bluuebunny/crossref_metadata_2025 huggingface dataset:
Semla: a versatile toolkit for spatially resolved transcriptomics analysis and visualization
Authors: Larsson Ludvig , Franzén Lovisa , Ståhl Patrik L , Lundeberg Joakim
Published: October 2023

Spatially resolved transcriptomics technologies generate gene expression data with retained positional information from a tissue section, often accompanied by a corresponding histological image. Computational tools should make it effortless to incorporate spatial information into data analyses and present analysis results in their histological context. Here, we present semla, an R package for processing, analysis, and visualization of spatially resolved transcriptomics data generated by the Visium platform, that includes interactive web applications for data exploration and tissue annotation.

Availability and implementation

The R package semla is available on GitHub (https://github.com/ludvigla/semla), under the MIT License, and deposited on Zenodo (https://doi.org/10.5281/zenodo.8321645). Documentation and tutorials with detailed descriptions of usage can be found at https://ludvigla.github.io/semla/.
PICKLUSTER: a protein-interface clustering and analysis plug-in for UCSF ChimeraX
Authors: Genz Luca R , Mulvaney Thomas , Nair Sanjana , Topf Maya
Published: October 2023

The identification and characterization of interfaces in protein complexes is crucial for understanding the mechanisms of molecular recognition. These interfaces are also attractive targets for protein inhibition. However, targeting protein interfaces can be challenging for large interfaces that consist of multiple interacting regions. We present PICKLUSTER [Protein Interface C(K)luster]—a program for identifying “sub-interfaces” in protein–protein complexes using distance clustering. The division of the interface into smaller “sub-interfaces” offers a more focused approach for targeting protein–protein interfaces.

Availability and implementation

PICKLUSTER is implemented as a plug-in for the molecular visualization program UCSF ChimeraX 1.4 and subsequent versions. It is freely available for download in the ChimeraX Toolshed and https://gitlab.com/topf-lab/pickluster.git.
Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry
Authors: Lluch-Galcerá Juan José , Carrascosa Jose Manuel , González-Quesada Alicia , Rivera-Díaz Raquel , Sahuquillo-Torralba Antonio , Llamas-Velasco Mar , Gómez-García Francisco José , Herrera-Acosta Enrique , de la Cueva Pablo , Baniandrés-Rodríguez Ofelia , Lopez-Estebaranz Jose Luis , Belinchón Isabel , Ferrán Marta , Mateu Almudena , Rodríguez Lourdes , Riera-Monroig Josep , Abalde-Pintos M Teresa , Carretero Gregorio , García-Donoso Carmen , Pujol-Marco Conrad , Del Alcázar Elena , Santamaría-Domínguez Cristina , Suárez-Pérez Jorge Alonso , Nieto-Benito Lula María , Ruiz-Genao Diana Patricia , Salgado-Boquete Laura , Descalzo Miguel Ángel , García-Doval Ignacio
Published: October 2023

Background

Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The combination of a biologic agent and a conventional systemic drug [generally methotrexate (MTX)] is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis.

Objectives

The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX.

Methods

Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class.

Results

We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57–3.98; P < 0.002).

Conclusions

The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.
A critical role of the endothelial S-phase kinase-associated protein 2/phosphatase and tensin homologue axis in angiogenesis and psoriasis
Authors: Xie Xinya , Cui Qi , Jiang Tingting , Zhao Ziwei , Liu Zheyi , Liu Jia , Yao Qinyu , Wang Yuxin , Dang Erle , Wang Gang , Xiao Lei , Wang Nanping
Published: October 2023

Background

Psoriasis is a common chronic skin disorder. Pathologically, it features abnormal epidermal proliferation, infiltrating inflammatory cells and increased angiogenesis in the dermis. Aberrant expression of E3 ubiquitin ligase and a dysregulated protein ubiquitination system are implicated in the pathogenesis of psoriasis.

Objectives

To examine the potential role of S-phase kinase-associated protein 2 (Skp2), an E3 ligase and oncogene, in psoriasis.

Methods

Gene expression and protein levels were evaluated with quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence staining of skin samples from patients with psoriasis vulgaris and an imiquimod (IMQ)-induced mouse model, as well as from cultured endothelial cells (ECs). Protein interaction, substrate ubiquitination and degradation were examined using co-immunoprecipitation, Western blotting and a cycloheximide chase assay in human umbilical vein ECs. Angiogenesis was measured in vitro using human dermal microvascular ECs (HDMECs) for BrdU incorporation, migration and tube formation. In vivo angiogenesis assays included chick embryonic chorioallantoic membrane, the Matrigel plug assay and quantification of vasculature in the mouse lesions. Skp2 gene global knockout (KO) mice and endothelial-specific conditional KO mice were used.

Results

Skp2 was increased in skin samples from patients with psoriasis and IMQ-induced mouse lesions. Immunofluorescent double staining indicated a close association of Skp2 expression with excessive vascularity in the lesional dermal papillae. In HDMECs, Skp2 overexpression was enhanced, whereas Skp2 knockdown inhibited EC proliferation, migration and tube-like structure formation. Mechanistically, phosphatase and tensin homologue (PTEN), which suppresses the phosphoinositide 3-kinase/Akt pathway, was identified to be a novel substrate for Skp2-mediated ubiquitination. A selective inhibitor of Skp2 (C1) or Skp2 small interfering RNA significantly reduced vascular endothelial growth factor-triggered PTEN ubiquitination and degradation. In addition, Skp2-mediated ubiquitination depended on the phosphorylation of PTEN by glycogen synthase kinase 3β. In the mouse model, Skp2 gene deficiency alleviated IMQ-induced psoriasis. Importantly, tamoxifen-induced endothelial-specific Skp2 KO mice developed significantly ameliorated psoriasis with diminished angiogenesis of papillae. Furthermore, topical use of the Skp2 inhibitor C1 effectively prevented the experimental psoriasis.

Conclusions

The Skp2/PTEN axis may play an important role in psoriasis-associated angiogenesis. Thus, targeting Skp2-driven angiogenesis may be a potential approach to treating psoriasis.
Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss
Authors: Alimajstorovic Zerin , Mitchell James L , Yiangou Andreas , Hancox Thomas , Southam Andrew D , Grech Olivia , Ottridge Ryan , Winder Catherine L , Tahrani Abd A , Tan Tricia M , Mollan Susan P , Dunn Warwick B , Sinclair Alexandra J
Published: October 2023

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) n = 7, gastric banding n = 6 or sleeve gastrectomy n = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal-stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. RYGB was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving a reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy.
Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia
Authors: Nóbrega Paulo R , R. B. de Paiva Anderson , Souza Katiane S , de Souza Jorge Luiz B , G. S. B. Lima Pedro Lucas , da Silva Delson José , Pitombeira Milena Sales , Borges Viviennee K , Dias Daniel A , Bispo Luciana M , Santos Carolina F , Freua Fernando , Silva Paulo Diego S , Alves Isabela S , Portella Leonardo B , Cunha Paulina R , Salomao Rubens Paulo A , Pedroso José Luiz , Miyajima Veridiana P , Miyajima Fábio , Cali Elisa , Wade Charles , Sudarsanam Annapurna , O’Driscoll Mary , Hayton Tom , Barsottini Orlando G P , Klebe Stephan , Kok Fernando , Lucato Leandro Tavares , Houlden Henry , Depienne Christel , Lynch David S , Braga-Neto Pedro
Published: October 2023

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.
Functional brain connectivity in young adults with post-stroke epilepsy
Authors: Boot Esther M , Omes Quinty P M , Maaijwee Noortje , Schaapsmeerders Pauline , Arntz Renate M , Rutten-Jacobs Loes C A , Kessels Roy P C , de Leeuw Frank-Erik , Tuladhar Anil M
Published: October 2023

Approximately 1 in 10 young stroke patients (18–50 years) will develop post-stroke epilepsy, which is associated with cognitive impairment. While previous studies have shown altered brain connectivity in patients with epilepsy, little is however known about the changes in functional brain connectivity in young stroke patients with post-stroke epilepsy and their relationship with cognitive impairment. Therefore, we aimed to investigate whether young ischaemic stroke patients have altered functional networks and whether this alteration is related to cognitive impairment. We included 164 participants with a first-ever cerebral infarction at young age (18–50 years), along with 77 age- and sex-matched controls, from the Follow-Up of Transient Ischemic Attack and Stroke patients and Unelucidated Risk Factor Evaluation study. All participants underwent neuropsychological testing and resting-state functional MRI to generate functional connectivity networks. At follow-up (10.5 years after the index event), 23 participants developed post-stroke epilepsy. Graph theoretical analysis revealed functional network reorganization in participants with post-stroke epilepsy, in whom a weaker (i.e. network strength), less-integrated (i.e. global efficiency) and less-segregated (i.e. clustering coefficient and local efficiency) functional network was observed compared with the participants without post-stroke epilepsy group and the controls (P < 0.05). Regional analysis showed a trend towards decreased clustering coefficient, local efficiency and nodal efficiency in contralesional brain regions, including the caudal anterior cingulate cortex, posterior cingulate cortex, precuneus, superior frontal gyrus and insula in participants with post-stroke epilepsy compared with those without post-stroke epilepsy. Furthermore, participants with post-stroke epilepsy more often had impairment in the processing speed domain than the group without post-stroke epilepsy, in whom the network properties of the precuneus were positively associated with processing speed performance. Our findings suggest that post-stroke epilepsy is associated with functional reorganization of the brain network after stroke that is characterized by a weaker, less-integrated and less-segregated brain network in young ischaemic stroke patients compared with patients without post-stroke epilepsy. The contralesional brain regions, which are mostly considered as hub regions, might be particularly involved in the altered functional network and may contribute to cognitive impairment in post-stroke epilepsy patients. Overall, our findings provide additional evidence for a potential role of disrupted functional network as underlying pathophysiological mechanism for cognitive impairment in patients with post-stroke epilepsy.
Dermoscopy as a diagnostic aid in pityriasis lichenoides et varioliformis acuta
Authors: Peñuelas Leal Rodrigo , Labrandero Hoyos Carolina , Grau Echevarría Andrés , Blaya Imbernon Daniel , Finello Malena , Magdaleno Tapial Jorge , Alegre De Miguel Victor
Published: October 2023

Diagnosis of pityriasis lichenoides et varioliformis acuta (PLEVA) is based on the characteristic pattern of lesions in different stages of development, ranging from erythematous maculopapules to papules with a crusted and/or necrotic centre. However, it may raise the differential diagnosis with other entities. It is therefore not uncommon to have to perform skin biopsies to reach a diagnosis, including in infants. In this study, we report the cases of three patients with PLEVA, highlighting the correlations between the clinical, dermoscopic and histological features. Observation of the dermatoscopic findings described, such as punctate or glomerular vessels and erythematous globules surrounding a homogeneous orange or crusty central area, may allow for a rapid diagnosis, avoiding the need for invasive techniques.
Association of autoimmune hepatitis with melanoma and nonmelanoma skin cancer: a case–control study using the All of Us Research Program
Authors: Joshi Tejas P , Dodoo Grace N , Jain Shreya , Sampige Ritu , Thapar Ruhi , Wu Angela X , Zhang Stephanie , Dokic Yelena , Shimizu Ikue
Published: October 2023

The risk of developing melanoma and nonmelanoma skin cancer (NMSC) in patients with autoimmune hepatitis (AIH) has been poorly studied. Here, we use the National Institutes of Health's All of Us Research Program to show that AIH is associated with melanoma and NMSC, an association that persists in multivariate analysis accounting for potential confounders.
Reflectance confocal microscopy as a complementary diagnostic tool for greyish-brown dermatoses in children
Authors: Chen Lixin , Wang Ying , Gao Xibo , Li Qinfeng
Published: October 2023

Mastocytosis, lichen planus pigmentosus (LPP), fixed drug eruption (FDE) and café-au-lait macules (CALM) have a similar appearance, often lead to misdiagnosis and missed diagnoses. At the outpatient clinic at Tianjin Children’s Hospital in 21 patients with mastocytosis, 18 with LPP, 11 with FDE and 12 with CALM we evaluated the characteristics and distinguishing features of their dermatoses using reflectance confocal microscopy (RCM). In mastocytosis, the dermal papillary rings generally had a significantly increased bright refractive index and the superficial dermis was filled with moderate refractive flocculent material. In LPP, the dermal papillary rings were absent and numerous different-sized cellular structures were densely distributed in the superficial dermis. In FDE, the dermal papillary rings were intact with a significantly increased bright refractive index. In CALM, normal dermal papillary rings were detected with a uniformly slightly increased refractive index and no obvious abnormality in the superficial dermis. RCM allows for real-time visualization of the major key diagnostic and distinguishing features of four greyish-brown dermatoses in children.
A Real-World Prospective Cohort Study of Patients With Newly Diagnosed Crohn’s Disease Treated by a Multidisciplinary Team: 1-Year Outcomes
Authors: Yanai Henit , Sharar Fischler Tali , Goren Idan , Eran-Banai Hagar , Ollech Jacob E , Snir Yifat , Broitman Yelena , Barkan Revital , Pfeffer-Gik Tamar , Godny Lihi , Kutokov Yelena , Friedeberg Adi , Pauker Maor H , Rabinowitz Keren Masha , Avni-Biron Irit , Dotan Iris
Published: October 2023

Background

Real-world data on outcomes of patients with newly diagnosed Crohn’s disease (ndCD) is limited. We aimed to assess the achievement of corticosteroid-free clinical remission (CS-free CR) and other therapeutic targets 1 year after diagnosis in a cohort of patients with ndCD treated by a multidisciplinary team (MDT).

Methods

A prospective observational cohort study was conducted on consecutive treatment-naïve adults with ndCD. Patients received management at the treating physician’s discretion, along with a tailored nutritional plan provided by an inflammatory bowel disease (IBD)-oriented dietitian. Patients were guided and educated by an IBD nurse, with flexible communication access to the IBD team. Therapeutic targets were assessed at 1 year. Multivariable logistic regression was used to evaluate predictors of CS-free CR.

Results

Seventy-six patients (50% female) with a median age of 27 (22–39) years were eligible. Over 75% of patients were assessed by IBD-oriented dietitians and the IBD nurse. Within a median of 4.3 (2.5–6.7) months from diagnosis 60.5% initiated biologics (96% anti- tumor necrosis factor). Dietary intervention was applied to 77.6% of the cohort, either monotherapy (33.9%) or add-on (66.1%). At 1 year, 64.5% of patients achieved sustained CS-free CR, 56.6% biochemical remission, 55.8% endoscopic response, 44.2% endoscopic remission, 30.8% deep remission, and in 39.5% there was an improvement in health-related quality of life (HRQoL). Predictors for CS-free CR were uncomplicated phenotype (B1/P0), lower body mass index, and lower patient-reported outcome 2 scores at diagnosis.

Conclusions

In a real-world setting at a tertiary medical center, a cohort of ndCD patients treated by an MDT resulted in favorable 1-year outcomes. Over 60% achieved CS-free CR, along with significant improvements in biomarkers and HRQoL.
DISPEL: database for ascertaining the best medicinal plants to cure human diseases
Authors: Singh Kavya , Maurya Harshit , Singh Parthasarathi , Panda Pujarani , Behera Amit Kumar , Jamal Arshad , Eslavath Ganesh , Mohapatra Somesh , Chauhan Harsh , Sharma Deepak
Published: October 2023

Medicinal plants are anticipated to be one of the most valuable resources for the remedial usage in the treatment of various ailments. The data on key medicinal plants and their therapeutic efficacy against various ailments are quite scattered and not available on a single platform. Moreover, currently there is no means/mechanism of finding the best medicinal plant(s) from numerous plants known to cure any disease. DISPEL (Diseases Plants Eliminate) is a compendium of medicinal plants available across the world that are used to cure infectious as well as non-infectious diseases in humans. The association of a medicinal plant with a disease it cures is hereby referred to as ‘medicinal plant–disease cured’ linkage. The DISPEL database hosts ∼60 000 ‘medicinal plant–disease cured’ linkages encompassing ∼5500 medicinal plants and ∼1000 diseases. This platform provides interactive and detailed visualization of medicinal plants, diseases and their relations using comprehensible network graph representation. The user has the freedom to search the database by specifying the name of disease(s) as well as the scientific/common name(s) of plant. Each ‘medicinal plant–disease cured’ relation is scored based on the availability of any medicine/product derived from that medicinal plant, information about active compound(s), knowledge regarding the part of plant that is effective and number of distinct articles/books/websites confirming the effectiveness of the medicinal plant. The user can find the best plant(s) that can be used to cure any desired disease(s). The DISPEL database is the first step towards generating the ‘most-effective’ combination of plants to cure a disease since it delineates as well as ranks all the therapeutic medicinal plants for that disease. The combination of best medicinal plants can then be used to conduct clinical trials and thus pave the way for their use in clinics for treatment of diseases.

Database URL https://compbio.iitr.ac.in/dispel
Association between non-alcoholic fatty liver disease and subclinical left ventricular dysfunction in the general population
Authors: Hirose Kazutoshi , Nakanishi Koki , Di Tullio Marco R , Homma Shunichi , Sawada Naoko , Yoshida Yuriko , Hirokawa Megumi , Koyama Katsuhiro , Kimura Koichi , Nakao Tomoko , Daimon Masao , Morita Hiroyuki , Kurano Makoto , Komuro Issei
Published: October 2023

Aims

Emerging evidence suggests an association between non-alcoholic fatty liver disease (NAFLD) and heart failure (HF). We investigated the relationship between NAFLD and left ventricular (LV) functional remodelling in a general population sample without overt cardiac and liver disease.

Methods and results

We included 481 individuals without significant alcohol consumption who voluntarily underwent an extensive cardiovascular health check. The fatty liver index (FLI) was calculated for each participant, and NAFLD was defined as FLI ≥ 60. All participants underwent 2D transthoracic echocardiography; LV global longitudinal strain (LVGLS) was assessed with speckle-tracking analysis. Univariable and multivariable linear regression models were constructed to investigate the possible association between NAFLD and LVGLS. Seventy-one (14.8%) participants were diagnosed with NAFLD. Individuals with NAFLD exhibited larger LV size and LV mass index than those without NAFLD, although left atrial size and E/e′ ratio did not differ between groups. Left ventricular global longitudinal strain was significantly reduced in participants with vs. without NAFLD (17.1% ± 2.4% vs. 19.5% ± 3.1%, respectively; P < 0.001). The NAFLD group had a significantly higher frequency of abnormal LVGLS (<16%) than the non-NAFLD group (31.0% vs. 10.7%, respectively; P < 0.001). Multivariable linear regression analysis demonstrated that higher FLI score was significantly associated with impaired LVGLS independent of age, sex, conventional cardiovascular risk factors, and echocardiographic parameters (standardized β −0.11, P = 0.031).

Conclusion

In the general population without overt cardiac and liver disease, the presence of NAFLD was significantly associated with subclinical LV dysfunction, which may partly explain the elevated risk of HF in individuals with NAFLD.
Health-promoting lifestyle and life satisfaction in full-time employed adults with congenital heart disease: grit as a mediator
Authors: Liu Yu-Shiu , Lu Chun-Wei , Chung Hung-Tao , Wang Jou-Kou , Su Wen-Jen , Chen Chi-Wen
Published: October 2023

Aims

Enhancing life satisfaction is vital for adults with congenital heart disease (ACHD). Life satisfaction potentially correlates with a health-promoting lifestyle and grit. However, the mediating role of grit—a trait marked by perseverance and long-term goal-oriented passion—between a health-promoting lifestyle and life satisfaction in ACHD remains unverified. This study aimed to examine the relationships between health-promoting lifestyle, grit, and life satisfaction in full-time employed ACHD and to confirm the mediating role of grit.

Methods and results

A total of 181 full-time employed ACHD aged 20–59 years with patient-reported New York Heart Association classes I–IV were recruited from two medical centres in northern Taiwan. Participants completed questionnaires, including the short version of the Chinese Health-Promoting Lifestyle Profile Scale, Grit-10 Scale, and Satisfaction with Life Scale between February and December 2022. Data analysis employed the Hayes PROCESS macro. Health-promoting lifestyle, grit, and life satisfaction were discovered to be positively correlated. Overall grit score was a partial mediator between a health-promoting lifestyle and life satisfaction, accounting for 20% of the total variation. Of the grit domains, perseverance served as a partial mediator between a health-promoting lifestyle and life satisfaction, accounting for 32% of the total variation, whereas passion had a nonsignificant mediation effect.

Conclusion

A health-promoting lifestyle boosts ACHD individuals’ life satisfaction through grit, particularly perseverance. Integrating grit into such a lifestyle could benefit from comprehending support systems and influential factors aiding grit development for enhanced life satisfaction.
Germline mutation rate is elevated in young and old parents in Caenorhabditis remanei
Authors: Chen Hwei-yen , Krieg Therese , Mautz Brian , Jolly Cécile , Scofield Douglas , Maklakov Alexei A , Immler Simone
Published: October 2023

The effect of parental age on germline mutation rate across generations is not fully understood. While some studies report a positive linear relationship of mutation rate with increasing age, others suggest that mutation rate varies with age but not in a linear fashion. We investigated the effect of parental age on germline mutations by generating replicated mutation accumulation lines in Caenorhabditis remanei at three parental ages (“Young T1” [Day 1], “Peak T2” [Day 2], and “Old T5” [Day 5] parents). We conducted whole-genome resequencing and variant calling to compare differences in mutation rates after three generations of mutation accumulation. We found that Peak T2 lines had an overall reduced mutation rate compared to Young T1 and Old T5 lines, but this pattern of the effect varied depending on the variant impact. Specifically, we found no high-impact variants in Peak T2 lines, and modifiers and up- and downstream gene variants were less frequent in these lines. These results suggest that animals at the peak of reproduction have better DNA maintenance and repair compared to young and old animals. We propose that C. remanei start to reproduce before they optimize their DNA maintenance and repair, trading the benefits of earlier onset of reproduction against offspring mutation load. The increase in offspring mutation load with age likely represents germline senescence.
Impact of Heat Stress on Transposable Element Expression and Derived Small RNAs in Drosophila subobscura
Authors: Bodelón Alejandra , Fablet Marie , Siqueira de Oliveira Daniel , Vieira Cristina , García Guerreiro Maria Pilar
Published: October 2023

Global warming is forcing insect populations to move and adapt, triggering adaptive genetic responses. Thermal stress is known to alter gene expression, repressing the transcription of active genes, and inducing others, such as those encoding heat shock proteins. It has also been related to the activation of some specific transposable element (TE) families. However, the actual magnitude of this stress on the whole genome and the factors involved in these genomic changes are still unclear. We studied mRNAs and small RNAs in gonads of two Drosophila subobscura populations, considered a good model to study adaptation to temperature changes. In control conditions, we found that a few genes and TE families were differentially expressed between populations, pointing out their putative involvement in the adaptation of populations to their different environments. Under heat stress, sex-specific changes in gene expression together with a trend toward overexpression, mainly of heat shock response-related genes, were observed. We did not observe large changes of TE expression nor small RNA production due to stress. Only population and sex-specific expression changes of some TE families (mainly retrotransposons), or the amounts of siRNAs and piRNAs, derived from specific TE families were observed, as well as the piRNA production from some piRNA clusters. Changes in small RNA amounts and TE expression could not be clearly correlated, indicating that other factors as chromatin modulation could also be involved. This work provides the first whole transcriptomic study including genes, TEs, and small RNAs after a heat stress in D. subobscura.
Development and Validation of a Revised Ambivalent Ageism Scale for Use in the Health Care Sector: The AAShc
Authors: D’hondt Sylvie , Aujoulat Isabelle , Degryse Jean-Marie
Published: October 2023

Background and Objectives

The aim of this study was to adapt and validate the Ambivalent Ageism Scale (AAS) among paramedical students for use in the health care sector.

Research Design and Methods

A cross-sectional study was conducted among the following paramedical students: physiotherapy, occupational therapy, and nursing students. A total of 6 items were added based on the literature and the scale was evaluated by students and professors with experience working with older adults. The following psychometric properties were evaluated: internal consistency, concurrent validity, structural validity (exploratory factor analysis), and reliability.

Results

A total of 265 students participated: 19.2% physiotherapy students, 27.5% occupational therapy students, 50.6% nursing students, and 2.6% other paramedical students. The concurrent validity study showed a significant correlation between AAShc (Ambivalent Ageism Scale in the health care sector) and UCLA-GAS-F (French version of the University of California, Los Angeles Geriatric Attitudes Scale) with r (265) = 0.491 (p < .001). The factor analyses produced an 18-item (α = 0.866) scale composed of 5 factors: Infantilization (5 items, α = 0.766), Control (2 items, α = 0.789), Overaccommodation (2 items, α = 0.829), Unwanted help (2 items, α = 0.656), and Hostile Ageism (7 items, α = 0.717). Finally, the generalizability analysis revealed a G-coefficient of 0.86, a Phi-coefficient of 0.83, and a standard error of measurement of 2.31%.

Discussion and Implications

The AAShc appears to be a valid and reliable scale to measure ageism among paramedical students. This scale can be a useful tool to reduce ageism toward older adults in the health care sector.
GERONIMO: A tool for systematic retrieval of structural RNAs in a broad evolutionary context
Authors: Kilar Agata M , Fajkus Petr , Fajkus Jiří
Published: October 2023

Background

While web-based tools such as BLAST have made identifying conserved gene homologs appear easy, genes with variable sequences pose significant challenges. Functionally important noncoding RNAs (ncRNA) often show low sequence conservation due to genetic variations, including insertions and deletions. Rather than conserved sequences, these RNAs possess highly conserved structural features across a broad phylogenetic range. Such features can be identified using the covariance models approach, which combines sequence alignment with a secondary RNA structure consensus. However, running standard implementation of that approach (Infernal) requires advanced bioinformatics knowledge compared to user-friendly web services like BLAST. The issue is partially addressed by RNAcentral, which can be used to search for homologs across a broad range of ncRNA sequence collections from diverse organisms but not across the genome assemblies.

Results

Here, we present GERONIMO, which conducts evolutionary searches across hundreds of genomes in a fully automated way. It provides results extended with taxonomy context, as summary tables and visualizations, to facilitate analysis for user convenience. Additionally, GERONIMO supplements homologous sequences with genomic regions to analyze promoter motifs or gene collinearity, enhancing the validation of results.

Conclusion

GERONIMO, built using Snakemake, has undergone extensive testing on hundreds of genomes, establishing itself as a valuable tool in the identification of ncRNA homologs across diverse taxonomic groups. Consequently, GERONIMO facilitates the investigation of the evolutionary patterns of functionally significant ncRNA players, whose understanding has previously been limited to individual organisms and close relatives.
Katdetectr: an R/bioconductor package utilizing unsupervised changepoint analysis for robust kataegis detection
Authors: Hazelaar Daan M , van Riet Job , Hoogstrate Youri , van de Werken Harmen J G
Published: October 2023

Background

Kataegis refers to the occurrence of regional genomic hypermutation in cancer and is a phenomenon that has been observed in a wide range of malignancies. A kataegis locus constitutes a genomic region with a high mutation rate (i.e., a higher frequency of closely interspersed somatic variants than the overall mutational background). It has been shown that kataegis is of biological significance and possibly clinically relevant. Therefore, an accurate and robust workflow for kataegis detection is paramount.

Findings

Here we present Katdetectr, an open-source R/Bioconductor-based package for the robust yet flexible and fast detection of kataegis loci in genomic data. In addition, Katdetectr houses functionalities to characterize and visualize kataegis and provides results in a standardized format useful for subsequent analysis. In brief, Katdetectr imports industry-standard formats (MAF, VCF, and VRanges), determines the intermutation distance of the genomic variants, and performs unsupervised changepoint analysis utilizing the Pruned Exact Linear Time search algorithm followed by kataegis calling according to user-defined parameters.

We used synthetic data and an a priori labeled pan-cancer dataset of whole-genome sequenced malignancies for the performance evaluation of Katdetectr and 5 publicly available kataegis detection packages. Our performance evaluation shows that Katdetectr is robust regarding tumor mutational burden and shows the fastest mean computation time. Additionally, Katdetectr reveals the highest accuracy (0.99, 0.99) and normalized Matthews correlation coefficient (0.98, 0.92) of all evaluated tools for both datasets.

Conclusions

Katdetectr is a robust workflow for the detection, characterization, and visualization of kataegis and is available on Bioconductor: https://doi.org/doi:10.18129/B9.bioc.katdetectr.
Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors
Authors: Orozco-Moreno Margarita , Visser Eline A , Hodgson Kirsty , Hipgrave Ederveen Agnes L , Bastian Kayla , Goode Emily Archer , Öztürk Özden , Pijnenborg Johan F A , Eerden Nienke , Moons Sam J , Rossing Emiel , Wang Ning , de Haan Noortje , Büll Christian , Boltje Thomas J , Munkley Jennifer
Published: October 2023

Aberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumor progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumor-associated glycans are currently being tested in clinical trials for several tumor types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumor pathology and may pave the way for the development of new therapies for prostate cancer.
Balancing the Basics
Authors: Carey Mary , Knowles Cathy
Published: October 2023

This chapter looks into balancing the basics of financial statements. It defines the statement of profit or loss, the statement of financial position, and the statement of cash flows as the three financial statements that make a set of accounts. Then, the chapter discusses the layout of the statement of financial position which shows the finance of a business's assets and liabilities. It includes the payment options recorded on a trial balance. This is called accrual and prepayment. The chapter highlights how the historic cost concept is indisputable since it requires transactions to be recorded at their original cost to the business. The going concern concept, as the chapter argues, raises the assumption that the business will continue operations in the foreseeable future.
Financial Accounting
Authors: Carey Mary , Knowles Cathy
Published: October 2023

Hotel Chocolat is a premium chocolate brand, manufacturing and selling their chocolates through their stores, online and direct to customers via subscription. They have 104 stores in the UK, nine international stores and one boutique hotel in St Lucia, where they also own a cocoa...
Budgeting
Authors: Carey Mary , Knowles Cathy
Published: October 2023

This chapter highlights the significance of budgeting. It describes the process of preparing a budget, citing benefits such as planning, coordination, communication, and authorization. The chapter explains that an incremental budget is calculated by taking the previous year's actual figures and adjusting for changes like price inflation, while zero-based budgets calculate every number from scratch. The chapter also outlines a criticism of top down budgets and bottom up budgets. It also looks into the purpose of simple variance analysis. Next, the chapter mentions how budgeting is conducted to monitor the performance of variance and flexible budgeting. It cites the principles of variance analysis.
Pricing and Costs
Authors: Carey Mary , Knowles Cathy
Published: October 2023

This chapter discusses pricing and costs. It cites how various methods of costing can affect pricing. The chapter shows equations used to calculate prices using cost-plus, sales-margin, and discount methods. It notes how various pricing strategies can be used, including how target costing and life-cycle costing can impact product pricing. Additionally, cost-plus pricing is the method of pricing a product with a standard mark-up, while margin pricing is based on a standard margin linked to the selling price. The chapter explains the calculation of internal transfer prices. The chapter looks at concepts of discounts and distribution margins.
Understanding Financial Accounting
Authors: Winfield Jimmy , Graham Mark , Miller Taryn
Published: October 2023

Understanding Financial Accounting focuses on how to extract information that will contribute to business decision making. A recurring case study, contextual examples, and real-world financial statements from multinational companies are included, demonstrating the principles in practice. The text consists of fourteen chapters. The first looks at financial accounting in context. The basics are then covered. Next, the text looks at income and expenses, cash flows, assets, and liabilities. There's a chapter on leases, foreign exchange, and deferred tax. Then the chapters move on to look at group financial statements, equity, financial analysis, and business valuations. Finally, there are chapters on creative accounting and trends in corporate reporting.
The technological regime and barriers to entry
Authors: Lee Sung Hoon
Published: October 2023

The impact of the technological regime, defined in terms of appropriability, cumulativeness, and opportunity conditions on firms, has been examined in multiple studies. Within the analysis of technological regimes, firm entry has been of consistent interest due to its implications on competition and how firms may decide to enter an industry. However, studies show that two sources of nonlinearities warrant closer inspection, which could be achieved by looking at the entry of individual firms. The first is the interaction effects of the various dimensions of technological regimes. Their relevance is supported by both theoretical and empirical evidence, the analysis of which could be valuable for identifying the mechanisms behind the relationship between the technological regime and firm entry. Another is the role heterogeneity among entrants plays on the impact of the technological regime on firm entry, which has been found to be an important factor in many other aspects of firm behavior. This study thus aims to examine these two sources of nonlinearities, which can have significant implications for both firm strategy and policy.
Minimizing CM Degree and Specially K-stable Varieties
Authors: Hattori Masafumi
Published: October 2023

We prove that the degree of the CM line bundle for a normal family over a curve with fixed general fibers is strictly minimized if the special fiber is either a smooth projective manifold with a unique cscK metric or “specially K-stable”, which is a new class we introduce in this paper. This phenomenon, as conjectured by Odaka (cf., [ 46]), is a quantitative strengthening of the separatedness conjecture of moduli spaces of polarized K-stable varieties. The above-mentioned special K-stability implies the original K-stability and a lot of cases satisfy it, for example, K-stable log Fano, klt Calabi-Yau (i.e., $K_{X}\equiv 0$), lc varieties with the ample canonical divisor and uniformly adiabatically K-stable klt-trivial fibrations over curves (cf., [ 27]).
Melting the Archive: The Irreconcilable Cover Song and Rock’s Recorded History
Authors: Rings Michael
Published: October 2023

In this article, I consider a set of curious cases from the world of rock music: putative “cover versions” that differ from their corresponding canonical tracks to such an extent that it seems doubtful whether they even count as performances of the same songs. Though I address the ontological question of how or whether these tracks could be classified as actual cover songs, in this paper I am more concerned with the evaluative question of how we should attempt to appreciate them as such (as we are invited to do, I argue, according to the recordings’ metatextual cues). I will argue that these irreconcilable covers, as I call them, are best appreciated as conceptual artworks that function in a manner somewhat analogous to how Arthur Danto argues that Andy Warhol’s famed Brillo Box sculptures function; prompting us to reflect on the nature of art (and non-art). Through adopting a strategy that is, in some respects, the inverse of Warhol’s, these covers make a similar invitation to listeners to consider the nature of rock covers and covering practices, and to reflect on the stances that we—listeners and artists alike—might take in relation to rock’s past and its ever-available recorded archive.