bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factor VIII mutated with Lys1813Ala within the factor IXa-binding region enhances intrinsic coagulation potential
Authors: Nakajima Yuto , Takeyama Masahiro , Oda Akihisa , Shimonishi Naruto , Nogami Keiji 
Published: November 2022

Abstract
Factor VIII (FVIII) functions as a cofactor of FIXa for FX activation in the intrinsic tenase complex. The 1811-1818 region in the FVIII A3 domain was observed to contribute to FIXa binding, and the K1813A/K1818A mutant increased the binding affinity for FIXa. The current study aims to identify mutated FVIII protein(s) that increase FVIIIa cofactor activity in the 1811-1818 region. FVIII mutants with K1813A, K1818A, and K1813A/K1818A were expressed in baby hamster kidney cells and were followed by assessments using purified and global coagulation assays for mouse models with hemophilia A (HA). A surface plasmon resonance–based assay revealed that the Kd value of FVIII-K1813A for FIXa interaction was lower than that of the wild-type (WT) (3.9±0.7/6.3±0.3 nM). However, the Km value of FVIII-K1813A for FIXa on tenase activity was comparable with that of the WT, whereas the kcat of this mutant was significantly greater than that of the WT. Thrombin-catalyzed FVIII-K1813A activation was ∼1.3-fold more enhanced than that of the WT, and the spontaneous decay of activated FVIII-K1813A was ∼2.5-fold slower than that of WT. The heat stability assay revealed that the decay rate of FVIII-K1813A was ∼2.5-fold slower than that of WT. Thrombin generation assay and rotational thromboelastometry using blood samples from patients with HA demonstrated that the addition of FVIII-K1813A (0.5 nM) exhibited a coagulation potential compatible with that of WT (1 nM). In the tail clip assay of HA mice, FVIII-K1813A showed a two- to fourfold higher hemostatic potential than that of the WT. FVIII-K1813A, with higher a FIXa binding affinity, enhances the global coagulation potential because of the stability of FVIII/FVIIIa molecules.
GMMchi: gene expression clustering using Gaussian mixture modeling
Authors: Liu Ta-Chun , Kalugin Peter N. , Wilding Jennifer L. , Bodmer Walter F. 
Published: November 2022

AbstractBackgroundCancer evolution consists of a stepwise acquisition of genetic and epigenetic changes, which alter the gene expression profiles of cells in a particular tissue and result in phenotypic alterations acted upon by natural selection. The recurrent appearance of specific genetic lesions across individual cancers and cancer types suggests the existence of certain “driver mutations,” which likely make up the major contribution to tumors’ selective advantages over surrounding normal tissue and as such are responsible for the most consequential aspects of the cancer cells’ gene expression patterns and phenotypes. We hypothesize that such mutations are likely to cluster with specific dichotomous shifts in the expression of the genes they most closely control, and propose GMMchi, a Python package that leverages Gaussian Mixture Modeling to detect and characterize bimodal gene expression patterns across cancer samples, as a tool to analyze such correlations using 2 × 2 contingency table statistics.ResultsUsing well-defined simulated data, we were able to confirm the robust performance of GMMchi, reaching 85% accuracy with a sample size of n = 90. We were also able to demonstrate a few examples of the application of GMMchi with respect to its capacity to characterize background florescent signals in microarray data, filter out uninformative background probe sets, as well as uncover novel genetic interrelationships and tumor characteristics. Our approach to analysing gene expression analysis in cancers provides an additional lens to supplement traditional continuous-valued statistical analysis by maximizing the information that can be gathered from bulk gene expression data.ConclusionsWe confirm that GMMchi robustly and reliably extracts bimodal patterns from both colorectal cancer (CRC) cell line-derived microarray and tumor-derived RNA-Seq data and verify previously reported gene expression correlates of some well-characterized CRC phenotypes.AvailabilityThe Python package GMMchi and our cell line microarray data used in this paper is available for downloading on GitHub athttps://github.com/jeffliu6068/GMMchi.
Species and genetic diversity relationships in benthic macroinvertebrate communities along a salinity gradient
Authors: Petersen H. Cecilie , Hansen Benni W. , Knott K. Emily , Banta Gary T. 
Published: November 2022

Abstract
Background
Species- and genetic diversity can change in parallel, resulting in a species-genetic diversity correlation (SGDC) and raising the question if the same drivers influence both biological levels of diversity. The SGDC can be either positive or negative, depending on whether the species diversity and the genetic diversity of the measured species respond in the same or opposite way to drivers. Using a traditional species diversity approach together with ultra-conserved elements and high throughput sequencing, we evaluated the SGDCs in benthic macrofauna communities in the Baltic Sea, a geologically young brackish water sea characterised by its steep salinity gradient and low species richness. Assessing SGDCs from six focal marine invertebrate species from different taxonomic groups and with differing life histories and ecological functions on both a spatial and temporal scale gives a more comprehensive insight into the community dynamics of this young ecosystem and the extrinsic factors that might drive the SGDCs.

Results
No significant correlations between species diversity and genetic diversity were found for any of the focal species. However, both negative and positive trends of SGDCs for the individual focal species were observed. When examining the environmental drivers, no common trends between the species were found, even when restricting the analysis to specific taxonomic classes. Additionally, there were no common environmental factors driving the diversity relationships for species sharing the same SGDC trend (positive or negative). Local population dynamics, together with the invasion history of the individual species and their unique adaptation to the distinctive environment of the Baltic Sea, are expected to be of major influence on the outcome of the SGDCs.

Conclusions
The present results highlight the importance of assessing SGDCs using multiple species, not just a single indicator species. This emphasises a need to pay attention to the ecology and life history of the focal species. This study also provides insight into the large differences in both patterns and drivers of genetic diversity, which is important when including genetic biodiversity in conservation plans. We conclude that the effects of environmental and biological factors and processes that affects diversity patterns at both the community and genetic levels are likely species dependent, even in an environment such as the Baltic Sea with strong environmental gradients.
Genome-wide characterization and expression analysis of the growth-regulating factor family in Saccharum
Authors: Wu Zilin , Chen Xinglong , Fu Danwen , Zeng Qiaoying , Gao Xiaoning , Zhang Nannan , Wu Jiayun 
Published: November 2022

Abstract
Background
Growth regulating factors (GRFs) are transcription factors that regulate diverse biological and physiological processes in plants, including growth, development, and abiotic stress. Although GRF family genes have been studied in a variety of plant species, knowledge about the identification and expression patterns of GRFs in sugarcane (Saccharum spp.) is still lacking.

Results
In the present study, a comprehensive analysis was conducted in the genome of wild sugarcane (Saccharum spontaneum) and 10 SsGRF genes were identified and characterized. The phylogenetic relationship, gene structure, and expression profiling of these genes were analyzed entirely under both regular growth and low-nitrogen stress conditions. Phylogenetic analysis suggested that the 10 SsGRF members were categorized into six clusters. Gene structure analysis indicated that the SsGRF members in the same group were greatly conserved. Expression profiling demonstrated that most SsGRF genes were extremely expressed in immature tissues, implying their critical roles in sugarcane growth and development. Expression analysis based on transcriptome data and real-time quantitative PCR verification revealed that GRF1 and GRF3 were distinctly differentially expressed in response to low-nitrogen stress, which meant that they were additional participated in sugarcane stress tolerance.

Conclusion
Our study provides a scientific basis for the potential functional prediction of SsGRF and will be further scrutinized by examining their regulatory network in sugarcane development and abiotic stress response, and ultimately facilitating their application in cultivated sugarcane breeding.
The impact of COVID-19 on an Irish Emergency Department (ED): a cross-sectional study exploring the factors influencing ED utilisation prior to and during the pandemic from the patient perspective
Authors: Cummins Niamh M. , Garavan Carrie , Barry Louise A. , Devlin Collette , Corey Gillian , Cummins Fergal , Ryan Damien , McCarthy Gerard , Galvin Rose 
Published: November 2022

Abstract
Background
The collateral damage of SARS-CoV-2 is a serious concern in the Emergency Medicine (EM) community, specifically in relation to delayed care increasing morbidity and mortality in attendances unrelated to COVID-19. The objectives of this study are to describe the profile of patients attending an Irish ED prior to, and during the pandemic, and to investigate the factors influencing ED utilisation in this cohort.

Methods
This was a cross-sectional study with recruitment at three time-points prior to the onset of COVID-19 in December 2019 (n = 47) and February 2020 (n = 57) and post-Lockdown 1 in July 2020 (n = 70). At each time-point all adults presenting over a 24 h period were eligible for inclusion. Clinical data were collected via electronic records and a questionnaire provided information on demographics, healthcare utilisation, service awareness and factors influencing the decision to attend the ED. Data analysis was performed in SPSS and included descriptive and inferential statistics.

Results
The demographic and clinical profile of patients across time-points was comparable in terms of age (p = 0.904), gender (p = 0.584) and presenting complaint (p = 0.556). Median length of stay in the ED decreased from 7.25 h (IQR 4.18–11.22) in February to 3.86 h (IQR 0.41–9.14) in July (p ≤ 0.005) and differences were observed in disposition (p ≤ 0.001). COVID-19 influenced decision to attend the ED for 31% of patients with 9% delaying presentation. Post-lockdown, patients were less likely to attend the ED for reassurance (p ≤ 0.005), for a second opinion (p ≤ 0.005) or to see a specialist (p ≤ 0.05).

Conclusions
Demographic and clinical presentations of ED patients prior to the first COVID-19 lockdown and during the reopening phase were comparable, however, COVID-19 significantly impacted health-seeking behaviour and operational metrics in the ED at this phase of the pandemic. These findings provide useful information for hospitals with regard to pandemic preparedness and also have wider implications for planning of future health service delivery.
Clinical application of artificial neural network (ANN) modeling to predict BRCA1/2 germline deleterious variants in Chinese bilateral primary breast cancer patients
Authors: Li Yan , Chen Lili , Lv Jinxing , Chen Xiaobin , Zeng Bangwei , Chen Minyan , Guo Wenhui , Lin Yuxiang , Yu Liuwen , Hou Jialin , Li Jing , Zhou Peng , Zhang Wenzhe , Li Shengmei , Jin Xuan , Cai Weifeng , Zhang Kun , Huang Yeyuan , Wang Chuan , Fu Fangmeng 
Published: November 2022

Abstract
Background
Bilateral breast cancer (BBC), as well as ovarian cancer, are significantly associated with germline deleterious variants in BRCA1/2, while BRCA1/2 germline deleterious variants carriers can exquisitely benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. However, formal genetic testing could not be carried out for all patients due to extensive use of healthcare resources, which in turn results in high medical costs. To date, existing BRCA1/2 deleterious variants prediction models have been developed in women of European or other descent who are quite genetically different from Asian population. Therefore, there is an urgent clinical need for tools to predict the frequency of BRCA1/2 deleterious variants in Asian BBC patients balancing the increased demand for and cost of cancer genetics services.

Methods
The entire coding region of BRCA1/2 was screened for the presence of germline deleterious variants by the next generation sequencing in 123 Chinese BBC patients. Chi-square test, univariate and multivariate logistic regression were used to assess the relationship between BRCA1/2 germline deleterious variants and clinicopathological characteristics. The R software was utilized to develop artificial neural network (ANN) and nomogram modeling for BRCA1/2 germline deleterious variants prediction.

Results
Among 123 BBC patients, we identified a total of 20 deleterious variants in BRCA1 (8; 6.5%) and BRCA2 (12; 9.8%). c.5485del in BRCA1 is novel frameshift deleterious variant. Deleterious variants carriers were younger at first diagnosis (P = 0.0003), with longer interval between two tumors (P = 0.015), at least one medullary carcinoma (P = 0.001), and more likely to be hormone receptor negative (P = 0.006) and HER2 negative (P = 0.001). Area under the receiver operating characteristic curve was 0.903 in ANN and 0.828 in nomogram modeling individually (P = 0.02).

Conclusion
This study shows the spectrum of the BRCA1/2 germline deleterious variants in Chinese BBC patients and indicates that the ANN can accurately predict BRCA deleterious variants than conventional statistical linear approach, which confirms the BRCA1/2 deleterious variants carriers at the lowest costs without adding any additional examinations.
The predictive value of fibrinogen in the occurrence of mild cognitive impairment events in patients with diabetic peripheral neuropathy
Authors: Zhuang Yong , Huang Huibin , Fu Zhenfei , Zhang Jinying , Cai Qingyan 
Published: November 2022

Abstract
Background
Research suggests that fibrinogen (Fib) is related to mild cognitive impairment (MCI) and diabetic peripheral neuropathy (DPN) and the risk of MCI in patients with DPN is greatly increased, although no studies have evaluated the predictive value of Fib for the risk of MCI in patients with DPN.

Methods
This prospective observational clinical study enrolled 207 type 2 diabetes mellitus (T2DM) patients, who were divided into diabetes with no neuropathy (102 cases) and diabetes with neuropathy (105 cases) groups. Meanwhile, 90 healthy unrelated subjects were recruited as controls. The incidence of MCI in the DPN patients was followed up for 2 years. Divide patients in the DPN group into subgroups according to whether MCI occur, use multivariate logistic regression to analyze independent factors of MCIs in DPN patients within 2 years, and use ROC curve to analyze the predictive value of Fib for MCI in DPN patients.

Results
Fib levels were significantly higher in diabetic subjects with neuropathy compared with those without (P < 0.001). In further subgroup analysis of DPN patients who were divided according to the occurrence of MCI, baseline data of the MCI subgroup showed Fib levels were higher than that in the non-MCI group while education levels declined (P < 0.001). The education level and increased Fib levels were independent factors for the occurrence of MCI within 2 years after the onset of DPN (OR = 0.769, 95% CI: 0.605 ~ 0.968, P = 0.037; OR = 2.674, 95% CI: 1.094 ~ 3.168, P = 0.002). The ROC curve indicated that the predictive value of Fib was (AUC = 0.764, 95% CI: 0.671 ~ 0.842, P < 0.001).

Conclusions
Fib may function as a predictor for assessing the risk of MCI in DPN patients.
“I wouldn’t have joined if it wasn’t online”: understanding older people’s engagement with teleyoga classes for fall prevention
Authors: Haynes Abby , Gilchrist Heidi , Oliveira Juliana S , Sherrington Catherine , Tiedemann Anne 
Published: November 2022

Abstract
Background
Yoga-based exercise is a promising strategy for promoting healthy ageing, with the potential to reduce falls and increase physical, cognitive and psychological wellbeing. Teleyoga (real-time yoga provided via interactive videoconferencing) can deliver yoga programs at scale, potentially reducing costs, increasing convenience, and reaching people who cannot attend studio-based classes. But better understanding of how older people perceive and engage with teleyoga is needed to optimise its design, implementation and promotion.

Methods
This study built on a previous realist process evaluation of the SAGE yoga trial which is testing the effect of a yoga-based exercise program on falls among 700 community-dwelling people aged 60 + years. In this second phase of evaluation we conducted focus groups with participants who had completed the SAGE program online and with the yoga instructors who were delivering it. We also conducted interviews with participants who had withdrawn from the trial. Six program theories developed in the earlier evaluation provided a framework for data analysis, supplemented by inductive coding and an analytical workshop.

Results
Participants described physical and psychological benefits from the SAGE teleyoga program. While noting that teleyoga cannot facilitate hands-on correction or the same quality of observation or interaction as studio classes, participants were highly appreciative of their yoga instructors’ strategies for optimising visibility, instruction, social connection and therapeutic alliance, and for adapting to constrained home environments. Some participants argued that teleyoga was superior to studio classes due to its accessibility and convenience, its lower exposure to potential embarrassment about physical appearance or capabilities, and a reduced sense of peer competition and distraction. Our program theories applied across studio and online modes of delivery.

Conclusion
Teleyoga increases accessibility for people in diverse locations and circumstances; it provides a psychologically safer space which combats self-consciousness and unwanted competitiveness; it may enhance embodiment and mindfulness for some; and it has the potential to be offered relatively cheaply at scale which could support free or reduced price classes for people on low incomes and pensions, thereby encouraging a wider population to engage in yoga for healthy ageing and fall prevention.
Targeting hypoxia in solid and haematological malignancies
Authors: Harris Bill , Saleem Sana , Cook Natalie , Searle Emma 
Published: November 2022

AbstractTumour hypoxia is a known and extensively researched phenomenon that occurs in both solid and haematological malignancies. As cancer cells proliferate, demand for oxygen can outstrip supply reducing tumour oxygenation. In solid tumours this is contributed to by disorganized blood vessel development. Tumour hypoxia is associated with resistance to treatment, more aggressive disease behaviour and an increased likelihood of metastatic progression. It can be measured using both invasive and non-invasive methods to varying degrees of accuracy. The presence of hypoxia stimulates a complex cellular network of downstream factors including Hypoxia Inducible Factor 1 (HIF1), C-X-C motif chemokine 4 (CXCR4) and Hypoxia‐inducible glycolytic enzyme hexokinase‐2 (HK2) amongst many others. They work by affecting different mechanisms including influencing angiogenesis, treatment resistance, immune surveillance and the ability to metastasize all of which contribute to a more aggressive disease pattern. Tumour hypoxia has been correlated with poorer outcomes and worse prognosis in patients. The correlation between hypoxic microenvironments and poor prognosis has led to an interest in trying to therapeutically target this phenomenon. Various methods have been used to target hypoxic microenvironments. Hypoxia-activated prodrugs (HAPs) are drugs that are only activated within hypoxic environments and these agents have been subject to investigation in several clinical trials. Drugs that target downstream factors of hypoxic environments including HIF inhibitors, mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (anti-VEGF) therapies are also in development and being used in combination in clinical trials. Despite promising pre-clinical data, clinical trials of hypoxia targeting strategies have proven challenging. Further understanding of the effect of hypoxia and related molecular mechanisms in human rather than animal models is required to guide novel therapeutic strategies and future trial design. This review will discuss the currently available methods of hypoxia targeting and assessments that may be considered in planning future clinical trials. It will also outline key trials to date in both the solid and haemato-oncology treatment spheres and discuss the limitations that may have impacted on clinical success to date.
Analysis of N7-(2-carbamoyl-2-hydroxyethyl)guanine in dried blood spot after food exposure by Ultra High Performance Liquid Chromatography–Tandem Mass Spectrometry
Authors: Harahap Yahdiana , Safitri Winning Bekti , Sunarsih Sunarsih 
Published: November 2022

AbstractN7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-CAG) is a DNA adduct formed by glycidamide, which is the metabolite of acrylamide. Acrylamide can be found in foods containing reducing sugars and asparagine that are heated at high temperatures. Analysis of N7-CAG was performed in Dried Blood Spot (DBS) samples from 25 subjects of group test who consumed a lot of acrylamide-containing foods and 25 subjects of negative control group. This study aimed to determine whether there is a significant difference in the levels of N7-CAG between the two groups. DBS samples were extracted using the QIAamp DNA Mini Blood Kit and analyzed using Ultra High Performance Liquid Chromatography–Tandem Mass Spectrometry (UHPLC-MS/MS). Separation was performed using an Acquity UPLC BEH C18 column (2.1 mm × 100 mm; 1.7 μm), eluted a flow rate of 0.1 ml/min under an isocratic of mobile phase of 0.1% formic acid and acetonitrile. The bioanalytical method of N7-CAG in DBS with allopurinol as the internal standard by using UHPLC-MS/MS has been validated. The calibration curve range of N7-CAG obtained was 10–300 ng/ml with a coefficient of correlation of 0.997. The results of the analysis on 25 test group subjects showed that the concentration of N7-CAG ranged from 1.87 to 23.71 ng/ml, while the 25 subjects in the negative group ranged from 1.18 to 8.47 ng/ml. The results of the Mann Whitney test showed that there was a significant difference in the levels of N7-CAG between the test group and the negative control group with p value less than 0.001.