bluuebunny/crossref_metadata_2025 huggingface dataset:
The Upper Extremity Functional Index: Reliability and Validity in Patients with Chronic Obstructive Pulmonary Disease
Authors: Alnahdi Ali H. , Albarrati Ali
Published: October 2021

The aim of the current study was to examine the psychometric properties of the upper extremity functional index (UEFI) in patients with chronic obstructive pulmonary disease (COPD). Seventy patients with stable COPD completed the UEFI and St. George Respiratory Questionnaire (SGRQ) and performed lung function tests in the first testing session. They completed the UEFI and the Global Rating of Change Scale in the second session, which was within ten days of the first session. The UEFI floor and ceiling effects, internal consistency, test–retest reliability, measurement error, and construct validity were examined. The UEFI was found to have no floor and ceiling effects. The UEFI was also found to have an excellent internal consistency (Cronbach’s alpha = 0.955) and an excellent test–retest reliability (ICC2,1 = 0.91). Totals of 4.85 points and 11.32 points represent the scale’s standard error of measurement, and a minimal detectable change at 90% confidence was used. The UEFI scores showed a significant correlation with the SGRQ activity domain (r = −0.66, p < 0.001) and differed significantly between participants with severe disease and those with mild disease (p = 0.03). The UEFI had no floor or ceiling issues, an excellent internal consistency, a good test–retest reliability, and an acceptable measurement error. The UEFI also demonstrated evidence supporting its construct validity as a measure of upper extremity-related activity limitations in patients with COPD.
Short Physical Performance Battery as a Measure of Physical Performance and Mortality Predictor in Older Adults: A Comprehensive Literature Review
Authors: de Fátima Ribeiro Silva Caroline , Ohara Daniela Gonçalves , Matos Areolino Pena , Pinto Ana Carolina Pereira Nunes , Pegorari Maycon Sousa
Published: October 2021

The association between the Short Physical Performance Battery (SPPB) score and several adverse health outcomes, including mortality, has been reported in the scientific literature. We conducted a comprehensive literature review of studies on the relationship between SPPB and mortality. The current paper synthesizes the characteristics and main findings of longitudinal studies available in the literature that investigated the role of the SPPB in predicting mortality in older adults. The studies (n = 40) are from North America, South America, Europe, and Asia; the majority (n = 16) were conducted with community-dwelling older adults and reported an association between lower SPPB scores and a higher risk of mortality, and between higher SPPB scores and higher survival. Nevertheless, few studies have analyzed the accuracy of the instrument to predict mortality. The only study that established cut-off points was conducted with older adults discharged from an acute care hospital. Although an SPPB score lower than 10 seems to predict all-cause mortality, further studies showing cut-off points in specific settings and loco-regional specificities are still necessary.
Have Elderly Individuals in Urban China Been Satisfied with Nursing Services during the COVID-19 Pandemic?
Authors: Shan Shoujin , Sun Zhonggen , Zhang Furong , Zhang Ruilian , Yang Bingqing
Published: October 2021

Based on the customer satisfaction index model, we constructed an elderly care service satisfaction model that includes 5 latent variables and 16 observed variables. To analyze the degree of satisfaction of elderly individuals in nursing homes, we used structural equation model (SEM) to test the nursing service elderly satisfaction model. With the help of AMOS 22.0 software, we analyzed the degree of model fit and the behavioral relationships between the variables that affect the path. We found that the satisfaction of Chinese urban elderly individuals in nursing homes is at a moderate level, which is lower than the quality expected by elderly individuals. The customer satisfaction index model can be applied to assess satisfaction with nursing services. Furthermore, perceived quality and value have a significant impact on satisfaction.
Ecological Effect of Ecological Engineering Projects on Low-Temperature Forest Cover in Great Khingan Mountain, China
Authors: Wang Shuqing , Zhong Run , Liu Lin , Zhang Jianjun
Published: October 2021

The evaluation of ecological restoration projects can provide support for further strengthening the efforts of ecological restoration work and implementing the strategic objectives of the ecological region. Considering the current problem of the single evaluation index, this study evaluated the implementation effect of ecological projects from different temporal and spatial dimensions. Based on the MODIS vegetation index time series data, this study first computed the Sustainable Development Goal (SDG) indicator 15.3.1 of Great Khingan Mountain (GKM) to evaluate the impact of ecological engineering on land use change and land productivity. As a common indicator, the Normalized Difference Vegetation Index (NDVI) values showed a trend of a decrease and then gradual increase after the start of the Natural Forest Protection Project (NFPP) II, which was related to the land use changes from the forest to the grassland during the implementation of the NFPP. However, land productivity maintained a steady trend because of the transition between the forest and grassland. Meanwhile, to detect changes in vegetation at a smaller scale, the LandTrendr algorithm was used to identify the magnitude of forest disturbance, the years when it occurred, and the year of restoration. After implementing the ecological project, the forests in the GKM region were only partially disturbed, and most of the forests in most areas maintained a stable trend. Our study highlighted the varying effectiveness of different indexes for NFPP and evaluated the ecological impact of ecological projects from multiple perspectives.
First- and Third-Trimester Urinary Phthalate Metabolites in the Development of Hypertensive Diseases of Pregnancy
Authors: Bedell Sabrina M. , Lyden Grace R. , Sathyanarayana Sheela , Barrett Emily S. , Ferguson Kelly K. , Santilli Ashley , Bush Nicole R. , Swan Shanna H. , McElrath Thomas F. , Nguyen Ruby H.N.
Published: October 2021

The purpose of this study was to determine whether maternal urinary phthalate metabolite concentrations are associated with the development of higher blood pressure or pregnancy-induced hypertension (PIH). Participants were women without chronic hypertension who enrolled in The Infant Development and the Environment Study, a prospective pregnancy cohort conducted at four U.S. academic medical centers from 2010–2012. Prenatal records were reviewed to obtain blood pressure measurements and diagnoses of PIH (gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome, defined as hemolysis, elevated liver enzymes, and low platelet count). Complete-case analyses used multivariable linear and logistic regression for analysis of blood pressure measurements and PIH diagnoses, respectively. In the final dataset (N = 668), higher concentrations of first-trimester monoethyl phthalate (MEP) and mono-3-carboxypropyl phthalate (MCPP) and third-trimester mono-isobutyl phthalate (MiBP) were significantly associated with a medical chart diagnosis of PIH. First-trimester mono-n-butyl phthalate (MBP) and MEP along with the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) were each associated with increased systolic blood pressure across pregnancy. In conclusion, several phthalate metabolite concentrations were significantly associated with PIH and greater increases in systolic blood pressure across pregnancy.
Phytotoxic Effects of Polyethylene Microplastics on the Growth of Food Crops Soybean (Glycine max) and Mung Bean (Vigna radiata)
Authors: Wang Lin , Liu Yi , Kaur Mandeep , Yao Zhisheng , Chen Taizheng , Xu Ming
Published: October 2021

Accumulation of micro-plastics (MPs) in the environment has resulted in various ecological and health concerns. Nowadays, however, studies are mainly focused on toxicity of MPs on aquatic organisms, but only a few studies assess the toxic effects of micro-plastics on terrestrial plants, especially edible agricultural crops. The present study was aimed to investigate the adverse effects of polyethylene (PE) microplastics on the germination of two common food crops of China, i.e., soybean (Glycine max) and mung bean (Vigna radiata). Both the crops were treated with polyethylene microplastics (PE-MPs) of two sizes (6.5 μm and 13 μm) with six different concentrations (0, 10, 50, 100, 200, and 500 mg/L). Parameters studied were (i) seed vigor (e.g., germination energy, germination index, vigor index, mean germination speed, germination rate); (ii) morphology (e.g., root length, shoot length) and (iii) dry weight. It was found that the phyto-toxicity of PE-MPs to soybean (Glycine max) was greater than that of mung bean (Vigna radiata). On the 3rd day, the dry weight of soybean was inhibited at different concentrations as compared to the control and the inhibition showed decline with the increase in the concentration of PE-MPs. After the 7th day, the root length of soybean was inhibited by PE-MPs of 13 μm size, and the inhibition degree was positively correlated with the concentration, whereas the root length of mung bean was increased, and the promotion degree was positively correlated with the concentration. Present study indicated the necessity to explore the hazardous effects of different sizes of PE-MPs on the growth and germination process of agricultural crops. Additionally, our results can provide theoretical basis and data support for further investigation on the toxicity of PE-MPs to soybean and mung bean.
Empirical Investigation of the Verbal Cues Involved in Delivering Experiential Metaphors
Authors: Ramírez Eduar S. , Ruiz Francisco J. , Peña-Vargas Andrés , Bernal Paola A.
Published: October 2021

Delivering metaphors experientially has been emphasized in several psychotherapies, such as acceptance and commitment therapy. However, few research has analyzed the variables involved in the efficacy of metaphors. This experimental analog study aims to advance in this topic by analyzing the effect of two components involved in the experiential delivery of metaphors in psychotherapy. The first component is presenting the metaphor by asking the individual to imagine herself as the protagonist of the story versus presenting the metaphor in the third person (Self vs. Other). The second component is the inclusion of verbal cues prompting the relational elaboration of the rules derived from the metaphor content versus not including these prompts (Elaboration vs. No Elaboration). The effect of these components was tested in a double-blind, randomized, 2 × 2 factorial experiment that used the cold pressor task (CPT). Eighty-four participants were exposed to the CPT at the pretest. Afterward, participants were randomly assigned to four experimental protocols. The protocols were audiotaped and consisted of the same metaphor presented in four slightly different ways. Specifically, the protocol of Condition A involved a metaphor with Self and Elaboration, Condition B involved Self and No Elaboration, Condition C involved Other and Elaboration, and Condition D involved Other and No Elaboration. Then, participants were re-exposed to the CPT in the posttest. We hypothesized that Condition A (Self and Elaboration) would show a higher mean increase in pain tolerance than the remaining conditions, which would show similar results. The results were consistent with this hypothesis because Condition A showed a higher percentual increase in pain tolerance (Condition A: M = 268.21, SD = 167.47; Condition B: M = 180.86, SD = 73.01; Condition C: M = 204.81, SD = 100.19; Condition D: M = 175.41, SD = 76.00). A Bayesian informative hypothesis evaluation showed that this hypothesis obtained the highest posterior model probability. Thus, the results indicate that introducing metaphors by asking the individual to imagine herself as the protagonist of the story and providing prompts for relational elaboration might increase the therapeutic effect of the metaphor.
How Can Unintended Pregnancies Be Prevented among Adolescents Who Engaged in Sexual Intercourse at Earlier Ages? The Role of Female Education and Partner Age Difference
Authors: Pires Raquel , Araújo-Pedrosa Anabela , Pereira Joana , Canavarro Maria Cristina
Published: October 2021

Several studies have identified explicative factors for adolescents’ sexual risk behaviors and related outcomes such as unintended pregnancy; however, less is known about the mechanisms through which such factors act. Our study explored the role of female education and partner age difference as explicative mechanisms of the association between age at first sexual intercourse (AFSI) and unintended pregnancy while controlling for the role of other contextual factors (i.e., socioeconomic status, ethnicity, religious beliefs, and place of residence) and sexual-related mechanisms (i.e., number of sexual partners) that are known to be associated with adolescent pregnancy. The sample consisted of 613 sexually experienced female adolescents who did not intend to become pregnant: 349 were pregnant for the first time, and 264 had never been pregnant. Mediation and moderation analyses were performed. An earlier AFSI was associated with unintended pregnancy 1–6 years after first sexual intercourse by increasing the adolescents’ likelihood of having less education and being involved with partners older than themselves. There was no significant direct effect of AFSI on pregnancy occurrence after controlling for the mediators. Our findings bring to light nonsexual mechanisms that must be considered in public health interventions aimed at preventing unintended pregnancies among adolescents who engaged in sexual intercourse at early ages. Specific implications are discussed.
Consumer and Carer Perspectives of a Zero Suicide Prevention Program: A Qualitative Study
Authors: Ross Victoria , Mathieu Sharna , Hawgood Jacinta , Turner Kathryn , Stapelberg Nicolas J. C. , Welch Matthew , Davies Angela , Sveticic Jerneja , Walker Sarah , Kõlves Kairi
Published: October 2021

This study explored the experiences of healthcare consumers who had recently attempted suicide, and their carers, following placement on a Suicide Prevention Pathway based on the Zero Suicide framework. Qualitative interviews were conducted with 10 consumers and 5 carers using a semi-structured interview schedule. Interviews were transcribed and thematic analysis was applied to identify prominent themes and sub-themes. Three interrelated themes were identified. The first theme was ‘Feeling safe and valued’ with the associated sub-theme pertaining to perceived stigmatizing treatment and self-stigma. The second was ‘Intersection of consumer and staff/organizational needs’ with a related sub-theme of time pressure and reduced self-disclosure. The final theme was ‘Importance of the ‘whole picture’, highlighting the relevance of assessing and addressing psychosocial factors when planning for consumer recovery. Overall, consumers and their carers reported a favorable experience of the Suicide Prevention Pathway; however, there were several areas identified for improvement. These included reconciling the time-pressures of a busy health service system, ensuring consumers and carers feel their psychosocial concerns are addressed, and ensuring that adequate rapport is developed. Key to this is ensuring consumers feel cared for and reducing perceptions of stigma.
A Comprehensive Descriptive Epidemiological and Clinical Analysis of SARS-CoV-2 in West-Mexico during COVID-19 Pandemic 2020
Authors: Viera-Segura Oliver , Vega-Magaña Natali , García-Chagollán Mariel , Peña-Rodríguez Marcela , Muñoz-Sánchez Germán , Carranza-Aranda Ahtziri Socorro , Llamas-Covarrubias Iris Monserrat , Ramos-Solano Moisés , Mora-Mora Jesús , Díaz-Palomera Carlos Daniel , León Gabriela Espinoza-De , Zepeda-Nuño José Sergio , Santillán-López Enrique , García-Arellano Samuel , Hernández-Silva Christian David , Zerpa-Hernandez Darbi Alfredo , Muñoz-Rios Guillermina , Rodríguez-Sanabria J. Samael , Muñoz-Valle José Francisco
Published: October 2021

This study aimed to summarize the epidemiological and clinical characteristics of COVID-19 from Western Mexico people during 2020. A retrospective analysis from an electronic database of people visiting a sentinel center for molecular SARS-CoV-2 confirmatory diagnosis by RT-PCR from April to December 2020 was carried out for epidemiological and clinical description of COVID-19. Out of 23,211 patients evaluated, 6918 (29.8%) were confirmed for SARS-CoV-2 infection (mean age 38.5 ± 13.99), mostly females (53.8%). Comorbidities, such as diabetes (34.7%), obesity (31.15%), and hypertension (31.8%), presented an increased odds OR = 1.27, CI = 1.14–1.41; OR = 1.08, CI = 1.01–1.16; and OR = 1.09, CI = 0.99–1.19, respectively, for viral-infection. Moreover, fever, headache, and dry cough were the most frequent symptoms. No infection difference among sex was found. Those patients >60 years old were prone to COVID-19 severity (OR = 3.59, CI = 2.10–6.14), evaluated by the number of manifested symptoms, increasing with age. In conclusion, a high SARS-CoV-2 prevalence was found in Western Mexico. Comorbidities were frequent in infected people; nevertheless, no association with disease outcomes was observed, in contrast with the highest disease severity risk found in older patients; however, continuous monitoring should be carried since comorbidities have been reported as aggravating factors. This study can help the health officials for the elaboration of planning efforts of the disease management and others in the future.
A Web GIS-Based Integration of 3D Digital Models with Linked Open Data for Cultural Heritage Exploration
Authors: Nishanbaev Ikrom , Champion Erik , McMeekin David A.
Published: October 2021

In recent years, considerable efforts have been made by cultural heritage institutions across the globe to digitise cultural heritage sites, artifacts, historical maps, etc. for digital preservation and online representation. On the other hand, ample research projects and studies have been published that demonstrate the great capabilities of web-geographic information systems (web-GIS) for the dissemination and online representation of cultural heritage data. However, cultural heritage data and the associated metadata produced by many cultural heritage institutions are heterogeneous. To make this heterogeneous data more interoperable and structured, an ever-growing number of cultural heritage institutions are adopting linked data principles. Although the cultural heritage domain has already started implementing linked open data concepts to the cultural heritage data, there are not many research articles that present an easy-to-implement, free, and open-source-based web-GIS architecture that integrates 3D digital cultural heritage models with cloud computing and linked open data. Furthermore, the integration of web-GIS technologies with 3D web-based visualisation and linked open data may offer new dimensions of interaction and exploration of digital cultural heritage. To demonstrate the high potential of integration of these technologies, this study presents a novel cloud architecture that attempts to enhance digital cultural heritage exploration by integrating 3D digital cultural heritage models with linked open data from DBpedia and GeoNames platforms using web-GIS technologies. More specifically, a digital interactive map, 3D digital cultural heritage models, and linked open data from DBpedia and GeoNames platforms were integrated into a cloud-based web-GIS architecture. Thus, the users of the architecture can easily interact with the digital map, visualise 3D digital cultural heritage models, and explore linked open data from GeoNames and DBpedia platforms, which offer additional information and context related to the selected cultural heritage site as well as external web resources. The architecture was validated by applying it to specific case studies of Australian cultural heritage and seeking expert feedback on the system, its benefits, and scope for improvement in the near future.
Flaxseed Powder Attenuates Non-Alcoholic Steatohepatitis via Modulation of Gut Microbiota and Bile Acid Metabolism through Gut–Liver Axis
Authors: Yang Chao , Wan Min , Xu Dengfeng , Pan Da , Xia Hui , Yang Ligang , Sun Guiju
Published: October 2021

Non-alcoholic steatohepatitis (NASH) is gradually becoming one of the most common and health-endangering diseases; therefore, it is very important to prevent the occurrence of NASH and prevent simple non-alcoholic fatty liver (NAFL) from further developing into NASH. We fed mice a high-fat diet (HFD, 60% fat) for 14 weeks to induce NAFL and then fed different doses of flaxseed powder (low (10%), middle (20%), and high (30%)) to the mice for 28 weeks. After the animal experiment, we analyzed fecal bile acid (BA) profiles of the HFD mice, flaxseed-fed (FLA-fed) mice, and control mice with a normal diet (10% fat) using a targeted metabolomics approach, and we analyzed the gut microbiota at the same time. We also investigated the mechanistic role of BAs in NASH and identified whether the altered BAs strongly bind to colonic FXR or TGR5. In the present study, we found that 28-week FLA treatment notably alleviated NASH development in NAFL model mice fed with an HFD, and the beneficial effects may be attributed to the regulation of and improvement in the gut flora- and microbiota-related BAs, which then activate the intestinal FXR-FGF15 and TGR5-NF-κB pathways. Our data indicate that FLA might be a promising functional food for preventing NASH through regulating microbiomes and BAs.
An ArsR Transcriptional Regulator Facilitates Brucella sp. Survival via Regulating Self and Outer Membrane Protein
Authors: Zhi Feijie , Zhou Dong , Chen Jialu , Fang Jiaoyang , Zheng Weifang , Li Junmei , Hao Mingyue , Shi Yong , Jin Yaping , Wang Aihua
Published: October 2021

The arsenic acid-resistant (ArsR) family transcriptional regulators are widely distributed in microorganisms, including in the facultative intracellular pathogen Brucella spp. ArsR proteins are implicated in numerous biological processes. However, the specific roles of ArsR family members in Brucella remain obscure. Here, we show that ArsR6 (BSS2_RS07325) is required for Brucella survival both under heat, oxidative, and osmotic stress and in a murine infection model in vivo. RNA-seq and ChIP-seq reveal that 34 potential target genes for ArsR6 protein were identified, among which eight genes were up-regulated and 26 genes were down-regulated, including outer membrane protein 25D (Omp25D). ArsR6 autoregulates its own expression to maintain bacterial intracellular Cu/Ni homeostasis to benefit bacterial survival in hostile environments. Moreover, ArsR6 also regulates the production of virulence factor Omp25D, which is important for the survival of Brucella under stress conditions. Significantly, Omp25D deletion strain attenuated in a murine infection model in vivo. Altogether, our findings reveal a unique mechanism in which the ArsR family member ArsR6 autoregulates its expression and also modulates Omp25D expression to maintain metal ion homeostasis and virulence in Brucella.
Cryopreservation of Gametes and Embryos and Their Molecular Changes
Authors: Estudillo Enrique , Jiménez Adriana , Bustamante-Nieves Pablo Edson , Palacios-Reyes Carmen , Velasco Iván , López-Ornelas Adolfo
Published: October 2021

The process of freezing cells or tissues and depositing them in liquid nitrogen at –196 °C is called cryopreservation. Sub-zero temperature is not a physiological condition for cells and water ice crystals represent the main problem since they induce cell death, principally in large cells like oocytes, which have a meiotic spindle that degenerates during this process. Significantly, cryopreservation represents an option for fertility preservation in patients who develop gonadal failure for any condition and those who want to freeze their germ cells for later use. The possibility of freezing sperm, oocytes, and embryos has been available for a long time, and in 1983 the first birth with thawed oocytes was achieved. From the mid-2000s forward, the use of egg vitrification through intracytoplasmic sperm injection has improved pregnancy rates. Births using assisted reproductive technologies (ART) have some adverse conditions and events. These risks could be associated with ART procedures or related to infertility. Cryopreservation generates changes in the epigenome of gametes and embryos, given that ART occurs when the epigenome is most vulnerable. Furthermore, cryoprotective agents induce alterations in the integrity of germ cells and embryos. Notably, cryopreservation extensively affects cell viability, generates proteomic profile changes, compromises crucial cellular functions, and alters sperm motility. This technique has been widely employed since the 1980s and there is a lack of knowledge about molecular changes. The emerging view is that molecular changes are associated with cryopreservation, affecting metabolism, cytoarchitecture, calcium homeostasis, epigenetic state, and cell survival, which compromise the fertilization in ART.
Healthy Tissue Damage Following Cancer Ion Therapy: A Radiobiological Database Predicting Lymphocyte Chromosome Aberrations Based on the BIANCA Biophysical Model
Authors: Embriaco Alessia , Ramos Ricardo , Carante Mario , Ferrari Alfredo , Sala Paola , Vercesi Valerio , Ballarini Francesca
Published: October 2021

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage.
Correction: Feng et al. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Int. J. Mol. Sci. 2020, 21, 4655
Authors: Feng Duo , Xu DongZhu , Murakoshi Nobuyuki , Tajiri Kazuko , Qin Rujie , Yonebayashi Saori , Okabe Yuta , Li Siqi , Yuan Zixun , Aonuma Kazutaka , Ieda Masaki
Published: October 2021

The authors wish to make the following corrections to this paper [...]
Discovery of a Metabolic Signature Predisposing High Risk Patients with Mild Cognitive Impairment to Converting to Alzheimer’s Disease
Authors: Huang Yi-Long , Lin Chao-Hsiung , Tsai Tsung-Hsien , Huang Chen-Hua , Li Jie-Ling , Chen Liang-Kung , Li Chun-Hsien , Tsai Ting-Fen , Wang Pei-Ning
Published: October 2021

Assessing dementia conversion in patients with mild cognitive impairment (MCI) remains challenging owing to pathological heterogeneity. While many MCI patients ultimately proceed to Alzheimer’s disease (AD), a subset of patients remain stable for various times. Our aim was to characterize the plasma metabolites of nineteen MCI patients proceeding to AD (P-MCI) and twenty-nine stable MCI (S-MCI) patients by untargeted metabolomics profiling. Alterations in the plasma metabolites between the P-MCI and S-MCI groups, as well as between the P-MCI and AD groups, were compared over the observation period. With the help of machine learning-based stratification, a 20-metabolite signature panel was identified that was associated with the presence and progression of AD. Furthermore, when the metabolic signature panel was used for classification of the three patient groups, this gave an accuracy of 73.5% using the panel. Moreover, when specifically classifying the P-MCI and S-MCI subjects, a fivefold cross-validation accuracy of 80.3% was obtained using the random forest model. Importantly, indole-3-propionic acid, a bacteria-generated metabolite from tryptophan, was identified as a predictor of AD progression, suggesting a role for gut microbiota in AD pathophysiology. Our study establishes a metabolite panel to assist in the stratification of MCI patients and to predict conversion to AD.
Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans
Authors: Nicolai Merle M. , Weishaupt Ann-Kathrin , Baesler Jessica , Brinkmann Vanessa , Wellenberg Anna , Winkelbeiner Nicola , Gremme Anna , Aschner Michael , Fritz Gerhard , Schwerdtle Tanja , Bornhorst Julia
Published: October 2021

Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms.
AMaLa: Analysis of Directed Evolution Experiments via Annealed Mutational Approximated Landscape
Authors: Sesta Luca , Uguzzoni Guido , Fernandez-de-Cossio-Diaz Jorge , Pagnani Andrea
Published: October 2021

We present Annealed Mutational approximated Landscape (AMaLa), a new method to infer fitness landscapes from Directed Evolution experiments sequencing data. Such experiments typically start from a single wild-type sequence, which undergoes Darwinian in vitro evolution via multiple rounds of mutation and selection for a target phenotype. In the last years, Directed Evolution is emerging as a powerful instrument to probe fitness landscapes under controlled experimental conditions and as a relevant testing ground to develop accurate statistical models and inference algorithms (thanks to high-throughput screening and sequencing). Fitness landscape modeling either uses the enrichment of variants abundances as input, thus requiring the observation of the same variants at different rounds or assuming the last sequenced round as being sampled from an equilibrium distribution. AMaLa aims at effectively leveraging the information encoded in the whole time evolution. To do so, while assuming statistical sampling independence between sequenced rounds, the possible trajectories in sequence space are gauged with a time-dependent statistical weight consisting of two contributions: (i) an energy term accounting for the selection process and (ii) a generalized Jukes–Cantor model for the purely mutational step. This simple scheme enables accurately describing the Directed Evolution dynamics and inferring a fitness landscape that correctly reproduces the measures of the phenotype under selection (e.g., antibiotic drug resistance), notably outperforming widely used inference strategies. In addition, we assess the reliability of AMaLa by showing how the inferred statistical model could be used to predict relevant structural properties of the wild-type sequence.
Biochemical and Immunological implications of Lutein and Zeaxanthin
Authors: Zafar Javaria , Aqeel Amna , Shah Fatima Iftikhar , Ehsan Naureen , Gohar Umar Farooq , Moga Marius Alexandru , Festila Dana , Ciurea Codrut , Irimie Marius , Chicea Radu
Published: October 2021

Throughout history, nature has been acknowledged for being a primordial source of various bioactive molecules in which human macular carotenoids are gaining significant attention. Among 750 natural carotenoids, lutein, zeaxanthin and their oxidative metabolites are selectively accumulated in the macular region of living beings. Due to their vast applications in food, feed, pharmaceutical and nutraceuticals industries, the global market of lutein and zeaxanthin is continuously expanding but chemical synthesis, extraction and purification of these compounds from their natural repertoire e.g., plants, is somewhat costly and technically challenging. In this regard microbial as well as microalgal carotenoids are considered as an attractive alternative to aforementioned challenges. Through the techniques of genetic engineering and gene-editing tools like CRISPR/Cas9, the overproduction of lutein and zeaxanthin in microorganisms can be achieved but the commercial scale applications of such procedures needs to be done. Moreover, these carotenoids are highly unstable and susceptible to thermal and oxidative degradation. Therefore, esterification of these xanthophylls and microencapsulation with appropriate wall materials can increase their shelf-life and enhance their application in food industry. With their potent antioxidant activities, these carotenoids are emerging as molecules of vital importance in chronic degenerative, malignancies and antiviral diseases. Therefore, more research needs to be done to further expand the applications of lutein and zeaxanthin.
The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review
Authors: Wu Cheng-Yang , Wu Jiann-Der , Chen Chien-Chin
Published: October 2021

Ovarian teratomas are by far the most common ovarian germ cell tumor. Most teratomas are benign unless a somatic transformation occurs. The designation of teratoma refers to a neoplasm that differentiates toward somatic-type cell populations. Recent research shows a striking association between ovarian teratomas and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a rare and understudied paraneoplastic neurological syndrome (PNS). Among teratomas, mature teratomas are thought to have a greater relevance with those neurological impairments. PNS is described as a neurologic deficit triggered by an underlying remote tumor, whereas anti-NMDAR encephalitis is characterized by a complex neuropsychiatric syndrome and the presence of autoantibodies in cerebral spinal fluid against the GluN1 subunit of the NMDAR. This review aims to summarize recent reports on the association between anti-NMDAR encephalitis and ovarian teratoma. In particular, the molecular pathway of pathogenesis and the updated mechanism and disease models would be discussed. We hope to provide an in-depth review of this issue and, therefore, to better understand its epidemiology, diagnostic approach, and treatment strategies.
Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury
Authors: Mutchler Stephanie M. , Hasan Mahpara , Kohan Donald E. , Kleyman Thomas R. , Tan Roderick J.
Published: October 2021

Acute kidney injury due to renal ischemia-reperfusion injury (IRI) may lead to chronic or end stage kidney disease. A greater understanding of the cellular mechanisms underlying IRI are required to develop therapeutic options aimed at limiting or reversing damage from IRI. Prior work has shown that deletion of the α subunit of the epithelial Na+ channel (ENaC) in endothelial cells protects from IRI by increasing the availability of nitric oxide. While canonical ENaCs consist of an α, β, and γ subunit, there is evidence of non-canonical ENaC expression in endothelial cells involving the α subunit. We therefore tested whether the deletion of the γ subunit of ENaC also protects mice from IRI to differentiate between these channel configurations. Mice with endothelial-specific deletion of the γ subunit and control littermates were subjected to unilateral renal artery occlusion followed by 48 h of reperfusion. No significant difference was noted in injury between the two groups as assessed by serum creatinine and blood urea nitrogen, levels of specific kidney injury markers, and histological examination. While deletion of the γ subunit did not alter infiltration of immune cells or cytokine message, it was associated with an increase in levels of total and phosphorylated endothelial nitric oxide synthase (eNOS) in the injured kidneys. Our studies demonstrate that even though deletion of the γ subunit of ENaC may allow for greater activation of eNOS, this is not sufficient to prevent IRI, suggesting the protective effects of α subunit deletion may be due, in part, to other mechanisms.
Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study
Authors: Guo Yan , Liang Jianhuai , Liu Boping , Jin Yulong
Published: October 2021

In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy.
Loss of the R2R3 MYB Transcription Factor RsMYB1 Shapes Anthocyanin Biosynthesis and Accumulation in Raphanus sativus
Authors: Kim Da-Hye , Lee Jundae , Rhee JuHee , Lee Jong-Yeol , Lim Sun-Hyung
Published: October 2021

The red or purple color of radish (Raphanus sativus L.) taproots is due to anthocyanins, which have nutritional and aesthetic value, as well as antioxidant properties. Moreover, the varied patterns and levels of anthocyanin accumulation in radish roots make them an interesting system for studying the transcriptional regulation of anthocyanin biosynthesis. The R2R3 MYB transcription factor RsMYB1 is a key positive regulator of anthocyanin biosynthesis in radish. Here, we isolated an allele of RsMYB1, named RsMYB1Short, in radish cultivars with white taproots. The RsMYB1Short allele carried a 4 bp insertion in the first exon causing a frame-shift mutation of RsMYB1, generating a truncated protein with only a partial R2 domain at the N-terminus. Unlike RsMYB1Full, RsMYB1Short was localized to the nucleus and the cytoplasm and failed to interact with their cognate partner RsTT8. Transient expression of genomic or cDNA sequences for RsMYB1Short in radish cotyledons failed to induce anthocyanin accumulation, but that for RsMYB1Full activated it. Additionally, RsMYB1Short showed the lost ability to induce pigment accumulation and to enhance the transcript level of anthocyanin biosynthetic genes, while RsMYB1Full promoted both processes when co-expressed with RsTT8 in tobacco leaves. As the result of the transient assay, co-expressing RsTT8 and RsMYB1Full, but not RsMYB1Short, also enhanced the promoter activity of RsCHS and RsDFR. We designed a molecular marker for RsMYB1 genotyping, and revealed that the RsMYB1Short allele is common in white radish cultivars, underscoring the importance of variation at the RsMYB1 locus in anthocyanin biosynthesis in the radish taproot. Together, these results indicate that the nonsense mutation of RsMYB1 generated the truncated protein, RsMYB1Short, that had the loss of ability to regulate anthocyanin biosynthesis. Our findings highlight that the frame shift mutation of RsMYB1 plays a key role in anthocyanin biosynthesis in the radish taproot.
TMEM16A, a Homoharringtonine Receptor, as a Potential Endogenic Target for Lung Cancer Treatment
Authors: Guo Shuai , Bai Xue , Shi Sai , Deng Yawen , Kang Xianjiang , An Hailong
Published: October 2021

Lung cancer has the highest rate of incidence and mortality among all cancers. Most chemotherapeutic drugs used to treat lung cancer cause serious side effects and are susceptible to drug resistance. Therefore, exploring novel therapeutic targets for lung cancer is important. In this study, we evaluated the potential of TMEM16A as a drug target for lung cancer. Homoharringtonine (HHT) was identified as a novel natural product inhibitor of TMEM16A. Patch-clamp experiments showed that HHT inhibited TMEM16A activity in a concentration-dependent manner. HHT significantly inhibited the proliferation and migration of lung cancer cells with high TMEM16A expression but did not affect the growth of normal lung cells in the absence of TMEM16A expression. In vivo experiments showed that HHT inhibited the growth of lung tumors in mice and did not reduce their body weight. Finally, the molecular mechanism through which HHT inhibits lung cancer was explored by western blotting. The findings showed that HHT has the potential to regulate TMEM16A activity both in vitro and in vivo and could be a new lead compound for the development of anti-lung-cancer drugs.
Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives
Authors: Aleksakhina Svetlana N. , Imyanitov Evgeny N.
Published: October 2021

The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.
Mechanism of Phosgene-Induced Acute Lung Injury and Treatment Strategy
Authors: Lu Qianying , Huang Siyu , Meng Xiangyan , Zhang Jianfeng , Yu Sifan , Li Junfeng , Shi Mingyu , Fan Haojun , Zhao Yanmei
Published: October 2021

Phosgene (COCl2) was once used as a classic suffocation poison and currently plays an essential role in industrial production. Due to its high toxicity, the problem of poisoning caused by leakage during production, storage, and use cannot be ignored. Phosgene mainly acts on the lungs, causing long-lasting respiratory depression, refractory pulmonary edema, and other related lung injuries, which may cause acute respiratory distress syndrome or even death in severe cases. Due to the high mortality, poor prognosis, and frequent sequelae, targeted therapies for phosgene exposure are needed. However, there is currently no specific antidote for phosgene poisoning. This paper reviews the literature on the mechanism and treatment strategies to explore new ideas for the treatment of phosgene poisoning.
Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data
Authors: Giugliani Roberto , Martins Ana Maria , Okuyama Torayuki , Eto Yoshikatsu , Sakai Norio , Nakamura Kimitoshi , Morimoto Hideto , Minami Kohtaro , Yamamoto Tatsuyoshi , Yamaoka Mariko , Ikeda Toshiaki , So Sairei , Tanizawa Kazunori , Sonoda Hiroyuki , Schmidt Mathias , Sato Yuji
Published: October 2021

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.