bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accelerated first-in-human clinical trial of EIDD-2801/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2
Authors: Holman Wendy , Holman Wayne , McIntosh Stacy , Painter Wendy , Painter George , Bush Jim , Cohen Oren 
Published: August 2021

AbstractA recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK). Single and multiple ascending dose (SAD and MAD, respectively) cohorts were dosed in randomized, double-blind, and placebo-controlled fashion, with a 6:2 active-to-placebo ratio in each cohort. A food-effect (FE) cohort included 10 subjects who were randomized to receive drug in the fasted or fed state followed by the fed or fasted state to complete a fed and fasted sequence for each subject. Dose escalation decisions were accelerated and MAD cohorts were initiated prior to completion of all SAD cohorts with the provision that the total daily dose in a MAD cohort would not exceed a dose proven to be safe and well-tolerated in a SAD cohort. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the Research Ethics Committee (REC) and Medicines and Healthcare products Regulatory Agency (MHRA). Working to standard industry timelines, the FIH study would have taken approximately 46 weeks to complete and 33 weeks to enable phase 2 dosing. Data from this study supported submission of a phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within 8 weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.
Recreational behaviour, risk perceptions, and protective practices against ticks: a cross-sectional comparative study before and during the lockdown enforced by the COVID-19 pandemic in Romania
Authors: Borșan Silvia-Diana , Trif Sabina Ramona , Mihalca Andrei Daniel 
Published: August 2021

Abstract
Background
Gaining insight into the risk perceptions and the knowledge evolution of the public about emerging or changing health risks is vital for the improvement of health promotion activities. Currently, scientific evidence regarding the attitudes of the Romanian public towards ticks is scanty. This study aimed to identify how the lockdown enforced by the COVID-19 pandemic in Romania impacted the recreational behaviour, risk perceptions, and protective practices of the Romanian population regarding ticks.

Methods
A cross-sectional, nationwide web-based questionnaire was designed and distributed via social media to evaluate if, and how, the COVID-19 lockdown impacted the behaviour of the Romanian public concerning ticks. The survey was available online from 6 May until 15 May 2020, which marked the last day of the travel ban in Romania. The collected data were processed by applying both uni- and multivariate methods.

Results
Respondents reported a higher frequency of finding ticks on themselves and their dogs during the lockdown. Bathing/showering and checking the body for ticks were the two most used protective behaviours both before and during the lockdown. Nevertheless, an overall lower usage rate of protective measures was registered during the lockdown. Almost all dog owners used a form of ectoparasite control for their dogs, and only three stopped due to lockdown-associated reasons. Respondent characteristics that were found to be positively associated with risk perceptions were being female and living in peri-urban/suburban/rural environments.

Conclusions
Despite spending less time outdoors during the lockdown, more respondents reported finding ticks on themselves or their dogs. Changes in the preferences for recreational locations, rates of protective practices usage, amount of time spent in specific areas, or tick seasonal activity might have contributed to this outcome. Concerning risk groups, men of all ages, senior citizens, and rural inhabitants should be targeted by the relevant Romanian authorities when promoting local or nationwide tick awareness campaigns.

Graphical abstract
Age-related alteration in characteristics, function, and transcription features of ADSCs
Authors: Li Keya , Shi Guiying , Lei Xuepei , Huang Yiying , Li Xinyue , Bai Lin , Qin Chuan 
Published: August 2021

Abstract
Background and objectives
Adipose tissue-derived stem cells (ADSCs) autologous transplantation has been a promising strategy for aging-related disorders. However, the relationship between ADSCs senescence and organismal aging has not been clearly established. Therefore, we aimed at evaluating senescence properties of ADSCs from different age donors and to verify the influence of organismal aging on the proliferation and function of ADSCs in vitro, providing the theoretical basis for the clinical application of autologous ADSCs transplantation.

Methods and results
The ADSCs were obtained from 1-month-old and 20-month-old mice. The cells characteristics, functions, gene expression levels, apoptosis proportion, cell cycle, SA-β-gal staining, and transcription features were evaluated. Compared to ADSCs from 1-month-old mice, ADSCs from 20-month-old mice exhibited some senescence-associated changes, including inhibited abilities to proliferate. Moreover, differentiation abilities, cell surface markers, and cytokines secreting differed between 1M and 20M ADSCs. SA-β-Gal staining did not reveal differences between the two donor groups, while cells exhibited more remarkable age-related changes through continuous passages. Based on transcriptome analysis and further detection, the CCL7-CCL2-CCR2 axis is the most probable mechanism for the differences.

Conclusions
ADSCs from old donors have some age-related alterations. The CCL7-CCL2-CCR2 axis is a potential target for gene therapy to reduce the harmful effects of ADSCs from old donors. To improve on autologous transplantation, we would recommend that ADSCs should be cryopreserved in youth with a minimum number of passages or block CCL7-CCL2-CCR2 to abolish the effects of age-related alterations in ADSCs through the Chemokine signaling pathway.
Linking common human diseases to their phenotypes; development of a resource for human phenomics
Authors: Kafkas Şenay , Althubaiti Sara , Gkoutos Georgios V. , Hoehndorf Robert , Schofield Paul N. 
Published: August 2021

Abstract
Background
In recent years a large volume of clinical genomics data has become available due to rapid advances in sequencing technologies. Efficient exploitation of this genomics data requires linkage to patient phenotype profiles. Current resources providing disease-phenotype associations are not comprehensive, and they often do not have broad coverage of the disease terminologies, particularly ICD-10, which is still the primary terminology used in clinical settings.

Methods
We developed two approaches to gather disease-phenotype associations. First, we used a text mining method that utilizes semantic relations in phenotype ontologies, and applies statistical methods to extract associations between diseases in ICD-10 and phenotype ontology classes from the literature. Second, we developed a semi-automatic way to collect ICD-10–phenotype associations from existing resources containing known relationships.

Results
We generated four datasets. Two of them are independent datasets linking diseases to their phenotypes based on text mining and semi-automatic strategies. The remaining two datasets are generated from these datasets and cover a subset of ICD-10 classes of common diseases contained in UK Biobank. We extensively validated our text mined and semi-automatically curated datasets by: comparing them against an expert-curated validation dataset containing disease–phenotype associations, measuring their similarity to disease–phenotype associations found in public databases, and assessing how well they could be used to recover gene–disease associations using phenotype similarity.

Conclusion
We find that our text mining method can produce phenotype annotations of diseases that are correct but often too general to have significant information content, or too specific to accurately reflect the typical manifestations of the sporadic disease. On the other hand, the datasets generated from integrating multiple knowledgebases are more complete (i.e., cover more of the required phenotype annotations for a given disease). We make all data freely available at 10.5281/zenodo.4726713.
Sex correction improves the accuracy of clinical dopamine transporter imaging
Authors: Honkanen Emma A. , Noponen Tommi , Hirvilammi Risto , Lindholm Kari , Parkkola Riitta , Joutsa Juho , Varrone Andrea , Kaasinen Valtteri 
Published: August 2021

Abstract
Background
In clinical diagnostic imaging, dopamine transporter (DAT) SPECT scans are commonly evaluated using automated semiquantitative analysis software. Age correction is routinely implemented, but usually no sex correction of DAT binding is performed. Since there are sex differences in presynaptic dopaminergic function, we investigated the effect of DAT sex correction in a sample of healthy volunteers who underwent brain [123I]-FP-CIT SPECT.

Methods
Forty healthy elderly individuals (21 men and 19 women) underwent brain [123I]-FP-CIT SPECT, and each subject was examined clinically for motor and non-motor parkinsonian symptoms and signs. Regional specific DAT binding ratios (SBR = [ROI-occ]/occ) were calculated using age correction, and the results were compared to those in normal databases with and without sex correction. The level of regional abnormality was set at 2 standard deviations below the mean values of the reference databases.

Results
In the analysis without sex correction, compared to the mean ratio of the reference database, ten healthy individuals (8 men and 2 women) had abnormally low DAT binding ratios, and four individuals (3 men and 1 woman) had borderline low DAT binding ratios in at least one striatal region. When sex correction was implemented, the ratio of one individual was abnormal, and the ratio of one individual was borderline (both males). There were no clinically significant differences in motor or non-motor symptoms between healthy volunteers with abnormal and normal binding.

Conclusions
A considerable number of elderly healthy male subjects can be interpreted to be dopaminergically abnormal if no sex correction of DAT binding is performed. Sex differences in striatal dopaminergic function should be taken into account when DAT imaging is used to assist clinical diagnostics in patients with suspected neurological disorders.
Complex factors and educational tools for social change and empowerment for severely marginalized Nepalese women working in hospitality and tourism
Authors: Deagon Jay R. , Ham Miriam , Hillman Wendy 
Published: August 2021

AbstractEducated and skilled women are active change agents. This paper focuses on informal hospitality education as a tool for social change and empowerment for severely marginalized Nepalese women. Studied over 18 months, a small group of women cooking for a boutique local and international tourist market in Kathmandu participated in cookery skills training. The Australian educator/researchers focused on the educational experience to uptake and retention of cookery skills and technical language. As a result of the educational intervention, changes in personal attributes and perceptions of inherent sociocultural gender roles/caste emerged. Participation in the cookery skills training program contributed partially as a catalyst that improved confidence, communication skills and exposed to the women pathways toward self-sustainability, emancipation and empowerment within an often-hostile working environment for women from severely disadvantaged backgrounds in Nepal.
Investigation and analysis of groundwater-derived damage to the Shahe ancient bridge site in Xi’an, China
Authors: Cao Jing , Mai Bingjie , Chen Hua , Li Yuhu , Wang Juanli 
Published: August 2021

Abstract
Earthen cultural ruins and their subsurface environments act as carriers or support for aboveground cultural heritage artefacts, and groundwater has been identified as the most important factor accelerating the destruction of ruins. In this paper, a wooden structure on the site of the Xianyang Shahe ancient bridge is taken as the research object. Through geotechnical surveys and site sample analyses, the relationship between the environment and cause of damage at the site is explored. Fluctuations in groundwater level are found to affect the movement of water and salt, thereby accelerating deterioration and allowing microbes and other soil inhabitants and plants to erode the ruins. Furthermore, strong correlations are revealed between the stratigraphy of the area and both ruin status and sample analysis results. Geotechnical investigation data are used to predict the effects of various damaging factors on long-term preservation and the underlying mechanisms and to propose feasible, long-term countermeasures for preservation studies.
Towards building a Cathodoluminescence (CL) database for pigments: characterization of white pigments
Authors: Palamara E. , Das P. P. , Nicolopoulos S. , Tormo Cifuentes L. , Kouloumpi E. , Terlixi A. , Zacharias N. 
Published: August 2021

Abstract
Paintings and painted surfaces are considered to be extremely complex due to their multitude of materials and thus form the basis for particularly intricate Cultural Heritage studies. The combination of Scanning Electron Microscopy (SEM) with Cathodoluminescence (CL) can serve as a powerful tool for the identification of individual pigments. SEM/CL has the potential of identifying both organic and inorganic pigments and can focus on a micrometer or even nanometer scale. The combination with Energy Dispersive Spectrometry (EDS) allows for robust, cross-checked, elemental and mineralogical characterization of pigments. In order to apply SEM/CL in a routine-based way for the identification of pigments, it is necessary to have a robust, open-access database of characteristic CL spectra of pigments. A large project has been undertaken to create such a database, focusing primarily at the pigments, both organic and inorganic, which were most commonly used from antiquity until today. In the present paper, the CL characterization of common white pigments is presented. White pigments were selected, due to their significance and frequency of use, since they were also present on the ground layers or mixed with other pigments in most of the painting layers. More specifically, the CL spectra of samples in pure form of calcite, kaolinite, lead white, zinc oxide, barium sulfate, lithopone and titanium white are presented. In all cases, the CL spectra present characteristic bands, which allow for a secure identification of the pigments. In order to facilitate comparison with other databases, EDS and RAMAN spectra are also presented. Additionally, the effect of weathering on the CL spectra was evaluated, by comparison to naturally and artificially aged samples and to pigments identified on areas of two paintings, of the 19th and 20th c., respectively. Finally, the effect of binding media was also studied, using combination of pigments with four common media: egg yolk, linseed, walnut and poppy oil. Overall, both weathering and binding media appear to cause minor differences in the occurring spectra, without preventing the identification of pigments.
α-Farnesene production from lipid by engineered Yarrowia lipolytica
Authors: Liu Yinghang , Wang Zhaoxuan , Cui Zhiyong , Qi Qingsheng , Hou Jin 
Published: August 2021

AbstractProducing high value-added products from waste lipid feedstock by microbial cell factory has great advantages to minimize the pollution as well as improve the economic value of wasted oils and fats. Yarrowia lipolytica is a non-conventional oleaginous yeast and can grow on a variety of hydrophobic substrates. In this study, we explored its ability to synthesize α-farnesene, an important sesquiterpene, using lipid feedstock. Based on the α-farnesene production strain, we constructed previously, we identified that Erg12 was the key limiting factor to further increase the α-farnesene production. The α-farnesene production was improved by 35.8% through increasing the copy number of ERG12 and FSERG20 on oleic acid substrate. Expression of heterologous VHb further improved α-farnesene production by 12.7%. Combining metabolic engineering with the optimization of fermentation conditions, the α-farnesene titer and yield reached 10.2 g/L and 0.1 g/g oleic acid, respectively, in fed-batch cultivation. The α-farnesene synthesis ability on waste cooking oil and other edible oils were also explored. Compared with using glucose as carbon source, using lipid substrates obtained higher α-farnesene yield and titer, but lower by-products accumulation, demonstrating the advantage of Y. lipolytica to synthesize high value-added products using lipid feedstock.
Mass movements susceptibility mapping by using heuristic approach. Case study: province of Tétouan (North of Morocco)
Authors: Elmoulat Meryem , Brahim Lahcen Ait , Elmahsani Abderrahman , Abdelouafi Abdellah , Mastere Mohammed 
Published: August 2021

AbstractThis research paper aims to model Mass Movements Susceptibility (MMS) in the province of Tétouan. First, we identified the characteristics and spatial mapping of the different types of MM (collapse, mudflows, and complex landslides) by means of the interpretation of satellite images and from fieldwork. Subsequently, we selected the predictive parameters controlling the occurrence of MM e.g. lithology, land use, fault density, hydrographic network density, slope degrees, slope aspects, and elevation. We used the heuristic method for Modeling Mass Movements Susceptibility (MMMS). The choice of this method compared to other methods (fractal, factorial, and neurons) is justified by the possibilities of intervention and the judgment of the expert who relies on the ground truth to select the parameters, to identify the classes, and to assign the weights to each one; unlike to other methods with steps that are done automatically and randomly. The results of the validation of the susceptibility map correspond to 70% compared to the field data and it includes five susceptibility classes (not susceptible, low, moderate, high, and very high). Indeed, the originality of this paper relies on the fact that the creation of our susceptibility map will eventually indicate the areas of roads, dwellings, the extension of urbanization, and dams, which are located in areas at risk of MM. Our map is also a powerful decision-making tool to conduct management plans and to guide the selection of sites to build new projects; which help mitigate the socio-economic impacts usually encountered when mass movements in Tétouan province are triggered.
Understanding and controlling filamentous growth of fungal cell factories: novel tools and opportunities for targeted morphology engineering
Authors: Meyer Vera , Cairns Timothy , Barthel Lars , King Rudibert , Kunz Philipp , Schmideder Stefan , Müller Henri , Briesen Heiko , Dinius Anna , Krull Rainer 
Published: August 2021

AbstractFilamentous fungal cell factories are efficient producers of platform chemicals, proteins, enzymes and natural products. Stirred-tank bioreactors up to a scale of several hundred m³ are commonly used for their cultivation. Fungal hyphae self-assemble into various cellular macromorphologies ranging from dispersed mycelia, loose clumps, to compact pellets. Development of these macromorphologies is so far unpredictable but strongly impacts productivities of fungal bioprocesses. Depending on the strain and the desired product, the morphological forms vary, but no strain- or product-related correlations currently exist to improve process understanding of fungal production systems. However, novel genomic, genetic, metabolic, imaging and modelling tools have recently been established that will provide fundamental new insights into filamentous fungal growth and how it is balanced with product formation. In this primer, these tools will be highlighted and their revolutionary impact on rational morphology engineering and bioprocess control will be discussed.
Effect of implantoplasty on the elastic limit of dental implants of different diameters
Authors: Diéguez-Pereira Markel , Chávarri-Prado David , Viteri-Agustín Iratxe , Montalban-Vadillo Oier , Pérez-Pevida Esteban , Brizuela-Velasco Aritza 
Published: August 2021

Abstract
Background
Implantoplasty reduces both implant diameter and the thickness of its walls, subsequently reducing the ability of the implant to resist fracture in response to functional load. In combination with an increase in the crown-implant ratio due to bone loss, this could increase the lever effect, which in presence of high masticatory forces or parafunctional habits, could lead to complications such as fracture of the implant or loosening of the prosthetic screw.

Objectives
To determine the elastic limits of internal connection, dental implants of different designs and diameters after an implantoplasty.

Materials and methods
This in vitro study included 315 tapered internal connection titanium dental implants, the threads of which were removed with an industrial milling machine—for standardized implantoplasty (IMP1; n = 105)—or with the conventional approach—manually, using high-speed burs (IMP2; n = 105). The remaining 105 implants were used as controls. The final implant diameters were recorded. The quality of the newly polished surfaces was assessed by scanning electron microscopy. All implants were subjected to a mechanical pressure resistance test. A Tukey’s test for multiple comparisons was used to detect differences in the elastic limit and final implant diameters between the implant groups.

Results
There were statistically significant differences in the elastic limit between the IMP1, IMP2, and control groups (p < 0.05). Furthermore, the implant diameter was significantly smaller in the IMP1 and IMP2 groups (p < 0.05). Scanning electron microscopy revealed smooth implant surfaces in the IMP1 and IMP2 groups, with some titanium particles visible in the IMP1 group.

Conclusions
Implantoplasty significantly decreased the elastic limit of internal connection titanium dental implants, especially in those with a smaller diameter (3-3.5 mm).