bluuebunny/crossref_metadata_2025_split huggingface dataset:
The burden of untreated insomnia disorder in a sample of 1 million adults: a cohort study
Authors: Grandner Michael , Olivieri Antonio , Ahuja Ajay , Büsser Alexander , Freidank Moritz , McCall William V. 
Published: August 2023

Abstract
Background
Insomnia disorder is a highly prevalent, significant public health concern associated with substantial and growing health burden. There are limited real-world data assessing the burden of insomnia disorder on daytime functioning and its association with comorbidities. The objective of this study was to leverage large-scale, real-world data to assess the burden of untreated insomnia disorder in terms of daytime impairment and clinical outcomes.

Methods
This United States medical claims database study compares patients diagnosed with insomnia disorder but not receiving treatment (‘untreated insomnia’ cohort) to patients without an insomnia disorder diagnosis and without treatment (‘non-insomnia’ cohort). International Classification of Disease, Tenth Revision codes were used as a proxy to represent the three symptom domains (Sleepiness, Alert/Cognition, Mood) of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a newly developed and validated tool used in clinical studies to assess daytime functioning in insomnia disorder. Chronic Fatigue (R53.83) and Other Fatigue (R53.83), Somnolence (R40.0) and Disorientation (R41.0) were selected as categories representing one or more IDSIQ domains. Clinical outcomes included cardiovascular events, psychiatric disorders, cognitive impairment and metabolic disorders.

Results
Approximately 1 million patients were included (untreated insomnia: n = 139,959; non-insomnia: n = 836,975). Compared with the ‘non-insomnia’ cohort, the ‘untreated insomnia’ cohort was more likely to experience daytime impairments, with mean differences in occurrences per 100 patient-years for: (a) fatigue, at 27.35 (95% confidence interval [CI] 26.81, 27.77, p < 0.01); (b) dizziness, at 4.66 (95% CI 4.40, 4.90, p < 0.01); (c) somnolence, at 4.18 (95% CI 3.94, 4.43, p < 0.01); and (d) disorientation, at 0.92 (95% CI 0.77, 1.06, p < 0.01). During the 1-year look-back period, patients in the ‘untreated insomnia’ cohort were also more likely to have been diagnosed with arterial hypertension (40.9% vs. 26.3%), psychiatric comorbidities (40.1% vs. 13.2%), anxiety (29.2% vs. 8.5%), depression (26.1% vs. 8.1%) or obesity (21.3% vs. 11.1%) compared with those in the ‘non-insomnia’ cohort.

Conclusions
This large-scale study confirms the substantial burden of insomnia disorder on patients in a real-world setting, with significant daytime impairment and numerous comorbidities. This reinforces the need for timely insomnia disorder diagnosis and treatments that improve both sleep, as well as daytime functioning.
A nano-Liposomal formulation potentiates antioxidant, anti-inflammatory, and fibrinolytic activities of Allolobophora caliginosa coelomic fluid: formulation and characterization
Authors: Farouk Asmaa E. , Fahmy Sohair R. , Soliman Amel M. , Ibrahim Sherif Abdelaziz , Sadek Shimaa A. 
Published: August 2023

Abstract
Background
Coelomic fluid, a pharmacologically active compound in earthworms, exhibits a range of biological activities, including antioxidant, anti-inflammatory, and anticancer. However, the biological activities exerted by the coelomic fluid can be restrained by its low bioavailability and stability. Liposomes are progressively utilized as an entrapment system for natural bioactive compounds with poor bioavailability and stability, which could be appropriate for coelomic fluid. Thus, the present study was designed to fabricate, characterize, and evaluate the stability of liposomal formulation for Allolobophora caliginosa coelomic fluid (ACCF) as a natural antioxidant compound.

Methods
The ACCF-liposomes were developed with a subsequent characterization of their physicochemical attributes. The physical stability, ACCF release behavior, and gastrointestinal stability were evaluated in vitro. The biological activities of ACCF and its liposomal formulation were also determined.

Results
The liposomal formulation of ACCF had a steady characteristic absorption band at 201 nm and a transmittance of 99.20 ± 0.10%. Its average hydrodynamic particle size was 98 nm, with a PDI of 0.29 ± 0.04 and a negative zeta potential (-38.66 ± 0.33mV). TEM further confirmed the formation of vesicular, spherical nano-liposomes with unilamellar configuration. Additionally, a remarkable entrapment efficiency percent (77.58 ± 0.82%) with a permeability rate equal to 3.20 ± 0.31% and a high retention rate (54.16 ± 2.20%) for ACCF-liposomes were observed. The Fourier transform infrared spectroscopy (FTIR) result demonstrated that ACCF successfully entrapped inside liposomes. The ACCF-liposomes exhibited a slow and controlled ACCF release in vitro. Regarding stability studies, the liposomal formulation enhanced the stability of ACCF during storage and at different pH. Furthermore, ACCF-liposomes are highly stable in intestinal digestion conditions comparable to gastric digestion. The current study disclosed that liposomal formulation potentiates the biological activities of ACCF, especially antioxidant, anti-inflammatory, and thrombolytic activities.

Conclusion
These promising results offer a novel approach to increasing the bioaccessibility of ACCF, which may be crucial for the development of pharmaceuticals and nutraceutical-enriched functional foods.
Associations between weight-adjusted waist index and bone mineral density: results of a nationwide survey
Authors: Zhang Ya , Wu Haiyang , Li Cheng , Liu Changxiong , Liu Mingjiang , Liu Xiaozhu , Yin Qiming , Li Xianzhe , Xie Ruijie 
Published: August 2023

Abstract
Background
The weight-adjusted waist circumference index (WWI) is a novel obesity indicator that offers improved accuracy in assessing both muscle and fat mass compared to traditional measures. This study aimed to investigate the association between WWI and bone mineral density (BMD) in adults.

Methods
Weighted multivariate logistic regression, subgroup analysis, interaction tests and restricted cubic spline (RCS) curves were used to explore the relationship between WWI and BMD based on data from the National Health and Nutrition Examination Survey (NHANES).

Results
This study had 40,568 individuals in total. At all four measurement sites, we detected a negative linear correlation between WWI and BMD. Even when quartile factors for WWI were created, this unfavorable connection maintained. In comparison to those in the lowest quartile, those in the highest percentile of WWI showed declines in lumbar BMD of 0.08 g/cm2 and femoral neck BMD of 0.03 g/cm2, respectively. This adverse correlation, nevertheless, differed among several categories.

Conclusions
Our findings suggest an adverse correlation between WWI and BMD among US adults. Employing WWI as a tool for osteoporosis prevention in the general population may enhance interventions.
Genetic diversity and natural selection of Plasmodium vivax reticulocyte invasion genes in Ecuador
Authors: Núñez Andrés , Ntumngia Francis B. , Guerra Yasel , Adams John H. , Sáenz Fabián E. 
Published: August 2023

Abstract
Background
Knowledge of the diversity of invasion ligands in malaria parasites in endemic regions is essential to understand how natural selection influences genetic diversity of these ligands and their feasibility as possible targets for future vaccine development. In this study the diversity of four genes for merozoite invasion ligands was studied in Ecuadorian isolates of Plasmodium vivax.

Methods
Eighty-eight samples from P. vivax infected individuals from the Coast and Amazon region of Ecuador were obtained between 2012 and 2015. The merozoite invasion genes pvmsp-1-19, pvdbpII, pvrbp1a-2 and pvama1 were amplified, sequenced, and compared to the Sal-1 strain. Polymorphisms were mapped and genetic relationships between haplotypes were determined.

Results
Only one nonsynonymous polymorphism was detected in pvmsp-1-19, while 44 nonsynonymous polymorphisms were detected in pvdbpII, 56 in pvrbp1a-2 and 33 in pvama1. While haplotypes appeared to be more related within each area of study and there was less relationship between parasites of the coastal and Amazon regions of the country, diversification processes were observed in the two Amazon regions. The highest haplotypic diversity for most genes occurred in the East Amazon of the country. The high diversity observed in Ecuadorian samples is closer to Brazilian and Venezuelan isolates, but lower than reported in other endemic regions. In addition, departure from neutrality was observed in Ecuadorian pvama1. Polymorphisms for pvdbpII and pvama1 were associated to B-cell epitopes.

Conclusions
pvdbpII and pvama1 genetic diversity found in Ecuadorian P. vivax was very similar to that encountered in other malaria endemic countries with varying transmission levels and segregated by geographic region. The highest diversity of P. vivax invasion genes in Ecuador was found in the Amazonian region. Although selection appeared to have small effect on pvdbpII and pvrbp1a-2, pvama1 was influenced by significant balancing selection.
Identifying meaningful subpopulation segments among older public assistance recipients: a mixed methods study to develop tailor-made health and welfare interventions
Authors: Ueno Keiko , Nishioka Daisuke , Saito Junko , Kino Shiho , Kondo Naoki 
Published: August 2023

AbstractBackgroundPublic assistance recipients have diverse and complex needs for health and social support in addition to financial support. Segmentation, which means dividing the population into subgroups (segments) with similar sociodemographic characteristics, is a useful approach for allocating support resources to the targeted segments. Clustering is a commonly used statistical method of segmentation in a data-driven marketing approach. This explanatory sequential mixed methods study applied a clustering technique, aiming to identify segments among older public assistance recipients quantitatively, and assess the meaningfulness of the identified segments in consultation and support activities for older recipients qualitatively.MethodsWe identified the segments of older recipients in two municipalities using probabilistic latent semantic analysis, a machine learning-based soft clustering method. Semi-structured interviews were subsequently conducted with caseworkers to ask whether the identified segments could be meaningful for them in practice and to provide a reason if they could not think of any older recipients from the segment.ResultsA total of 3,165 older people on public assistance were included in the analysis. Five distinct segments of older recipients were identified for each sex from 1,483 men and 1,682 women. The qualitative findings suggested most of identified segments reflected older recipients in practice, especially two of them: female Cluster 1 (facility residents aged over 85 years with disability/psychiatric disorder), and female Cluster 2 (workers). Some caseworkers, however, did not recall older recipients in practice when working with certain segments.ConclusionsA clustering technique can be useful to identify the meaningful segments among older recipients and can potentially discover previously unrecognized segments that may not emerge through regular consultation practices followed by caseworkers. Future research should investigate whether tailored support interventions for these identified segments are effective.
Anoikis resistance––protagonists of breast cancer cells survive and metastasize after ECM detachment
Authors: Dai Yalan , Zhang Xinyi , Ou Yingjun , Zou Linglin , Zhang Duoli , Yang Qingfan , Qin Yi , Du Xiuju , Li Wei , Yuan Zhanpeng , Xiao Zhangang , Wen Qinglian 
Published: August 2023

AbstractBreast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive.
Enhancer RNAs: mechanisms in transcriptional regulation and functions in diseases
Authors: Li Qianhui , Liu Xin , Wen Jingtao , Chen Xi , Xie Bumin , Zhao Yang 
Published: August 2023

AbstractIn recent years, increasingly more non-coding RNAs have been detected with the development of high-throughput sequencing technology, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs), and piwi-interacting RNA (piRNAs). The discovery of enhancer RNAs (eRNAs) in 2010 has further broadened the range of non-coding RNAs revealed. eRNAs are non-coding RNA molecules produced by the transcription of DNA cis-acting elements, enhancer fragments. Recent studies revealed that the transcription of eRNAs may be a biological marker responding to enhancer activity that can participate in the regulation of coding gene transcription. In this review, we discussed the biological characteristics of eRNAs, their functions in transcriptional regulation, the regulation factors of eRNAs production, and the research progress of eRNAs in different diseases.
Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration
Authors: Bastin Jean , Sroussi Marine , Nemazanyy Ivan , Laurent-Puig Pierre , Mouillet-Richard Sophie , Djouadi Fatima 
Published: August 2023

Abstract
Background
Colorectal cancer (CRC) can be classified into four molecular subtypes (CMS) among which CMS1 is associated with the best prognosis, while CMS4, the mesenchymal subtype, has the worst outcome. Although mitochondria are considered to be hubs of numerous signaling pathways, the study of mitochondrial metabolism has been neglected for many years. Mitochondrial Complex I (CI) plays a dual role, both in energy and reactive oxygen species (ROS) production. However, the possible contribution of CI to tumorigenesis in cancer remains unclear. The purpose of this study was to investigate the CI under the prism of the CMS classification of CRC in ex vivo models.

Methods
Biochemical dosages, bioenergetics analysis and western-blot were used to characterize CI expression, function and redox balance in LoVo and MDST8 cell lines, belonging to CMS1 and CMS4 subgroups, respectively. Cell proliferation and migration were assessed by xCELLigence technology. Overproduction or scavenging of mitochondrial ROS (mtROS) were performed to analyze the effect of mtROS on proliferation, migration, and mesenchymal markers. Focal adhesion kinase (FAK) and its activation were analyzed by immunofluorescence. We assessed the distribution of two CI scores in CRC cohorts according to CMS classification and their relevance for patient survival.

Results
We found that CI is downregulated in CMS4 cells and is associated with elevated mtROS. We establish for the first time that in these migrating cells, mtROS production is maintained at optimal levels not only through changes in CI activity but also by inactivation/acetylation of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. We show that promoting or scavenging mtROS both mitigate CMS4 cells’ migration. Our results also point to a mtROS-mediated focal adhesion kinase (FAK) activation, which likely sustains their migratory phenotype. Using cohorts of CRC patients, we document that the expression of CI is downregulated in the CMS4 subgroup, and that low CI expression is associated with poor prognosis. Patients’ datasets reveal an inverse correlation between CI and the epithelial-mesenchymal transition (EMT) pathway.

Conclusion
We showed that inhibition of CI contributes to heighten mtROS, which likely foster MDST8 migration and might account for the specific EMT signature of CMS4 tumors. These data reveal a novel role of mitochondrial CI in CRC, with biological consequences that may be targeted with anti- or pro-oxidant drugs in clinical practice.
phyBWT2: phylogeny reconstruction via eBWT positional clustering
Authors: Guerrini Veronica , Conte Alessio , Grossi Roberto , Liti Gianni , Rosone Giovanna , Tattini Lorenzo 
Published: August 2023

Abstract
Background
Molecular phylogenetics studies the evolutionary relationships among the individuals of a population through their biological sequences. It may provide insights about the origin and the evolution of viral diseases, or highlight complex evolutionary trajectories. A key task is inferring phylogenetic trees from any type of sequencing data, including raw short reads. Yet, several tools require pre-processed input data e.g. from complex computational pipelines based on de novo assembly or from mappings against a reference genome. As sequencing technologies keep becoming cheaper, this puts increasing pressure on designing methods that perform analysis directly on their outputs. From this viewpoint, there is a growing interest in alignment-, assembly-, and reference-free methods that could work on several data including raw reads data.

Results
We present phyBWT2, a newly improved version of phyBWT (Guerrini et al. in 22nd International Workshop on Algorithms in Bioinformatics (WABI) 242:23–12319, 2022). Both of them directly reconstruct phylogenetic trees bypassing both the alignment against a reference genome and de novo assembly. They exploit the combinatorial properties of the extended Burrows-Wheeler Transform (eBWT) and the corresponding eBWT positional clustering framework to detect relevant blocks of the longest shared substrings of varying length (unlike the k-mer-based approaches that need to fix the length k a priori). As a result, they provide novel alignment-, assembly-, and reference-free methods that build partition trees without relying on the pairwise comparison of sequences, thus avoiding to use a distance matrix to infer phylogeny. In addition, phyBWT2 outperforms phyBWT in terms of running time, as the former reconstructs phylogenetic trees step-by-step by considering multiple partitions, instead of just one partition at a time, as previously done by the latter.

Conclusions
Based on the results of the experiments on sequencing data, we conclude that our method can produce trees of quality comparable to the benchmark phylogeny by handling datasets of different types (short reads, contigs, or entire genomes). Overall, the experiments confirm the effectiveness of phyBWT2 that improves the performance of its previous version phyBWT, while preserving the accuracy of the results.
Evaluating the effectiveness of a social and emotional learning program among preschool children in Japan: an experimental cohort study
Authors: Hosokawa Rikuya , Matsumoto Yuki , Nishida Chizuko , Funato Keiko , Mitani Aki 
Published: August 2023

Abstract
Background
Research on school maladjustment has increasingly focused on social skills, such as the ability to control emotions, collaborate with others, and achieve goals. Social and emotional learning (SEL) is one approach to nurturing social skills. However, few preventive interventions to promote SEL have been conducted among young children, particularly in Asian countries, including Japan. Therefore, this study examined the effectiveness of an SEL program—Fun FRIENDS—among children in Japan.

Methods
In mid-2022, the Fun FRIENDS program was administered to 115 children aged 4–5 years, who were enrolled in two kindergartens. The program was administered to the entire class as part of their kindergarten activities. The control group included 93 children in three kindergartens. This study included 94 participants (81.7%) in the intervention group and 66 (71.0%) in the control group, whose parents agreed with the assessment of their skills. Fun FRIENDS is a support program based on a cognitive–behavioral approach. The program aims to teach children how to cope with anxiety and stress and develop resilience and confidence to face difficulties. The program includes 10 sessions, each lasting approximately 1 h and conducted once per week. To examine the program’s effectiveness, teachers evaluated these children’s social skills before and after program implementation using the Social Skill Scale.

Results
Results showed significant post-intervention improvements in self-control and cooperation scores among children in the intervention group, compared with pre-intervention. Further, post-intervention self-control and cooperation scores were significantly higher among children in the intervention group than the control group.

Conclusions
SEL implemented on a class-wide basis could be effective in early childhood. An early approach targeting preschool-aged children is necessary to prevent school maladjustment. A universal approach implemented on a whole-class basis could contribute to improving children’s social skills.
A high-throughput dual system to screen polyphosphate kinase mutants for efficient ATP regeneration in L-theanine biocatalysis
Authors: Gao Hui , Li Mengxuan , Wang Qing , Liu Tingting , Zhang Xian , Yang Taowei , Xu Meijuan , Rao Zhiming 
Published: August 2023

AbstractATP, an important cofactor, is involved in many biocatalytic reactions that require energy. Polyphosphate kinases (PPK) can provide energy for ATP-consuming reactions due to their cheap and readily available substrate polyphosphate. We determined the catalytic properties of PPK from different sources and found that PPK from Cytophaga hutchinsonii (ChPPK) had the best catalytic activity for the substrates ADP and polyP6. An extracellular–intracellular dual system was constructed to high-throughput screen for better catalytic activity of ChPPK mutants. Finally, the specific activity of ChPPKD82N-K103E mutant was increased by 4.3 times. Therefore, we focused on the production of L-theanine catalyzed by GMAS as a model of ATP regeneration. Supplying 150 mM ATP, GMAS enzyme could produce 16.8 ± 1.3 g/L L-theanine from 100 mM glutamate. When 5 mM ATP and 5 U/mL ChPPKD82N-K103E were added, the yield of L-theanine was 16.6 ± 0.79 g/L with the conversion rate of 95.6 ± 4.5% at 4 h. Subsequently, this system was scaled up to 200 mM and 400 mM glutamate, resulting in the yields of L-theanine for 32.3 ± 1.6 g/L and 62.7 ± 1.1 g/L, with the conversion rate of 92.8 ± 4.6% and 90.1 ± 1.6%, respectively. In addition, we also constructed an efficient ATP regeneration system from glutamate to glutamine, and 13.8 ± 0.2 g/L glutamine was obtained with the conversion rate of 94.4 ± 1.4% in 4 h after adding 6 U/ mL GS enzyme and 5 U/ mL ChPPKD82N-K103E, which further laid the foundation from glutamine to L-theanine catalyzed by GGT enzyme. This proved that giving the reaction an efficient ATP supply driven by the mutant enzyme enhanced the conversion rate of substrate to product and maximized the substrate value. This is a positively combination of high yield, high conversion rate and high economic value of enzyme catalysis. The mutant enzyme will further power the ATP-consuming biocatalytic reaction platform sustainably.