bluuebunny/crossref_metadata_2025 huggingface dataset:
A versatile microfluidic tool for the 3D culture of HepaRG cells seeded at various stages of differentiation
Authors: Boul Manon , Benzoubir Nassima , Messina Antonietta , Ghasemi Rasta , Mosbah Ismail Ben , Duclos-Vallée Jean-Charles , Dubart-Kupperschmitt Anne , Le Pioufle Bruno
Published: July 2021

The development of livers-on-a-chip aims to provide pharmaceutical companies with reliable systems to perform drug screening and toxicological studies. To that end, microfluidic systems are engineered to mimic the functions and architecture of this organ. In this context we have designed a device that reproduces series of liver microarchitectures, each permitting the 3D culture of hepatocytes by confining them to a chamber that is separated from the medium conveying channel by very thin slits. We modified the structure to ensure its compatibility with the culture of hepatocytes from different sources. Our device was adapted to the migratory and adhesion properties of the human HepaRG cell line at various stages of differentiation. Using this device, it was possible to keep the cells alive for more than 14 days, during which they achieved a 3D organisation and acquired or maintained their differentiation into hepatocytes. Albumin secretion as well as functional bile canaliculi were confirmed on the liver-on-a-chip. Finally, an acetaminophen toxicological assay was performed. With its multiple micro-chambers for hepatocyte culture, this microfluidic device architecture offers a promising opportunity to provide new tools for drug screening applications.
A comparison of time to event analysis methods, using weight status and breast cancer as a case study
Authors: Aivaliotis Georgios , Palczewski Jan , Atkinson Rebecca , Cade Janet E. , Morris Michelle A.
Published: July 2021

Survival analysis with cohort study data has been traditionally performed using Cox proportional hazards models. Random survival forests (RSFs), a machine learning method, now present an alternative method. Using the UK Women’s Cohort Study (n = 34,493) we evaluate two methods: a Cox model and an RSF, to investigate the association between Body Mass Index and time to breast cancer incidence. Robustness of the models were assessed by cross validation and bootstraping. Histograms of bootstrap coefficients are reported. C-Indices and Integrated Brier Scores are reported for all models. In post-menopausal women, the Cox model Hazard Ratios (HR) for Overweight (OW) and Obese (O) were 1.25 (1.04, 1.51) and 1.28 (0.98, 1.68) respectively and the RSF Odds Ratios (OR) with partial dependence on menopause for OW and O were 1.34 (1.31, 1.70) and 1.45 (1.42, 1.48). HR are non-significant results. Only the RSF appears confident about the effect of weight status on time to event. Bootstrapping demonstrated Cox model coefficients can vary significantly, weakening interpretation potential. An RSF was used to produce partial dependence plots (PDPs) showing OW and O weight status increase the probability of breast cancer incidence in post-menopausal women. All models have relatively low C-Index and high Integrated Brier Score. The RSF overfits the data. In our study, RSF can identify complex non-proportional hazard type patterns in the data, and allow more complicated relationships to be investigated using PDPs, but it overfits limiting extrapolation of results to new instances. Moreover, it is less easily interpreted than Cox models. The value of survival analysis remains paramount and therefore machine learning techniques like RSF should be considered as another method for analysis.
A high plane of nutrition during early life alters the hypothalamic transcriptome of heifer calves
Authors: Sánchez José M. , Keogh Kate , Kelly Alan K. , Byrne Colin J. , Lonergan Pat , Kenny David A.
Published: July 2021

The aim was to examine the effect of rapid body weight gain during early calfhood consistent with earlier sexual development on the transcriptional profile of the hypothalamus. Angus X Holstein–Friesian heifer calves (19 ± 5 days of age) were offered a high (HI, n = 14) or moderate (MOD, n = 15) plane of nutrition from 3 to 21 weeks of age to achieve a growth rate of 1.2 kg/d and 0.5 kg/d, respectively. Following euthanasia at 21 weeks, the arcuate nucleus (ARC) region was separated from the remainder of the hypothalamus and both were subjected to RNA-Seq. HI calves exhibited altered expression of 80 and 39 transcripts in the ARC and the remaining hypothalamus, respectively (P < 0.05) including downregulation of AGRP and NPY and upregulation of POMC, previously implicated in precocious sexual development. Stress-signaling pathways were amongst the most highly dysregulated. Organ morphology, reproductive system development and function, and developmental disorder were amongst the networks derived from differentially expressed genes (DEGs) in the ARC. Gene co-expression analysis revealed DEGs within the ARC (POMC, CBLN2, CHGA) and hypothalamus (PENK) as hub genes. In conclusion, enhanced nutrition during early calfhood alters the biochemical regulation of the hypothalamus consistent with advanced sexual development in the prepubertal heifer.
Depression predictions from GPS-based mobility do not generalize well to large demographically heterogeneous samples
Authors: Müller Sandrine R. , Chen Xi , Peters Heinrich , Chaintreau Augustin , Matz Sandra C.
Published: July 2021

Depression is one of the most common mental health issues in the United States, affecting the lives of millions of people suffering from it as well as those close to them. Recent advances in research on mobile sensing technologies and machine learning have suggested that a person’s depression can be passively measured by observing patterns in people’s mobility behaviors. However, the majority of work in this area has relied on highly homogeneous samples, most frequently college students. In this study, we analyse over 57 million GPS data points to show that the same procedure that leads to high prediction accuracy in a homogeneous student sample (N = 57; AUC = 0.82), leads to accuracies only slightly higher than chance in a U.S.-wide sample that is heterogeneous in its socio-demographic composition as well as mobility patterns (N = 5,262; AUC = 0.57). This pattern holds across three different modelling approaches which consider both linear and non-linear relationships. Further analyses suggest that the prediction accuracy is low across different socio-demographic groups, and that training the models on more homogeneous subsamples does not substantially improve prediction accuracy. Overall, the findings highlight the challenge of applying mobility-based predictions of depression at scale.
Scientists have favorable opinions on immunity certificates but raise concerns regarding fairness and inequality
Authors: Aranzales Iván , Chan Ho Fai , Eichenberger Reiner , Hegselmann Rainer , Stadelmann David , Torgler Benno
Published: July 2021

During the first wave of the COVID-19 pandemic, we collected over 12,000 responses from a survey of scientists, who were asked to express their opinions on immunity certificates (also called “immunity passports”) as a potential instrument to lessen the impact of the crisis. Overall, we find that scientists perceive immunity certificates as favorable for public health (50.2%) and the state of the economy (54.4%) while one-fifth (19.1%) and one-sixth (15.4%) disagree. Scientists stipulate some concerns about fairness (36.5%) and inequality (22.4%) arising from implementation of immunity certification. We find some smaller differences among scientific fields, particularly between health scientists and social scientists, with the latter being slightly more positive about the effect of immunity certification. Scholars in the United States, including health scientists, are more likely to view the immunity certificates favorably and mention fewer concerns about this policy’s effect on fairness and inequality. Female scholars are significantly less in favor of immunity certificates, while scientists with more conservative political views hold more favorable opinions. Our results reveal that given the uncertainties during an early phase of a pandemic, scientists see scope for immunity certification to lessen the general societal impacts of the crisis.
Cardiac and skeletal muscle predictors of impaired cardiorespiratory fitness post-anthracycline chemotherapy for breast cancer
Authors: Kirkham Amy A. , Haykowsky Mark J. , Beaudry Rhys I. , Grenier Justin G. , Mackey John R. , Pituskin Edith , Paterson D. Ian , Thompson Richard B.
Published: July 2021

This study aimed to characterize peak exercise cardiac function and thigh muscle fatty infiltration and their relationships with VO2peak among anthracycline-treated breast cancer survivors (BCS). BCS who received anthracycline chemotherapy ~ 1 year earlier (n = 16) and matched controls (matched-CON, n = 16) were enrolled. Resting and peak exercise cardiac function, myocardial T1mapping (marker of fibrosis), and thigh muscle fat infiltration were assessed by magnetic resonance imaging, and VO2peak by cycle test. Compared to matched-CON, BCS had lower peak SV (64 ± 9 vs 57 ± 10 mL/m2, p = 0.038), GLS (− 30.4 ± 2.2 vs − 28.0 ± 2.5%, p = 0.008), and arteriovenous oxygen difference (16.4 ± 3.6 vs 15.2 ± 3.9 mL/100 mL, p = 0.054). Mediation analysis showed: (1) greater myocardial T1time (fibrosis) is inversely related to cardiac output and end-systolic volume exercise reserve; (2) greater thigh muscle fatty infiltration is inversely related to arteriovenous oxygen difference; both of which negatively influence VO2peak. Peak SV (R2 = 65%) and thigh muscle fat fraction (R2 = 68%) were similarly strong independent predictors of VO2peak in BCS and matched-CON combined. Post-anthracyclines, myocardial fibrosis is associated with impaired cardiac reserve, and thigh muscle fatty infiltration is associated with impaired oxygen extraction, which both contribute to VO2peak.
The relation between childhood adversity and adult obesity in a population-based study in women and men
Authors: Fleischer Toni , Ulke Christine , Beutel Manfred , Binder Harald , Brähler Elmar , Johar Hamimatunnisa , Atasoy Seryan , Kruse Johannes , Otten Daniëlle , Tibubos Ana N. , Zöller Daniela , Speerforck Sven , Grabe Hans J. , Ladwig Karl-Heinz , Schomerus Georg
Published: July 2021

Childhood maltreatment has been shown to relate to adult obesity. In this epidemiological study, we investigate the association between childhood maltreatment and waist-to-height-ratio (WHtR) in a sample of the German adult population, comprising of N = 2936 participants. WHtR, an indicator for risk of obesity, was the primary outcome. Childhood maltreatment was assessed by the Childhood Trauma Screener (CTS), which assesses emotional and physical neglect, abuse as well as sexual abuse. Cohort-data were harmonized and analyzed within DataSHIELD. We used multivariable regression models to estimate the association of childhood maltreatment and WHtR at different levels of adjustments for potential confounders. Overall childhood maltreatment was associated with a higher WHtR in both sexes (women: p = 0.004, men: p < 0.001); associations were no longer significant in women after adding socioeconomic variables, but remained significant in men (p = 0.013). Additionally, we were able to identify sex specific patterns for childhood maltreatment predicting the WHtR. Emotional neglect and abuse had stronger impacts on the WHtR in women than in men, whereas physical neglect and abuse had stronger impacts in men. To our knowledge, this is the first comprehensive population-based study testing various types of childhood maltreatment with WHtR in sex-, region- and weight-stratified analyses. Future studies in clinical populations are warranted to examine U-shaped correlations between increased WHtR and childhood maltreatment.
Taphonomic and spatial analyses from the Early Pleistocene site of Venta Micena 4 (Orce, Guadix-Baza Basin, southern Spain)
Authors: Luzón Carmen , Yravedra Jose , Courtenay Lloyd A. , Saarinen Juha , Blain Hugues-Alexandre , DeMiguel Daniel , Viranta Suvi , Azanza Beatriz , Rodríguez-Alba Juan José , Herranz-Rodrigo Darío , Serrano-Ramos Alexia , Solano Jose A. , Oms Oriol , Agustí Jordi , Fortelius Mikael , Jiménez-Arenas Juan Manuel
Published: July 2021

Venta Micena is an area containing several palaeontological sites marking the beginning of the Calabrian stage (Early Pleistocene). The richness of the fossil accumulation including species of Asian, African and European origin, makes Venta Micena a key site for the the palaeoecological and palaeoenvironmental study of southern Europe during the Early Pleistocene. Thus, research has been focused on Venta Micena 3, which was originally interpreted as a single palaeosurface associated with a marshy context, in which most of the fauna was accumulated byPachycrocuta brevirostris. Recent excavations have unearthed a new site, Venta Micena 4, located in the same stratigraphic unit (Unit C) and in close proximity to Venta Micena 3. Here we show the first analyses regarding the taphonomic and spatial nature of this new site, defining two stratigraphic boundaries corresponding to two different depositional events. Furthermore, the taphonomic analyses of fossil remains seem to indicate a different accumulative agent thanPachycrocuta, thus adding more complexity to the palaeobiological interpretation of the Venta Micena area. These results contribute to the discussion of traditional interpretations made from Venta Micena 3.
Effects of steam sterilization on reduction of fungal colony forming units, cannabinoids and terpene levels in medical cannabis inflorescences
Authors: Jerushalmi Shachar , Maymon Marcel , Dombrovsky Aviv , Regev Rafi , Schmilovitch Ze’ev , Namdar Dvora , Shalev Nurit , Koltai Hinanit , Freeman Stanley
Published: July 2021

Medical cannabis (MC) production is a rapidly expanding industry. Over the past ten years, many additional phytocannabinoids have been discovered and used for different purposes. MC was reported beneficial for the treatment of a variety of clinical conditions such as analgesia, multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy, glaucoma, Parkinson disease and more. Yet, there is still a major lack of research and knowledge related to MC plant diseases, both at the pre- and postharvest stages. Many of the fungi that infect MC, such as Aspergillus and Penicillium spp., are capable of producing mycotoxins that are carcinogenic, or otherwise harmful when consumed, and especially by those patients who suffer from a weakened immune system, causing invasive contamination in humans. Therefore, there are strict limits regarding the permitted levels of fungal colony forming units (CFU) in commercial MC inflorescences. Furthermore, the strict regulation on pesticide appliance application in MC cultivation exacerbates the problem. In order to meet the permitted CFU limit levels, there is a need for pesticide-free postharvest treatments relying on natural non-chemical methods. Thus, a decontamination approach is required that will not damage or significantly alter the chemical composition of the plant product. In this research, a new method for sterilization of MC inflorescences for reduction of fungal contaminantstes was assessed, without affecting the composition of plant secondary metabolites. Inflorescences were exposed to short pulses of steam (10, 15 and 20 s exposure) and CFU levels and plant chemical compositions, pre- and post-treatment, were evaluated. Steam treatments were very effective in reducing fungal colonization to below detection limits. The effect of these treatments on terpene profiles was minor, resulting mainly in the detection of certain terpenes that were not present in the untreated control. Steaming decreased cannabinoid concentrations as the treatment prolonged, although insignificantly. These results indicate that the steam sterilization method at the tested exposure periods was very effective in reducing CFU levels while preserving the initial molecular biochemical composition of the treated inflorescences.
Micro-patterned deposition of MoS2 ultrathin-films by a controlled droplet dragging approach
Authors: Pareek Devendra , Roach Kathryna G. , Gonzalez Marco A. , Büsing Lukas , Parisi Jürgen , Gütay Levent , Schäfer Sascha
Published: July 2021

Micropatterning of transition metal dichalcogenide (TMDC) ultrathin-films and monolayers has been demonstrated by various multi-step approaches. However, directly achieving a patterned growth of TMDC films is still considered to be challenging. Here, we report a solution-based approach for the synthesis of patterned MoS2 layers by dragging a precursor solution droplet with variable velocities across a substrate. Utilizing the pronounced shearing velocity dependence in a Landau-Levich deposition regime, MoS2 films with a spatially modulated thickness with alternating mono/bi- and few-layer regions are obtained after precursor annealing. Generally, the presented facile methodology allows for the direct preparation of micro-structured functional materials, extendable to other TMDC materials and even van der Waals heterostructures.
Life cycle assessment of edible insects (Protaetia brevitarsis seulensis larvae) as a future protein and fat source
Authors: Nikkhah Amin , Van Haute Sam , Jovanovic Vesna , Jung Heejung , Dewulf Jo , Cirkovic Velickovic Tanja , Ghnimi Sami
Published: July 2021

Because it is important to develop new sustainable sources of edible protein, insects have been recommended as a new protein source. This study applied Life Cycle Assessment (LCA) to investigate the environmental impact of small-scale edible insect production unit in South Korea. IMPACT 2002 + was applied as the baseline impact assessment (IA) methodology. The CML-IA baseline, EDIP 2003, EDP 2013, ILCD 2011 Midpoint, and ReCiPe midpoint IA methodologies were also used for LCIA methodology sensitivity analysis. The protein, fat contents, and fatty acid profile of the investigated insect (Protaetia brevitarsis seulensis larvae) were analyzed to determine its potential food application. The results revealed that the studied edible insect production system has beneficial environmental effects on various impact categories (ICs), i.e., land occupation, mineral extraction, aquatic and terrestrial ecotoxicity, due to utilization of bio-waste to feed insects. This food production system can mitigate the negative environmental effects of those ICs, but has negative environmental impact on some other ICs such as global warming potential. By managing the consumption of various inputs, edible insects can become an environmentally efficient food production system for human nutrition.
Preparation and characterization of silver orthophosphate photocatalytic coating on glass substrate
Authors: Hagiri Masahide , Uchida Kenichi , Kamo Sasaki Mika , Sakinah Shofiyah
Published: July 2021

The photocatalytic activity of silver orthophosphate Ag3PO4 has been studied and shown to have a high photo-oxidation capability. However, there is few reported example of a simple method to prepare Ag3PO4 coatings on various substrates. In this study a novel and simple method to immobilize Ag3PO4 on the surface of glass substrates has been developed. A silver phosphate paste based on a polyelectrolyte solution was applied to a smooth glass surface. The resulting dried material was calcined to obtain a coating that remained on the glass substrate. The coating layer was characterized by X-ray diffraction and energy dispersive X-ray spectrometry, and the optical band gap of the material was determined. The results indicated that an Ag3PO4 coating responsive to visible light was successfully prepared. The coating, under visible light irradiation, has the ability to decompose methylene blue. Although the coating contained some elemental silver, this did not adversely affect the optical band gap or the photocatalytic ability.
Functional characteristics of a novel odorant binding protein in the legume pod borer, Maruca vitrata
Authors: Ai Hui , Liu Yuying , Long Guangyan , Yuan Yuan , Huang Shaopei , Chen Yan
Published: July 2021

Insect olfaction system plays a key role in the foraging food, pollination, mating, oviposition, reproduction and other insect physiological behavior. Odorant binding protein are widely found in the various olfactory sensilla of different insect antennae and involved in chemical signals discrimination from natural environment. In this study, a novel OBP gene, MvitOBP3 is identified from the legume pod borer, Maruca vitrata, which it mainly harms important legume vegetables including cowpea, soybean and lablab bean. Real-time PCR results demonstrated that MvitOBP3 gene was abundantly expressed in the antennal tissue of M. vitrata, while low levels were distributed in the head, thorax, abdomen, leg and wing of adult moths. The recombinant OBP3 protein was purified using the prokaryotic expression and affinity chromatography system. Fluorescence competitive binding experiments indicated that that MvitOBP3 protein exhibited greater binding affinities with host-plant flower volatiles including Butanoic acid butyl ester, Limonene, 1H-indol-4-ol and 2-methyl-3-phenylpropanal, highlighting they may have attractant activities for the oviposition of female moths on the legume vegetables. Moreover, protein homology modeling and molecular docking analysis revealed that there are six amino acid sites of MvitOBP3 involved in the binding of the host-plant volatiles. These findings will further promote to understand the key role of odorant binding protein during host perception and oviposition of M. vitrata moths, which improve the efficiency of semiochemical-based prevention and monitoring for this pest in the legume vegetables field.
X-ray dark-field tomography reveals tooth cracks
Authors: Jud Christoph , Sharma Yash , Günther Benedikt , Weitz Jochen , Pfeiffer Franz , Pfeiffer Daniela
Published: July 2021

Cracked tooth syndrome (CTS) is a common clinical finding for teeth, it affects about 5% of all adults each year. The finding of CTS is favored by several risk factors such as restorations, bruxism, occlusion habits, and age. Treatment options range, depending on the severity, from no treatment at all to tooth extraction. Early diagnosis of CTS is crucial for optimal treatment and symptom reduction. There is no standard procedure for an evidence-based diagnosis up to date. The diagnosis is a challenge by the fact that the symptoms, including pain and sensitivity to temperature stimuli, cannot be clearly linked to the disease. Commonly used visual inspection does not provide in-depth information and is limited by the resolution of human eyes. This can be overcome by magnifying optics or contrast enhancers, but the diagnosis will still strongly rely on the practicians experience. Other methods are symptom reproduction with percussions, thermal pulp tests or bite tests. Dental X-ray radiography, as well as computed tomography, rarely detect cracks as they are limited in resolution. Here, we investigate X-ray dark-field tomography (XDT) for the detection of tooth microcracks. XDT simultaneously detects X-ray small-angle scattering (SAXS) in addition to the attenuation, whereas it is most sensitive to the micrometer regime. Since SAXS originates from gradients in electron density, the signal is sensitive to the sample morphology. Microcracks create manifold interfaces which lead to a strong signal. Therefore, it is possible to detect structural changes originating from subpixel-sized structures without directly resolving them. Together with complementary attenuation information, which visualizes comparatively large cracks, cracks are detected on all length-scales for a whole tooth in a non-destructive way. Hence, this proof-of principle study on three ex-vivo teeth shows the potential of X-ray scattering for evidence-based detection of cracked teeth.
A simple label-free electrochemical sensor for sensitive detection of alpha-fetoprotein based on specific aptamer immobilized platinum nanoparticles/carboxylated-graphene oxide
Authors: Upan Jantima , Youngvises Napaporn , Tuantranont Adisorn , Karuwan Chanpen , Banet Philippe , Aubert Pierre-Henri , Jakmunee Jaroon
Published: July 2021

A label-free electrochemical aptamer-based sensor has been fabricated for alpha-fetoprotein (AFP) detection. Platinum nanoparticles on carboxylated-graphene oxide (PtNPs/GO-COOH) modified screen-printed graphene-carbon paste electrode (SPGE) was utilized as an immobilization platform, and the AFP aptamer was employed as a bio-recognition element. The synthesized GO-COOH helps to increase the surface area and amounts of the immobilized aptamer. Subsequently, PtNPs are decorated on GO-COOH to enhance electrical conductivity and an oxidation current of the hydroquinone electrochemical probe. The aptamer selectively interacts with AFP, causing a decrease in the peak current of the hydroquinone because the binding biomolecules on the electrode surface hinder the electron transfer of the redox probe. Effects of aptamer concentration and AFP incubation time were studied, and the current changes of the redox probe before and after AFP binding were investigated by square wave voltammetry. The developed aptasensor provides a linear range from 3.0–30 ng mL−1 with a detection limit of 1.22 ng mL−1. Moreover, the aptamer immobilized electrode offers high selectivity to AFP molecules, good stability, and sensitive determination of AFP in human serum samples with high recoveries.
Early overnutrition in male mice negates metabolic benefits of a diet high in monounsaturated and omega-3 fats
Authors: Glavas Maria M. , Hui Queenie , Miao Ian , Yang Fan , Erener Suheda , Prentice Kacey J. , Wheeler Michael B. , Kieffer Timothy J.
Published: July 2021

Overconsumption of saturated fats promotes obesity and type 2 diabetes. Excess weight gain in early life may be particularly detrimental by promoting earlier diabetes onset and potentially by adversely affecting normal development. In the present study we investigated the effects of dietary fat composition on early overnutrition-induced body weight and glucose regulation in Swiss Webster mice, which show susceptibility to high-fat diet-induced diabetes. We compared glucose homeostasis between a high-fat lard-based (HFL) diet, high in saturated fats, and a high-fat olive oil/fish oil-based (HFO) diet, high in monounsaturated and omega-3 fats. We hypothesized that the healthier fat profile of the latter diet would improve early overnutrition-induced glucose dysregulation. However, early overnutrition HFO pups gained more weight and adiposity and had higher diabetes incidence compared to HFL. In contrast, control pups had less weight gain, adiposity, and lower diabetes incidence. Plasma metabolomics revealed reductions in various phosphatidylcholine species in early overnutrition HFO mice as well as with diabetes. These findings suggest that early overnutrition may negate any beneficial effects of a high-fat diet that favours monounsaturated and omega-3 fats over saturated fats. Thus, quantity, quality, and timing of fat intake throughout life should be considered with respect to metabolic health outcomes.
Health economics modeling of antiretroviral interventions amongst HIV serodiscordant couples
Authors: Wu Haisheng , Yu Qiuyan , Ma Liping , Zhang Lin , Chen Yuliang , Guo Pi , Xu Peng
Published: July 2021

Antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP) for HIV-serodiscordant couples, effectively reduce mortality, transmission events and influence quality of life at the expense of increased costs. We aimed to evaluate health economics of antiretroviral-based strategies for HIV-serodiscordant couples in the China context. A deterministic model of HIV evolution and transmission within a cohort of serodiscordant couples was parameterized using the real-world database of Zhoukou city and published literature. We evaluated the mid-ART (a historical strategy, initiating ART with CD4 < 500 cells/mm3), early-ART (the current strategy, offering ART regardless of CD4 cell counts) and a hypothetical strategy (early-ART combined short-term daily PrEP) versus the late-ART (the baseline strategy, initiating ART with CD4 < 350 cells/mm3) offered by 2008 national guidelines. We estimated the incremental cost-effectiveness ratios (ICER) and incremental cost-utility ratios (ICUR) from a societal perspective, derived by clinical benefits and HIV-caused life quality respectively, and portrayed their changes over a 0–30 year’s timeframe. The model projections indicated that the antiretroviral-based interventions were more likely to obtain clinical benefits but difficult to improve quality of life, and cumulative ICER and ICUR were generally decreasing without achieving cost-saving. Scale-up access to ART for the HIV-positive among serodiscordant couples was easily fallen within the range of paying for incremental life-years and quality adjusted life years by the societal willingness. The hypothetical strategy had the potential to prevent most seroconversion events within marriages but required enormous upfront costs, thus it took a long time to reach established thresholds. The current strategy of early-ART is the most cost-effective. Clarifying the obstacles of high cost of PrEP and improving life quality for HIV-serodiscordant couples have emerged as an urgent requisition.
SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy
Authors: Ji Xiaolin , Liu Yan , Mei Fang , Li Xinyang , Zhang Mengxue , Yao Buwen , Wu Rui , You Jiangfeng , Pei Fei
Published: July 2021

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer.
Detection of unknown ototoxic adverse drug reactions: an electronic healthcare record-based longitudinal nationwide cohort analysis
Authors: Lee Suehyun , Cha Jaehun , Kim Jong-Yeup , Son Gil Myeong , Kim Dong-Kyu
Published: July 2021

Ototoxic medications can lead to significant morbidity. Thus, pre-marketing clinical trials have assessed new drugs that have ototoxic potential. Nevertheless, several ototoxic side effects of drugs may remain undetected. Hence, we sought to retrospectively investigate the potential risk of ototoxic adverse drug reactions among commonly used drugs via a longitudinal cohort study. An electronic health records-based data analysis with a propensity-matched comparator group was carried out. This study was conducted using the MetaNurse algorithm for standard nursing statements on electronic healthcare records and the National Sample Cohort obtained from the South Korea National Health Insurance Service. Five target drugs capable of causing ototoxic adverse drug reactions were identified using MetaNurse; two drugs were excluded after database-based analysis because of the absence of bilateral hearing loss events in patients. Survival analysis, log-rank test, and Cox proportional hazards regression models were used to calculate the incidence, survival rate, and hazard ratio of bilateral hearing loss among patients who were prescribed candidate ototoxic drugs. The adjusted hazard ratio of bilateral hearing loss was 1.31 (1.03–1.68), 2.20 (1.05–4.60), and 2.26 (1.18–4.33) in cimetidine, hydroxyzine, and sucralfate users, respectively. Our results indicated that hydroxyzine and sucralfate may cause ototoxic adverse drug reactions in patients. Thus, clinicians should consider avoiding co-administration of these drugs with other well-confirmed ototoxic drugs should be emphasized.
Labelling experiments in red deer provide a general model for early bone growth dynamics in ruminants
Authors: Calderón Teresa , Arnold Walter , Stalder Gabrielle , Painer Johanna , Köhler Meike
Published: July 2021

Growth rates importantly determine developmental time and are, therefore, a key variable of a species' life history. A widely used method to reconstruct growth rates and to estimate age at death in extant and particularly in fossil vertebrates is the analysis of bone tissue apposition rates. Lines of arrested growth (LAGs) are of special interest here, as they indicate a halt in bone growth. However, although of great importance, the time intervals between, and particularly the reason of growth arrests remains unknown. Therefore, experiments are increasingly called for to calibrate growth rates with tissue types and life history events, and to provide reliable measurements of the time involved in the formation of LAGs. Based on in vivo bone labelling, we calibrated periods of bone tissue apposition, growth arrest, drift and resorption over the period from birth to post-weaning in a large mammal, the red deer. We found that bone growth rates tightly matched the daily weight gain curve, i.e. decreased with age, with two discrete periods of growth rate disruption that coincided with the life history events birth and weaning, that were visually recognisable in bone tissue as either partial LAGs or annuli. Our study identified for the first time in a large mammal a general pattern for juvenile bone growth rates, including periods of growth arrest. The tight correlation between daily weight gain and bone tissue apposition suggests that the red deer bone growth model is valid for ruminants in general where the daily weight gain curve is comparable.
Biomechanical evaluation of the human mandible after temporomandibular joint replacement under different biting conditions
Authors: Pinheiro Manuel , Willaert Robin , Khan Afaq , Krairi Anouar , Van Paepegem Wim
Published: July 2021

Temporomandibular joint (TMJ) replacement with an implant is only used when all other conservative treatments fail. Despite the promising short-term results, the long-term implications of TMJ replacement in masticatory function are not fully understood. Previous human and animal studies have shown that perturbations to the normal masticatory function can lead to morphological and functional changes in the craniomaxillofacial system. A clearer understanding of the biomechanical implications of TMJ replacement in masticatory function may help identify design shortcomings that hinder their long-term success. In this study, patient-specific finite element models of the intact and implanted mandible were developed and simulated under four different biting tasks. In addition, the impact of re-attaching of the lateral pterygoid was also evaluated. The biomechanics of both models was compared regarding both mandibular displacements and principal strain patterns. The results show an excessive mediolateral and anteroposterior displacement of the TMJ implant compared to the intact joint in three biting tasks, namely incisor (INC), left moral (LML), and right molar (RML) biting. The main differences in principal strain distributions were found across the entire mandible, most notably from the symphysis to the ramus of the implanted side. Furthermore, the re-attachment of the lateral pterygoid seems to increase joint anteroposterior displacement in both INC, LML and RML biting while reducing it during LGF. Accordingly, any new TMJ implant design must consider stabilising both mediolateral and anteroposterior movement of the condyle during biting activities and promoting a more natural load transmission along the entire mandible.
Conserved residues in the extracellular loop 2 regulate Stachel-mediated activation of ADGRG2
Authors: Gad Abanoub A. , Azimzadeh Pedram , Balenga Nariman
Published: July 2021

Cleavage and dissociation of a large N-terminal fragment and the consequent unmasking of a short sequence (Stachel) remaining on the N-terminus have been proposed as mechanisms of activation of some members of the adhesion G protein-coupled receptor (aGPCR) family. However, the identity of residues that play a role in the activation of aGPCRs by the cognate Stachel remains largely unknown. Protein sequence alignments revealed a conserved stretch of residues in the extracellular loop 2 (ECL2) of all 33 members of the aGPCR family. ADGRG2, an orphan aGPCR, plays a major role in male fertility, Ewing sarcoma cell proliferation, and parathyroid cell function. We used ADGRG2 as a model aGPCR and generated mutants of the conserved residues in the ECL2 via site-directed mutagenesis. We show that tryptophan and isoleucine in the ECL2 are essential for receptor stability and surface expression in the HEK293 cells. By adjusting the receptor surface expression levels, we show that mutation of these residues of ECL2 ablates the Stachel-mediated activation of multiple signaling pathways of ADGRG2. This study provides a novel understanding of the role of the ECL2 in Stachel-mediated signaling and degradation of ADGRG2, which may lay the foundation for the rational design of therapeutics to target aGPCRs.
Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
Authors: Schwinn Stefanie , Mokhtari Zeinab , Thusek Sina , Schneider Theresa , Sirén Anna-Leena , Tiemeyer Nicola , Caruana Ignazio , Miele Evelina , Schlegel Paul G. , Beilhack Andreas , Wölfl Matthias
Published: July 2021

Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.
A recent update about seroprevalence of ovine neosporosis in Northern Egypt and its associated risk factors
Authors: Selim Abdelfattah , Khater Hanem , Almohammed Hamdan I.
Published: July 2021

Neospora caninum (Family: Sarcocystidae) is an obligate intracellular protozoan. It is one of the most critical abortifacients in ruminants. The seroprevalence of antibodies against N. caninum and its risk factors was investigated among 430 sheep from four North Egyptian governorates, Alexandria, Gharbia, Menofia, and Qalyubia, during the period from 2017 to 2018. Generally, the overall prevalence rate of N. caninum among sheep was 8.6%. The logistic regression analysis for the obtained data revealed that N. caninum increased significantly with age (OR = 2.4, 95% CI: 8.4–18.7) of the ewe (OR = 3.3, 95% CI: 7.6–14.9), particularly among sheep in contact with dogs (OR = 4.9, 95% CI: 7.5–14.3). Besides, locality, season, and pregnancy status of examined sheep had no significant effect on the appearance of N. caninum infection. the present findings confirm the presence of N. caninum among sheep in Egypt which probably play a role in reproductive failure in sheep. Therefore, sanitary measures and monitoring of the infection should be implemented to reduce the spreading of the infection.
An engineered tetra-valent antibody fully activates the Tie2 receptor with comparable potency to its natural ligand angiopoietin-1
Authors: Koya Yukari , Nara Hiromi , Yagi Shigenori , Ueno Chihoko , Kamohara Masazumi
Published: July 2021

Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.
Retraction: Rhodium nanocubes and nanotripods for highly sensitive ultraviolet surface-enhanced Raman spectroscopy
Authors: Ross Philippa
Published: July 2021

Retraction of ‘Rhodium nanocubes and nanotripods for highly sensitive ultraviolet surface-enhanced Raman spectroscopy’ by Rupali Das et al., Analyst, 2018, 143, 2310–2322, DOI: 10.1039/C8AN00341F
A pH-triggered fluorescence-switchable extracellular vesicle for tracing drug release and improving drug delivery
Authors: Su Rui , Xiong Xiang , Li Yingping , Wei Xiaoqing , Zheng Sibo , Zhao Jingya , Zhou Shaobing
Published: July 2021

A pH-triggered fluorescence-switchable extracellular vesicle is developed by loading zwitterionic fluorescent carbon dots into macrophage cell-secreted vesicles, which enables to improve drug delivery and monitor drug release in real time.
Rhodium(iii)-catalyzed [5+1] annulation of 2-alkenylphenols with maleimides: access to highly functionalized spirocyclic skeletons
Authors: Kumar Anil , Prabhu Kandikere Ramaiah
Published: July 2021

A new edition of [5+1] annulation reaction of maleimides with 2-alkenylphenols has been discovered under a Rh(iii)-catalytic system.
Reversible regulation of metallo-base-pair interactions for DNA dehybridization by ultrasound
Authors: Huo Shuaidong , Zhou Yu , Liao Zhihuan , Zhao Pengkun , Zou Miancheng , Göstl Robert , Herrmann Andreas
Published: July 2021

Ultrasound leads to the reversible dissociation of DNA metallo-base-pairs when these motifs are functionalized with oligodeoxynucleotide sequences of sufficient length.
Probing optical and magnetic properties via subtle stereoelectronic effects in mononuclear DyIII-complexes
Authors: Kitos Alexandros A. , Gálico Diogo A. , Mavragani Niki , Castañeda Raúl , Moilanen Jani O. , Brusso Jaclyn L. , Murugesu Muralee
Published: July 2021

Probing optical and magnetic properties via subtle stereoelectronic effects in mononuclear DyIII-complexes.
Redox of naphthalenediimide radicals in a 3D polyimide for stable Li-ion batteries
Authors: Gu Shuai , Chen Yatu , Hao Rui , Zhou Jun , Hussain Iftikhar , Qin Ning , Li Muqing , Chen Jingjing , Wang Zhiqiang , Zheng Wei , Gan Qingmeng , Li Zhiqiang , Guo Hao , Li Yingzhi , Zhang Kaili , Lu Zhouguang
Published: July 2021

The 3D rigid structure contributes to the stability of the radical intermediates in polyimide electrodes for high-performance organic batteries.
MAPbI3 microcrystals integrated with Ti3C2Tx MXene nanosheets for efficient visible-light photocatalytic H2 evolution
Authors: Li Wenbo , Wang Fang , Zhang Zhengguo , Min Shixiong
Published: July 2021

MAPbI3 microcrystals integrated with Ti3C2Tx nanosheets as an advanced composite photocatalyst achieving superior photocatalytic H2 evolution activity using visible light.
Aromatic amine-assisted pseudo-solution-phase ligand exchange in CsPbI3 perovskite quantum dot solar cells
Authors: Zhang Xuliang , Huang Hehe , Maung Yin Maung , Yuan Jianyu , Ma Wanli
Published: July 2021

Here, a pseudo-solution-phase ligand exchange (p-SPLE) strategy is developed for fabricating a CsPbI3 quantum dot (QD) solar cell.
B(C6F5)3-Catalyzed site-selective N1-alkylation of benzotriazoles with diazoalkanes
Authors: Zhao Yunbo , Mandal Dipendu , Guo Jing , Wu Yile , Stephan Douglas W.
Published: July 2021

The site-selective N1-alkylation of benzotriazoles with diazoalkanes is achieved using 10 mol% of B(C6F5)3 as a catalyst.
An amorphous WC thin film enabled high-efficiency N2 reduction electrocatalysis under ambient conditions
Authors: Li Shaoxiong , Luo Yonglan , Yue Luchao , Li Tingshuai , Wang Yan , Liu Qian , Cui Guanwei , Zhang Fang , Asiri Abdullah M. , Sun Xuping
Published: July 2021

As an electrocatalyst for N2-to-NH3 conversion, an amorphous WC thin film shows a large NH3 yield of 43.37 μg h−1 mg−1cat. with a high faradaic efficiency of 21.65% at −0.10 V vs. RHE in 0.5 M LiClO4.
Sequential C–H activation enabled expedient delivery of polyfunctional arenes
Authors: Ouyang Wensen , Cai Xiaoqing , Chen Xiaojian , Wang Jie , Rao Jianhang , Gao Yang , Huo Yanping , Chen Qian , Li Xianwei
Published: July 2021

A sequential C–H activation of versatile imidates was realized, affording to polyfunctional arenes was developed, which were key precursors for drugs and materials.
Surface energy driven miscibility gap suppression during nucleation of III–V ternary alloys
Authors: Leshchenko Egor D. , Johansson Jonas
Published: July 2021

We have explained how the surface energy influences the miscibility gap during nucleation from a liquid melt.
Novel copper fluoride analogs of cuprates
Authors: Rybin Nikita , Novoselov Dmitry Y. , Korotin Dmitry M. , Anisimov Vladimir I. , Oganov Artem R.
Published: July 2021

On the basis of the first-principles evolutionary crystal structure prediction of stable compounds in the Cu–F system, we predict two experimentally unknown stable phases – Cu2F5 and CuF3.