorsen Study Investigators
Published: August 2020

Abstract

Aims
Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods and results
This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides &gt;150 mg/dL (&gt;1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild.

Conclusion
Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.
Efficacy and safety of left atrial appendage electrical isolation during catheter ablation of atrial fibrillation: an updated meta-analysis
Authors: Romero Jorge , Gabr Mohamed , Patel Kavisha , Briceno David , Diaz Juan Carlos , Alviz Isabella , Trivedi Chintan , Mohanty Sanghamitra , Polanco Dalvert , Della Rocca Domenico Giovanni , Lakkireddy Dhanunjaya , Natale Andrea , Di Biase Luigi 
Published: August 2020

AbstractAimsLeft atrial appendage electrical isolation (LAAEI) has been shown to improve freedom from all-atrial arrhythmia recurrence in patients with non-paroxysmal atrial fibrillation (AF). The aim of this study is to investigate the long-term efficacy and safety outcomes of LAAEI in patients with non-paroxysmal AF undergoing catheter ablation.Methods and resultsA systematic review of Medline, Cochrane, and Embase was performed for clinical studies evaluating the benefit of LAAEI in non-paroxysmal AF. Nine studies with a total of 2336 patients were included (mean age: 65 ± 9 years, 63% male). All studies included patients with persistent AF, long-standing persistent AF, or both. At a mean follow-up of 40.5 months, patients who underwent LAAEI had significantly higher freedom from all-atrial arrhythmia recurrence than patients who underwent standard ablation alone [69.3% vs. 46.4%; risk ratio (RR) 0.54; 95% confidence interval (CI) 0.42–0.69; P &lt; 0.0001]. A 46% relative risk reduction and 22.9% absolute risk reduction in atrial-arrhythmia recurrence was noted with LAAEI. Rates of cerebral thromboembolism were not significantly different between the two groups (LAAEI 3% vs. standard ablation 1.6%, respectively; RR 1.76; 95% CI 0.61–5.04; P = 0.29). Furthermore, there was no significant difference in the acute procedural complication rates between the two groups (LAAEI 4% vs. standard ablation 3%, respectively; RR 1.29; 95% CI 0.83–2.02; P = 0.26).ConclusionAt long-term follow-up, LAAEI led to a significantly higher improvement in freedom from all-atrial arrhythmia recurrence in patients with non-paroxysmal AF, when compared to standard ablation alone. Importantly, this benefit was achieved without an increased risk of acute procedural complications or cerebral thromboembolic events.
The influence of fault reactivation on injection-induced dynamic triggering of permeability evolution
Authors: Yildirim Elif Cihan , Im Kyungjae , Elsworth Derek 
Published: August 2020

SUMMARYMechanisms controlling fracture permeability enhancement during injection-induced and natural dynamic stressing remain unresolved. We explore pressure-driven permeability (k) evolution by step-increasing fluid pressure (p) on near-critically stressed laboratory fractures in shale and schist as representative of faults in sedimentary reservoirs/seals and basement rocks. Fluid is pulsed through the fracture with successively incremented pressure to first examine sub-reactivation permeability response that then progresses through fracture reactivation. Transient pore pressure pulses result in a permeability increase that persists even after the return of spiked pore pressure to the null background level. We show that fracture sealing is systematically reversible with the perturbing pressure pulses and pressure-driven permeability enhancement is eminently reproducible even absent shear slip and in the very short term (order of minutes). These characteristics of the observed fracture sealing following a pressure perturbation appear similar to those of the response by rate-and-state frictional healing upon stress/velocity perturbations. Dynamic permeability increase scales with the pore pressure magnitude and fracture sealing controls the following per-pulse permeability increase, both in the absence and presence of reactivation. However, initiation of the injection-induced reactivation results in a significant increase in the rate of permeability enhancement (dk/dp). These results demonstrate the role of frictional healing and sealing of fractures at interplay with other probable processes in pore pressure-driven permeability stimulation, such as particle mobilization.
Introducing Ecohealth education in a Teacher Training Institute in Lao PDR: a case study
Authors: Tomokawa Sachi , Asakura Takashi , Keosada Ngouay , Bouasangthong Vannasouk , Souvanhxay Vanthala , Navamal Phetnoy , Kanyasan Kethsana , Miyake Kimihiro , Kokudo Shohei , Watanabe Ryuichi , Soukhavong Sithane , Thalangsy Khamseng , Moji Kazuhiko 
Published: August 2020

Summary
This paper argues the effectiveness of Ecohealth education for improving the quality of health and environmental education and for achieving sustainable development in developing countries. To illustrate the need for Ecohealth education, we review the transitions in health education, environmental education and Education for Sustainable Development (ESD) in various developing countries. Moreover, we discuss issues relating to these disciplines and consider the possible roles that Ecohealth education can play. Then, drawing on a case study conducted in Lao PDR, we propose a concrete example of the teaching content of Ecohealth education. We conclude that Ecohealth education can embody the concepts of ESD with respect to health and environmental issues, and thus can contribute to improvements in the quality of health and environmental education, and of ESD. In addition, we propose the following five actions for implementing Ecohealth education in developing countries: (i) promote research based on the approaches of public health and anthropology, and develop teaching materials that use the research results, (ii) empower school-aged children, (iii) encourage the active involvement and sharing of problems among communities, (iv) strengthen participatory teaching and learning methodology and (v) build a training system and train relevant teachers.
The Imperial War Graves Commission, the war dead and the burial of a royal body, 1914–32.
Authors: Connelly Mark , Goebel Stefan 
Published: August 2020

Abstract
The mass deaths of British and imperial soldiers during the First World War created a crisis of commemoration. How could the bereaved come to terms with the losses when their deceased loved ones were buried so far from home, or had disappeared completely? Attempting to impose a common solution, the Imperial War Graves Commission (founded in 1917) committed itself to non-repatriation of bodies and standard treatment of war graves. In doing so, it ran the risk of contradicting the wishes of bereaved families. This article explores how the grave of Prince Maurice of Battenberg became a test case for the Commission in its quest for legitimacy and the aptness of its approach against the opposition of Maurice’s mother, Princess Beatrice, daughter of Queen Victoria. It reveals the I.W.G.C.’s desire to avoid public controversy while sticking to its guiding principles, and its belief that far from being exempt from those principles through her royal status, Princess Beatrice had a moral obligation to accept and embrace them.
Excess mortality during the COVID-19 outbreak in Italy: a two-stage interrupted time-series analysis
Authors: Scortichini Matteo , Schneider dos Santos Rochelle , De’ Donato Francesca , De Sario Manuela , Michelozzi Paola , Davoli Marina , Masselot Pierre , Sera Francesco , Gasparrini Antonio 
Published: August 2020

Abstract

Background
Italy was the first country outside China to experience the impact of the COVID-19 pandemic, which resulted in a significant health burden. This study presents an analysis of the excess mortality across the 107 Italian provinces, stratified by sex, age group and period of the outbreak.

Methods
The analysis was performed using a two-stage interrupted time-series design using daily mortality data for the period January 2015–May 2020. In the first stage, we performed province-level quasi-Poisson regression models, with smooth functions to define a baseline risk while accounting for trends and weather conditions and to flexibly estimate the variation in excess risk during the outbreak. Estimates were pooled in the second stage using a mixed-effects multivariate meta-analysis.

Results
In the period 15 February–15 May 2020, we estimated an excess of 47 490 [95% empirical confidence intervals (eCIs): 43 984 to 50 362] deaths in Italy, corresponding to an increase of 29.5% (95% eCI: 26.8 to 31.9%) from the expected mortality. The analysis indicates a strong geographical pattern, with the majority of excess deaths occurring in northern regions, where few provinces experienced increases up to 800% during the peak in late March. There were differences by sex, age and area both in the overall impact and in its temporal distribution.

Conclusion
This study offers a detailed picture of excess mortality during the first months of the COVID-19 pandemic in Italy. The strong geographical and temporal patterns can be related to the implementation of lockdown policies and multiple direct and indirect pathways in mortality risk.
Reflection on modern methods: building causal evidence within high-dimensional molecular epidemiological studies of moderate size
Authors: Ponsonby Anne-Louise 
Published: August 2020

AbstractThis commentary provides a practical perspective on epidemiological analysis within a single high-dimensional study of moderate size to consider a causal question. In this setting, non-causal confounding is important. This occurs when a factor is a determinant of outcome and the underlying association between exposure and the factor is non-causal. That is, the association arises due to chance, confounding or other bias rather than reflecting that exposure and the factor are causally related. In particular, the influence of technical processing factors must be accounted for by pre-processing measures to remove artefact or to control for these factors such as batch run. Work steps include the evaluation of alternative non-causal explanations for observed exposure-disease associations and strategies to obtain the highest level of causal inference possible within the study. A systematic approach is required to work through a question set and obtain insights on not only the exposure-disease association but also the multifactorial causal structure of the underlying data where possible. The appropriate inclusion of molecular findings will enhance the quest to better understand multifactorial disease causation in modern observational epidemiological studies.
Effects of evaporation parameters on recuperative transcritical organic Rankine cycle using binary mixture fluids
Authors: Hsieh Jui-Ching , Cheng Chu-Hong 
Published: August 2020

Abstract
In this study, thermodynamic analysis was performed on basic and recuperative transcritical organic Rankine cycles by using five pure and six mixed fluids. The effects of evaporation parameters on the first- and second-law efficiencies (ηI and ηII) as well as power output were investigated. The results indicate that a recuperator had a positive effect on the ηI and ηII and negative effects on the specific power. The total irreversibility of the system was improved by the recuperator. However, the total irreversibility considerably increased with an increase in the expander inlet temperature (Texp,in) due to the significant increase in irreversibility in the condenser, particularly for working fluids with low critical temperatures, namely R134a, R1234yf and R290, and low proportions of R245fa and R600a in mixed fluids. For both the pure and mixed fluids, the specific power linearly increased with an increase in the expander inlet pressure (Pexp,in) and Texp,in. However, with an increase in Pexp,in, the ηI and ηII first increased and then decreased. Finally, for ηI and ηII, the effect of the recuperator increased with an increase in Texp,in even though the recuperator had a relatively small effect on the working fluids with high critical temperature, especially when Pexp,in was high.