bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecule glucagon release inhibitors with activity in human islets
Authors: Kalwat Michael A. , Rodrigues-dos-Santos Karina , Binns Derk D. , Wei Shuguang , Zhou Anwu , Evans Matthew R. , Posner Bruce A. , Roth Michael G. , Cobb Melanie H. 
Published: April 2023

PurposeType 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting pancreatic islet β-cells are destroyed by the immune system, but glucagon-secreting islet α-cells survive. These remaining α-cells no longer respond properly to fluctuating blood glucose concentrations. Dysregulated α-cell function contributes to hyper- and hypoglycemia which can lead to macrovascular and microvascular complications. To this end, we sought to discover small molecules that suppress α-cell function for their potential as preclinical candidate compounds. Prior high-throughput screening identified a set of glucagon-suppressing compounds using a rodent α-cell line model, but these compounds were not validated in human systems. ResultsHere, we dissociated and replated primary human islet cells and exposed them to 24 h treatment with this set of candidate glucagon-suppressing compounds. Glucagon accumulation in the medium was measured and we determined that compounds SW049164 and SW088799 exhibited significant activity. Candidate compounds were also counter-screened in our InsGLuc-MIN6 β-cell insulin secretion reporter assay. SW049164 and SW088799 had minimal impact on insulin release after a 24 h exposure. To further validate these hits, we treated intact human islets with a selection of the top candidates for 24 h. SW049164 and SW088799 significantly inhibited glucagon release into the medium without significantly altering whole islet glucagon or insulin content. In concentration-response curves SW088799 exhibited significant inhibition of glucagon release with an IC50 of 1.26 µM. ConclusionGiven the set of tested candidates were all top hits from the primary screen in rodent α-cells, this suggests some conservation of mechanism of action between human and rodents, at least for SW088799. Future structure-activity relationship studies of SW088799 may aid in elucidating its protein target(s) or enable its use as a tool compound to suppress α-cell activity in vitro.
Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?
Authors: Fanciulli Giuseppe , Modica Roberta , La Salvia Anna , Grossrubatscher Erika Maria , Florio Tullio , Ferraù Francesco , Veresani Alessandro , Russo Flaminia , Colao Annamaria , Faggiano Antongiulio 
Published: April 2023

IntroductionMedullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.Aim of the studyThis review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC.Materials and methodsWe performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories.ResultsOur search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials.ConclusionWe found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials’ implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients’ outcome and survival.
Association of NAD+ levels with metabolic disease in a community-based study
Authors: Liu Yuhe , Chen Xueyu , Deng Xuan , Yang Fan , Zheng Jinping , Zhou Tianyun , Xu Ling , Xie Xiaomei , Ju Zhenyu , Wang Baoguo , Zhang Caiping , Zhou Yong 
Published: April 2023

BackgroundNicotinamide adenine dinucleotide (NAD+) is a coenzyme and plays a crucial role in several metabolic processes. This study explored the association of nicotinamide adenine dinucleotide (NAD+) levels with metabolic disease (MD) in adults.MethodsIn this cross-sectional study, all data were collected from the Jidong community. MD was defined as the presence of one or more of the following disease components: hypertension, dyslipidemia, diabetes, hyperuricemia, obesity, and non-alcoholic fatty liver disease (NAFLD). The MD components were categorized into three groups: those with one component, those with two components, and those with three to six components. The whole blood NAD+ level was measured using a cycling assay and LC-MS/MS analysis. The participants were divided into four groups based on their NAD+ level quartiles. Multivariable logistic regression was used to evaluate the association of the whole blood NAD+ levels with MD.ResultsOf the 1,394 eligible participants, the average age was 43.2 years, and 74.3% had MD. In the top quartile of NAD+, the prevalence of MD and each of its components (hypertension, hyperlipidemia, diabetes, hyperuricemia, obesity, and NAFLD) were 87.9% 35.2%, 62.3%, 8.7%, 36.9%, 21.0%, and 60.5%, respectively. As compared with the lowest NAD+ quartile (≤29.4 μmol/L), the adjusted odds ratios and 95% confidence interval of the highest quartile were 3.01 (1.87-4.87) for MD, 2.48 (1.44-4.29) for 1 MD component, 2.74 (1.45-5.17) for 2 MD components, and 4.30 (2.32-7.98) for 3-6 MD components. The risk of MD began to increase at NAD+ levels of 31.0 μmol/L, as revealed by the gradient associations of NAD+ levels with MD. There was no significant interaction between age, sex, drinking, smoking, and NAD+ for MD (p for interaction ≥0.10).ConclusionsIncreased NAD+ was significantly associated with MD, as well as its individual components. Our findings provide new evidence for the relationship between blood NAD+ levels and MD.
Territorial planning and sustainable development—case study: Protected areas in the territory of the Aspiring West Geopark, Portugal
Authors: Dias Alline , Robina-Ramírez Rafael , Sánchez-Oro Sánchez Marcelo 
Published: April 2023

Introduction:The holistic concept of the sustainable development of United Nations Educational, Scientific and Cultural Organization (UNESCO) Global Geoparks encompasses the promotion of connected protected areas and activities that link geological heritage with other aspects of natural and cultural heritage. This case study aims to identify points of articulation and/or to identify conflicts in the overlap between protected areas and UNESCO World Geoparks in Portugal, and to provide information to improve the interrelation of these designations.Methods:The methodological procedures in analysing the organisational structures of different classified areas from the respective management documents. The technical procedure consisted of document consultation and on-site activities carried out between September 2020 and November 2021.Results:The study resulted in the identification of points of natural objects that can be held together by protected natural spaces and aspiring Oeste Geopark. A proposal for synergistic action was presented, with the main pillars of integration in the territory. The different designations for sustainable territorial management in complementary to the conservation of natural heritage. The results of the analyses indicate that the overlap of the different designations of areas and territories studied here can act both in a joint and complementary way to conserve natural heritage.Discussion:This reinforcement study, which has different designations of areas and/or territories for sustainable territorial planning at the local, regional, national, and international levels, is fundamental for nature conservation, lacking more in terms of efficient management and integration of the social component.
Heterogeneous impact of artificial intelligence on carbon emission intensity: Empirical test based on provincial panel data in China
Authors: Du Meng , Zhang Yifan , Dong Hai , Zhou Xiangjun 
Published: April 2023

IntroductionEnergy conservation and emission reduction, as a major policy of China for a long time, has been put on the key strategic position. Based on the panel data of 30 provinces, cities and districts in China from 2006 to 2019.MethodsThis paper uses fixed effect model and spatial Durbin model to explore the effect and mechanism of artificial intelligence (AI) on regional carbon emission intensity (CEI).ResultsThe results show that: (1) there is a significant inverted U-shaped between AI and CEI, that is, with the deepening of the development of AI, CEI first increases and then decreases. (2) There is a significant spatial correlation between the development of AI and CEI in China. (3) AI has a significant spatial spillover effect on CEI of adjacent regions, and it shows an inverted U-shaped track-from promoting to restraining.DiscussionThe conclusion provides policy implications for the formulation of AI development strategy and so on during the specific period.
False perspectives on human language: Why statistics needs linguistics
Authors: Greco Matteo , Cometa Andrea , Artoni Fiorenzo , Frank Robert , Moro Andrea 
Published: April 2023

A sharp tension exists about the nature of human language between two opposite parties: those who believe that statistical surface distributions, in particular using measures like surprisal, provide a better understanding of language processing, vs. those who believe that discrete hierarchical structures implementing linguistic information such as syntactic ones are a better tool. In this paper, we show that this dichotomy is a false one. Relying on the fact that statistical measures can be defined on the basis of either structural or non-structural models, we provide empirical evidence that only models of surprisal that reflect syntactic structure are able to account for language regularities.One-sentence summaryLanguage processing does not only rely on some statistical surface distributions, but it needs to be integrated with syntactic information.
Impact of race and ethnicity on family participation in systemic lupus erythematosus genetic studies
Authors: Scofield R Hal , Sharma Rohan , Aberle Teresa , Cooney Carisa M , Kelly Jennifer A , Harley John B , Rasmussen Astrid 
Published: April 2023

ObjectiveSystemic lupus erythematosus (SLE) has a higher prevalence and is more severe in African Americans and Hispanics than in non-Hispanic Whites. To understand the shared and unique genetic risk factors of these populations, an adequate representation of African Americans and Hispanics in clinical and genetic research is indispensable while challenging. The goal of this study was to identify differences in research participation of families of different racial and ethnic backgrounds and the potential causes for the disparities.MethodsFamilies were screened for eligibility to the Lupus Family Registry and Repository (LFRR) after self-referral or physician referral. We recorded the sociodemographic characteristics, self-identified race and ethnicity, ACR-SLE criteria, and the reasons given for not completing study participation for all families.ResultsA total of 1,472 families (950 non-Hispanic White, 405 African American, and 117 Hispanic) were screened but only 366 completed study participation (25%). Participation rates and reasons for non-participation varied between racial and ethnic groups. The main reason for African American families to not participate was that subjects critical to the family structure declined participation (OR = 1.6, p = 0.0001), while for White families, the main cause was that purported SLE patients did not meet ACR SLE criteria (OR = 1.81, p &lt; 0.00002). Hispanics were the most likely to complete participation (OR = 4.25, p &lt; 0.0001).ConclusionsSuccessful recruitment of patients, families, and specific demographic groups is critical for the study of genetically complex diseases, such as SLE. There are significant disparities in SLE family recruitment across groups of people, likely due to their richly different cultures and environments.
Disrespect and abuse of women during childbirth at health facilities in Eastern Africa: systematic review and meta-analysis
Authors: Gebeyehu Natnael Atnafu , Adella Gtachew Asmare , Tegegne Kirubel Dagnaw 
Published: April 2023

BackgroundDisrespectful and abusive maternity care is a sign of poor treatment that influences women’s choice to deliver their babies in institutions. Such malpractices continue to go unreported and are rarely exposed in developing countries, despite their serious burden. Therefore, this meta-analysis study aimed to estimate disrespect and abuse of women during childbirth in East Africa.MethodsPubMed, Google Scholar, Scopus, and Science Direct databases were searched. Data were extracted using Microsoft Excel and analyzed using STATA statistical software (v. 14). Publication bias was checked by forest plot, Begg’s rank test, and Egger’s regression test. To look for heterogeneity, I2 was computed, and an overall estimated analysis was carried out. Subgroup analysis was done by study region, sample size, and publication. The pooled odds ratio for associated factors was also computed.ResultsOut of 654 articles assessed, 18 met the criteria and were included in this study. There were a total of 12,434 study participants. The pooled prevalence of disrespect and abuse of women during childbirth in East Africa was 46.85% (95% CI: 45.26.72–66.98), I2 = 81.9%. It was lower in studies with sample size greater than 5000 (33%). The disrespect and abuse rates between community-based studies (44.96%) and institutional-based studies (47.35%) did not differ significantly, though. Instrumental delivery (AOR = 2.70; 95%CI: 1.79–4.08), presence of complications (AOR = 6.41; 95% CI: 1.36–30.14), receiving care at government hospitals (AOR = 3.66; 95% CI: 1.09–12.23), and poor wealth index (AOR = 2.16; 95% CI: 1.26–3.70) were associated factors.ConclusionIn East Africa, disrespect and abuse of women during childbirth was high. Instrumental delivery, presence of complications during childbirth, receiving care at government hospitals and poor wealth index were predictors of maternal disrespect and abuse. Safe delivery practice should be promoted. Training in compassionate and respectful maternity care, particularly in public hospitals, has also been recommended.
Combination therapy with 3% diquafosol tetrasodium ophthalmic solution and sodium hyaluronate: an effective therapy for patients with dry eye after femtosecond laser-assisted in situ keratomileusis
Authors: Wang Tianjiao , Di Yu , Li Ying 
Published: April 2023

PurposeTo assess the effect of combination therapy with 3% diquafosol tetrasodium (DQS) and sodium hyaluronate (HA) for dry eye after femtosecond laser-assisted in situ keratomileusis (FS-LASIK).DesignProspective nonrandomized comparative trial.MethodsThe prospective study included 80 eyes of 40 patients who underwent FS-LASIK with or without preoperative dry eye. Patients were divided into a combination group and a HA group according to their willingness and the doctor’s advice. The combination group was treated with DQS six times a day and HA four times a day, and the HA group was treated with HA four times a day after FS-LASIK. Ocular surface disease index (OSDI), ocular symptom score, vision-related score, environmental score, tear meniscus height (TMH), first non-invasive tear breakup time (NIBUT-First), average non-invasive tear breakup time (NIBUT-Ave), tear breakup time (TBUT), Schirmer I test (SIT), corneal fluorescein staining score (CFS), bulbar redness score, limbal redness score, lipid layer grade (LLG), meiboscore, lid margin abnormality, corneal sensitivity, and corneal nerve parameters were examined before surgery and at 1 week and 1 month after surgery. Surface regularity index (SRI) was also examined before surgery and at 1 month postoperatively.ResultsOSDI score (p = 0.024) and vision-related score (p = 0.026) were significantly lower in the combination group than in the HA group at 1 month after FS-LASIK, especially in patients with preoperative dry eye symptoms. The increasements of CFS (p = 0.018), bulbar redness score (p = 0.021), and limbal redness score (p = 0.009) were significantly lower in the combination group than in the HA group at 1 week after FS-LASIK. But other ocular surface parameters showed no difference between both groups at 1 week and 1 month after FS-LASIK. LLG was significantly higher in the combination group than in the HA group at 1 week (p = 0.004) and 1 month (p &lt; 0.001) after surgery, especially in patients with high meiboscore. Additional DQS significantly improved corneal sensitivity in patients without preoperative dry eye symptoms at 1 month after FS-LASIK (p = 0.041).ConclusionThe combination therapy with DQS and HA significantly relieved subjective symptoms, improved ocular surface status, and had the potential to promote corneal nerve growth in patients after FS-LASIK.
Meta-Analysis of Caenorhabditis elegans Transcriptomics Implicates Hedgehog-Like Signaling in Host-Microbe Interactions
Authors: Zárate-Potes Alejandra , Ali Irtiqa , Ribeiro Camacho Margarida , Brownless Hayley , Benedetto Alexandre 
Published: April 2023

Graphical AbstractGraphical abstract of the approach employed in this study. Combined analyses of C. elegans-microbe transcriptomics (1) and gene tissue expression maps (2), with high-throughput stress and infection assays following host-gene inactivation (3), can guide predictions and accelerate identification of genetic interactions involved in nematode-microbe interactions.
DNA extraction protocol impacts ocular surface microbiome profile
Authors: Delbeke Heleen , Casteels Ingele , Joossens Marie 
Published: April 2023

PurposeThe aim of this study is to provide a reference frame to allow the comparison and interpretation of currently published studies on 16S ribosomal ribonucleic acid amplicon sequencing of ocular microbiome samples using different DNA extraction protocols. Alongside, the quantitative and qualitative yield and the reproducibility of different protocols has been assessed.MethodsBoth eyes of 7 eligible volunteers were sampled. Five commercially available DNA extraction protocols were selected based on previous publications in the field of the ocular surface microbiome and 2 host DNA depletion protocols were added based on their reported effective host DNA depletion without significant reduction in bacterial DNA concentration. The V3-V4 region of the 16S rRNA gene was targeted using Illumina MiSeq sequencing. The DADA2 pipeline in R was used to perform the bio-informatic processing and taxonomical assignment was done using the SILVA v132 database. The Vegdist function was used to calculate Bray-Curtis distances and the Galaxy web application was used to identify potential metagenomic biomarkers via linear discriminant analysis Effect Size (LEfSe). The R package Decontam was applied to control for potential contaminants.ResultsSamples analysed with PowerSoil, RNeasy and NucleoSpin had the highest DNA yield. The host DNA depletion kits showed a very low microbial DNA yield; and these samples were pooled per kit before sequencing. Despite pooling, 1 of both failed to construct a library.Looking at the beta-diversity, clear microbial compositional differences - dependent on the extraction protocol used – were observed and remained present after decontamination. Eighteen genera were consistently retrieved from the ocular surface of every volunteer by all non-pooled extraction kits and a comprehensive list of differentially abundant bacteria per extraction method was generated using LefSe analysis.ConclusionHigh-quality papers have been published in the field of the ocular surface microbiome but consensus on the importance of the extraction protocol used are lacking. Potential contaminants and discriminative genera per extraction protocol used, were introduced and a reference frame was built to facilitate both the interpretation of currently published papers and to ease future choice – making based on the research question at hand.
Influence of surface characteristics of implant materials on MRSA biofilm formation and effects of antimicrobial treatment
Authors: van Dun Sven C. J. , Verheul Mariëlle , Pijls Bart G. C. W. , van Prehn Joffrey , Scheper Henk , Galli Federica , Nibbering Peter H. , de Boer Mark G. J. 
Published: April 2023

IntroductionOne of the main causes of treatment failure in bacterial prosthetic joint infections (PJI) is biofilm formation. The topography of the biofilm may be associated with susceptibility to antimicrobial treatment. The aims of this study were to assess differences in topography of biofilms on different implant materials and the correlation thereof with susceptibility to antimicrobial treatment.MethodsMethicillin-resistant Staphylococcus aureus (MRSA) 7-day mature biofilms were generated on disks made from titanium alloys (Ti-6Al-7Nb and Ti-6Al-4V), synthetic polymer and orthopedic bone cement, commonly used in implant surgery. The surface topography of these implant materials and the biofilms cultured on them was assessed using atomic force microscopy. This provided detailed images, as well as average roughness (Ra) and peak-to-valley roughness (Rt) values in nanometers, of the biofilm and the material surfaces. Bacterial counts within biofilms were assessed microbiologically. Antimicrobial treatment of biofilms was performed by 24-h exposure to the combination of rifampicin and ciprofloxacin in concentrations of 1-, 5- and 10-times the minimal bactericidal concentration (MBC). Finally, treatment-induced differences in bacterial loads and their correlation with biofilm surface parameters were assessed.ResultsThe biofilm surfaces on titanium alloys Ti-6Al-7Nb (Ra = 186 nm) and Ti-6Al-4V (Ra = 270 nm) were less rough than those of biofilms on silicone (Ra = 636 nm). The highest roughness was observed for biofilms on orthopedic bone cement with an Ra of 1,551 nm. Interestingly, the roughness parameters of the titanium alloys themselves were lower than the value for silicone, whereas the surface of the bone cement was the roughest. Treatment with 1- and 5-times the MBC of antibiotics resulted in inter-material differences in colony forming units (CFU) counts, ultimately showing comparable reductions of 2.4–3.0 log CFU/mL at the highest tested concentration. No significant differences in bacterial loads within MRSA biofilms were observed between the various implant materials, upon exposure to increasing concentrations of antibiotics.DiscussionThe surface parameters of MRSA biofilms were determined by those of the implant materials on which they were formed. The antibiotic susceptibility of MRSA biofilms on the various tested implant materials did not differ, indicating that the efficacy of antibiotics was not affected by the roughness of the biofilm.