bluuebunny/crossref_metadata_2025 huggingface dataset:
An isoflavone catabolism gene cluster underlying interkingdom interactions in the soybean rhizosphere
Authors: Aoki Noritaka , Shimasaki Tomohisa , Yazaki Wataru , Sato Tomoaki , Nakayasu Masaru , Ando Akinori , Kishino Shigenobu , Ogawa Jun , Masuda Sachiko , Shibata Arisa , Shirasu Ken , Yazaki Kazufumi , Sugiyama Akifumi
Published: April 2024

Plant roots secrete various metabolites, including plant specialized metabolites, into the rhizosphere, and shape the rhizosphere microbiome, which is crucial for the plant health and growth. Isoflavones are major plant specialized metabolites found in legume plants, and are involved in interactions with soil microorganisms as initiation signals in rhizobial symbiosis and as modulators of the legume root microbiota. However, it remains largely unknown the molecular basis underlying the isoflavone-mediated interkingdom interactions in the legume rhizosphere. Here, we isolated Variovorax sp. strain V35, a member of the Comamonadaceae that harbors isoflavone-degrading activity, from soybean roots and discovered a gene cluster responsible for isoflavone degradation named ifc. The characterization of ifc mutants and heterologously expressed Ifc enzymes revealed that isoflavones undergo oxidative catabolism, which is different from the reductive metabolic pathways observed in gut microbiota. We further demonstrated that the ifc genes are frequently found in bacterial strains isolated from legume plants, including mutualistic rhizobia, and contribute to the detoxification of the antibacterial activity of isoflavones. Taken together, our findings reveal an isoflavone catabolism gene cluster in the soybean root microbiota, providing molecular insights into isoflavone-mediated legume–microbiota interactions.
Diplomatic Representation and Online/Offline Interactions: EU Coordination and Digital Sociability
Authors: Hedling Elsa
Published: April 2024

European Union (EU) diplomatic representation in third countries is performed by both the Member States and by the EU Delegation. This hybrid system of representation functions through EU coordination. As social media have become important channels of state representation, coordination also takes place in the domain of digital diplomacy. This article analyzes how the EU Member State embassies and the EU Delegation coordinate EU representation through online and offline interactions. It investigates the practices of coordination and maps routines of digital sociability. The United States’ capital Washington, DC provides a context of both strong bilateral relations and a history of shared EU interests. The study draws on observations on Twitter (later renamed X) between 2019 and 2021 and reflections from diplomats who engage in the coordination of EU representation, collected through an online survey and interviews. By examining the reciprocity between online and offline interactions, the study illuminates how relationships are cultivated, a sense of collective belonging is fostered, and social order is negotiated. The findings enhance our understanding of how digital diplomacy is deeply embedded within diplomatic contexts and their distinctive practices. They contribute to advancing knowledge about the interplay of digital diplomacy, multilateral representation, and the dynamics that shape diplomatic engagements.
Positionality Statements as a Function of Coloniality: Interrogating Reflexive Methodologies
Authors: Gani Jasmine K , Khan Rabea M
Published: April 2024

Abstracts

Declaration of positionality and the confession of privilege as a way of revealing unequal power dynamics in knowledge production has become an increasingly encouraged reflexive practice in international relations and other disciplines. However, we interrogate the potentially negative implications of this methodology, occurring through a reification of material, assumed, and imagined hierarchies between people, which then is advertised and (re)produced by its utterance. We further query the modernist origins of reflexive methodology, which has inspired the practice of declaring positionality, and argue that its underpinning coloniality has bearings for its use today. We then explore how this coloniality manifests: Thus, first, we consider the extent to which publicly acknowledging privilege paradoxically acts as a means of centering whiteness through the narcissistic gaze and an assertion of legitimacy. Second, we argue positionality statements offer a redemption of guilt for the hegemonic researcher. And lastly, rather than ameliorating unequal power dynamics in the production of knowledge, we contend positionality statements may constitute hidden power moves in which one is able to signal and reinstate one’s authority vis-à-vis people, but especially women, of color. We end with a call for a reparative scholarship that acknowledges these limitations in positionality statements.
On-time denosumab dosing recovered rapidly during the COVID-19 pandemic, yet remains suboptimal
Authors: Rzepka Anna M , Cheung Angela M , Kim Sandra , Gomes Tara , Cadarette Suzanne M
Published: April 2024

Timely administration of denosumab every 6 mo is critical in osteoporosis treatment to avoid multiple vertebral fracture risk upon denosumab discontinuation or delay. This study aimed to estimate the immediate and prolonged impact of the COVID-19 pandemic on the timing of denosumab doses. We identified older adults (≥66 yr) residing in the community who were due to receive denosumab between January 2016 and December 2020 using Ontario Drug Benefit data. We completed an interrupted time-series analysis to estimate the impact of the COVID-19 pandemic (March 2020) on the monthly proportion of on-time denosumab doses (183 +/−30 d). Analyses were stratified by user type: patients due for their second dose (novice users), third or fourth dose (intermediate users), or ≥5th dose (established users). In additional analyses, we considered patients living in nursing homes, switching to other osteoporosis drugs, and reported trends until February 2022. We studied 148 554 patients (90.9% female, mean [SD] age 79.6 [8.0] yr) receiving 648 221 denosumab doses. The average pre-pandemic proportion of on-time therapy was steady in the community, yet differed by user type: 64.9% novice users, 72.3% intermediate users, and 78.0% established users. We identified an immediate overall decline in the proportion of on-time doses across all user types at the start of the pandemic: −17.8% (95% CI, −19.6, −16.0). In nursing homes, the pre-pandemic proportion of on-time therapy was similar across user types (average 83.5%), with a small decline at the start of the pandemic: −3.2% (95% CI, −5.0, −1.2). On-time therapy returned to pre-pandemic levels by October 2020 and was not impacted by therapy switching. Although on-time dosing remains stable as of February 2022, approximately one-fourth of patients in the community do not receive denosumab on-time. In conclusion, although pandemic disruptions to denosumab dosing were temporary, levels of on-time therapy remain suboptimal.
Factor IV Estimation in Conditional Moment Models with an Application to Inflation Dynamics
Authors: Antoine Bertille , Sun Xiaolin
Published: April 2024

In a conditional moment model, we develop a new integrated conditional moment (ICM) estimator which directly exploits factor-based conditional moment restrictions without having to first parametrize, or estimate such restrictions. We focus on a time series framework where the large number of available instruments and associated lags is driven by a relatively small number of unobserved factors. We build on the ICM principle originally proposed by Bierens (1982) and combine it with information reduction methods to handle the large number of potential instruments which may exceed the sample size. Under the maintained validity of the true factors, but not that of observed instruments, and standard regularity assumptions, our estimator is consistent, asymptotically normally distributed, and easy to compute. In our simulation studies, we document its reliability and power in cases where the underlying relationship between the endogenous variables and the instruments may be heterogeneous, non-linear, or even unstable over time. Our estimation of the New Keynesian Phillips curve with U.S. data reveals that forward- and backward-looking behaviors are quantitatively equally as important, while the driver’s role is nil.
Anterior insula is more vulnerable than posterior insula to TDP-43 pathology in common dementias and ALS
Authors: Lochner Riley H , Arumanayagam Anithachristy S , Powell Suzanne Z , Masdeu Joseph C , Pascual Belen , Cykowski Matthew D
Published: April 2024

Based on the anatomic proximity, connectivity, and functional similarities between the anterior insula and amygdala, we tested the hypothesis that the anterior insula is an important focus in the progression of TDP-43 pathology in LATE-NC. Blinded to clinical and neuropathologic data, phospho-TDP (pTDP) inclusion pathology was assessed in paired anterior and posterior insula samples in 105 autopsied patients with Alzheimer disease, Lewy body disease, LATE-NC and hippocampal sclerosis (HS), amyotrophic lateral sclerosis (ALS), and other conditions. Insular pTDP pathology was present in 34.3% of the study cohort, most commonly as neuronal inclusions and/or short neurites in lamina II, and less commonly as subpial processes resembling those described in the amygdala region. Among positive samples, pTDP pathology was limited to the anterior insula (41.7%), or occurred in both anterior and posterior insula (58.3%); inclusion density was greater in anterior insula across all diseases (p < .001). pTDP pathology occurred in 46.7% of ALS samples, typically without a widespread TDP-43 proteinopathy. In LATE-NC, it was seen in 30.4% of samples (mostly LATE-NC stages 2 and 3), often co-occurring with basal forebrain pathology and comorbid HS, suggesting this is an important step in the evolution of this pathology beyond the medial temporal lobe.
Allelopathic potentials of surrounding vegetation on seedling establishment of alpine cushion Arenaria polytrichoides
Authors: Chen Xu-Fang , Qian Li-Shen , Shi Hong-Hua , Zhang Ya-Zhou , Song Min-Shu , Sun Hang , Chen Jian-Guo
Published: April 2024

When facilitating other species and sustaining plant community structures and biodiversity, alpine cushion plants simultaneously experience negative feedback effects from surrounding vegetation. However, the impact of surrounding vegetation on cushion dynamics remains poorly understood, particularly in terms of allelopathic potentials. To investigate the allelopathic potentials of surrounding vegetation on seedling establishment of the typical cushion plant Arenaria polytrichoides Edgew. along an elevational gradient, we extracted potential allelopathic compounds and tested their impacts on seed germination and seedling growth of A. polytrichoides. In addition, exclusion experiments using activated carbon were conducted to further elucidate these effects. Our results demonstrate that surrounding vegetation exhibits certain allelopathic potentials on A. polytrichoides seedling establishment, with variations observed based on elevation, source and concentration of allelopathy compounds, as well as growing season. Specifically, low-elevation vegetation exerts pronounced suppression on seedling establishment. Conversely, higher-elevation vegetation generally shows no effect on seed germination but stimulates seedling growth through allelopathy mechanisms. Moreover, aboveground vegetation predominantly inhibits both seed germination and seedling growth in low-elevation communities; however, the effects of belowground vegetation depend on elevation and extract concentration levels. The identified allelopathic potentials of surrounding vegetation significantly influence the population dynamics of cushion A. polytrichoides by potentially accelerating population degeneration in lower-elevation communities while ensuring consistent population recruitment and expansion in higher-elevation communities.
Off-label Use of Long-Acting Injectable Antiretroviral Therapy: A Single Center Retrospective Review of Youth Living With HIV With Detectable HIV RNA Starting Injectable Therapy
Authors: Rousseau Alison , McGrath Eric , Benjamins Laura , Cockern Salome , Meade Jill , Houston Keshaum , Breaux Melina , Secord Elizabeth
Published: April 2024

Nineteen youth living with HIV (YLWH) opted for injectable cabotegravir and rilpivirine without oral lead in and without achieving an undetectable HIV viral load (VL) for the 3 months prior to initiation. All achieved undetectable status within 3 months (3 injections) and maintained an undetectable status through 6–12 months of therapy.
How do perceptions, fears, and experiences of violence and conflict affect considerations of moving internally and internationally?
Authors: Hagen-Zanker Jessica , Rubio Marcela G , Erdal Marta Bivand
Published: April 2024

This article draws on cross-country survey and qualitative data for local areas within Afghanistan, Ethiopia, Nigeria, and Somalia to explore how perceptions, fears, and experiences of violence affect how young adults consider whether or not to move, internally, within their own countries, or internationally. We shed new light on how different forms and intensities of violence and conflict, ranging from tribal violence in Northern Nigeria to the encroachment of the Taliban in Afghanistan, affect these considerations. We show that, in most cases, perceiving insecurity, fearing, or having experienced violence does not result in people considering moving. However, where significant, it is specific fears and experiences that affect considerations, rather than general perceptions of insecurity. We observe distinct patterns across the local areas, related to the duration, intensity, and nature of the conflict, underscoring the salience of sub-national-level data to better understand the interplay of conflict and mobility.
Covariate-adaptive randomization inference in matched designs
Authors: Pimentel Samuel D , Huang Yaxuan
Published: April 2024

It is common to conduct causal inference in matched observational studies by proceeding as though treatment assignments within matched sets are assigned uniformly at random and using this distribution as the basis for inference. This approach ignores observed discrepancies in matched sets that may be consequential for the distribution of treatment, which are succinctly captured by within-set differences in the propensity score. We address this problem via covariate-adaptive randomization inference, which modifies the permutation probabilities to vary with estimated propensity score discrepancies and avoids requirements to exclude matched pairs or model an outcome variable. We show that the test achieves type I error control arbitrarily close to the nominal level when large samples are available for propensity score estimation. We characterize the large-sample behaviour of the new randomization test for a difference-in-means estimator of a constant additive effect. We also show that existing methods of sensitivity analysis generalize effectively to covariate-adaptive randomization inference. Finally, we evaluate the empirical value of combining matching and covariate-adaptive randomization procedures using simulations and analyses of genetic damage among welders and right-heart catheterization in surgical patients.
Long-term variability in debris transiting white dwarfs
Authors: Aungwerojwit Amornrat , Gänsicke Boris T , Dhillon Vikram S , Drake Andrew , Inight Keith , Kaye Thomas G , Marsh T R , Mullen Ed , Pelisoli Ingrid , Swan Andrew
Published: April 2024

Combining archival photometric observations from multiple large-area surveys spanning the past 17 years, we detect long-term variability in the light curves of ZTF J032833.52−121945.27 (ZTF J0328−1219), ZTF J092311.41+423634.16 (ZTF J0923+4236), and WD 1145+017, all known to exhibit transits from planetary debris. ZTF J0328−1219 showed an overall fading in brightness from 2011 through to 2015, with a maximum dimming of ≃0.3 mag, and still remains ≃0.1 mag fainter compared to 2006. We complement the analysis of the long-term behaviour of these systems with high-speed photometry. In the case of ZTF J0923+4236 and WD 1145+017, the time-series photometry exhibits vast variations in the level of transit activity, both in terms of numbers of transits, as well as their shapes and depths, and these variations correlate with the overall brightness of the systems. Inspecting the current known sample of white dwarfs with transiting debris, we estimate that similar photometric signatures may be detectable in one in a few hundred of all white dwarfs. Accounting for the highly aligned geometry required to detect transits, our estimates imply that a substantial fraction of all white dwarfs exhibiting photospheric metal pollution from accreted debris host close-in planetesimals that are currently undergoing disintegration.
Evidence that Eddington ratio depends upon a supermassive black hole’s mass and redshift: implications for radiative efficiency
Authors: Aggarwal Yash
Published: April 2024

Presently, it is unclear whether the Eddington ratio (λ) and radiative efficiency (ε) depend on a supermassive black hole’s (SMBH’s) redshift z and mass MBH. We attempt to resolve this issue using published data for 132 000 SMBHs with MBH ≥ 107 Msun (solar masses) at ∼0.1 < z < 2.4 covering ∼10 billion years of cosmic time, with MBH determined using Mg ii lines and bolometric luminosities Lbol based on a weighted mean of Lbol from two or more monochromatic luminosities and a single uniformly applied correction factor. The SMBHs are sorted into seven MBH bins separated from each other by half an order of magnitude. The λ and z data in each bin are subjected to spline regression analysis. The results unambiguously show that for similar-size SMBHs, λ decreases as z decreases, and that for a given redshift, larger SMBHs have a lower λ. These findings require that either an SMBH’s accretion rate and/or its radiative efficiency be a function of z and MBH and, in the context of the Bondi accretion model, imply that radiative efficiency is an inverse function of z and MBH. These findings suggest that SMBHs become less efficient (higher ε) in accreting gases as the ambient gas density decreases with z and that larger SMBHs are more efficient (lower ε) than smaller ones. The results leave little doubt that the current widespread practice of assigning ε a standard value is untenable and gives erroneous estimates of accretion rates and growth times of SMBHs.
Pushing the limits of near-infrared photometry with the Gemini Multi-Conjugate Adaptive Optics System: study of crowded fields in the globular cluster M5
Authors: Kumar Tarun , Turri Paolo , Venn Kim A , Andersen David R , Stetson Peter B , McConnachie Alan W , Taheri Mojtaba
Published: April 2024

We present the deepest J −Ks near-infrared photometry of the globular cluster M5 (NGC 5904) from observations taken with the Gemini South Adaptive Optics Imager in tandem with the Gemini Multi-conjugate adaptive optics System (GeMS) on the 8.1-m Gemini South telescope. Point spread function (PSF) photometry was carried out using a spatially variable PSF, zero-point calibrations based on correlations to a standard photometric catalogue, colour corrections, and crowding corrections. The latter corrections provided a new challenge given the field variations of the adaptive optics corrections in the central crowded regions of this cluster. The final photometric precision in our J− Ks colour–magnitude diagram exposes a dispersion among the lower main-sequence stars of M5 for the first time. This dispersion occurs below a main-sequence knee due to variations in the helium and CNO (carbon, nitrogen, and oxygen) abundances from multiple stellar populations, consistent with results from the bright evolved stars in this cluster from ultraviolet to near-infrared Hubble Space Telescope photometry and ground-based spectroscopy. This paper completes our original GeMS quality analysis programme, providing insights into adaptive optics analyses in crowded fields.
PHL 5038AB: is the brown dwarf causing pollution of its white dwarf host star?
Authors: Casewell S L , Debes J , Dupuy T J , Dufour P , Bonsor A , Rebassa-Mansergas A , Murillo-Ojeda R , French J R , Alexander R D , Xu Siyi , Martin E , Manjavacas E
Published: April 2024

We present new results on PHL 5038AB, a widely separated binary system composed of a white dwarf and a brown dwarf, refining the white and brown dwarf parameters and determining the binary separation to be $66^{+12}_{-24}$ au. New spectra of the white dwarf show calcium absorption lines suggesting that the hydrogen-rich atmosphere is weakly polluted, inferring the presence of planetesimals in the system, which we determine are in an S-type orbit around the white dwarf in orbits closer than 17–32 au. We do not detect any infrared excess that would indicate the presence of a disc, suggesting that all dust present either has been totally accreted or is optically thin. In this system, we suggest that the metal pollution in the white dwarf atmosphere can be directly attributed to the presence of the brown dwarf companion disrupting the orbits of planetesimals within the system.
Tracing the evolving X-ray reverberation lags within an individual AGN light curve
Authors: Nakhonthong N , Chainakun P , Luangtip W , Young A J
Published: April 2024

We present the Granger causality (GC) test for the X-ray reverberation analysis of Active Galactic Nuclei (AGNs). If the light curves in the continuum-dominated band help predict (Granger cause) those dominated by reflection, the Granger lags that associate to the intrinsic reverberation lags can be inferred. We focus on six AGNs observed by XMM–Newton, including the sources well-known to exhibit clear X-ray reverberation lags (IRAS 13224−3809 and 1H 0707−495) and those in which reverberation signatures are not well confirmed (MCG–6-30-15, IZW1, Mrk 704, and Mrk 1040). We employ the sliding-window algorithm and estimate the Granger (intrinsic) Fe-L lags along the light curve as the window moves through. This reveals the evolving lags towards the end of some individual observations, suggesting that the corona varies progressively. Occasionally, we observe two clearly separate lags that suggest an extended corona consisting of two zones while producing competing reverberation of two lags. While the GC test is purely hypothetical and might not explain true causality, our conclusion is that the lags are present and could be understood as reverberation lags. Assuming the lags changing solely with the corona, we find that the IRAS 13224−3809 corona varies between ∼10 and 25 rg and sometimes move to ≳50 rg. The corona of 1H 0707−495 and MCG–6-30-15 may be analogous to that of IRAS 13224−3809, while in IZw1, Mrk 704, and Mrk 1040, a more compact corona is expected.
Remove First Detect Later: a counter-intuitive approach for detecting radio frequency interference in radio sky imagery
Authors: van Zyl Daniel J , Grobler Trienko L
Published: April 2024

The modern era has witnessed a rapid uptake of technological use – from air travel to mobile cellphones. Technological advancement has however come at the cost of radio spectrum crowding and as such the efficient detection of radio frequency interference (RFI) from radio sky images has become more paramount. Detecting RFI is a complex task that blends semantic segmentation and anomaly detection, further complicated by the limited availability of public data sets with accurate ground truth labels. Recent studies show that deep learning models improve RFI detection compared to current state-of-the-art tools. However, many astronomers are hesitant to adopt these models, possibly due to the dependence of these models on noisy labels from existing tools when accurate ground truth labels are largely unavailable in the public domain. This study argues that utilizing large weakly labelled training data sets yields lower performance than appropriately employing a modest set of expertly annotated samples. Further, Remove First Detect Later (RFDL), an augmented deep learning framework, is proposed. First, counter-intuitively, removing RFI with inpainting, RFDL feeds the difference between the original and inpainted images into existing detection models. RFDL’s performance is benchmarked against current state-of-the-art deep learning methods and the prevalent AOFlagger pipeline, using AUROC, AUPRC, and F1 score metrics. It is shown that RFDL significantly outperforms the state-of-the-art while only necessitating the use of 20 expertly labelled images.
MeerKAT and ALMA view of the AGAL045.804 − 0.356 clump
Authors: Seidu Mavis , Chibueze J O , Fuller Gary A , Avison A , Asabre Frimpong N
Published: April 2024

This study presents a detailed analysis of the GAL045.804 − 0.356 massive star-forming clump. A high-angular resolution and sensitivity observations were conducted using MeerKAT at 1.28 GHz and ALMA interferometer at 1.3 mm. Two distinct centimetre radio continuum emissions (source A and source B) were identified within the clump. A comprehensive investigation was carried out on source A, the G45.804 − 0.355 star-forming region (SFR) due to its association with Extended Green Object (EGO), 6.7 GHz methanol maser and the spatial coincidence with the peak of the dust continuum emission at 870 µm. The ALMA observations revealed seven dense dust condensations (MM1–MM7) in source A. The brightest (Sν ∼ 87 mJy) and massive main dense core, MM1, was co-located with the 6.7 GHz methanol maser. Explorations into the kinematics revealed gas motions characterized by a velocity gradient across the MM1 core. Furthermore, molecular line emission showed the presence of an extended arm-like structure, with a physical size of 0.25 pc × 0.18 pc (∼ 50 000 au × 30 000 au) at a distance of 7.3 kpc. Amongst these arms, two arms were prominently identified in both the dust continuum and some of the molecular lines. A blue-shifted absorption P-Cygni profile was seen in the H2CO line spectrum. The findings of this study are both intriguing and new, utilizing data from MeerKAT and ALMA to investigate the characteristics of the AGAL45 clump. The evidence of spiral arms, the compact nature of the EGO and < 2 km s−1 velocity gradient are all indicative of G45.804 − 0.355 being oriented face-on.
SIDE-real: Supernova Ia Dust Extinction with truncated marginal neural ratio estimation applied to real data
Authors: Karchev Konstantin , Grayling Matthew , Boyd Benjamin M , Trotta Roberto , Mandel Kaisey S , Weniger Christoph
Published: April 2024

We present the first fully simulation-based hierarchical analysis of the light curves of a population of low-redshift type Ia supernovæ (SNæ Ia). Our hardware-accelerated forward model, released in the Python package slicsim, includes stochastic variations of each SN’s spectral flux distribution (based on the pre-trained BayeSN model), extinction from dust in the host and in the Milky Way, redshift, and realistic instrumental noise. By utilizing truncated marginal neural ratio estimation (TMNRE), a neural network-enabled simulation-based inference technique, we implicitly marginalize over 4000 latent variables (for a set of ≈100 SNæ Ia) to efficiently infer SN Ia absolute magnitudes and host-galaxy dust properties at the population level while also constraining the parameters of individual objects. Amortization of the inference procedure allows us to obtain coverage guarantees for our results through Bayesian validation and frequentist calibration. Furthermore, we show a detailed comparison to full likelihood-based inference, implemented through Hamiltonian Monte Carlo, on simulated data and then apply TMNRE to the light curves of 86 SNæ Ia from the Carnegie Supernova Project, deriving marginal posteriors in excellent agreement with previous work. Given its ability to accommodate arbitrarily complex extensions to the forward model, e.g. different populations based on host properties, redshift evolution, complicated photometric redshift estimates, selection effects, and non-Ia contamination, without significant modifications to the inference procedure, TMNRE has the potential to become the tool of choice for cosmological parameter inference from future, large SN Ia samples.
The relationship between Behçet’s disease and the quality of life for pediatric patients and their parents
Authors: Şahin Nihal , Bayrak Yunus E , Sönmez Hafize E , Sözeri Betül
Published: April 2024

Objectives

Chronic diseases impact people’s quality of life (QoL). Behçet’s disease (BD) is a multisystemic chronic disease characterized by vasculitis of various vessels. We aimed to assess QoL in paediatric BD (PEDBD) patients and their parents.

Methods

We conducted a cross-sectional study from June to December 2022, including PEDBD patients meeting classification criteria. We recorded clinical characteristics and assessed QoL using PedsQL for patients and WHOQOL-Bref for parents.

Results

A study of 38 patients (60.5% girls, 39.5% boys), median age 15.5 years (range 10–17), with oral aphthae and various mucocutaneous symptoms: genital ulcers (78.9%), pseudofolliculitis (76.3%), erythema nodosum (23.6%), and some with uveitis (13.1%), vascular (13.1%), neurological (10.5%), and gastrointestinal (5.2%) involvement. All were in remission under treatment. Median PedsQL scores: total 74.5 (range 40–94.8), physical health 76.5 (43–100), psychosocial health 75 (25–92); 14 patients scored below cutoff. Girls had lower physical health scores (P = .004), and disease duration correlated negatively with PedsQL score (r = -0.648, P = .001). Median WHOQOL score for parents: 50 (25–100), with 20 scoring below cutoff.

Conclusion

One-third of PEDBD children and over half of their parents had low QoL. Disease duration and gender, as with many chronic illnesses, correlated with QoL in PEDBD.
Self-amplifying RNAs generated with the modified nucleotides 5-methylcytidine and 5-methyluridine mediate strong expression and immunogenicity in vivo
Authors: Azizi Hiva , Renner Tyler M , Agbayani Gerard , Simard Bryan , Dudani Renu , Harrison Blair A , Iqbal Umar , Jia Yimei , McCluskie Michael J , Akache Bassel
Published: April 2024

When utilized in therapeutic applications, synthetic self-amplifying RNA (saRNA) can lead to higher and more sustained expression than standard messenger RNA (mRNA). This feature is particularly important for gene replacement therapy applications where prolonged expression could reduce the dose and frequency of treatments. The inclusion of modified nucleotides in synthetic non-amplifying mRNA has been shown to increase RNA stability, reduce immune activation and enhance gene expression. Preclinical and clinical studies with saRNA have so far exclusively relied on RNA containing the canonical nucleotides adenosine, cytidine, guanosine and uridine. For the first time, we show that noncanonical nucleotides, such as 5-methylcytidine (m5C) and 5-methyluridine (m5U), are sufficiently compatible with a replicon derived from Venezuelan equine encephalitis alphavirus mediating protein translation in vitro, while those containing N1-methylpseudouridine in place of uridine show no detectable expression. When administered in vivo, saRNA generated with m5C or m5U mediates sustained gene expression of the luciferase reporter gene, with those incorporating m5U appearing to lead to more prolonged expression. Finally, distinct antigen-specific humoral and cellular immune responses were induced by modified saRNA encoding the model antigen ovalbumin. The use of modified nucleotides with saRNA-based platforms could enhance their potential to be used effectively in a variety of applications.
Efficacy of Lamivudine Plus Dolutegravir vs Dolutegravir-Based 3-Drug Regimens in People With HIV Who Are Virologically Suppressed
Authors: Borghetti Alberto , Ciccullo Arturo , Lombardi Francesca , Giannarelli Diana , Passerotto Rosa Anna , Lamanna Francesco , Carcagnì Antonella , Farinacci Damiano , Dusina Alex , Baldin Gianmaria , Zazzi Maurizio , Di Giambenedetto Simona
Published: April 2024

Background

Lamivudine + dolutegravir maintenance dual therapy (DT) could be less effective than 3-drug therapy (TT) in the context of resistance-associated mutations to nucleoside reverse transcriptase inhibitors (NRTIs). The ARCA database was queried to test this hypothesis with a trial emulation strategy.

Methods

People with HIV taking 2 NRTIs plus a protease inhibitor or a non-NRTI who switched to DT or dolutegravir-based TT were followed up from the first HIV RNA <50 copies/mL (baseline) to virologic failure (VF; ie, 2 consecutive HIV RNA ≥50 copies/mL or 1 HIV RNA ≥200 copies/mL). Those switching to DT within 6 months were assigned to the treatment arm and all other patients to the control arm. Each participant was also cloned, assigned to the opposite strategy, and censored at the time of deviation from that strategy. Using inverse probability of censoring weight Cox regression models, we calculated hazard ratios of VF for DT vs TT stratified for the presence of resistance-associated mutations.

Results

Overall 626 people were analyzed: 204 with DT and 422 with TT (73% men; mean age, 44 years). Ten and 31 VFs occurred with DT and TT, respectively, over a median 5.8 years. When compared with a fully active TT, the DT had similar efficacy (adjusted hazard ratio, 0.88; 95% CI, .29–2.61; P = .812) when full susceptibility was confirmed at historical genotype. When previous M184V/I was present in both groups, the risk of VF was higher for DT vs TT but was not statistically significant (adjusted hazard ratio, 3.06; 95% CI, .45–20.84; P = .252).

Conclusions

DT was not associated with a significantly higher risk of VF than dolutegravir-based TT.
Syndromic Gastrointestinal Panel Diagnostic Tests Have Changed our Understanding of the Epidemiology of Yersiniosis—Foodborne Diseases Active Surveillance Network, 2010-2021
Authors: Ray Logan C , Payne Daniel C , Rounds Joshua , Trevejo Rosalie T , Wilson Elisha , Burzlaff Kari , Garman Katie N , Lathrop Sarah , Rissman Tamara , Wymore Katie , Wozny Sophia , Wilson Siri , Francois Watkins Louise K , Bruce Beau B , Weller Daniel L
Published: April 2024

Background

In the US, yersinosis was understood to predominantly occur in winter and among Black or African American infants and Asian children. Increased use of culture-independent diagnostic tests (CIDTs) has led to marked increases in yersinosis diagnoses.

Methods

We describe differences in the epidemiology of yersiniosis diagnosed by CIDT versus culture in 10 US sites, and identify determinants of health associated with diagnostic method.

Results

Annual reported incidence increased from 0.3/100 000 in 2010 to 1.3/100 000 in 2021, particularly among adults ≥18 years, regardless of race and ethnicity, and during summer months. The proportion of CIDT-diagnosed infections increased from 3% in 2012 to 89% in 2021. An ill person’s demographic characteristics and location of residence had a significant impact on their odds of being diagnosed by CIDT.

Conclusions

Improved detection due to increased CIDT use has altered our understanding of yersinosis epidemiology, however differential access to CIDTs may still affect our understanding of yersinosis.
APX2 Is an Ascorbate Peroxidase–Related Protein that Regulates the Levels of Plastocyanin in Chlamydomonas
Authors: Caccamo Anna , Vega de Luna Félix , Misztak Agnieszka E , Pyr dit Ruys Sébastien , Vertommen Didier , Cardol Pierre , Messens Joris , Remacle Claire
Published: April 2024

The function of ascorbate peroxidase–related (APX-R) proteins, present in all green photosynthetic eukaryotes, remains unclear. This study focuses on APX-R from Chlamydomonas reinhardtii, namely, ascorbate peroxidase 2 (APX2). We showed that apx2 mutants exhibited a faster oxidation of the photosystem I primary electron donor, P700, upon sudden light increase and a slower re-reduction rate compared to the wild type, pointing to a limitation of plastocyanin. Spectroscopic, proteomic and immunoblot analyses confirmed that the phenotype was a result of lower levels of plastocyanin in the apx2 mutants. The redox state of P700 did not differ between wild type and apx2 mutants when the loss of function in plastocyanin was nutritionally complemented by growing apx2 mutants under copper deficiency. In this case, cytochrome c6 functionally replaces plastocyanin, confirming that lower levels of plastocyanin were the primary defect caused by the absence of APX2. Overall, the results presented here shed light on an unexpected regulation of plastocyanin level under copper-replete conditions, induced by APX2 in Chlamydomonas.
The Arabidopsis Mitochondrial Nucleoid–Associated Protein WHIRLY2 Is Required for a Proper Response to Salt Stress
Authors: Negroni Yuri L , Doro Irene , Tamborrino Alberto , Luzzi Irene , Fortunato Stefania , Hensel Götz , Khosravi Solmaz , Maretto Laura , Stevanato Piergiorgio , Lo Schiavo Fiorella , de Pinto Maria Concetta , Krupinska Karin , Zottini Michela
Published: April 2024

In the last years, plant organelles have emerged as central coordinators of responses to internal and external stimuli, which can induce stress. Mitochondria play a fundamental role as stress sensors being part of a complex communication network between the organelles and the nucleus. Among the different environmental stresses, salt stress poses a significant challenge and requires efficient signaling and protective mechanisms. By using the why2 T-DNA insertion mutant and a novel knock-out mutant prepared by CRISPR/Cas9–mediated genome editing, this study revealed that WHIRLY2 is crucial for protecting mitochondrial DNA (mtDNA) integrity during salt stress. Loss-of-function mutants show an enhanced sensitivity to salt stress. The disruption of WHIRLY2 causes the impairment of mtDNA repair that results in the accumulation of aberrant recombination products, coinciding with severe alterations in nucleoid integrity and overall mitochondria morphology besides a compromised redox-dependent response and misregulation of antioxidant enzymes. The results of this study revealed that WHIRLY2-mediated structural features in mitochondria (nucleoid compactness and cristae) are important for an effective response to salt stress.
Multiple Roles of Brassinosteroid Signaling in Vascular Development
Authors: Furuya Tomoyuki , Ohashi-Ito Kyoko , Kondo Yuki
Published: April 2024

Brassinosteroids (BRs) are plant steroid hormones that control growth and stress responses. In the context of development, BRs play diverse roles in controlling cell differentiation and tissue patterning. The vascular system, which is essential for transporting water and nutrients throughout the plant body, initially establishes a tissue pattern during primary development and then dramatically increases the number of vascular cells during secondary development. This complex developmental process is properly regulated by a network consisting of various hormonal signaling pathways. Genetic studies have revealed that mutants that are defective in BR biosynthesis or the BR signaling cascade exhibit a multifaceted vascular development phenotype. Furthermore, BR crosstalk with other plant hormones, including peptide hormones, coordinately regulates vascular development. Recently, the involvement of BR in vascular development, especially in xylem differentiation, has also been suggested in plant species other than the model plant Arabidopsis thaliana. In this review, we briefly summarize the recent findings on the roles of BR in primary and secondary vascular development in Arabidopsis and other species.
ATML1 Regulates the Differentiation of ER Body–Containing Large Pavement Cells in Rosette Leaves of Brassicaceae Plants
Authors: Wilkens Alwine , Czerniawski Paweł , Bednarek Paweł , Libik-Konieczny Marta , Yamada Kenji
Published: April 2024

Endoplasmic reticulum (ER)–derived organelles, ER bodies, participate in the defense against herbivores in Brassicaceae plants. ER bodies accumulate β-glucosidases, which hydrolyze specialized thioglucosides known as glucosinolates to generate bioactive substances. In Arabidopsis thaliana, the leaf ER (LER) bodies are formed in large pavement cells, which are found in the petioles, margins and blades of rosette leaves. However, the regulatory mechanisms involved in establishing large pavement cells are unknown. Here, we show that the ARABIDOPSIS THALIANA MERISTEM L1 LAYER (ATML1) transcription factor regulates the formation of LER bodies in large pavement cells of rosette leaves. Overexpression of ATML1 enhanced the expression of LER body–related genes and the number of LER body–containing large pavement cells, whereas its knock-out resulted in opposite effects. ATML1 enhances endoreduplication and cell size through LOSS OF GIANT CELLS FROM ORGANS (LGO). Although the overexpression and knock-out of LGO affected the appearance of large pavement cells in Arabidopsis, the effect on LER body–related gene expression and LER body formation was weak. LER body–containing large pavement cells were also found in Eutrema salsugineum, another Brassicaceae species. Our results demonstrate that ATML1 establishes large pavement cells to induce LER body formation in Brassicaceae plants and thereby possibly contribute to the defense against herbivores.
The Y locus encodes a REPRESSOR OF PHOTOSYNTHETIC GENES protein that represses carotenoid biosynthesis via interaction with APRR2 in carrot
Authors: Wang Ying-Gang , Zhang Yu-Min , Wang Ya-Hui , Zhang Kai , Ma Jing , Hang Jia-Xin , Su Yu-Ting , Tan Shan-Shan , Liu Hui , Xiong Ai-Sheng , Xu Zhi-Sheng
Published: April 2024

Little is known about the factors regulating carotenoid biosynthesis in roots. In this study, we characterized DCAR_032551, the candidate gene of the Y locus responsible for the transition of root color from ancestral white to yellow during carrot (Daucus carota) domestication. We show that DCAR_032551 encodes a REPRESSOR OF PHOTOSYNTHETIC GENES (RPGE) protein, named DcRPGE1. DcRPGE1 from wild carrot (DcRPGE1W) is a repressor of carotenoid biosynthesis. Specifically, DcRPGE1W physically interacts with DcAPRR2, an ARABIDOPSIS PSEUDO-RESPONSE REGULATOR2 (APRR2)-like transcription factor. Through this interaction, DcRPGE1W suppresses DcAPRR2-mediated transcriptional activation of the key carotenogenic genes phytoene synthase 1 (DcPSY1), DcPSY2, and lycopene ε-cyclase (DcLCYE), which strongly decreases carotenoid biosynthesis. We also demonstrate that the DcRPGE1W–DcAPRR2 interaction prevents DcAPRR2 from binding to the RGATTY elements in the promoter regions of DcPSY1, DcPSY2, and DcLCYE. Additionally, we identified a mutation in the DcRPGE1 coding region of yellow and orange carrots that leads to the generation of alternatively spliced transcripts encoding truncated DcRPGE1 proteins unable to interact with DcAPRR2, thereby failing to suppress carotenoid biosynthesis. These findings provide insights into the transcriptional regulation of carotenoid biosynthesis and offer potential target genes for enhancing carotenoid accumulation in crop plants.
Trk-fused gene plays a critical role in diet-induced adipose tissue expansion and is also involved in thyroid hormone action
Authors: Yamamotoya Takeshi , Ohata Yukino , Akasaka Yasuyuki , Hasei Shun , Inoue Masa-Ki , Nakatsu Yusuke , Kanna Machi , Yamazaki Hiroki , Kushiyama Akifumi , Fujishiro Midori , Ono Hiraku , Sakoda Hideyuki , Yamada Tetsuya , Ishihara Hisamitsu , Asano Tomoichiro
Published: April 2024

Mutations in the Trk-fused gene (TFG) cause hereditary motor and sensory neuropathy with proximal dominant involvement, which reportedly has high co-incidences with diabetes and dyslipidemia, suggesting critical roles of the TFG in metabolism as well. We found that TFG expression levels in white adipose tissues (WATs) were elevated in both genetically and diet-induced obese mice and that TFG deletion in preadipocytes from the stromal vascular fraction (SVF) markedly inhibited adipogenesis. To investigate its role in vivo, we generated tamoxifen-inducible adipocyte-specific TFG knockout (AiTFG KO) mice. While a marked down-regulation of the peroxisome proliferator-activated receptor gamma target, de novo lipogenesis (DNL), and mitochondria-related gene expressions were observed in subcutaneous WAT (scWAT) from AiTFG KO mice, these effects were blunted in SVF-derived adipocytes when the TFG was deleted after differentiation into adipocytes, implying cell nonautonomous effects. Intriguingly, expressions of thyroid hormone receptors, as well as carbohydrate responsive element-binding protein β, which mediates the metabolic actions of thyroid hormone, were drastically down-regulated in scWAT from AiTFG KO mice. Reduced DNL and thermogenic gene expressions in AiTFG KO mice might be attributable to impaired thyroid hormone action in vivo. Finally, when adipocyte TFG was deleted in either the early or the late phase of high-fat diet feeding, the former brought about an impaired expansion of epididymal WAT, whereas the latter caused prominent adipocyte cell death. TFG deletion in adipocytes markedly exacerbated hepatic steatosis in both experimental settings. Collectively, these observations indicate that the TFG plays essential roles in maintaining normal adipocyte functions, including an enlargement of adipose tissue, thyroid hormone function, and thermogenic gene expressions, and in preserving hypertrophic adipocytes.
Validation of the Cervical Torsion Test and Head-Neck Differentiation Test in Patients With Peripheral Vestibular Hypofunction
Authors: Nüesch Andrea , Treleaven Julia , Ernst Markus J
Published: April 2024

Objective

This study compared adults with peripheral vestibular hypofunction (VH) to healthy controls and assessed the sensitivity and specificity of the Cervical Torsion Test (CTT) and the Head-Neck Differentiation Test (HNDT). This study aimed to determine whether neck problems affected primary outcomes.

Methods

This cross-sectional study included adults from a specialist consultation for dizziness. VH had been diagnosed with the video Head Impulse Test. Exclusion criteria were conditions following head or neck trauma and diseases of the central nervous system. The sensitivity and specificity of the index tests were calculated, and regression analyses were performed to test for contributing factors.

Results

A total of 19 patients with VH and a historical cohort of 19 matched healthy controls were included. Most patients with VH (84.2%) experienced symptoms in at least 1 test component, compared to 5.2% of the control group. Of patients with VH, 78.9% had symptoms during the HNDT “en bloc” (en bloc = head and trunk rotated together), whereas only 26.3% reported symptoms during the CTT en bloc. The best discriminatory validity was found for the HNDT en bloc, with a sensitivity of 0.79 (95% CI = 0.54–0.94), a specificity of 0.86 (95% CI = 0.65–0.97), and a positive likelihood ratio of 5.79 (95% CI = 1.97–17.00). The number of symptoms of CTT “in torsion” (in torsion = trunk rotated actively with fixed head) was increased by a factor of 1.13 (95% CI = 1.01–1.27) for every additional point on the Neck Disability Index.

Conclusion

The CTT and HNDT can serve as non-laboratory tests for patients with dizziness. The HNDT en bloc has the best discriminatory validity, finding those with and those without VH. Symptom reproduction during torsion may help to identify when neck problems may contribute to dizziness.

Impact

The HNDT en bloc may be useful for ruling VH in or out in patients with dizziness. Positive CTT and HNDT in torsion components may verify the likelihood of additional neck involvement.