bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel thrombocytopenia‐4‐causing CYCS gene variant decreases caspase activity: Three‐generation study
Authors: Štika Jiří , Pešová Michaela , Kozubík Kateřina Staňo , Skalníková Magdalena , Dostálová Lenka , Loja Tomáš , Radová Lenka , Palušová Veronika , Réblová Kamila , Vrzalová Zuzana , Blaháková Ivona , Trizuljak Jakub , Uldrijan Stjepan , Blatný Jan , Šmída Michal , Pospíšilová Šárka , Doubek Michael 
Published: August 2024

SummaryThe CYCS gene is highly evolutionarily conserved, with only a few pathogenic variants that cause thrombocytopenia‐4 (THC4). Here, we report a novel CYCS variant NM_018947.6: c.59C>T [NP_061820.1:p.(Thr20Ile)] segregating with thrombocytopenia in three generations of a Czech family. The phenotype of the patients corresponds to THC4 with platelets of normal size and morphology and dominant inheritance. Intriguingly, a gradual decline in platelet counts was observed across generations. CRISPR/Cas9‐mediated gene editing was used to introduce the new CYCS gene variant into a megakaryoblast cell line (MEG‐01). Subsequently, the adhesion, shape, size, ploidy, viability, mitochondrial respiration, cytochrome c protein (CYCS) expression, cell surface antigen expression and caspase activity were analysed in cells carrying the studied variant. Interestingly, the variant decreases the expression of CYCS while increasing mitochondrial respiration and the expression of CD9 cell surface antigen. Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants. Some reports indicate that caspases may be involved in thrombopoiesis; thus, the observed dysregulation of caspase activity might contribute to thrombocytopenia. The findings significantly enhance our understanding of the molecular mechanisms underlying inherited thrombocytopenia and may have implications for diagnosis, prognosis and future targeted therapies.
Incorporation mutational profile might reduce the importance of blast count in prognostication of low‐risk myelodysplastic syndromes
Authors: García‐Culebras Marta , Alcalde Patricia , Márquez‐Malaver Francisco J. , Carrillo Estrella , Soria Elena , Prats Concepción , Morales Rosario , Vargas María T. , Pérez‐Simón Jose Antonio , Falantes Jose F. 
Published: August 2024

SummaryAddition of molecular data to prognostic models has improved risk stratification of myelodysplastic neoplasms (MDS). However, the role of molecular lesions, particularly in the group of low‐risk disease (LR‐MDS), is uncertain. We evaluated a set of 227 patients with LR‐MDS. Overall survival (OS) and probability of leukaemic progression were the main endpoints. RUNX1 was associated with lower OS and SF3B1 with a reduced risk of death (HR: 1.7, 95% CI, 1.1–2.9; p = 0.05; and HR: 0.23, 95% CI 0.1–0.5; p < 0.001; respectively). TP53 and RUNX1 mutations were predictive covariates for the probability of leukaemic progression (p < 0.001). Blast percentage, neither analysed as categorical (<5% vs. 5%–9%; HR: 1.3, 95% CI, 0.7–2.9; p = 0.2) nor as a continuous variable (HR: 1.07, 95% CI, 0.9–1.1; p = 0.07), had impact on survival or probability of progression (sHR: 1.05, 95% CI, 0.9–1.1; p = 0.2). These results retained statistical significance when analysis was restricted to the definition of LR‐MDS according to the WHO 2022 and ICC classifications (<5% blasts). Thus, with the incorporation of molecular data, blast percentage happens to lose clinical significance both for survival and probability of progression in the group of patients with LR‐MDS.
WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia
Authors: Xu Nan , Dao Feng‐Ting , Shi Zong‐Yan , Sun Kai , Qin Ya‐Zhen 
Published: August 2024

SummaryWilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low WT1 expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with RUNX1::RUNX1T1, whereas it had an opposite role in AML with non‐favourable cytogenetic risk (RUNX1::RUNX1T1‐deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of WT1 in AML remains unknown. In the present study, first we validated the prognostic significance of WT1 expression in AML. Then by using the established transfected cell lines and xenograft tumour model, we found that WT1 suppresses proliferation and enhances effect of cytarabine in RUNX1::RUNX1T1(+) AML but has opposite functions in AML cells without RUNX1::RUNX1T1. Furthermore, as a transcription factor, WT1 physically interacts with RUNX1::RUNX1T1 and acts as a co‐factor together with RUNX1::RUNX1T1 to activate the expression of its target gene DUSP6 to dampen extracellular signal‐regulated kinase (ERK) activity. When RUNX1::RUNX1T1‐deficient, WT1 can activate the mitogen‐activated extracellular signal‐regulated kinase/ERK axis but not through targeting DUSP6. These results provide a mechanism by which WT1 together with RUNX1::RUNX1T1 suppresses cell proliferation through WT1/DUSP6/ERK axis in AML. The current study provides an explanation for the controversial prognostic significance of WT1 expression in AML patients.
Palaeogeography and 3D variability of a dynamically uplifted shelf: Observations from seismic stratigraphy of the Palaeocene East Shetland Platform
Authors: Valore Lucas Albanese , Sømme Tor Oftedal , Patruno Stefano , Robin Cécile , Guillocheau François , Eide Christian Haug 
Published: August 2024

AbstractIn the Palaeocene North Sea, pulses in turbidite fan deposition and shelfal progradation have been correlated with episodes of regional uplift caused by a precursor of the Icelandic Plume. In the East Shetland Platform, the specific impacts of dynamic uplift on the regional palaeogeographic evolution are less understood. Using new, high‐resolution 3D seismic data from an underexplored proximal area, we investigate the palaeogeography of the East Shetland Platform in terms of the extent and timing of erosion versus deposition, focusing on how these can be used to reconstruct changes in relative sea‐level along strike. Using a combination of well data, clinoform‐based seismic stratigraphy and seismic attribute analysis of >60,000 km2 of 3D data, we have obtained palaeogeographic maps of multiple Palaeocene to Early Eocene units, with high temporal resolution for the Late Palaeocene–Early Eocene Moray Group. This includes six unconformity‐bounded units marked by prograding clinoforms of the Dornoch Formation, which are covered by backstepping sequences of the Beauly Member (Balder Formation). Temporal and spatial changes in the distribution of downdip depocentres and updip unconformities indicate strong lateral variability in patterns of shelf accommodation/erosion and local sediment supply. This results from a complex interplay among laterally uneven relative sea‐level fall, inherited topography, time‐varied sediment entry point distribution and along‐shore sediment transport regimes. Unconformities and palaeogeographic maps suggest a first‐order control on erosion and sediment distribution promoted by the transiently and differentially uplifted topography of Shetland, which is characterized by an anomalous erosive history in the Bressay High, in the centre of our study area, where the Lower Dornoch Formation has been eroded and marked fluvial incision is observed. Ultimately, results indicate shorter‐wavelength and shorter‐period variations in uplift than what is typically assumed for dynamic topography, perhaps as a result of additional modulation by lithospheric structures or influence of previous rift‐related faults.
Non‐immune hydrops fetalis is associated with bi‐allelic pathogenic variants in the MYB Binding Protein 1a (MYBBP1A) gene
Authors: Tenorio‐Castano Jair , Mansilla Aparicio Elena , García Santiago Fe Amalia , Klotz Cherise M. , Regojo Rita María , Anguita Estefanía , Ryan Erin , Juusola Jane , Herrero Beatriz , Arias Pedro , Parra Alejandro , Pascual Patricia , Gallego Natalia , Cazalla Mario , Rodriguez‐González Roberto , Antolín Eugenia , Nevado Julián , Ruiz‐Perez Víctor L. , Lapunzina Pablo 
Published: August 2024

AbstractNon‐immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF.
Fish oil supplementation in relation to the risk of chronic kidney disease among patients with diabetes
Authors: Ao Yang , Ye Hao , Liu Xiaohui , Li Yin , Liu Haoyin , Ye Shu , Hu Yepeng , Zhuang Pan , Zhang Yu , Zheng Chao , Jiao Jingjing 
Published: August 2024

AbstractAimTo investigate the association between fish oil supplementation and subsequent risk of chronic kidney disease (CKD) among patients with diabetes, and further evaluate the mediation effect of typical glycolipid and inflammatory biomarkers.MethodsIn total, 24 497 patients with diabetes from the UK Biobank were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD risk, and the rate advancement period was calculated to quantify and communicate the impact of fish oil upon that risk. In addition, we also used mediation analysis to assess the mediating role of plasma biomarkers.ResultsOverall, 7122 patients reported taking fish oil supplements. During a mean of 11.3 years of follow‐up, 3533 CKD cases occurred. In the fully adjusted model, fish oil use was inversely associated with the incidence of CKD (HR 0.90; 95% CI: 0.83, 0.97), which was mediated by serum levels of HbA1c (4.7%), C‐reactive protein (CRP) (3.4%) and high‐density lipoprotein cholesterol (HDL‐C) (2.3%). Participants who took fish oil supplements displayed the same risk of CKD events, but that risk was delayed by approximately 2.79 years compared with non‐users of fish oil.ConclusionsOur findings advocate the beneficial role of fish oil use in preventing CKD among patients with diabetes, which may be mediated by serum levels of HbA1c, CRP and HDL‐C, and support public health policies aiming to promote fish oil supplementation for the prevention of diabetes complications.
Use of continuous glucose monitoring when initiating glucagon‐like peptide‐1 receptor agonist therapy in insulin‐treated diabetes
Authors: Hirsch Irl B. , Parkin Christopher G. , Cavaiola Tricia Santos , Bergenstal Richard M. 
Published: August 2024

AbstractGlucagon‐like peptide‐1 receptor agonist (GLP‐1RA) medications have been shown to be effective in achieving optimal glucose control and reducing all‐cause death, cardiovascular death, nonfatal myocardial infarction, hospitalization for heart failure, and end‐stage kidney disease in individuals with type 1 (T1D) and type 2 diabetes (T2D). However, use of these medications has been associated with increased hypoglycaemia risk in patients treated with concomitant antihyperglycaemic medications. The risk is particularly high in patients with T1D due to their loss of glucagon counter‐regulatory response. This article reviews the effect of GLP‐1RA formulations on the development of hypoglycaemia in individuals with T1D and T2D treated with insulin therapy, discusses the benefits of continuous glucose monitoring with GLP‐1RA treatment, and presents strategies for safely initiating GLP‐1RA therapy in these individuals.
Health‐related quality of life of people with type 1 diabetes: An IMI2 SOPHIA post hoc analysis of FUTURE and ADJUNCT‐ONE
Authors: Steenackers Nele , Sparsø Thomas , Charleer Sara , De Block Christophe , De Cock Diederik , Delfin Carl , Mathieu Chantal , Nobels Frank , Pazmino Sofia , Rosen Jonathan , del Pozo Carmen Hurtado , Gillard Pieter , Van der Schueren Bart 
Published: August 2024

AbstractAimTo characterize and stratify health‐related quality of life in individuals with type 1 diabetes (T1D) using body mass index (BMI) and clustering analysis.Material and MethodsBaseline data on individuals with T1D were pooled from two studies. A post hoc analysis of health‐related quality of life, measured using the 36‐item Short‐Form questionnaire, was performed, referenced to the 2010 US general population. Descriptive statistics were presented for the pooled cohort and per BMI category. K‐means clustering was performed. One‐way analysis of variance was conducted to examine differences in clinical characteristics between clusters.ResultsThe pooled cohort consisted of 2256 individuals with T1D (age: 45.4 ± 15.0 years, BMI: 26.2 ± 4.6 kg/m2, diabetes duration: 22.7 ± 13.5 years). All quality‐of‐life domains were slightly lower than 50(the general population's mean), except for vitality. Individuals with a BMI ≥30 kg/m2 reported lower scores for bodily pain, physical functioning, general health, and vitality. A first cluster with a high and a second cluster with a low quality of life were identified, with significant differences in the mental (Cluster 1: 53.8 ± 6.8 vs. Cluster 2: 39.5 ± 10.7; p < 0.001) and physical component summary scores (Cluster 1: 49.6 ± 6.3 vs. Cluster 2: 35.2 ± 12.0; p < 0.001), which exceeded differences found between BMI categories.ConclusionsIn our population of people living with T1D, higher BMI may have adversely impacted physical domains of quality of life, but larger differences between the high‐ and low‐quality‐of‐life cluster indicate that more factors play a role.
Achieving normoglycaemia with tirzepatide: Post hoc exploratory analysis of the SURPASS J‐mono and J‐combo studies
Authors: Fujihara Kazuya , Matsubayashi Yasuhiro , Kitazawa Masaru , Sato Takaaki , Takeuchi Masakazu , Oura Tomonori , Sone Hirohito 
Published: August 2024

AbstractAimNormoglycaemia was achieved in a significant proportion of Japanese participants with type 2 diabetes in two phase 3 studies of tirzepatide. This post hoc exploratory analysis aimed to identify predictive factors associated with normoglycaemia achievement.Materials and MethodsSURPASS J‐mono and SURPASS J‐combo study data were pooled for this analysis. Characteristics of participants in whom normoglycaemia [glycated haemoglobin (HbA1c) <5.7%] was achieved were summarized. Logistic regression analyses were performed with HbA1c <5.7% achievement as the target variable.ResultsOf 912 participants, normoglycaemia was achieved in 553 (60.6%) following 52 weeks of tirzepatide treatment. Overall, the mean (SD) age was 56.7 (10.6) years and mean diabetes duration was 7.7 (6.0) years, and 76% of participants were men. Mean (SD) change from baseline in HbA1c and bodyweight was −2.87% (0.95) versus −2.47% (1.1) and −10.30 (5.8) kg versus −3.75 (4.3) kg for participants in whom normoglycaemia was and was not reached, respectively. Multivariate regression analyses showed that lower baseline body mass index, shorter disease duration and lower baseline HbA1c were significantly associated with higher rates of normoglycaemia achievement (p = 0.009, p = 0.008, p < 0.001, respectively) as was a tirzepatide dose of 10 or 15 mg compared with 5 mg (p < 0.001). The highest percentage of participants in whom normoglycaemia (94%) was achieved were those with lower baseline HbA1c (<8%) and the greatest weight reduction (≥15%).ConclusionsBaseline HbA1c and body mass index, disease duration and the tirzepatide treatment group were shown to be predictive factors for achieving normoglycaemia. A lower baseline HbA1c was most strongly associated with normoglycaemia achievement.
Elucidating the role of weight loss and glycaemic control in patients with type 2 diabetes
Authors: Sharma Anukriti , Mariam Arshiya , Zacherle Emily , Milinovich Alex , Bauman Janine , Sugano David S. , Noone Josh , Rajpura Jigar R. , Zimmerman Robert S. , Burguera Bartolome , Kattan Michael W. , Misra‐Hebert Anita D. , Pantalone Kevin M. , Rotroff Daniel M. 
Published: August 2024

AbstractAimsTo investigate the independent contributions of glycated haemoglobin (HbA1c) reduction and weight loss to clinical outcomes in patients with type 2 diabetes (T2D) treated with antidiabetic drugs, including glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs).Materials and MethodsThis observational, retrospective cohort study used deidentified electronic health record‐derived data from patients evaluated at the Cleveland Clinic (1 January 2000–31 December 2020). Cohort A included 8876 patients with newly diagnosed T2D treated with any of six antidiabetic drug classes. Cohort B included 4161 patients with T2D initiating GLP‐1RA treatment. The effects of body mass index (BMI) and HbA1c reduction, variability, and durability on clinical outcomes were investigated.ResultsIn Cohort A, each 1% BMI reduction was associated with 3%, 1%, and 4% reduced risk of heart failure (p = 0.017), hypertension (p = 0.006), and insulin initiation (p = 0.001), respectively. Each 1% (~11 mmol/mol) HbA1c reduction was associated with 4% and 29% reduced risk of hypertension (p = 0.041) and insulin initiation (p = 0.001), respectively. In Cohort B, each 1% BMI reduction was associated with 4% and 3% reduced risk of cardiovascular disease (p = 0.008) and insulin initiation (p = 0.002), respectively. Each 1% (~11 mmol/mol) HbA1c reduction was associated with 4% and 16% reduced risk of chronic kidney disease (p = 0.014) and insulin initiation (p = 1 × 10−4), respectively. Lower BMI variability and greater BMI durability were associated with decreased risk of clinical outcomes in both cohorts.ConclusionsAntidiabetic medication‐associated, and specifically GLP‐1RA‐associated, weight loss and HbA1c reductions independently reduce real‐world clinical outcome risk.
Real‐time fMRI neurofeedback of the anterior insula using arterial spin labelling
Authors: Grössinger Doris , Spann Stefan M. , Stollberger Rudolf , Pfeuffer Josef , Koten Jan Willem , Wood Guilherme 
Published: August 2024

AbstractArterial spin labelling (ASL) is the only non‐invasive technique that allows absolute quantification of perfusion and is increasingly used in brain activation studies. Contrary to the blood oxygen level‐dependent (BOLD) effect ASL measures the cerebral blood flow (CBF) directly. However, the ASL signal has a lower signal‐to‐noise ratio (SNR), than the BOLD signal, which constrains its utilization in neurofeedback studies. If successful, ASL neurofeedback can be used to aid in the rehabilitation of health conditions with impaired blood flow, for example, stroke. We provide the first ASL‐based neurofeedback study incorporating a double‐blind, sham‐controlled design. A pseudo‐continuous ASL (pCASL) approach with background suppression and 3D GRASE readout was combined with a real‐time post‐processing pipeline. The real‐time pipeline allows to monitor the ASL signal and provides real‐time feedback on the neural activity to the subject. In total 41 healthy adults (19–56 years) divided into three groups underwent a neurofeedback‐based emotion imagery training of the left anterior insula. Two groups differing only in the explicitness level of instruction received real training and a third group received sham feedback. Only those participants receiving real feedback with explicit instruction showed significantly higher absolute CBF values in the trained region during neurofeedback than participants receiving sham feedback. However, responder analyses of percent signal change values show no differences in activation between the three groups. Persisting limitations, such as the lower SNR, confounding effects of arterial transit time and partial volume effects still impact negatively the implementation of ASL neurofeedback.
Conditioning‐ and reward‐related dendritic and presynaptic plasticity of nucleus accumbens neurons in male and female sign‐tracker rats
Authors: Colom Morgane , Kraev Igor , Stramek Agata K. , Loza Iwona B. , Rostron Claire L. , Heath Christopher J. , Dommett Eleanor J. , Singer Bryan F. 
Published: August 2024

AbstractFor a subset of individuals known as sign‐trackers, discrete Pavlovian cues associated with rewarding stimuli can acquire incentive properties and exert control over behaviour. Because responsiveness to cues is a feature of various neuropsychiatric conditions, rodent models of sign‐tracking may prove useful for exploring the neurobiology of individual variation in psychiatric vulnerabilities. Converging evidence points towards the involvement of dopaminergic neurotransmission in the nucleus accumbens core (NAc) in the development of sign‐tracking, yet whether this phenotype is associated with specific accumbal postsynaptic properties is unknown. Here, we examined dendritic spine structural organisation, as well as presynaptic and postsynaptic markers of activity, in the NAc core of male and female rats following a Pavlovian‐conditioned approach procedure. In contrast to our prediction that cue re‐exposure would increase spine density, experiencing the discrete lever‐cue without reward delivery resulted in lower spine density than control rats for which the lever was unpaired with reward during training; this effect was tempered in the most robust sign‐trackers. Interestingly, this same behavioural test (lever presentation without reward) resulted in increased levels of a marker of presynaptic activity (synaptophysin), and this effect was greatest in female rats. Whilst some behavioural differences were observed in females during initial Pavlovian training, final conditioning scores did not differ from males and were unaffected by the oestrous cycle. This work provides novel insights into how conditioning impacts the neuronal plasticity of the NAc core, whilst highlighting the importance of studying the behaviour and neurobiology of both male and female rats.