bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-flowering richness has variable effects on pollen quantity and quality limitation in four Clarkia species
Authors: Albor Cristopher , Eisen Katherine , Moore Emma , Geber Monica , Ashman Tia-Lynn , Raguso Robert A , Arceo-Gómez Gerardo
Published: August 2024

Background and Aims

Pollination failure occurs from insufficient pollen quantity or quality. However, the relative contributions of pollen quantity vs. quality to overall pollen limitation, and how this is affected by the co-flowering context, remain unknown for most plant populations. Here, we studied patterns of pollen deposition and pollen tube formation across populations of four predominately outcrossing species in the genus Clarkia to evaluate how the richness of co-flowering congeners affects the contribution of pollen quantity and quality to pollen limitation.

Methods

We partition variation in pollen deposition and pollen tube production across individuals, populations and species to identify the main sources of variation in components of reproductive success. We further quantify the relative contribution of pollen quantity and quality limitation to the reproductive success of the four Clarkia species using piecewise regression analyses. Finally, we evaluate how variation in the number of co-flowering Clarkia species in the community affects the strength of pollen quality and quality limitation.

Results

Across all contexts, pollen deposition and the proportion of pollen tubes produced varied greatly among individuals, populations and species, and these were not always correlated. For instance, C. xantiana received the smallest pollen loads yet produced the highest proportion of pollen tubes, while C. speciosa exhibited the opposite pattern. Yet, co-flowering richness had variable effects on the strength of pollen quantity and quality limitation among populations. Specifically, breakpoint values, which are an indicator of overall pollen limitation, were two-fold higher in the four-species community compared with one- and two-species communities for two Clarkia species, suggesting that pollen limitation can increase with increasing richness of co-flowering congeners.

Conclusions

Our results reveal a complex interplay between the quantity and quality of pollen limitation and co-flowering context that may have different evolutionary outcomes across species and populations.
Automated Neuropsychological Assessment Metrics: Normative Reference Values for U. S. Army National Guard Soldiers
Authors: Heaton Kristin J , Donovan Ashley A , Haven Caitlin , Finkelstein Katherine , Ekon Nicole , Choffnes Sarah , Nguyen Vy T , Vincent Andrea S , Proctor Susan P
Published: August 2024

Objective

The Automated Neuropsychological Assessment Metrics (ANAM) is a computerized cognitive test system used extensively with military service members. The aim of this study was to develop a nationally representative normative dataset of Army National Guard (ARNG) personnel and to explore potential relationships between ANAM performances and select military service, demographic, and health factors.

Methods

ANAM performance data were collected using standardized procedures from a representative sample of ARNG service members in six U.S. states. Normative performance values, stratified by age, sex, and military occupational category, were calculated for each ANAM subtest and descriptive measures were computed, along with base rates of below-average performance. The effect of demographic (e.g., age, sex, education, race) and military service and health factors (e.g., deployment, job category, history of head injury) was examined.

Results

Data from 1,436 ARNG service members (14.3% female) were analyzed, and normative values calculated. Overall, differences in ANAM performance based on demographic, military service, and health factors were small. A total of 8.9% of the sample had scores on two or more subtests that were ≥ 1.3 SD below the mean; this dropped to 1.9% using a more stringent cut point (≥2 SD below the mean).

Conclusion

The ANAM normative data reported herein ensure that healthcare providers and researchers have access to reference data that more accurately reflect the larger population of ARNG service members. These data support the assessment and management of ARNG service members’ health, as well as future ANAM research involving ARNG service members.
Performance assessment of computational tools to detect microsatellite instability
Authors: Anthony Harrison , Seoighe Cathal
Published: August 2024

Microsatellite instability (MSI) is a phenomenon seen in several cancer types, which can be used as a biomarker to help guide immune checkpoint inhibitor treatment. To facilitate this, researchers have developed computational tools to categorize samples as having high microsatellite instability, or as being microsatellite stable using next-generation sequencing data. Most of these tools were published with unclear scope and usage, and they have yet to be independently benchmarked. To address these issues, we assessed the performance of eight leading MSI tools across several unique datasets that encompass a wide variety of sequencing methods. While we were able to replicate the original findings of each tool on whole exome sequencing data, most tools had worse receiver operating characteristic and precision-recall area under the curve values on whole genome sequencing data. We also found that they lacked agreement with one another and with commercial MSI software on gene panel data, and that optimal threshold cut-offs vary by sequencing type. Lastly, we tested tools made specifically for RNA sequencing data and found they were outperformed by tools designed for use with DNA sequencing data. Out of all, two tools (MSIsensor2, MANTIS) performed well across nearly all datasets, but when all datasets were combined, their precision decreased. Our results caution that MSI tools can have much lower performance on datasets other than those on which they were originally evaluated, and in the case of RNA sequencing tools, can even perform poorly on the type of data for which they were created.
Synthesis of geometrically realistic and watertight neuronal ultrastructure manifolds for in silico modeling
Authors: Abdellah Marwan , Foni Alessandro , Cantero Juan José García , Guerrero Nadir Román , Boci Elvis , Fleury Adrien , Coggan Jay S , Keller Daniel , Planas Judit , Courcol Jean-Denis , Khazen Georges
Published: August 2024

Understanding the intracellular dynamics of brain cells entails performing three-dimensional molecular simulations incorporating ultrastructural models that can capture cellular membrane geometries at nanometer scales. While there is an abundance of neuronal morphologies available online, e.g. from NeuroMorpho.Org, converting those fairly abstract point-and-diameter representations into geometrically realistic and simulation-ready, i.e. watertight, manifolds is challenging. Many neuronal mesh reconstruction methods have been proposed; however, their resulting meshes are either biologically unplausible or non-watertight. We present an effective and unconditionally robust method capable of generating geometrically realistic and watertight surface manifolds of spiny cortical neurons from their morphological descriptions. The robustness of our method is assessed based on a mixed dataset of cortical neurons with a wide variety of morphological classes. The implementation is seamlessly extended and applied to synthetic astrocytic morphologies that are also plausibly biological in detail. Resulting meshes are ultimately used to create volumetric meshes with tetrahedral domains to perform scalable in silico reaction-diffusion simulations for revealing cellular structure–function relationships. Availability and implementation: Our method is implemented in NeuroMorphoVis, a neuroscience-specific open source Blender add-on, making it freely accessible for neuroscience researchers.
Pustular mycosis fungoides has a poor outcome: a multicentric clinicopathological and molecular case series
Authors: Bontoux Christophe , Badrignans Marine , Afach Sivem , Sbidian Emilie , Mboumba Diana-Laure , Ingen-Housz-Oro Saskia , Claudel Alexis , Aubriot-Lorton Marie-Hélène , Chong-Si-Tsaon Arnaud , Le Masson Gilles , Attencourt Christophe , Dubois Romain , Beltzung Fanny , Koubaa Wafa , Beltraminelli Helmut , Cardot-Leccia Nathalie , Balme Brigitte , Nguyen Anh tuan , Bagny Kelly , Legoupil Delphine , Moustaghfir Ibtissam , Denamps Juliette , Mortier Laurent , Hammami-Ghorbel Houda , Skrek Sergey , Rafaa Mostefa , Fougerousse Anne-Claire , Deschamps Thibaut , Dalle Stéphane , D’incan Michel , Chaby Guillaume , Beylot-Barry Marie , Dalac Sophie , Ortonne Nicolas
Published: August 2024

Background

Mycosis fungoides (MF) usually has an indolent course. However, some patients develop more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis.

Objectives

To describe the clinicopathological characteristics and prognostic value of pMF.

Methods

We retrospectively collected data from all patients with MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinicopathological characteristics of pMF at diagnosis (pMFD) were compared with those of a cohort of patients with nonpustular MF (NpMF).

Results

Thirty-three patients with pMF (including 22 with pMFD) and 86 with NpMF were included. Median age at diagnosis of pMF was 61 years [interquartile range (IQR) 50–75]. The median duration of follow-up for patients with pMFD was 32 months (IQR 14–49). Clinically, 33% of patients with pMF had pustules. Large cell transformation (LCT) occurred in 17 patients. Patients with pMFD had significantly more advanced-stage disease and showed more LCT at diagnosis than those with NpMF [50% vs. 7% (P < 0.001) and 23% vs. 0% (P < 0.001), respectively]. On multivariate Cox analysis, the presence of histological pustules at diagnosis was associated with shorter overall survival (OS) in all patients [hazard ratio (HR) 13.90, 95% confidence interval (CI) 2.40–79.00); P = 0.003] and in patients with early-stage disease (HR 11.09, 95% CI 1.56–78.82; P = 0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (subdistribution HR 13.90, 95% CI 2.43–79.00; P = 0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up in all patients with pMF was 37 months, with a 5-year OS rate of 25% (95% CI 0.06–0.50).

Conclusions

pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for patients with early-stage disease. Histological pustules at diagnosis of MF might represent an independent poor prognostic factor, to be confirmed by further studies. As pustules are not always identified clinically, pustules found on histology should be mentioned in MF pathology reports and should prompt discussion of closer follow-up.
JC virus spread is potentiated by glial replication and demyelination-linked glial proliferation
Authors: Li Cui , Huynh Nguyen P T , Schanz Steven J , Windrem Martha S , Goldman Steven A
Published: August 2024

Progressive multifocal leukoencephalopathy is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T-antigen-triggered mitosis, enabling viral replication. We asked whether JCV spread might therefore be accelerated by glial proliferation.

Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single-cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of glial progenitor cells. Importantly, in vivo infection triggered the death of both uninfected and infected glia, reflecting significant bystander death.

Together, these data suggest that JCV propagation in progressive multifocal leukoencephalopathy might be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination might provide an especially favourable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.
Histological features of immune cell infiltrate in lesional skin correlate with therapeutic response to dupilumab
Authors: Gori Niccolò , Chiricozzi Andrea , Sfregola Stefania , Ippoliti Elena , Di Stefani Alessandro , Malvaso Dalma , Di Nardo Lucia , Federico Francesco , Zannoni Gian Franco , Peris Ketty
Published: August 2024

Over the past decade, dupilumab, a monoclonal human antibody that inhibits interleukin (IL)-4 and IL-13 signalling, has revolutionized the therapeutic management of moderate-to-severe atopic dermatitis (AD), facilitating long-term control of its signs and symptoms. The aim of this study was to identify histological predictors of the efficacy of dupilumab after 16 weeks of treatment in a cohort of 40 adults with moderate-to-severe AD who had undergone a skin biopsy for diagnostic purposes before treatment initiation. We found that Eczema Area and Severity Index (EASI) 75 and EASI 90 responses at week 16 were significantly associated with perivascular localization [odds ratio (OR) 17.6; P = 0.04] and lichenoid distribution (OR 31.8; P = 0.03) of the immune infiltrate. Moreover, for each unit increase in the number (cells mm–2) of CD4+ cells, the likelihood of achieving an EASI 75 response decreased by 1% (OR 0.99; P = 0.04). In conclusion, our study found promising pretreatment immunohistochemical markers that could predict how well patients with AD respond to dupilumab.
Prevalence and clinical significance of anti-SSA antibody in the Chinese health screening population
Authors: Jia Yimeng , Luan Shuqi , Huang Sicheng , Zhang Wen , Li Mengtao , Xu Tengda , Fei Yunyun
Published: August 2024

Anti-Sjögren's syndrome type A (anti-SSA) antibodies are non-organ-specific autoantibodies highly prevalent in various autoimmune diseases. This study primarily investigated the prevalence of anti-SSA antibodies in the health screening population. Additionally, we explored the clinical features of the anti-SSA antibody-positive population and evaluated the development of connective tissue diseases (CTD) over the years in individuals with anti-SSA antibodies for whom follow-up was available. A total of, 64 045 individuals without a history of CTD from 2013 to 2022 who visited Peking Union Medical College Hospital for health screening were screened for autoimmune antibodies: 1.7% (1091/64 045) of the Chinese health screening population were positive for anti-SSA antibodies, with a prevalence of 0.9% (290/33 829) in men and 2.7% (801/30 216) in women. Compared with matched autoantibody-negative controls, anti-SSA antibody-positive individuals had higher levels of serological abnormalities, including erythrocyte sedimentation rate (ESR) [10 (6–15) mm/h vs. 7 (4–12) mm/h, P < 0.0001], rheumatoid factor (RF) [7.15 (4.30–16.90) IU/ml vs. 5.00 (3.20–7.90) IU/ml, P < 0.0001], and immunoglobulin G [13.09 (11.20–15.45) g/L vs. 11.34 (9.85–13.18) g/L, P < 0.0001], and lower levels of white blood cells (WBC; 5.49 ± 1.50 × 109/L vs. 5.82 ± 1.49 × 109/L, P < 0.0001). Additionally, they had a higher proportion of coexisting thyroid autoantibodies, including anti-thyroid peroxidase antibodies (TPO-Ab) (17.1% vs. 11.3%, P < 0.0001) and anti-thyroglobulin antibodies (Tg-Ab) (17.8% vs. 11.0%, P < 0.0001). Among the 381 subjects who were anti-SSA positive and followed up for a median of 4.6 years, 146 (38.3%) individuals developed CTD, including 68 (17.8%) cases of primary Sjögren’s syndrome (pSS), 10 (2.6%) cases of rheumatoid arthritis (RA), 5 (1.3%) cases of systemic lupus erythematosus (SLE), 4 (1.0%) cases of secondary Sjögren’s syndrome (sSS), and 59 (15.5%) cases of undifferentiated connective tissue disease (UCTD). In all, 235 (61.7%) individuals did not develop CTD over a median time of 5.9 (2.9–8.1) years after the earliest autoantibody detection. Elevated ESR (>20 mm/h), RF positivity (>20 IU/ml), and female gender were identified as independent risk factors for CTD among the anti-SSA antibody-positive individuals. Anti-SSA antibodies were found in 17 among approximately 1000 individuals without a history of autoimmune diseases. Anti-SSA antibody-positive individuals are advised to periodically monitor thyroid function. Elevated ESR (>20 mm/h), female gender, and RF positivity may delineate a high-risk cohort for CTDs.
Medial to lateral frontal functional connectivity mapping reveals the organization of cingulate cortex
Authors: Ducret Marion , Giacometti Camille , Dirheimer Manon , Dureux Audrey , Autran-Clavagnier Delphine , Hadj-Bouziane Fadila , Verstraete Charles , Lamberton Franck , Wilson Charles R E , Amiez Céline , Procyk Emmanuel
Published: August 2024

The functional organization of the frontal lobe is a source of debate, focusing on broad functional subdivisions, large-scale networks, or local refined specificities. Multiple neurocognitive models have tried to explain how functional interactions between cingulate and lateral frontal regions contribute to decision making and cognitive control, but their neuroanatomical bases remain unclear. We provide a detailed description of the functional connectivity between cingulate and lateral frontal regions using resting-state functional MRI in rhesus macaques. The analysis focuses on the functional connectivity of the rostral part of the cingulate sulcus with the lateral frontal cortex. Data-driven and seed-based analysis revealed three clusters within the cingulate sulcus organized along the rostro-caudal axis: the anterior, mid, and posterior clusters display increased functional connectivity with, respectively, the anterior lateral prefrontal regions, face–eye lateral frontal motor cortical areas, and hand lateral frontal motor cortex. The location of these clusters can be predicted in individual subjects based on morphological landmarks. These results suggest that the anterior cluster corresponds to the anterior cingulate cortex, whereas the posterior clusters correspond to the face–eye and hand cingulate motor areas within the anterior midcingulate cortex. These data provide a comprehensive framework to identify cingulate subregions based on functional connectivity and local organization.
Anterior cingulate cortex lesions impair multiple facets of task engagement not mediated by dorsomedial striatum neuron firing
Authors: Vázquez Daniela , Peña-Flores Norma , Maulhardt Sean R , Solway Alec , Charpentier Caroline J , Roesch Matthew R
Published: August 2024

The anterior cingulate cortex (ACC) has been implicated across multiple highly specialized cognitive functions—including task engagement, motivation, error detection, attention allocation, value processing, and action selection. Here, we ask if ACC lesions disrupt task performance and firing in dorsomedial striatum (DMS) during the performance of a reward-guided decision-making task that engages many of these cognitive functions. We found that ACC lesions impacted several facets of task performance—including decreasing the initiation and completion of trials, slowing reaction times, and resulting in suboptimal and inaccurate action selection. Reductions in movement times towards the end of behavioral sessions further suggested attenuations in motivation, which paralleled reductions in directional action selection signals in the DMS that were observed later in recording sessions. Surprisingly, however, beyond altered action signals late in sessions—neural correlates in the DMS were largely unaffected, even though behavior was disrupted at multiple levels. We conclude that ACC lesions result in overall deficits in task engagement that impact multiple facets of task performance during our reward-guided decision-making task, which—beyond impacting motivated action signals—arise from dysregulated attentional signals in the ACC and are mediated via downstream targets other than DMS.
Laminar pattern of sensory-evoked dynamic high-frequency oscillatory activity in the macaque auditory cortex
Authors: Kajikawa Yoshinao , Mackey Chase A , O’Connell Monica Noelle
Published: August 2024

High-frequency (>60 Hz) neuroelectric signals likely have functional roles distinct from low-frequency (<30 Hz) signals. While high-gamma activity (>60 Hz) does not simply equate to neuronal spiking, they are highly correlated, having similar information encoding. High-gamma activity is typically considered broadband and poorly phase-locked to sensory stimuli and thus is typically analyzed after transformations into absolute amplitude or spectral power. However, those analyses discard signal polarity, compromising the interpretation of neuroelectric events that are essentially dipolar. In the spectrotemporal profiles of field potentials in auditory cortex, we show high-frequency spectral peaks not phase-locked to sound onset, which follow the broadband peak of phase-locked onset responses. Isolating the signal components comprising the high-frequency peaks reveals narrow-band high-frequency oscillatory events, whose instantaneous frequency changes rapidly from >150 to 60 Hz, which may underlie broadband high-frequency spectral peaks in previous reports. The laminar amplitude distributions of the isolated activity had two peak positions, while the laminar phase patterns showed a counterphase relationship between those peaks, indicating the formation of dipoles. Our findings suggest that nonphase-locked HGA arises in part from oscillatory or recurring activity of supragranular-layer neuronal ensembles in auditory cortex.
PITX2 deficiency leads to atrial mitochondrial dysfunction
Authors: Reyat Jasmeet S , Sommerfeld Laura C , O’Reilly Molly , Roth Cardoso Victor , Thiemann Ellen , Khan Abdullah O , O’Shea Christopher , Harder Sönke , Müller Christian , Barlow Jonathan , Stapley Rachel J , Chua Winnie , Kabir S Nashitha , Grech Olivia , Hummel Oliver , Hübner Norbert , Kääb Stefan , Mont Lluis , Hatem Stéphane N , Winters Joris , Zeemering Stef , Morgan Neil V , Rayes Julie , Gehmlich Katja , Stoll Monika , Brand Theresa , Schweizer Michaela , Piasecki Angelika , Schotten Ulrich , Gkoutos Georgios V , Lorenz Kristina , Cuello Friederike , Kirchhof Paulus , Fabritz Larissa
Published: August 2024

Aims

Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood.

Methods and results

To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria.

Conclusion

PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.
Evaluating the impacts of digital ECG denoising on the interpretive capabilities of healthcare professionals
Authors: McKenna Stacey , McCord Naomi , Diven Jordan , Fitzpatrick Matthew , Easlea Holly , Gibbs Austin , Mitchell Andrew R J
Published: August 2024

Aims

Electrocardiogram (ECG) interpretation is an essential skill across multiple medical disciplines; yet, studies have consistently identified deficiencies in the interpretive performance of healthcare professionals linked to a variety of educational and technological factors. Despite the established correlation between noise interference and erroneous diagnoses, research evaluating the impacts of digital denoising software on clinical ECG interpretation proficiency is lacking.

Methods and results

Forty-eight participants from a variety of medical professions and experience levels were prospectively recruited for this study. Participants’ capabilities in classifying common cardiac rhythms were evaluated using a sequential blinded and semi-blinded interpretation protocol on a challenging set of single-lead ECG signals (42 × 10 s) pre- and post-denoising with robust, cloud-based ECG processing software. Participants’ ECG rhythm interpretation performance was greatest when raw and denoised signals were viewed in a combined format that enabled comparative evaluation. The combined view resulted in a 4.9% increase in mean rhythm classification accuracy (raw: 75.7% ± 14.5% vs. combined: 80.6% ± 12.5%, P = 0.0087), a 6.2% improvement in mean five-point graded confidence score (raw: 4.05 ± 0.58 vs. combined: 4.30 ± 0.48, P < 0.001), and 9.7% reduction in the mean proportion of undiagnosable data (raw: 14.2% ± 8.2% vs. combined: 4.5% ± 2.4%, P < 0.001), relative to raw signals alone. Participants also had a predominantly positive perception of denoising as it related to revealing previously unseen pathologies, improving ECG readability, and reducing time to diagnosis.

Conclusion

Our findings have demonstrated that digital denoising software improves the efficacy of rhythm interpretation on single-lead ECGs, particularly when raw and denoised signals are provided in a combined viewing format, warranting further investigation into the impact of such technology on clinical decision-making and patient outcomes.
The AORTA Gene score for detection and risk stratification of ascending aortic dilation
Authors: Pirruccello James P , Khurshid Shaan , Lin Honghuang , Weng Lu-Chen , Zamirpour Siavash , Kany Shinwan , Raghavan Avanthi , Koyama Satoshi , Vasan Ramachandran S , Benjamin Emelia J , Lindsay Mark E , Ellinor Patrick T
Published: August 2024

Background and Aims

This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone.

Methods

Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants.

Results

AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%–41.8%) vs. 29.3% (27.0%–31.5%) in UK Biobank, 36.5% (34.4%–38.5%) vs. 32.5% (30.4%–34.5%) in MGB, 41.8% (37.7%–45.9%) vs. 33.0% (28.9%–37.2%) in FHS, and 34.9% (28.8%–41.0%) vs. 28.9% (22.9%–35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P < .0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P < .0001), 0.856 vs. 0.818 in FHS (P < .0001), and 0.827 vs. 0.791 (P = .0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P = .0042) and All of Us (P = .049).

Conclusions

A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%–41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors.
Towards a thorough understanding of mammalian glycosylphosphatidylinositol-anchored protein biosynthesis
Authors: Kinoshita Taroh
Published: August 2024

Glycosylphosphatidylinositols (GPIs) are glycolipids found ubiquitously in eukaryotes. They consist of a glycan and an inositol phospholipid, and act as membrane anchors of many cell-surface proteins by covalently linking to their C-termini. GPIs also exist as unlinked, free glycolipids on the cell surface. In human cells, at least 160 proteins with various functions are GPI-anchored proteins. Because the attachment of GPI is required for the cell-surface expression of GPI-anchored proteins, a thorough knowledge of the molecular basis of mammalian GPI-anchored protein biosynthesis is important for understanding the basic biochemistry and biology of GPI-anchored proteins and their medical significance. In this paper, I review our previous knowledge of the biosynthesis of mammalian GPI-anchored proteins and then examine new findings made since 2020.
Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer
Authors: Tuesley Karen M , Spilsbury Katrina , Webb Penelope M , Pearson Sallie-Anne , Donovan Peter , Coory Michael D , Steer Christopher B , Stewart Louise M , Pandeya Nirmala , Protani Melinda M , Dixon-Suen Suzanne , Marquart-Wilson Louise , Jordan Susan J
Published: August 2024

Background

Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users.

Methods

Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004–12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients.

Results

Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up.

Conclusions

Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.
The Limits of Enforcement in Global Financial Governance: Blacklisting in FATF as Rational Myth
Authors: Case-Ruchala Devin , Nance Mark
Published: August 2024

How might international institutions matter? To consider this central question of International Relations, we analyze a most-likely case for the importance of materially driven enforcement: the Financial Action Task Force’s (FATF) use of blacklisting in the global regime targeting money laundering and terrorism financing. Scholars and practitioners often argue that fear of financial harm caused by FATF’s lists explains the near-global commitment to FATF’s standards, even if compliance lags. We search for statistical evidence of this impact across four different measures of financial flows and find that listing is not correlated with financial harm. To explain these null results, we examine bank decision-making and find that the lists’ impact is likely diminished by two overlooked factors: the existence of multiple, competing lists and banks’ access to more fine-grained, client-specific information provided by third-party companies. We interpret this contradiction—a commitment to compliance generated in part by a fear of enforcement, despite a lack of evidence for enforcement’s impact—as a “rational myth.” The results challenge a common understanding of a major global governance regime, confirm ideas about the limited ability of states or International Organizations to control governance outcomes, and advance a new research agenda on the impact of bank decision-making on global governance.
Ecofaunistic Study and Egg Morphology: Egg Laying Behavior of Hydrometra stagnorum (Linnaeus, 1753) (Gerromorpha: Heteroptera) Newly Recorded From the Karabük Province of Western Black Sea (Türkiye)
Authors: Ozdamar Hakan , Kiyak Suat
Published: August 2024

This study examines the egg-laying behavior and egg morphology of Hydrometra stagnorum (Linnaeus, 1753) (Gerromorpha: Heteroptera) to provide ecofaunistic information about the species. Newly recorded H. stagnorum samples were collected from the Karabük province of Western Black Sea region of Türkiye. Physicochemical parameters of the water were also recorded. The morphology and egg-laying behavior of H. stagnorum eggs were identified using a stereo, light and electron microscopy. Mature eggs were observed to be blackish dark brown in color. The study reveals distinctive characteristics of the egg structure and micropyle areas, which may contribute to the classification of the species at the subfamily level. Additionally, it was found that H. stagnorum inhabits high-quality waters.
Photoionization of hydrogen halides using the r-matrix method
Authors: Mahla Sapna , Antony Bobby
Published: August 2024

In this study, we use the UK Molecular r-matrix (ukrmol) codes in the close-coupling approximation to examine the photoionization of hydrogen halides (hydrogen fluoride, hydrogen chloride, and hydrogen bromide). This article reports the total and partial photoionization cross-sections for the $\mathrm{X}^2 \Pi$, $\mathrm{A}^2 \Sigma ^{+}$, and $\mathrm{B}^2 \Sigma ^{+}$ ionic states of these halides. The calculated cross-sections are compared with the available literature, which does not accurately represent the effective cross-sections near the threshold region, which is dominated by the Rydberg series autoionization resonances converging to the $\mathrm{A}^2 \Sigma ^{+}$ ionic state. There seems to have been minimal effort to investigate the Rydberg-bound states of these halides. Meanwhile, the r-matrix approaches have traditionally excelled at characterizing such studies. This indicates the effectiveness of this method for molecular photoionization as well as for understanding the resonant contribution to the photoionization cross-sections. The detailed cross-sections calculated comprise the complex autoionizing resonance structures capable of significantly contributing to the computations of total photoionization rates, which are necessary to maintain a steady state of ionization in astrophysical plasmas. Comparisons with the experimental measurements and the theoretical data generally show reasonable agreement across the reported energy range.
Pain, inconvenience and blame: defining work-related injuries in the veterinary workplace
Authors: Furtado T , Whiting M , Schofield I , Jackson R , Tulloch J S P
Published: August 2024

Background

The veterinary workplace carries a high risk of staff accidents and injuries, yet there is scant research exploring it in comparison with other comparable fields, such as human medicine.

Aims

To understand how veterinary professionals define injuries and to understand what injuries they do, or do not, deem reportable.

Methods

A cross-sectional survey comprising demographic questions and open-text questions was shared with veterinary practice staff across the UK. Data were analysed descriptively and using an inductive content analysis.

Results

There were 740 respondents, who were broadly representative of the veterinary profession. There were differences in how injuries were defined; for example, small animal veterinarians expected injuries to involve blood, while equine and production animal veterinarians were more likely to expect injuries to reduce their ability to perform work and require medical treatment. Many suggested that ‘all’ workplace injuries should be reported; however, ‘minor’ injuries were often overlooked, for example, needlestick injuries did not always meet the criteria of being an ‘injury’. Injuries caused by staff themselves (e.g. trips) were less likely to be reported than injuries that could be blamed on an external factor (e.g. dog bite).

Conclusions

Collectively, the data suggest a wide-ranging perception of risk of injury in practice, with some harms seen as ‘everyday norms’. Veterinary practices should interpret their injury statistics with a high degree of caution. They should explore the microcultures within their practices relating to worker perception of risk, injury and barriers to reporting.
Clarifying Mutual Consent’s Role in Agency Law
Authors: Leow Rachel
Published: August 2024

Important cases and academic commentators have suggested that the mutual consent of principal and agent is necessary for actual authority to be conferred on the agent. The chief purpose of this article is to show that this view of mutual consent’s role in agency law is inaccurate and misleading. Its central claim is that the agent’s consent is not a necessary pre-condition for the conferral of authority. Instead, a principal can confer authority on an agent unilaterally. However, when authority is conferred unilaterally on an agent, the external aspect of agency is fully present, but the internal principal–agent relationship possesses two unique features, one relating to the agent’s duties and the other relating to the agent’s ability to disclaim. The account presented here thus clarifies the proper scope of ‘mutual consent’ justifications in agency. Mutual consent may justify some incidents of agency, but it does not justify them all.
Single nucleotide polymorphisms in SEPALLATA 2 underlie fruit length variation in cucurbits
Authors: Song Weiyuan , Xie Yang , Liu Bin , Huang Yuxiang , Cheng Zhihua , Zhao Zilong , Tian Di , Geng Yan , Guo Jingyu , Li Chuang , She Daixi , Zhong Yanting , Li Min , Liu Liu , Chen Jiacai , Sun Chengzhen , Zhang Xuejun , Zhou Zhaoyang , Lai Jinsheng , Xin Ming , Yan Liying , Zhao Jianyu , Zhang Xiaolan
Published: August 2024

Complete disruption of critical genes is generally accompanied by severe growth and developmental defects, which dramatically hinder its utilization in crop breeding. Identifying subtle changes, such as single-nucleotide polymorphisms (SNPs), in critical genes that specifically modulate a favorable trait is a prerequisite to fulfill breeding potential. Here, we found 2 SNPs in the E-class floral organ identity gene cucumber (Cucumis sativus) SEPALLATA2 (CsSEP2) that specifically regulate fruit length. Haplotype (HAP) 1 (8G2667A) and HAP2 (8G2667T) exist in natural populations, whereas HAP3 (8A2667T) is induced by ethyl methanesulfonate mutagenesis. Phenotypic characterization of 4 near-isogenic lines and a mutant line showed that HAP2 fruits are significantly longer than those of HAP1, and those of HAP3 are 37.8% longer than HAP2 fruit. The increasing fruit length in HAP1-3 was caused by a decreasing inhibitory effect on CRABS CLAW (CsCRC) transcription (a reported positive regulator of fruit length), resulting in enhanced cell expansion. Moreover, a 7638G/A-SNP in melon (Cucumis melo) CmSEP2 modulates fruit length in a natural melon population via the conserved SEP2-CRC module. Our findings provide a strategy for utilizing essential regulators with pleiotropic effects during crop breeding.
Rhizobia cystathionine γ-lyase-derived H2S delays nodule senescence in soybean
Authors: Liu Wuyu , Zhang Weiqin , Cheng Huaping , Ding Yuxin , Yao Baihui , Shangguan Zhouping , Wei Gehong , Chen Juan
Published: August 2024

Hydrogen sulfide (H2S) is required for optimal establishment of soybean (Glycine max)-Sinorhizobium fredii symbiotic interaction, yet its role in regulating the nitrogen fixation-senescence transition remains poorly understood. A S. fredii cystathionine γ-lyase (CSE) mutant deficient in H2S synthesis showed early nodule senescence characterized by reduced nitrogenase activity, structural changes in nodule cells, and accelerated bacteroid death. In parallel, the CSE mutant facilitated the generation of reactive oxygen species (ROS) and elicited antioxidant responses. We observed that H2S-mediated persulfidation of cysteine C31/C80 in ascorbate peroxidase (APX) and C32 in APX2-modulated enzyme activity, thereby participating in hydrogen peroxide (H2O2) detoxification and delaying nodule senescence. Comparative transcriptomic analysis revealed a significant upregulation of GmMYB128, an MYB transcription factor (TF), in the CSE mutant nodules. Functional analysis through overexpression and RNAi lines of GmMYB128 demonstrated its role as a positive regulator in nodule senescence. MYB128-OE inoculated with the CSE mutant strain exhibited a reduction in nitrogenase activity and a significant increase in DD15 expression, both of which were mitigated by NaHS addition. Changes at the protein level encompassed the activation of plant defenses alongside turnover in carbohydrates and amino acids. Our results suggest that H2S plays an important role in maintaining efficient symbiosis and preventing premature senescence of soybean nodules.
A Survey of Short-Selling Regulations
Authors: Edwards Amy K , Reed Adam V , Saffi Pedro A C
Published: August 2024

Given the complex and controversial nature of short-selling regulation, we review the academic literature and provide insights for policy makers and academics. We organize the complex history of short-selling regulation into three areas: trading restrictions, securities lending regulations, and disclosure requirements. We identify, analyze, and discuss 45 distinct regulations promulgated from 1896 to 2021, primarily by reviewing the academic literature and the data sources employed. We provide several insights regarding the effectiveness of regulatory approaches and the wider impact of short-selling regulation on markets. (JEL G2, G12, G14, G15, G34)
Predicting RSO populations using a neighbouring orbits technique
Authors: Cooke Benjamin F , Blake James A , Chote Paul , McCormac James , Pollacco Don
Published: August 2024

The determination of the full population of resident space objects (RSOs) in low Earth orbit (LEO) is a key issue in the field of space situational awareness that will only increase in importance in the coming years. We endeavour to describe a novel method of inferring the population of RSOs as a function of orbital height and inclination for a range of magnitudes. The method described uses observations of an orbit of known height and inclination to detect RSOs on neighbouring orbits. These neighbouring orbit targets move slowly relative to our tracked orbit, and are thus detectable down to faint magnitudes. We conduct simulations to show that, by observing multiple passes of a known orbit, we can infer the population of RSOs within a defined region of orbital parameter space. Observing a range of orbits from different orbital sites will allow for the inference of a population of LEO RSOs as a function of their orbital parameters and object magnitude.
Definitions of and instruments for disease activity, remission and relapse in polymyalgia rheumatica: a systematic literature review
Authors: Bolhuis Thomas E , Bosch Philipp , Falzon Louise , Owen Claire E , Yates Max , Mackie Sarah L , van der Maas Aatke , Dejaco Christian
Published: August 2024

Objective

To perform a systematic literature review on definitions and instruments used to measure remission, relapse and disease activity in polymyalgia rheumatica (PMR), to inform an OMERACT project to endorse instruments for these outcomes.

Methods

A search of Pubmed/MEDLINE, EMBASE, CINAHL, Cochrane and Epistemonikos was performed May 2021 and updated August 2023. Qualitative and quantitative studies published in English were included if they recruited people with isolated PMR regardless of treatment. Study selection and data extraction was performed independently by two investigators and disagreement was resolved through discussion. Data extracted encompassed definitions of disease activity, remission and relapse, and details regarding the instruments used to measure these outcomes.

Results

From the 5718 records, we included 26 articles on disease activity, 36 on remission and 53 on relapse; 64 studies were observational and 15 interventional, and none used qualitative methods. Some heterogeneity was found regarding definitions and instruments encompassing the domains pain, stiffness, fatigue, laboratory markers (mainly acute phase reactants), and patient and physician global assessment of disease activity. However, instruments for clinical signs were often poorly described. Whilst measurement properties of the polymyalgia rheumatica activity score (PMR-AS) have been assessed, data to support its use for measurement of remission and relapse are limited.

Conclusion

Remission, relapse and disease activity have been defined heterogeneously in clinical studies. Instruments to measure these disease states still need to be validated. Qualitative research is needed to better understand the concepts of remission and relapse in PMR.

Review registration

PROSPERO identification: CRD42021255925.
Legal Certainty of Rights and Freedoms in Algeria: Beyond the Constitutionalization
Authors: Ait Aoudia Belkheir Mohamed
Published: August 2024

The principle of legal certainty serves as a crucial safeguard, preventing rights and freedoms from being lost in a vast, complex, and often unstable legal framework. This study delves into the gap in Algerian law between the constitutional text ensuring the legal certainty of rights and freedoms and the lack of detailed measures to implement this provision. By examining how each certainty requirement of rights legislation is applied within the national legal landscape, the study uncovers significant deficiencies in ensuring citizens’ easy access to legislation encompassing their rights and freedoms. Addressing these challenges necessitates the implementation of various legal and technical measures. Furthermore, ensuring the clarity of these laws demands a systematic review process to rectify any drafting flaws. Legislative stability, closely linked to legality in the Algerian constitution, benefits from relatively reliable guarantees in the field of fundamental rights.