bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells
Authors: Passariello Margherita , Vetrei Cinzia , Sasso Emanuele , Froechlich Guendalina , Gentile Chiara , D'Alise Anna Morena , Zambrano Nicola , Scarselli Elisa , Nicosia Alfredo , De Lorenzo Claudia
Published: August 2020

The cytotoxic T lymphocyte-antigen 4 (CTLA-4) has been considered an IC exclusively expressed on T cells, where it counteracts the co-stimulatory CD28 receptor, by competing for its binding to CD-80 and CD-86. We recently found that it is expressed also on tumor and NK cells, suggesting other possible unknown roles of CTLA-4. To shed light on these novel aspects of CTLA-4, we used Ipilimumab, the first FDA approved human antibody targeting CTLA-4, in parallel studies with two novel human mAbs we isolated by using an efficient phage display selection strategy on live activated lymphocytes and purified mouse and human CTLA-4. The selection for cross-reactive mAbs was guaranteed by a high throughput sequencing to identify the sequences commonly enriched by two parallel pannings on human and mouse CTLA-4. Two isolated antibodies were found to bind with high affinity to both human and mouse CTLA-4 and lymphocytes, showing nanomolar or sub-nanomolar Kd values. They were able to kill Treg cells by ADCC, and to activate both human and mouse PBMCs, by strongly increasing cytokines secretion. Interestingly, they activated NK cells, exhibited cytotoxicity against cancer cells by inducing ADCC and inhibited tumor cell growth by affecting CTLA-4 downstream pathways in a similar fashion to CD-80 and CD-86 ligands and differently from Ipilimumab. Moreover, the novel mAbs showed a reduced ability to interfere in the binding of CD-80 ligands to CTLA-4 on T cells with respect to Ipilimumab, suggesting that they could allow for anti-tumor effects without the irAEs associated with the potent antagonistic activity of Ipilimumab.
Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer
Authors: Sanchez-Herrero Alvaro , Calvo Isabel A. , Flandes-Iparraguirre Maria , Landgraf Marietta , Lahr Christoph A. , Shafiee Abbas , Granero-Molto Froilán , Saez Borja , Mazo Manuel M. , Paiva Bruno , de Juan Pardo Elena , Nicol Andrew , Prosper Felipe , Bray Laura J. , McGovern Jacqui A.
Published: August 2020

Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour–microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform.
Revealing the Effect of Nickel Particle Size on Carbon Formation Type in the Methane Decomposition Reaction
Authors: Liang Wei , Yan Hao , Chen Chen , Lin Dong , Tan Kexin , Feng Xiang , Liu Yibin , Chen Xiaobo , Yang Chaohe , Shan Honghong
Published: August 2020

Carbon species deposition is recognized as the primary cause of catalyst deactivation for hydrocarbon cracking and reforming reactions. Exploring the formation mechanism and influencing factors for carbon deposits is crucial for the design of rational catalysts. In this work, a series of NixMgyAl-800 catalysts with nickel particles of varying mean sizes between 13.2 and 25.4 nm were obtained by co-precipitation method. These catalysts showed different deactivation behaviors in the catalytic decomposition of methane (CDM) reaction and the deactivation rate of catalysts increased with the decrease in nickel particle size. Employing TG-MS and TEM characterizations, we found that carbon nanotubes which could keep catalyst activity were more prone to form on large nickel particles, while encapsulated carbon species that led to deactivation were inclined to deposit on small particles. Supported by DFT calculations, we proposed the insufficient supply of carbon atoms and rapid nucleation of carbon precursors caused by the lesser terrace/step ratio on smaller nickel particles, compared with large particles, inhibit the formation of carbon nanotube, leading to the formation of encapsulated carbon species. The findings in this work may provide guidance for the rational design of nickel-based catalysts for CDM and other methane conversion reactions.
Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production
Authors: Argon Yair , Bresson Sophie E. , Marzec Michal T. , Grimberg Adda
Published: August 2020

Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF–GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.
Amelioration of Congenital Tufting Enteropathy in EpCAM (TROP1)-Deficient Mice via Heterotopic Expression of TROP2 in Intestinal Epithelial Cells
Authors: Nakato Gaku , Morimura Sohshi , Lu Michael , Feng Xu , Wu Chuanjin , Udey Mark C.
Published: August 2020

TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. Adult intestinal epithelial cells (IEC) express high levels of EpCAM, while TROP2 is not expressed. EpCAM deficiency causes congenital tufting enteropathy (CTE) in humans and a corresponding lethal condition in mice. We expressed TROP2 and EpCAM in the IEC of EpCAM-deficient mice utilizing a villin promoter to assess EpCAM and TROP2 function. Expression of EpCAM or TROP2 in the IEC of EpCAM knockout mice prevented CTE. TROP2 rescue (T2R) mice were smaller than controls, while EpCAM rescue (EpR) mice were not. Abnormalities were observed in the diameters and histology of T2R small intestine, and Paneth and stem cell markers were decreased. T2R mice also exhibited enlarged mesenteric lymph nodes, enhanced permeability to 4 kDa FITC-dextran and increased sensitivity to detergent-induced colitis, consistent with compromised barrier function. Studies of IEC organoids and spheroids revealed that stem cell function was also compromised in T2R mice. We conclude that EpCAM and TROP2 exhibit functional redundancy, but they are not equivalent.
Schwann Cell Cultures: Biology, Technology and Therapeutics
Authors: Monje Paula V.
Published: August 2020

Schwann cell (SC) cultures from experimental animals and human donors can be prepared using nearly any type of nerve at any stage of maturation to render stage- and patient-specific populations. Methods to isolate, purify, expand in number, and differentiate SCs from adult, postnatal and embryonic sources are efficient and reproducible as these have resulted from accumulated refinements introduced over many decades of work. Albeit some exceptions, SCs can be passaged extensively while maintaining their normal proliferation and differentiation controls. Due to their lineage commitment and strong resistance to tumorigenic transformation, SCs are safe for use in therapeutic approaches in the peripheral and central nervous systems. This review summarizes the evolution of work that led to the robust technologies used today in SC culturing along with the main features of the primary and expanded SCs that make them irreplaceable models to understand SC biology in health and disease. Traditional and emerging approaches in SC culture are discussed in light of their prospective applications. Lastly, some basic assumptions in vitro SC models are identified in an attempt to uncover the combined value of old and new trends in culture protocols and the cellular products that are derived.
Adverse Neurological Effects of Short-Term Sleep Deprivation in Aging Mice Are Prevented by SS31 Peptide
Authors: Wu Jinzi , Dou Yan , Ladiges Warren C.
Published: August 2020

Sleep deprivation is a potent stress factor that disrupts regulatory pathways in the brain resulting in cognitive dysfunction and increased risk of neurodegenerative disease with increasing age. Prevention of the adverse effects of sleep deprivation could be beneficial in older individuals by restoring healthy brain function. We report here on the ability of SS31, a mitochondrial specific peptide, to attenuate the negative neurological effects of short-term sleep deprivation in aging mice. C57BL/6 female mice, 20 months old, were subcutaneously injected with SS31 (3 mg/kg) or saline daily for four days. Sleep deprivation was 4 h daily for the last two days of SS31 treatment. Mice were immediately tested for learning ability followed by collection of brain and other tissues. In sleep deprived mice treated with SS31, learning impairment was prevented, brain mitochondrial ATP levels and synaptic plasticity regulatory proteins were restored, and reactive oxygen species (ROS) and inflammatory cytokines levels were decreased in the hippocampus. This observation suggests possible therapeutic benefits of SS31 for alleviating adverse neurological effects of short-term sleep loss.
Perceptions of Similarity Can Mislead Provenancing Strategies—An Example from Five Co-Distributed Acacia Species
Authors: Rossetto Maurizio , Wilson Peter D. , Bragg Jason , Cohen Joel , Fahey Monica , Yap Jia-Yee Samantha , van der Merwe Marlien
Published: August 2020

Ecological restoration requires balancing levels of genetic diversity to achieve present-day establishment as well as long-term sustainability. Assumptions based on distributional, taxonomic or functional generalizations are often made when deciding how to source plant material for restoration. We investigate this assumption and ask whether species-specific data is required to optimize provenancing strategies. We use population genetic and environmental data from five congeneric and largely co-distributed species of Acacia to specifically ask how different species-specific genetic provenancing strategies are based on empirical data and how well a simple, standardized collection strategy would work when applied to the same species. We find substantial variability in terms of patterns of genetic diversity and differentiation across the landscape among these five co-distributed Acacia species. This variation translates into substantial differences in genetic provenancing recommendations among species (ranging from 100% to less than 1% of observed genetic variation across species) that could not have been accurately predicted a priori based on simple observation or overall distributional patterns. Furthermore, when a common provenancing strategy was applied to each species, the recommended collection areas and the evolutionary representativeness of such artificially standardized areas were substantially different (smaller) from those identified based on environmental and genetic data. We recommend the implementation of the increasingly accessible array of evolutionary-based methodologies and information to optimize restoration efforts.
A Refinement of Recurrence Analysis to Determine the Time Delay of Causality in Presence of External Perturbations
Authors: Peluso Emmanuele , Craciunescu Teddy , Murari Andrea
Published: August 2020

This article describes a refinement of recurrence analysis to determine the delay in the causal influence between a driver and a target, in the presence of additional perturbations affecting the time series of the response observable. The methodology is based on the definition of a new type of recurrence plots, the Conditional Joint Recurrence plot. The potential of the proposed approach resides in the great flexibility of recurrence plots themselves, which allows extending the technique to more than three quantities. Autoregressive time series, both linear and nonlinear, with different couplings and percentage of additive Gaussian noise have been investigated in detail, with and without outliers. The approach has also been applied to the case of synthetic periodic signals, representing realistic situations of synchronization experiments in thermonuclear fusion. The results obtained have been very positive; the proposed Conditional Joint Recurrence plots have always managed to identify the right interval of the causal influences and are very competitive with alternative techniques such as the Conditional Transfer Entropy.
Lessons to Learn from Post-Installation Pollution Levels Assessment of Some Distribution Insulators
Authors: Fofana Issouf , N’cho Janvier Sylvestre , Betie Amidou , Hounton Epiphane , Meghnefi Fethi , Yapi Kouba Marie Lucia
Published: August 2020

Among the main causes of outdoor insulation failures is their poor specifications in terms of leakage distances. This happens when the selected criteria are unable to cope with all the stresses imposed by the changes in environmental pollutions. Therefore, it is important for utilities to fully understand the actual pollution characteristics of the service environment in which the insulators are operating. In this paper, the pollution severity and performance of some 13.2 kV ceramic insulators, sampled in different areas of a Canadian aluminum factory, are assessed. The investigations were performed taking into account the influence of air humidity. Various characteristics were investigated to assess the pollution levels of the insulators, such as equivalent salt deposit density (ESDD) and non-soluble deposit density (NSDD), surface resistance, and leakage current characteristics (density, 3rd harmonic amplitude, and phase). It was witnessed that the insulators, collected around the factory, were much more polluted in comparison to the initial expectation. The pollution level should not be considered static due to the environmental parameters’ dynamics. Lessons to learn: the reliability of an electrical grid is dependent on components whose own reliability is strongly affected by external factors, of which there is often a poor awareness. If care is not taken to re-evaluate the post-installation pollution levels of the insulators, the light may simply turn out!
EGCIR: Energy-Aware Graph Clustering and Intelligent Routing Using Supervised System in Wireless Sensor Networks
Authors: Saba Tanzila , Haseeb Khalid , Ud Din Ikram , Almogren Ahmad , Altameem Ayman , Fati Suliman Mohamed
Published: August 2020

In recent times, the field of wireless sensor networks (WSNs) has attained a growing popularity in observing the environment due to its dynamic factors. Sensor data are gathered and forwarded to the base station (BS) through a wireless transmission medium. The data from the BS is further distributed to end-users using the Internet for their post analysis and operations. However, all sensors except the BS have limited constraints in terms of memory, energy and computational resources that degrade the network performance concerning the network lifetime and trustworthy routing. Therefore, improving energy efficiency with reliable and secure transmissions is a valuable debate among researchers for critical applications based on low-powered sensor nodes. In addition, security plays a significant cause to achieve responsible communications among sensors due to their unfixed and variable infrastructures. Keeping in view the above-mentioned issues, this paper presents an energy-aware graph clustering and intelligent routing (EGCIR) using a supervised system for WSNs to balance the energy consumption and load distribution. Moreover, a secure and efficient key distribution in a hierarchy-based mechanism is adopted by the proposed solution to improve the network efficacy in terms of routes and links integrity. The experimental results demonstrated that the EGCIR protocol enhances the network throughput by an average of 14%, packet drop ratio by an average of 50%, energy consumption by an average of 13%, data latency by an average of 30.2% and data breaches by an average of 37.5% than other state-of-the-art protocols.
Influence of Degradation Processes in Lead–Acid Batteries on the Technoeconomic Analysis of Photovoltaic Systems
Authors: Delgado-Sanchez Jose-Maria , Lillo-Bravo Isidoro
Published: August 2020

Most technoeconomic feasibility studies of photovoltaic (PV) systems with batteries are mainly focused on the load demand, PV system profiles, total system costs, electricity price, and the remuneration rate. Nevertheless, most do not emphasise the influence degradation process such as corrosion, sulphation, stratification, active material seeding, and gassing on battery lifetime, efficiency, and capacity. In this paper, it is analysed the influence of the degradation processes in lead–acid batteries on the technoeconomic analysis of PV systems with and without battery. Results show that Net Present Value (NPV), Payback Period (PBP), and Discounted PayBack Period (DPBP) have a heavy dependence on the assumptions about the value of the battery performance parameters according to its degradation processes. Results show NPV differences in the range from −307% to 740%, PBP differences in the range from 9% to 188%, and DPBP differences in the range from 0% to 211%.
Yield and Nutrient Demand and Efficiency of Eucalyptus under Coppicing Regime
Authors: Silva Nathália Faria da , Barros Nairam Félix de , Neves Júlio César Lima , Schulthais Fernanda , Novais Roberto Ferreira de , Mattiello Edson Marcio
Published: August 2020

Eucalyptus stands can be managed by coppicing, however, in several Brazilian regions reduced yield has been observed with harvesting successions. This reduction can be attributed to reduced nutrient availability, among other factors. This study aimed to: to assess the nutritional demand of the Eucalyptus stand under a coppice regime; the effect of fertilization on the production of wood, distribution and compartmentalization of nutrients in eucalyptus stands managed by coppice; the effect of the height and number of shoots, on the occasion of the sprouting, in the production of eucalyptus managed by coppice and to compare the productivity of high eucalyptus wood with coppice management regime. The trial was conducted for clone GG157 (Eucalyptus urophylla hybrid), in Latossolo Vermelho-Amarelo (Oxisol), of the Cerrado region in Minas Gerais State, Brazil. Trees were originally planted at the 3.8 × 2.4 m spacing and, after the first harvesting, at age 84 months, the stand was managed by coppicing. Treatments consisted of: (a) fertilization or not; (b) one, two or four poles per stump; and (c) selection of 1-, 2- or 4-m-high poles and repeated three times. Sixty months after treatment application, plots of 80 trees were used for the assessments. The gain in trunk yield with fertilization and the combination between the height of poles at the time of pole selection and number of poles left varies between 140.2% for thinning when the pole is 2 m high and maintains 1 pole per strain and 128.6% when the plants are 1 m high and maintain 1 pole per strain. Not supplying nutrients in the coppicing system leads to lower accumulation of nutrients in the tree and reductions in both wood and trunk yields. Trees in the coppicing system use nutrients for trunk production more efficiently than those in high forest. Earlier pole selection enables the best use of growth resources, resulting in increased yield. Adequate nutritional management of coppiced stands results in the maintenance or increase of yield compared to the first rotation.
Mice and Habitat Complexity Attract Carnivorans to Recently Burnt Forests
Authors: Puig-Gironès Roger , Pons Pere
Published: August 2020

Faunal responses to wildfire depend on the fire effects on direct mortality, habitat structure, and resource availability for animals. Despite the importance of large predators in terrestrial trophic webs, little is still known about how fire affects carnivorans (the mammalian order Carnivora). To evaluate the responses of the carnivoran community to fire, we studied three recently burnt forest areas in the western Mediterranean basin. Line transects were used to quantify evidence of carnivorans (mainly feces) and to measure environmental variables and resources (small mammal abundance, fleshy fruit availability, and plant cover). Throughout the study, we found 212 carnivoran field signs, 93% of them produced by red fox and stone marten. Immediately after fire, carnivoran occurrence was more frequent close to the perimeter of the burnt area, where fire severity was low, and in places with greater small mammal abundance. Small mammal abundance and plant cover had the greatest effect on the frequency of occurrence of red fox in the burnt area surroundings, and this increased with time-since-fire in the burnt area. Furthermore, the presence of red fox did not affect stone marten occurrence. Stone martens were found around the burnt area perimeter, probably because of their preference for high plant cover, and they were not significantly affected by small mammal abundance. The scat frequency of occurrence of both species was not significantly related to fleshy fruit availability. Accordingly, rodents and carnivorans were more abundant where the habitat was more complex. Our results show that the responses of some carnivorans to fire are influenced, directly and indirectly, by habitat structure and resource availability.
The Effect of Muscular Strength on Depression Symptoms in Adults: A Systematic Review and Meta-Analysis
Authors: Marques Adilson , Gomez-Baya Diego , Peralta Miguel , Frasquilho Diana , Santos Teresa , Martins João , Ferrari Gerson , Gaspar de Matos Margarida
Published: August 2020

The aim was to systematically review the relationship between muscular strength (MS) and depression symptoms (DS) among adults, and conduct a meta-analysis to determine the pooled odds ratio (OR) for the relationship between MS and DS. The strategies employed in this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies published up to December 2019 were systematically identified by searching in the PubMed, Scopus, and Web of Science electronic databases. Inclusion criteria were: (1) cross-sectional, longitudinal and intervention studies; (2) outcomes included depression or DS; (3) participants were adults and older adults; and (4) the articles were published in English, French, Portuguese, or Spanish. A total of 21 studies were included in the review, totalling 87,508 adults aged ≥18 years, from 26 countries. The systematic review findings suggest that MS has a positive effect on reducing DS. Meta-analysis findings indicate that MS is inversely and significantly related to DS 0.85 (95% CI: 0.80, 0.89). Interventions aiming to improve MS have the potential to promote mental health and prevent depression. Thus, public health professionals could use MS assessment and improvement as a strategy to promote mental health and prevent depression.
A Comparative Study of Accident Risk Related to Speech-Based and Handheld Texting during a Sudden Braking Event in Urban Road Environments
Authors: Fu Rui , Chen Yunxing , Xu Qingjin , Guo Yuxi , Yuan Wei
Published: August 2020

The use of mobile phones while driving is a very common phenomenon that has become one of the main causes of traffic accidents. Many studies on the effects of mobile phone use on accident risk have focused on conversation and texting; however, few studies have directly compared the impacts of speech-based texting and handheld texting on accident risk, especially during sudden braking events. This study aims to statistically model and quantify the effects of potential factors on accident risk associated with a sudden braking event in terms of the driving behavior characteristics of young drivers, the behavior of the lead vehicle (LV), and mobile phone distraction tasks (i.e., both speech-based and handheld texting). For this purpose, a total of fifty-five licensed young drivers completed a driving simulator experiment in a Chinese urban road environment under five driving conditions: baseline (no phone use), simple speech-based texting, complex speech-based texting, simple handheld texting, and complex handheld texting. Generalized linear mixed models were developed for the brake reaction time and rear-end accident probability during the sudden braking events. The results showed that handheld texting tasks led to a delayed response to the sudden braking events as compared to the baseline. However, speech-based texting tasks did not slow down the response. Moreover, drivers responded faster when the initial time headway was shorter, when the initial speed was higher, or when the LV deceleration rate was greater. The rear-end accident probability respectively increased by 2.41 and 2.77 times in the presence of simple and complex handheld texting while driving. Surprisingly, the effects of speech-based texting tasks were not significant, but the accident risk increased if drivers drove the vehicle with a shorter initial time headway or a higher LV deceleration rate. In summary, these findings suggest that the effects of mobile phone distraction tasks, driving behavior characteristics, and the behavior of the LV should be taken into consideration when developing algorithms for forward collision warning systems.
Ecological Effects of Heavy Metal Pollution on Soil Microbial Community Structure and Diversity on Both Sides of a River around a Mining Area
Authors: Zhao Xingqing , Huang Jian , Zhu Xuyan , Chai Jinchun , Ji Xiaoli
Published: August 2020

The objectives of this study were to understand the characteristics of heavy metal pollution caused by mining activities on the two sides of the Shun’an river and the response of soil microorganisms to the habitats by different contamination levels and vegetation. This paper selected soil samples from the banks of the Shun’an River near the Shizishan mining area, which is at the left of the river, in Tongling, Anhui Province, China. Using Illumina MiSeq 2500 technology, we analyzed the relationship between environmental factors and microbial communities. As the distance from the mining area increased, the heavy metal comprehensive pollution and potential risk value decreased. Additionally, the pollution severity and risk value of the left bank, where the mining area lies, were generally higher than those of the right bank. Because the symmetric sampling points on both banks of the river had similar planting types, their environmental factors and microbial community structure were similar and clustered. However, under different vegetation, the paddy soils tended to have a higher nutrient content and community richness and diversity than the vegetable fields or the abandoned land. It was found that soil microbial communities in this area were mostly affected by pH and Nemerow pollution index (PN). The pH significantly affected the abundance and structure of most microorganisms. In addition, Proteobacteria, Acidobacteria, and Bacteroidetes had significant tolerance to Zn, Pb, and Cd. By exploring the potential use of these tolerant microorganisms, we seek to provide strains and the theoretical basis for the bioremediation of areas contaminated by heavy metal.
Comparison of Liquefied Petroleum Gas Cookstoves and Wood Cooking Fires on PM2.5 Trends in Brick Workers’ Homes in Nepal
Authors: Johnston James D. , Hawks Megan E. , Johnston Haley B. , Johnson Laurel A. , Beard John D.
Published: August 2020

Prior studies document a high prevalence of respiratory symptoms among brick workers in Nepal, which may be partially caused by non-occupational exposure to fine particulate matter (PM2.5) from cooking. In this study, we compared PM2.5 levels and 24 h trends in brick workers’ homes that used wood or liquefied petroleum gas (LPG) cooking fuel. PM2.5 filter-based and real-time nephelometer data were collected for approximately 24 h in homes and outdoors. PM2.5 was significantly associated with fuel type and location (p < 0.0001). Pairwise comparisons found significant differences between gas, indoor (geometric mean (GM): 79.32 μg/m3), and wood, indoor (GM: 541.14 μg/m3; p = 0.0002), and between wood, indoor, and outdoor (GM: 48.38 μg/m3; p = 0.0006) but not between gas, indoor, and outdoor (p = 0.56). For wood fuel homes, exposure peaks coincided with mealtimes. For LPG fuel homes, indoor levels may be explained by infiltration of ambient air pollution. In both wood and LPG fuel homes, PM2.5 levels exceeded the 24 h limit (25.0 µg/m3) proposed by the World Health Organization. Our findings suggest that increasing the adoption of LPG cookstoves and decreasing ambient air pollution in the Kathmandu valley will significantly lower daily PM2.5 exposures of brick workers and their families.
PTSD and Depressive Symptoms as Potential Mediators of the Association between World Trade Center Exposure and Subjective Cognitive Concerns in Rescue/Recovery Workers
Authors: Singh Ankura , Zeig-Owens Rachel , Rabin Laura , Schwartz Theresa , Webber Mayris P. , Appel David , Prezant David J. , Hall Charles B.
Published: August 2020

We observed that World Trade Center (WTC) exposure, post-traumatic stress disorder (PTSD) symptoms and depressive symptoms were associated with subjective cognitive concerns in Fire Department of the City of New York (FDNY) rescue/recovery workers. This follow-up study examined whether PTSD symptoms and/or depressive symptoms mediate the observed association between WTC exposure and subjective cognitive concerns. We included WTC-exposed FDNY workers who completed the Cognitive Function Instrument (CFI), measuring self-perceived cognitive decline (N = 9516). PTSD symptoms and depressive symptoms were assessed using the PCL-S and CES-D, respectively. Multivariable linear regression estimated the association between WTC exposure and CFI score, adjusting for confounders. Mediation analyses followed the methods of Vanderweele (2014). Participants’ average age at CFI assessment was 56.6 ± 7.6 years. Higher-intensity WTC exposure was associated with worse CFI score, an effect that was entirely mediated by PTSD symptoms (%mediated: 110.9%; 95%CI: 83.1–138.9). When substituting depressive symptoms for PTSD symptoms, the WTC exposure–CFI association was largely mediated (%mediated: 82.1%; 95%CI: 60.6–103.7). Our findings that PTSD symptoms and depressive symptoms mediate the association between WTC exposure and subjective cognitive concerns indicate that in the absence of these symptoms, WTC exposure in rescue/recovery workers would not be associated with subjective cognition. Interventions targeting PTSD and depression may have additional value in mitigating cognitive decline in WTC-exposed populations.
Antibiotic Susceptibility Testing (AST) Reports: A Basis for Environmental/Epidemiological Surveillance and Infection Control Amongst Environmental Vibrio cholerae
Authors: Igere Bright E. , Okoh Anthony I. , Nwodo Uchechukwu U.
Published: August 2020

Distribution, investigation, surveillance and control (DISC) of cholera outbreaks in endemic/non-endemic regions has been a concerted approach towards the management of the causal pathogen. Relevant organization, government, health systems and the public have implemented several steps towards controlling the menace, yet pathogen continues to occur with diverse phenotypes/genotypes of high clinical and epidemiological relevance. The study determines antibiotic susceptibility/resistance pattern of Vibrio cholerae isolates retrieved from six domestic water sources between March and August 2018. Serological and molecular typing methods (polymerase chain reaction or PCR) were used to confirm the isolates identity. Antibiotic susceptibility testing was conducted using six commonly employed antibiotics of V. cholerae according to the recommendation of Clinical Laboratory Standard and European Committee for Antimicrobial Susceptibility Testing with other relevant antibiotics of investigative epidemiology and infection control, employing both disc diffusion test and PCR gene detection. Samples presumptive counts ranged between 1.10 to 7.91 log10 CFU/mL. Amongst the 759 presumptive isolates retrieved, sixty-one were confirmed as V. cholerae which were further serogrouped as Non-O1/Non-O139 V. cholerae. Various V. cholerae resistant phenotypes/genoytypes were detected vis: carbapenemase (CR-Vc; 31.1%/5.3%). New Delhi Metallobetalactamase (NDM-1-Vc; 23.0%/42.5%), extended spectrum betalactamase (ESBL-Vc; 42.6%/blaTEM:86,7%), chloramphenicol resistance (62.3%/Flor: 46.2%}, tetracycline resistance (70.5%/46.7%), AmpC resistance (21.0 (34.4%/56.7%)) and various other resistant genotypes/phenotypes. It was observed that more than 50% of the confirmed V. cholerae isolates possess resistance to two or more antibiotic classes/groups with multiple antibiotic resistance index (MARI) ranging from 0.031 to 0.5. This observation provides necessary information and updates for surveillance, planning and implementation of control strategies for cholera. It would also encourage decision making, formulation of policy by the government and cholera control authorities.
Nursing Students’ Experiences of Clinical Practices in Emergency and Intensive Care Units
Authors: González-García María , Lana Alberto , Zurrón-Madera Paula , Valcárcel-Álvarez Yolanda , Fernández-Feito Ana
Published: August 2020

Clinical practices are key environments for skill acquisition during the education of nursing students, where it is important to encourage reflective learning. This study sought to explore the experience of final year nursing students during their clinical placement in emergency and intensive care units and to identify whether differences exist between female and male students. Using qualitative methodology, a documentary analysis of 28 reflective learning journals was carried out at a public university in Northern Spain. Four themes were identified: “an intense emotional experience”, “the importance of attitudes over and above techniques”, “identifying with nurses who dominate their environment and are close to the patient in complex and dehumanized units” and “how to improve care in critically ill patients and how to support their families”. The female students displayed a more emotional and reflective experience, with a strong focus on patient care, whereas male students identified more with individual aspects of learning and the organization and quality of the units. Both male and female students experienced intense emotions, improved their learning in complex environments and acquired attitudes linked to the humanization of care. However, the experience of these clinical rotations was different between female and male students.
Sex-Specific Features of Calcific Aortic Valve Disease
Authors: Summerhill Volha I. , Moschetta Donato , Orekhov Alexander N. , Poggio Paolo , Myasoedova Veronika A.
Published: August 2020

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in developed countries predominantly affecting the elderly population therefore posing a large economic burden. It is a gradually progressive condition ranging from mild valve calcification and thickening, without the hemodynamic obstruction, to severe calcification impairing leaflet motion, known as aortic stenosis (AS). The progression of CAVD occurs over many years, and it is extremely variable among individuals. It is also associated with an increased risk of coronary events and mortality. The recent insights into the CAVD pathophysiology included an important role of sex. Accumulating evidence suggests that, in patients with CAVD, sex can determine important differences in the relationship between valvular calcification process, fibrosis, and aortic stenosis hemodynamic severity between men and women. Consequently, it has implications on the development of different valvular phenotypes, left ventricular hypertrophy, and cardiovascular outcomes in men and women. Along these lines, taking into account the sex-related differences in diagnosis, prognosis, and treatment outcomes is of profound importance. In this review, the sex-related differences in patients with CAVD, in terms of pathobiology, clinical phenotypes, and outcomes were discussed.
A Foundational Study for Normal F8-Containing Mouse Models for the miRNA Regulation of Hemophilia A: Identification and Analysis of Mouse miRNAs that Downregulate the Murine F8 Gene
Authors: Jankowska Katarzyna I. , Chattopadhyay Maitreyi , Sauna Zuben E. , Atreya Chintamani D.
Published: August 2020

Hemophilia A (HA) is associated with defects in the F8 gene, encoding coagulation factor VIII (FVIII). Our previous studies show that F8-targeting micro RNAs (miRNAs), a group of small RNAs involved in gene regulation, can downregulate F8 expression causing HA in individuals with normal F8-genotypes and increased HA severity in patients with mutations in F8. Understanding the mechanistic underpinnings of human genetic diseases caused or modulated by miRNAs require a small animal model, such as a mouse model. Here, we report a foundational study to develop such a model system. We identified the mouse 3′untranslated region (3′UTR) on murine F8-mRNA (muF8-mRNA) that can bind to murine miRNAs. We then selected three miRNAs for evaluation: miR-208a, miR-351 and miR-125a. We first demonstrate that these three miRNAs directly target the 3′UTR of muF8-mRNA and reduce the expression of a reporter gene (luciferase) mRNA fused to the muF8-3′ UTR in mammalian cells. Furthermore, in mouse cells that endogenously express the F8 gene and produce FVIII protein, the ectopic expression of these miRNAs downregulated F8-mRNA and FVIII protein. These results provide proof-of-concept and reagents as a foundation for using a normal F8-containing mouse as a model for the miRNA regulation of normal F8 in causing or aggravating the genetic disease HA.
Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment
Authors: Fenwarth Laurène , Fournier Elise , Cheok Meyling , Boyer Thomas , Gonzales Fanny , Castaigne Sylvie , Boissel Nicolas , Lambert Juliette , Dombret Hervé , Preudhomme Claude , Duployez Nicolas
Published: August 2020

Gemtuzumab ozogamicin (GO, Mylotarg®) consists of a humanized CD33-targeted antibody-drug conjugated to a calicheamicin derivative. Growing evidence of GO efficacy in acute myeloid leukemia (AML), demonstrated by improved outcomes in CD33-positive AML patients across phase I to III clinical trials, led to the Food and Drug Administration (FDA) approval on 1 September 2017 in CD33-positive AML patients aged 2 years and older. Discrepancies in GO recipients outcome have raised significant efforts to characterize biomarkers predictive of GO response and have refined the subset of patients that may strongly benefit from GO. Among them, CD33 expression levels, favorable cytogenetics (t(8;21), inv(16)/t(16;16), t(15;17)) and molecular alterations, such as NPM1, FLT3-internal tandem duplications and other signaling mutations, represent well-known candidates. Additionally, in depth analyses including minimal residual disease monitoring, stemness expression (LSC17 score), mutations or single nucleotide polymorphisms in GO pathway genes (CD33, ABCB1) and molecular-derived scores, such as the recently set up CD33_PGx6_Score, represent promising markers to enhance GO response prediction and improve patient management.
Effects of Maternal Chewing on Prenatal Stress-Induced Cognitive Impairments in the Offspring via Multiple Molecular Pathways
Authors: Zhou Qian , Suzuki Ayumi , Iinuma Mitsuo , Wang Ke-Yong , Kubo Kin-ya , Azuma Kagaku
Published: August 2020

We aimed to investigate the effects of maternal chewing on prenatal stress-induced cognitive impairments in the offspring and to explore the molecular pathways of maternal chewing in a mice model. Maternal chewing ameliorated spatial learning impairments in the offspring in a Morris water maze test. Immunohistochemistry and Western blot findings revealed that maternal chewing alleviated hippocampal neurogenesis impairment and increased the expression of hippocampal brain-derived neurotrophic factor in the offspring. In addition, maternal chewing increased the expression of glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase isozyme 2 (11β-HSD2) and decreased the expression of 11β-HSD1 in the placenta, thereby attenuating the increase of glucocorticoid in the offspring. Furthermore, maternal chewing increased the expression of 11β-HSD2, FK506-binding protein 51 (FKBP51) and FKBP52 and decreased the expression of 11β-HSD1, thereby increasing hippocampal nuclear GR level. In addition, maternal chewing attenuated the increase in expression of DNMT1 and DNMT3a and the decrease in expression of histone H3 methylation at lysine 4, 9, 27 and histone H3 acetylation at lysine 9 induced by prenatal stress in the offspring. Our findings suggest that maternal chewing could ameliorate prenatal stress-induced cognitive impairments in the offspring at least in part by protecting placenta barrier function, alleviating hippocampal nuclear GR transport impairment and increasing the hippocampal brain-derived neurotrophic factor (BDNF) level.
Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population
Authors: Cho Yoon Young , Park So Young , Shin Jung Hee , Oh Young Lyun , Choe Jun-Ho , Kim Jung-Han , Kim Jee Soo , Yim Hyun Sook , Kim Yoo-Li , Ki Chang-Seok , Kim Tae Hyuk , Chung Jae Hoon , Kim Sun Wook
Published: August 2020

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70–80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.
Probing the Importance of the G-Quadruplex Grooves for the Activity of the Anti-HIV-Integrase Aptamer T30923
Authors: Esposito Veronica , Esposito Francesca , Pepe Antonietta , Gomez Monterrey Isabel , Tramontano Enzo , Mayol Luciano , Virgilio Antonella , Galeone Aldo
Published: August 2020

In this paper, we report studies concerning four variants of the G-quadruplex forming anti-HIV-integrase aptamer T30923, in which specific 2′-deoxyguanosines have been singly replaced by 8-methyl-2′-deoxyguanosine residues, with the aim to exploit the methyl group positioned in the G-quadruplex grooves as a steric probe to investigate the interaction aptamer/target. Although, the various modified aptamers differ in the localization of the methyl group, NMR, circular dichroism (CD), electrophoretic and molecular modeling data suggest that all of them preserve the ability to fold in a stable dimeric parallel G-quadruplex complex resembling that of their natural counterpart T30923. However, the biological data have shown that the T30923 variants are characterized by different efficiencies in inhibiting the HIV-integrase, thus suggesting the involvement of the G-quadruplex grooves in the aptamer/target interaction.
Assay Systems for Profiling Deubiquitinating Activity
Authors: Cho Jinhong , Park Jinyoung , Kim Eunice EunKyeong , Song Eun Joo
Published: August 2020

Deubiquitinating enzymes regulate various cellular processes, particularly protein degradation, localization, and protein–protein interactions. The dysregulation of deubiquitinating enzyme (DUB) activity has been linked to several diseases; however, the function of many DUBs has not been identified. Therefore, the development of methods to assess DUB activity is important to identify novel DUBs, characterize DUB selectivity, and profile dynamic DUB substrates. Here, we review various methods of evaluating DUB activity using cell lysates or purified DUBs, as well as the types of probes used in these methods. In addition, we introduce some techniques that can deliver DUB probes into the cells and cell-permeable activity-based probes to directly visualize and quantify DUB activity in live cells. This review could contribute to the development of DUB inhibitors by providing important information on the characteristics and applications of various probes used to evaluate and detect DUB activity in vitro and in vivo.