bluuebunny/crossref_metadata_2025_split huggingface dataset:
A highly sensitive XNA-based RT-qPCR assay for the identification of ALK, RET, and ROS1 fusions in lung cancer
Authors: Lee Bongyong , Chern Andrew , Fu Andrew Y. , Zhang Aiguo , Sha Michael Y. 
Published: January 2024

AbstractIn lung cancer, the progression of tumors is often fueled by genetic alterations leading to the expression of oncogenic tyrosine kinases. Specifically, chimeric tyrosine kinases involving ALK, RET, and ROS1 are observed in approximately 5-7%, 1-2%, and 1-2% of NSCLS patients, respectively. The presence of these ALK, RET, and ROS1 fusion genes determines the response to tyrosine kinase inhibitors. Consequently, accurate detection of these gene fusions is crucial in the realm of precision medicine. To address this need, we have developed a multiplexed RT-qPCR assay based on xenonucleic acids (XNA) molecular clamping technology for detecting lung cancer fusions. This assay is designed to quantitatively detect thirteen ALK, seven ROS1, and seven RET gene fusions in FFPE samples. The sensitivity of the assay was established at a limit of detection of 50 copies of the synthetic template. Our assay successfully identified all fusion transcripts using 50 ng of RNA from both reference FFPE samples and cell lines. Following this validation, we tested a total of 77 lung cancer patient FFPE samples, demonstrating the effectiveness of our XNA-based fusion gene assay with clinical samples. Notably, this assay is adaptable to highly degraded RNA samples with low input amounts. Our next phase involves expanding the testing to include a broader range of clinical samples as well as cell-free RNAs to further validate its applicability and reliability.
Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young
Authors: Cardoso Pedro , McDonald Timothy J. , Patel Kashyap A. , Pearson Ewan R. , Hattersley Andrew T. , Shields Beverley M. , McKinley Trevelyan J. 
Published: January 2024

AbstractBackgroundClinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges.MethodsWe compared three approaches for developing clinical prediction models for population-screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment (“offset”), shrinkage recalibration in the population-level dataset (“recalibration”), and a refitting of the model to the population-level dataset (“re-estimation”). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed prior information from the literature and other data sources to deal with missing biomarker and outcome information and to ensure the clinical validity of predictions for certain biomarker combinations.ResultsThe offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model’s predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities.ConclusionWe have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing.
Anemia, hemoglobin concentration and cognitive function in the Longitudinal Ageing Study in India-Harmonized Diagnostic Assessment of Dementia (LASI-DAD) and the Health and Retirement Study
Authors: Winchester Laura M. , Newby Danielle , Ghose Upamanyu , Hu Peifeng , Green Hunter , Chien Sandy , Ranson Janice , Faul Jessica , Llewellyn David , Lee Jinkook , Bauermeister Sarah , Nevado-Holgado Alejo 
Published: January 2024

AbstractBackgroundIn India, anemia is widely researched in children and women of reproductive age, however, studies in older populations are lacking. Given the adverse effect of anemia on cognitive function and dementia this older population group warrants further study. The Longitudinal Ageing Study in India – Harmonized Diagnostic Assessment of Dementia (LASI-DAD) dataset contains detailed measures to allow a better understanding of anaemia as a potential risk factor for dementia.Method2,758 respondents from the LASI-DAD cohort, aged 60 or older, had a complete blood count measured from venous blood as well as cognitive function tests including episodic memory, executive function and verbal fluency. Linear regression was used to test the associations between blood measures (including anemia and hemoglobin concentration (g/dL)) with 11 cognitive domains. All models were adjusted for age and gender with the full model containing adjustments for rural location, years of education, smoking, region, BMI and population weights.Results from LASI-DAD were validated using the USA-based Health and Retirement Study (HRS) cohort (n=5720) to replicate associations between blood cell measures and global cognition.ResultsIn LASI-DAD, we showed an association between anemia and poor memory (p=0.0054). We found a positive association between hemoglobin concentration and ten cognitive domains tested (β=0.041-0.071, p<0.05). The strongest association with hemoglobin was identified for memory-based tests (immediate episodic, delayed episodic and broad domain memory, β=0.061-0.071, p<0.005). Positive associations were also shown between the general cognitive score and the other red blood count tests including mean corpuscular hemoglobin concentration (MCHC, β=0.06, p=0.0001) and red cell distribution width (RDW, β =-0.11, p<0.0001). In the HRS cohort, positive associations were replicated between general cognitive score and other blood count tests (Red Blood Cell, MCHC and RDW, p<0.05).ConclusionWe have established in a large South Asian population that low hemoglobin and anaemia are associated with low cognitive function, therefore indicating that anaemia could be an important modifiable risk factor. We have validated this result in an external cohort demonstrating both the variability of this risk factor cross-nationally and its generalizable association with cognitive outcomes.
Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel
Authors: Parsons Michael T. , de la Hoya Miguel , Richardson Marcy E. , Tudini Emma , Anderson Michael , Berkofsky-Fessler Windy , Caputo Sandrine M. , Chan Raymond C. , Cline Melissa C. , Feng Bing-Jian , Fortuno Cristina , Gomez-Garcia Encarna , Hadler Johanna , Hiraki Susan , Holdren Megan , Houdayer Claude , Hruska Kathleen , James Paul , Karam Rachid , Leong Huei San , Martins Alexandra , Mensenkamp Arjen R. , Monteiro Alvaro N. , Nathan Vaishnavi , O’Connor Robert , Pedersen Inge Sokilde , Pesaran Tina , Radice Paolo , Schmidt Gunnar , Southey Melissa , Tavtigian Sean , Thompson Bryony A. , Toland Amanda E. , Turnbull Clare , Vogel Maartje J. , Weyandt Jamie , Wiggins George A.R. , Zec Lauren , Couch Fergus J. , Walker Logan C. , Vreeswijk Maaike P. G. , Goldgar David E. , Spurdle Amanda B. 
Published: January 2024

AbstractThe ENIGMA research consortium (https://enigmaconsortium.org/) develops and applies methods to determine clinical significance of variants in Hereditary Breast and Ovarian Cancer genes. An ENIGMABRCA1/2classification sub-group, originally formed in 2016 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Federal Drug Administration recognized processes for ClinVar contributions.The VCEP reviewed American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpretingBRCA1andBRCA2variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants, and documentation revised for clarity and ease-of-use.The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 Uncertain Significance or Conflicting, 14 Pathogenic and/or Likely Pathogenic, and 13 Benign and/or Likely Benign. Review resolved classification for 11/13 Uncertain Significance or Conflicting variants, and retained or improved confidence in classification for the remaining variants.Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in both the research processes and the baseline ACMG/AMP criteria. Calibration of evidence types was key to justify utility and strength of different evidence types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification ofBRCA1andBRCA2variants.
Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram
Authors: De Martino Enrico , Casali Adenauer , Casarotto Silvia , Hassan Gabriel , Nascimento Couto Bruno Andry , Rosanova Mario , Graven-Nielsen Thomas , de Andrade Daniel Ciampi 
Published: January 2024

ABSTRACTTemporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (Acute Pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, β1, and β2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, Acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all P<0.05). The remote (parietal-occipital) decrease in α-band phase synchronization during Acute Pain correlated with the cold (P=0.001) and heat pain thresholds (P=0.023) and to local (M1) α-band oscillatory power decrease (P=0.024). Over DLPFC, Acute Pain only decreased β1-band power locally compared with non-noxious warm (P=0.015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and β band oscillations and may have relevance for pain therapies.
“Embryonic piRNAs target horizontally transferred vertebrate transposons in assassin bugs”
Authors: Brito Tarcísio Fontenele , Cardoso Maira Arruda , Atinbayeva Nazerke , Brito Ingrid Alexandre de Abreu , da Costa Lucas Amaro , Iovino Nicola , Pane Attilio 
Published: January 2024

AbstractPiwi proteins and the associated Piwi-interacting RNAs (piRNAs) coordinate a surveillance system that protects the animal genome from DNA damage induced by transposable element (TE) mobilization. While the pathway has been described in detail in the fruit flyDrosophila melanogaster,much less is known in more basal insects. Here, we investigated the adaptation of the piRNA pathway to horizontally transferred transposons (HTTs) in the assassin bugRhodnius prolixus, a primary vector of Chagas disease.Rhodniusacquired specific classes of HTTs by feeding on bats, opossums and squirrel monkeys. By analyzing the temporal dynamics of piRNA cluster expression and piRNA production during critical stages ofRhodniusdevelopment, we show that peak levels of ∼28 nt long piRNAs correlate with reduced HTT and resident TE expression primarily during embryogenesis. Strikingly, while resident TEs piRNAs seem to engage in a typical ping-pong amplification mechanism, sense and antisense HTT piRNAs instead overlap by ∼20 nt or do not display ping-pong signatures. These features are explained at least in part by the low number of HTT copies inserted into the piRNA clusters and might point to a non-canonical mechanism of biogenesis. Our data reveal that the piRNA, but not the siRNA pathway, responded to HTTs that were recently transferred from vertebrate tetrapods to a hematophagous insect of medical relevance.
Extracellular matrix signals promotes actin-dependent mitochondrial elongation and activity
Authors: Gatti Priya , Mukherjee Pritha , Talukdar Priyanka Dey , Freppel Wesley , Kanou Joseph , Chatel-Chaix Laurent , Chatterji Urmi , Germain Marc 
Published: January 2024

AbstractMitochondria are crucial metabolic organelles that are regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signalling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from the general survival cues generated by the ECM, we used breast cancer-derived spheres (mammospheres) because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity, but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.
Transcriptomic Profile of Lin-Sca1+c-kit (LSK) cells in db/db mice with long-standing diabetes
Authors: Mahajan Neha , Luo Qianyi , Abhyankar Surabhi , Bhatwadekar Ashay D. 
Published: January 2024

SummaryThe Lin-Sca1+c-Kit+(LSK) fraction comprises multipotent hematopoietic stem cells (HSCs), vital to tissue homeostasis and vascular repair. While HSC homeostasis is impaired in diabetes, it is not known how chronic (>6 months) type 2 diabetes (T2D) alters the HSC transcriptome. Herein, we assessed the transcriptomic signature of HSCs in db/db mice employing mRNA and miRNA sequencing. We uncovered 2076 mRNAs and 35 miRNAs differentially expressed in db/db mice, including two novel miRNAs previously unreported in T2D. Further analysis of these transcripts showed a molecular shift with an increase in the pro-inflammatory cytokines and a decrease in anti-inflammatory cytokine expression. Also, pathway mapping unveiled inflammation and angiogenesis as one of the top pathways. These effects were reflected in bone marrow mobilopathy, retinal microglial inflammation, and neurovascular deficits in db/db mice. In conclusion, our study highlights that chronic diabetes alters HSCs’ at the transcriptomic level, thus potentially contributing to overall homeostasis and neurovascular deficits of diabetes, such as diabetic retinopathy.HighlightsBone marrow mobilopathy with long-standing diabetesSwitch in LSK transcriptomic profile towards inflammation and angiogenesisDiscovered 35 miRNAs, including two novel miRNAs, miR-3968 and miR-1971LSK dysfunction reflected in inflammation and neurovascular deficits of the retina
Cell surface morphology mimicking nano-bio platform for immune cell stimulation
Authors: Varghese Beena , González-Navarro José Alfredo , Guerra Valentino Libero Pio , Faizulina Margarita , Artemieva Daria , Chum Tomáš , Ramakrishna Tejaswini Rama Bangalore , Cebecauer Marek , Kovaříček Petr 
Published: January 2024

AbstractStudying the complex realm of cellular communication and interactions by fluorescence microscopy requires sample fixation on a transparent substrate. To activate T cells, which are pivotal in controlling the immune system, it is important to present the activating antigen in a spatial arrangement similar to the nature of the antigen-presenting cell, including the presence of ligands on microvilli. Similar arrangement is predicted for some other immune cells. In this work, immune cell-stimulating platform based on nanoparticle-ligand conjugates have been developed using a scalable, affordable, and broadly applicable technology, which can be readily deployed without the need for state-of-the-art nanofabrication instruments. The validation of surface biofunctionalization was performed by combination of fluorescence and atomic force microscopy techniques. We demonstrate that the targeted system serves as a biomimetic scaffold on which immune cells make primary contact with the microvilli-mimicking substrate and exhibit stimulus-specific activation.
Balancing safety and efficiency in human decision making
Authors: Mahajan Pranav , Tong Shuangyi , Lee Sang Wan , Seymour Ben 
Published: January 2024

ABSTRACTThe safety-efficiency dilemma describes the problem of maintaining safety during efficient exploration and is a special case of the exploration-exploitation dilemma in the face of potential dangers. Conventional exploration-exploitation solutions collapse punishment and reward into a single feedback signal, whereby early losses can be overcome by later gains. However, the brain has a separate system for Pavlovian fear learning, suggesting a possible computational advantage to maintaining a specific fear memory during exploratory decision-making. In a series of simulations, we show this promotes safe but efficient learning and is optimised by arbitrating Pavlovian avoidance of instrumental decision-making according to uncertainty. We provide a basic test of this model in a simple human approach-withdrawal experiment, and show that this flexible avoidance model captures choice and reaction times. These results show that the Pavlovian fear system has a more sophisticated role in decision-making than previously thought, by shaping flexible exploratory behaviour in a computationally precise manner.
Femininity penalties and rewards: obstacles and opportunities for Chinese female entrepreneurs in gender-segregated industries
Authors: LI Lulu 
Published: January 2024

Purpose
This study aims to answer two questions: (a) what obstacles and opportunities do Chinese female entrepreneurs face when doing business? And (b) how do they negotiate their entrepreneurial careers and gender identities in different gender-segregated markets?

Design/methodology/approach
This study uses qualitative research methods of participant observation and in-depth interviews with 41 female entrepreneurs in China and the theoretical lenses of gender role theory and doing gender in entrepreneurship.

Findings
The study findings reveal that Chinese female entrepreneurs face different obstacles and opportunities in gender-segregated industries. Their experiences vary in industries that are mainly occupied by males and females. On the one hand, women in female-dominated industries may be supported by a feminine working environment that is coherent with their domestic roles. However, they may also be questioned on the cultural impurity implied in some industries, which harms their class-based feminine virtue. On the other hand, women in male-dominated industries may be challenged and marginalized due to their gender. However, some find ways to turn the disadvantaged feminine characters into favourable conditions and break out of the stereotypical gender constraints in doing business.

Originality/value
This study contributes to the literature on gender and entrepreneurship in general. More specifically, it contributes to the study of doing gender in gender-segregated markets, and it also illustrates women’s gendered opportunities and constraints in Chinese society that are affected by the long-lasting traditional gender norms.
Forging an entrepreneur – gendered ideas and ideals
Authors: Roos Annie , Pettersson Katarina 
Published: January 2024

PurposeThe purpose of this study is to investigate the gendered ideas and ideals attached to an imagined ideal Entrepreneur in a post-industrial rural community in Sweden. While research has not yet clearly explained how the ideal entrepreneur is constructed, the result, i.e. the gendered representations of entrepreneurs, is well-researched. Previous results indicate a prevalent portrayal of entrepreneurship as a predominantly masculine construct characterised by qualities such as self-made success, confidence and assertiveness.Design/methodology/approachEthnographic fieldwork was conducted in a community that is attempting to re-brand itself through garden tourism. Through inductive reasoning, this study analyses the gendered ideas and ideals regarding the community’s imagined ideal Entrepreneur who is to help the community solve its problems.FindingsThis study finds that the community forges the Entrepreneur into an imagined masculine ideal as holy, a saviour and a god and is replacing its historical masculine ironmaster with a masculine Entrepreneur. This study develops forging as a metaphor for the construction of the masculine ideal Entrepreneur, giving the community, rather than the entrepreneur himself, a voice as constructors. From social constructionism, this study emphasises how gendered ideas and ideals are shaped not only by the individual realities but more so in the reciprocal process by the realities of others.Originality/valueThe metaphor of forging adds an innovative theoretical dimension to the feminist constructionist approach and suggests focusing on how the “maleness” of entrepreneurship is produced and reproduced in the local. Previously, light has been shed on how male entrepreneurs perform their identities collectively; the focus of this study is on the social construction of this envisioned Entrepreneur within a rural community. The development of forging thus contributes as a way of analysing entrepreneurship in place. The choice of an ethnographic study allowed the authors to be a part of the real-life world of community members, providing rich data to explore entrepreneurship and gender.