bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity
Authors: Lin Susan X N , Ahring Philip K , Keramidas Angelo , Liao Vivian W Y , Møller Rikke S , Chebib Mary , Absalom Nathan L 
Published: August 2023

Abstract
Genetic variants associated with developmental and epileptic encephalopathies have been identified in the GABRB3 gene that encodes the β3 subunit of GABAA receptors. Typically, variants alter receptor sensitivity to GABA resulting in either gain- or loss-of-function, which correlates with patient phenotypes. However, it is unclear how another important receptor property, desensitization, contributes to the greater clinical severity of gain-of-function variants.
Desensitization properties of 20 gain-of-function GABRB3 variant receptors were evaluated using two-electrode voltage-clamp electrophysiology. The parameters measured included current decay rates and steady-state currents. Selected variants with increased or reduced desensitization were also evaluated using whole-cell electrophysiology in transfected mammalian cell lines.
Of the 20 gain-of-function variants assessed, 13 were found to alter receptor desensitization properties. Seven variants reduced desensitization at equilibrium, which acts to worsen gain-of-function traits. Six variants accelerated current decay kinetics, which limits gain-of-function traits. All affected patients displayed severe clinical phenotypes with intellectual disability and difficult-to-treat epilepsy. Nevertheless, variants that reduced desensitization at equilibrium were associated with more severe clinical outcomes. This included younger age of first seizure onset (median 0.5 months), movement disorders (dystonia and dyskinesia), epilepsy of infancy with migrating focal seizures (EIMFS) and risk of early mortality. Variants that accelerated current decay kinetics were associated with slightly milder phenotypes with later seizure onset (median 4 months), unclassifiable developmental and epileptic encephalopathies or Lennox–Gastaut syndrome and no movement disorders.
Our study reveals that gain-of-function GABRB3 variants can increase or decrease receptor desensitization properties and that there is a correlation with the degree of disease severity. Variants that reduced the desensitization at equilibrium were clustered in the transmembrane regions that constitute the channel pore and correlated with greater disease severity, while variants that accelerated current decay were clustered in the coupling loops responsible for receptor activation and correlated with lesser severity.
Assessing the Skin and UV Neoplasia Transplant Risk Assessment Calculator in an Irish cohort of thoracic organ transplant recipients
Authors: Yoo Li Jie Helena , Bowe Stephanie , Quigley Claire , Victory Liana , Devenney Ciara , Lenane Patsy 
Published: August 2023

Abstract
The Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) is a tool that can be used to decide when to first screen for skin cancer in organ transplant recipients (OTRs). The objective of this study was to assess the applicability of this tool in thoracic OTRs. Based on data from patient files, the OTRs were categorized into four risk groups according to the SUNTRAC tool. The time of the first post-transplant skin cancer in each OTR was recorded. The proportion of OTRs with post-transplant skin cancer in the low-, medium-, high- and very high-risk groups was 0%, 28.3%, 58.3% and 100%, respectively. This positive correlation suggests that SUNTRAC can be used to determine when to first screen for skin cancer in heart and lung OTRs.
PDE4D mediates impaired β-adrenergic receptor signalling in the sinoatrial node in mice with hypertensive heart disease
Authors: Dorey Tristan W , McRae Megan D , Belke Darrell D , Rose Robert A 
Published: August 2023

Abstract

Aims
The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease.

Methods and results
C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice.

Conclusions
AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.
ZIF-1-mediated degradation of zinc finger proteins in the Caenorhabditis elegans germ line
Authors: Schwartz Aaron Z A , Abdu Yusuff , Nance Jeremy 
Published: August 2023

Abstract
Rapid and conditional protein depletion is the gold standard genetic tool for deciphering the molecular basis of developmental processes. Previously, we showed that by conditionally expressing the E3 ligase substrate adaptor ZIF-1 in Caenorhabditis elegans somatic cells, proteins tagged with the first CCCH Zn finger 1 (ZF1) domain from the germline regulator PIE-1 degrade rapidly, resulting in loss-of-function phenotypes. The described role of ZIF-1 is to clear PIE-1 and several other CCCH Zn finger proteins from early somatic cells, helping to enrich them in germline precursor cells. Here, we show that proteins tagged with the PIE-1 ZF1 domain are subsequently cleared from primordial germ cells (PGCs) in embryos and from undifferentiated germ cells in larvae and adults by ZIF-1. We harness germline ZIF-1 activity to degrade a ZF1-tagged fusion protein from PGCs and show that its depletion produces phenotypes equivalent to those of a null mutation. Our findings reveal that ZIF-1 transitions from degrading CCCH Zn finger proteins in somatic cells to clearing them from undifferentiated germ cells, and that ZIF-1 activity can be harnessed as a new genetic tool to study the early germline.
Effectiveness of the Australian MATES in Construction Suicide Prevention Program: a systematic review
Authors: Gullestrup Jorgen , King Tania , Thomas Samantha L , LaMontagne Anthony D 
Published: August 2023

Abstract
Suicide is a major public health issue globally. The World Health Organization has called for nations to create comprehensive national suicide prevention strategies including multisectoral collaboration, awareness raising, advocacy and capacity building. The workplace provides opportunity and structure for suicide prevention programs. However, many of these programs are poorly documented and evaluated. The MATES in Construction (MATES) program is a multimodal workplace-based suicide prevention program designed for and by the construction industry. This systematic review examined the available evidence for the effectiveness of the MATES program and is reported according to PRISMA guidelines. A literature search resulted in the inclusion of 12 peer-reviewed articles published between January 2010 and February 2023 containing primary data of evaluations of MATES. There was evidence of the effectiveness of the MATES program in improving mental health and suicide prevention literacy, helping intentions and reducing stigma. The results highlighted the importance of worker-to-worker peer approaches with workers consistently stating that supervisors were the least trusted resources for mental health and suicide concerns. Favourable results were found in relation to reduced suicide risk in the construction industry. The evidence base for MATES is limited in terms of causal inference with very few controlled evaluations and no experimental studies having been conducted to date. Improved understanding of how the program motivates volunteers, their experiences and research on the longer-term impacts of the program on the industry is required.
A Genetic Lab-on-Phone Test for Point-of-Care Diagnostic of Lactose Intolerance near Patient and in less than 90 Minutes
Authors: Conceição Mariana , Assunção Hugo , Doria Gonçalo , Coelho Eduardo , Clemente Carla , Gaspar César , Furtado Tiago , Yamaguchi Takumi , Santos António , Silva Mónica , Rodriguez Lidia , Rodrigues Liliana , Flores Orfeu 
Published: August 2023

Abstract

Background
The −13910 C/T single nucleotide polymorphism located within the MCM6 gene, an enhancer region located upstream of the lactase-phlorizin hydrolase gene, is associated with lactase persistence/non-persistence traits among the Caucasian population. The performance of a new point-of-care CE-IVD (In Vitro Diagnostic) marked isothermal lab-on-phone lactose intolerance assay, using crude samples, was assessed in comparison with Sanger sequencing using purified DNA, as reference method.

Methods
The study was conducted following a non-probability sampling using direct buccal swab (n = 63) and capillary blood (n = 43) clinical samples from a total of 63 volunteers. A 3 × 3 confusion matrix/contingency table was used to evaluate the performance of the isothermal lab-on-phone lactose intolerance assay.

Results
The isothermal lab-on-phone lactose intolerance assay successfully detected the −13910 C/T variant with a limit of detection of 5 cells/assay and demonstrated an overall accuracy of 98.41% (95% CI, 91.47%–99.96%) for buccal swab samples and 100% (95% CI, 91.19%–100%) for capillary blood, taking just 90 min from sample to result, with only 2 min hands-on.

Conclusions
The lab-on-phone pocket-sized assay displayed good performance when using direct buccal swab and capillary blood samples, enabling a low-cost, real-time, and accurate genotyping of the −13910 C/T region for the rapid diagnosis of primary lactose intolerance at point-of-care, which enables a prompt implementation of appropriate diet habits and/or intolerance therapies. To our knowledge, this is the first point-of-care genetic test for lactose intolerance to be made available on the market.
Effects of machine learning-based clinical decision support systems on decision-making, care delivery, and patient outcomes: a scoping review
Authors: Susanto Anindya Pradipta , Lyell David , Widyantoro Bambang , Berkovsky Shlomo , Magrabi Farah 
Published: August 2023

Abstract

Objective
This study aims to summarize the research literature evaluating machine learning (ML)-based clinical decision support (CDS) systems in healthcare settings.

Materials and methods
We conducted a review in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Review). Four databases, including PubMed, Medline, Embase, and Scopus were searched for studies published from January 2016 to April 2021 evaluating the use of ML-based CDS in clinical settings. We extracted the study design, care setting, clinical task, CDS task, and ML method. The level of CDS autonomy was examined using a previously published 3-level classification based on the division of clinical tasks between the clinician and CDS; effects on decision-making, care delivery, and patient outcomes were summarized.

Results
Thirty-two studies evaluating the use of ML-based CDS in clinical settings were identified. All were undertaken in developed countries and largely in secondary and tertiary care settings. The most common clinical tasks supported by ML-based CDS were image recognition and interpretation (n = 12) and risk assessment (n = 9). The majority of studies examined assistive CDS (n = 23) which required clinicians to confirm or approve CDS recommendations for risk assessment in sepsis and for interpreting cancerous lesions in colonoscopy. Effects on decision-making, care delivery, and patient outcomes were mixed.

Conclusion
ML-based CDS are being evaluated in many clinical areas. There remain many opportunities to apply and evaluate effects of ML-based CDS on decision-making, care delivery, and patient outcomes, particularly in resource-constrained settings.
The association of miR-204 and mir-483 5p expression with clinicopathological features of Wilms tumor: Could this provide foresight?
Authors: Orgen Calli Aylin , Issin Gizem , Yilmaz Ismail , Ince Dilek , Tural Ersin , Guzelis Ismail , Cecen Refik Emre , Olgun Hatice Nur , Gokcay Deniz , Ozer Erdener 
Published: August 2023

Abstract

Background
Wilms tumor is the most common cancer of the kidney that occurs during childhood, and histologically, it mimics renal embryogenesis. With the development and improvement of up-to-date treatment protocols, the survival rates of Wilms tumor have increased. However, metastases or local relapses are still observed in 15% of patients. The search for reliable biomarkers to identify at-risk patients is ongoing to predict the variability in treatment success. Currently, the evaluation of clinical, histopathological and genetic features are common diagnostic methods; however, epigenetic features can be examined with microRNA expression analyses and might allow us to comment on the behavior of the tumor and treatment response.

Methods
In this study, we aimed to evaluate the relationship between microRNA-204 and microRNA-483-5p expression with clinicopathological data and the effect on Wilms tumor survival. For this purpose, the expression levels of RNU6B, microRNA-204 and microRNA-483-5p were evaluated in tumor and normal tissue by qreal time-polymerase chain reaction. We also investigated the relationship between microRNA expression levels with the clinicopathological and histological features of Wilms tumor.

Results and conclusion
The results of our study indicate that the relative expression levels of microRNA-204 in Wilms tumor tissues were significantly lower than that in adjacent normal tissues. By contrast, tumor tissue had a higher microRNA-483-5p expression than the corresponding normal tissues. A statistically significant difference between microRNA-204 expression level with age and the presence of anaplasia was observed. The upregulation of microRNA-483-5p was found to have a significant correlation with patients after preoperative chemotherapy and complete tumor necrosis. Taken together, our data suggest that microRNA-204 could play a critical role as a tumor suppressor, whereas microRNA-483-5p acts as an oncogene in Wilms tumor progression. More importantly, microRNA-204 might be a novel predictive biomarker for anaplastic histology and could be useful for developing therapeutic interventions targeting this marker.
On the importance of disc chemistry in the formation of protoplanetary disc rings
Authors: Nolan C A , Zhao B , Caselli P , Li Z Y 
Published: August 2023

ABSTRACT
Radial substructures have now been observed in a wide range of protoplanetary discs (PPDs), from young to old systems; however, their formation is still an area of vigorous debate. Recent magnetohydrodynamic (MHD) simulations have shown that rings and gaps can form naturally in PPDs when non-ideal MHD effects are included. However, these simulations employ ad hoc approximations to the magnitudes of the magnetic diffusivities in order to facilitate ring growth. We replace the parametrization of these terms with a simple chemical network and grain distribution model to calculate the non-ideal effects in a more self-consistent way. We use a range of grain distributions to simulate grain formation for different disc conditions. Including ambipolar diffusion, we find that large grain populations (&gt;1 $\mu$m), and those including a population of very small polyaromatic hydrocarbons (PAHs) facilitate the growth of periodic, stable rings, while intermediate-sized grains suppress ring formation. Including Ohmic diffusion removes the positive influence of PAHs, with only large grain populations still producing periodic ring and gap structures. These results relate closely to the degree of coupling between the magnetic field and the neutral disc material, quantified by the non-dimensional Elsasser number Λ (the ratio of magnetic forces to Coriolis force). For both the ambipolar-only and ambipolar-ohmic cases, if the total Elsasser number is initially of the order of unity along the disc mid-plane, ring and gap structures may develop.
The plant-unique protein DRIF1 coordinates with sorting nexin 1 to regulate membrane protein homeostasis
Authors: Zhu Ying , Zhao Qiong , Cao Wenhan , Huang Shuxian , Ji Changyang , Zhang Wenxin , Trujillo Marco , Shen Jinbo , Jiang Liwen 
Published: August 2023

Abstract
Membrane protein homeostasis is fine-tuned by the cellular pathways for vacuolar degradation and recycling, which ultimately facilitate plant growth and cell–environment interactions. The endosomal sorting complex required for transport (ESCRT) machinery plays important roles in regulating intraluminal vesicle (ILV) formation and membrane protein sorting to vacuoles. We previously showed that the plant-specific ESCRT component FYVE DOMAIN PROTEIN REQUIRED FOR ENDOSOMAL SORTING1 (FREE1) performs multiple functions in plants, although the underlying mechanisms remain elusive. In this study, we performed a suppressor screen of the FREE1-RNAi mutant and identified and characterized 2 suppressor of free1 (sof) mutants in Arabidopsis (Arabidopsis thaliana). These mutants, sof10 and sof641, result in a premature stop codon or a missense mutation in AT5G10370, respectively. This gene was named DEAH and RING domain-containing protein as FREE1 suppressor 1 (DRIF1). DRIF1 has a homologous gene, DRIF2, in the Arabidopsis genome with 95% identity to DRIF1. The embryos of drif1 drif2 mutants arrested at the globular stage and formed enlarged multivesicular bodies (MVBs) with an increased number of ILVs. DRIF1 is a membrane-associated protein that coordinates with retromer component sorting nexin 1 to regulate PIN-FORMED2 recycling to the plasma membrane. Altogether, our data demonstrate that DRIF1 is a unique retromer interactor that orchestrates FREE1-mediated ILV formation of MVBs and vacuolar sorting of membrane proteins for degradation in plants.
Baseline predictors of disease severity in immune checkpoint inhibitor-induced inflammatory arthritis
Authors: Cappelli Laura C , Kamal Omer , Jones Michelle , Bingham Clifton O , Shah Ami A 
Published: August 2023

Abstract

Objectives
The objective of this study was to determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor–induced inflammatory arthritis (ICI–inflammatory arthritis).

Methods
Participants were adults with rheumatologist diagnosed ICI–inflammatory arthritis. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of inflammatory arthritis &gt;6 months after ICI cessation and requirement of CSs. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate.

Results
One hundred and twenty-six patients with ICI–inflammatory arthritis were included; 53 patients (42%) required a csDMARD/bDMARD. In the univariate logistic regression analysis, higher clinical disease activity index (CDAI), tenosynovitis, longer symptom duration before first rheumatology visit and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; in addition, there was a trend towards those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4)/PD-1 (Programmed cell death protein-1) therapy and CS use at baseline were associated with a higher risk of persistent inflammatory arthritis.

Conclusion
Higher levels of disease activity, tenosynovitis and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI–inflammatory arthritis, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial CS dose, earlier rheumatology referral, and adoption of immunosuppression beyond CSs to improve outcomes.
A four-asset technology-based growth policy
Authors: Tassey Gregory 
Published: August 2023

Abstract
This paper presents the rationale for a four-asset growth policy model, which the US economy has executed only on a partial and intermittent basis over the past four decades. The need for such a model is driven by (1) growing global competition, (2) resulting slower gross domestic product and personal income growth, and (3) a consequent rise in income inequality. Without a more effective growth model to both broaden and deepen the role of technology, declining growth and its skewed distribution among income classes will perpetuate current social and political unrest. To achieve both broader and deeper technology-based growth across the economy, the proposed technology element model specifies the four major asset categories that characterize technology-based economic development, which combine to drive more effective growth policy analysis and development.
Policy Effects on Mixed-Citizenship, Same-Sex Unions: A Triple-Difference Analysis
Authors: Hoffmann Nathan I , Velasco Kristopher 
Published: August 2023

Abstract
After the U.S. Supreme Court struck down the Defense of Marriage Act (DOMA) in 2013, same-sex partners of U.S. citizens became eligible for spousal visas. Since then, the United States has seen a rapid rise in same-sex, mixed-citizenship couples. However, this effect varies greatly depending on the lesbian, gay, and bisexual (LGB) policy context of the noncitizen’s country of origin. Using waves 2008–2019 of the American Community Survey, this study employs a triple-difference design to examine how the policy environment of the origin country moderates the effect of the end of DOMA on incidence of mixed-citizenship, same-sex couples in the United States. Quasi-Poisson models with two-way fixed effects show that, after 2013, individuals in mixed-citizenship, same-sex couples coming from countries with progressive LGB policies saw a more than 60% increase in incidence relative to those in different-sex or same-citizenship couples. Meanwhile, those from countries with regressive laws experienced no significant increase. These results are corroborated by analyses of individual policies. We argue that the country-of-origin policy context affects and is affected by local norms and attitudes as well as individuals’ material circumstances. This nexus of factors leaves a lasting impact on immigrants that shapes migration decisions, union formation, and responses to policy shifts.