bluuebunny/crossref_metadata_2025 huggingface dataset:
3D gap opening in non-ideal MHD protoplanetary discs: asymmetric accretion, meridional vortices, and observational signatures
Authors: Hu Xiao , Li Zhi-Yun , Bae Jaehan , Zhu Zhaohuan
Published: December 2024

Recent high angular resolution ALMA observations have revealed rich information about protoplanetary discs, including ubiquitous substructures and three-dimensional gas kinematics at different emission layers. One interpretation of these observations is embedded planets. Previous 3D planet–disc interaction studies are either based on viscous simulations or non-ideal magnetohydrodynamics (MHD) simulations with simple prescribed magnetic diffusivities. This study investigates the dynamics of gap formation in 3D non-ideal MHD discs using non-ideal MHD coefficients from the look-up table that is self-consistently calculated based on the thermochemical code. We find a concentration of the poloidal magnetic flux in the planet-opened gap (in agreement with previous work) and enhanced field-matter coupling due to gas depletion, which together enable efficient magnetic braking of the gap material, driving a fast accretion layer significantly displaced from the disc mid-plane. The fast accretion helps deplete the gap further and is expected to negatively impact the planet growth. It also affects the corotation torque by shrinking the region of horseshoe orbits on the trailing side of the planet. Together with the magnetically driven disc wind, the fast accretion layer generates a large, persistent meridional vortex in the gap, which breaks the mirror symmetry of gas kinematics between the top and bottom disc surfaces. Finally, by studying the kinematics at the emission surfaces, we discuss the implications of planets in realistic non-ideal MHD discs on kinematics observations.
Spider-Webb: JWST Near Infrared Camera resolved galaxy star formation and nuclear activities in the Spiderweb protocluster at z = 2.16
Authors: Shimakawa Rhythm , Koyama Yusei , Kodama Tadayuki , Dannerbauer Helmut , Pérez-Martínez J M , Röttgering Huub J A , Tanaka Ichi , D’Eugenio Chiara , Naufal Abdurrahman , Daikuhara Kazuki , Zhang Yuheng
Published: December 2024

Near-infrared (NIR) emission is less affected by dust than ultraviolet and optical emission and is therefore useful for studying the properties of dust-obscured galaxies. Although rest-frame NIR observations of high-redshift galaxies have long been made using space telescopes, their structures were unresolved due to the lack of angular resolution. This letter reports the early results from the analysis of high-resolution Pa$\beta$ imaging of the Spiderweb protocluster at $z=2.16$ with the JWST Near Infrared Camera. We investigate radial profiles of Pa$\beta$ lines and rest-frame NIR continua from luminous H $\alpha$-emitting galaxies (HAEs) in the protocluster. Particularly, we compare those of 11 HAEs (N-HAEs) on the star-forming main sequence with those of 8 HAEs (X-HAEs) with X-ray active galactic nuclei (AGNs). Resultant composite Pa$\beta$ line images of N-HAEs indicate significant star formation in galactic discs. In contrast, X-HAEs are dominated by point source components rather than outer star formation, as inferred from our earlier work based on multiwavelength spectral energy distribution fitting. Given their higher stellar potentials suggested from their rest-frame NIR images, the different characteristics may be driven by the impact of AGN feedback.
The sensory shark: high-quality morphological, genomic and transcriptomic data for the small-spotted catshark Scyliorhinus canicula reveal the molecular bases of sensory organ evolution in jawed vertebrates
Authors: Mayeur H , Leyhr J , Mulley J , Leurs N , Michel L , Sharma K , Lagadec R , Aury J -M , Osborne O G , Mulhair P , Poulain J , Mangenot S , Mead D , Smith M , Corton C , Olive K , Skelton J , Betteridge E , Dolucan J , Dudchenko O , Omer A D , Weisz D , Aiden E L , McCarthy S , Sims Y , Torrance J , Tracey A , Howe K , Baril T , Hayward A , Martinand-Mari C , Sanchez S , Haitina T , Martin K , Korsching S I , Mazan S , Debiais-Thibaud M
Published: December 2024

Cartilaginous fishes (chondrichthyans: chimaeras and elasmobranchs -sharks, skates and rays) hold a key phylogenetic position to explore the origin and diversifications of jawed vertebrates. Here, we report and integrate reference genomic, transcriptomic and morphological data in the small-spotted catshark Scyliorhinus canicula to shed light on the evolution of sensory organs. We first characterise general aspects of the catshark genome, confirming the high conservation of genome organisation across cartilaginous fishes, and investigate population genomic signatures. Taking advantage of a dense sampling of transcriptomic data, we also identify gene signatures for all major organs, including chondrichthyan specializations, and evaluate expression diversifications between paralogs within major gene families involved in sensory functions. Finally, we combine these data with 3D synchrotron imaging and in situ gene expression analyses to explore chondrichthyan-specific traits and more general evolutionary trends of sensory systems. This approach brings to light, among others, novel markers of the ampullae of Lorenzini electro-sensory cells, a duplication hotspot for crystallin genes conserved in jawed vertebrates, and a new metazoan clade of the transient-receptor potential (TRP) family. These resources and results, obtained in an experimentally tractable chondrichthyan model, open new avenues to integrate multiomics analyses for the study of elasmobranchs and jawed vertebrates.
Muscle vasculitis in patients with polymyalgia rheumatica: Three case series
Authors: Moriya Haruka , Fujieda Yuichiro , Inoue Yuta , Miyamoto Kenichi , Anada Mamiko , Tanaka Daiki , Kudo Akihiko , Abe Megumi , Nagai Azusa , Hisada Ryo , Kono Michihito , Kato Masaru , Amengual Olga , Matsuno Yoshihiro , Yabe Ichiro , Atsumi Tatsuya
Published: December 2024

Polymyalgia rheumatica (PMR) is a common inflammatory disorder characterized by myalgia/stiffness in proximal hip and shoulder girdle, elevated C reactive protein, and erythrocyte sedimentation rate, but its pathogenesis is not fully elucidated. We report three cases of PMR who do not respond adequately to standard treatment. Those patients had typical symptoms of myalgia and muscle weakness, with elevated C reactive protein in absence of creatine kinase elevation. Muscle specimen showed the findings of vasculitis in all cases; therefore, muscular-limited vasculitis may be an underlying pathology in PMR in those refractory cases.
Writing (Re)Considered
Authors: Barna Alyssa
Published: December 2024

Writing is the currency of our academic life as music theorists. Scholars entering the field are expected to demonstrate fluency in writing in order to participate in music-theoretical discourse. Inspired by my written work as a Public Music Theorist, I reconsider how writing is taught and assessed at various levels. Through an examination of literature on writing, music theory pedagogy, and Public Music Theory, I present my philosophy of writing along with recommendations for improving clarity and mentorship for writers. This article asks two questions: What can we learn from Public Music Theory to communicate our ideas more clearly in writing, promote inclusivity, and expand the definition of music theory? And who holds the power to make change within our written discourse and training?
Accurate quantification of nascent and mature RNAs from single-cell and single-nucleus RNA-seq
Authors: Sullivan Delaney K , Hjörleifsson Kristján Eldjárn , Swarna Nikhila P , Oakes Conrad , Holley Guillaume , Melsted Páll , Pachter Lior
Published: December 2024

In single-cell and single-nucleus RNA sequencing (RNA-seq), the coexistence of nascent (unprocessed) and mature (processed) messenger RNA (mRNA) poses challenges in accurate read mapping and the interpretation of count matrices. The traditional transcriptome reference, defining the “region of interest” in bulk RNA-seq, restricts its focus to mature mRNA transcripts. This restriction leads to two problems: reads originating outside of the “region of interest” are prone to mismapping within this region, and additionally, such external reads cannot be matched to specific transcript targets. Expanding the “region of interest” to encompass both nascent and mature mRNA transcript targets provides a more comprehensive framework for RNA-seq analysis. Here, we introduce the concept of distinguishing flanking k-mers (DFKs) to improve mapping of sequencing reads. We have developed an algorithm to identify DFKs, which serve as a sophisticated “background filter”, enhancing the accuracy of mRNA quantification. This dual strategy of an expanded region of interest coupled with the use of DFKs enhances the precision in quantifying both mature and nascent mRNA molecules, as well as in delineating reads of ambiguous status.
QClus: a droplet filtering algorithm for enhanced snRNA-seq data quality in challenging samples
Authors: Schmauch Eloi , Ojanen Johannes , Galani Kyriakitsa , Jalkanen Juho , Harju Kristiina , Hollmén Maija , Kokki Hannu , Gunn Jarmo , Halonen Jari , Hartikainen Juha , Kiviniemi Tuomas , Tavi Pasi , Kaikkonen Minna U , Kellis Manolis , Linna-Kuosmanen Suvi
Published: December 2024

Single-nuclei RNA sequencing remains a challenge for many human tissues, as incomplete removal of background signal masks cell-type-specific signals and interferes with downstream analyses. Here, we present Quality Clustering (QClus), a droplet filtering algorithm targeted toward challenging samples. QClus uses additional metrics, such as cell-type-specific marker gene expression, to cluster nuclei and filter empty and highly contaminated droplets, providing reliable filtering of samples with varying number of nuclei and contamination levels. In a benchmarking analysis against seven alternative methods across six datasets, consisting of 252 samples and over 1.9 million nuclei, QClus achieved the highest quality in the greatest number of samples over all evaluated quality metrics and recorded no processing failures, while robustly retaining numbers of nuclei within the expected range. QClus combines high quality, automation and robustness with flexibility and user-adjustability, catering to diverse experimental needs and datasets.
Degradation and stable maintenance of adeno-associated virus inverted terminal repeats in E. coli
Authors: Radukic Marco T , Le Dinh To , Krassuski Timo , Borchert Philipp , Leach David R F , Müller Kristian M
Published: December 2024

Current plasmid propagation in E. coli compromises large inverted repeats, such as inverted terminal repeats (ITRs) of adeno-associated virus (AAV). Direct long-read sequencing analyses upon varying strains and culture conditions revealed ITR instability caused by a slipped misalignment mechanism, although other mechanism probably contribute. ITRs stabilized in absence of SbcC, which is part of the SbcCD nuclease complex, a human Mre11–Rad50 homolog, or at elevated growth temperatures (e.g. 42°C), with a combination being optimal. Resulting full ITR transgene plasmids improved rAAV yield and purity in HEK-293 productions. The findings advance plasmid biology, cloneable sequences and therapeutic AAV manufacturing.
AnnoGCD: a generalized category discovery framework for automatic cell type annotation
Authors: Ceccarelli Francesco , Liò Pietro , Holden Sean B
Published: December 2024

The identification of cell types in single-cell RNA sequencing (scRNA-seq) data is a critical task in understanding complex biological systems. Traditional supervised machine learning methods rely on large, well-labeled datasets, which are often impractical to obtain in open-world scenarios due to budget constraints and incomplete information. To address these challenges, we propose a novel computational framework, named AnnoGCD, building on Generalized Category Discovery (GCD) and Anomaly Detection (AD) for automatic cell type annotation. Our semi-supervised method combines labeled and unlabeled data to accurately classify known cell types and to discover novel ones, even in imbalanced datasets. AnnoGCD includes a semi-supervised block to first classify known cell types, followed by an unsupervised block aimed at identifying and clustering novel cell types. We evaluated our approach on five human scRNA-seq datasets and a mouse model atlas, demonstrating superior performance in both known and novel cell type identification compared to existing methods. Our model also exhibited robustness in datasets with significant class imbalance. The results suggest that AnnoGCD is a powerful tool for the automatic annotation of cell types in scRNA-seq data, providing a scalable solution for biological research and clinical applications. Our code and the datasets used for evaluations are publicly available on GitHub: https://github.com/cecca46/AnnoGCD/.
The soluble guanylate cyclase activator runcaciguat significantly improves albuminuria in patients with chronic kidney disease: a randomized placebo-controlled clinical trial
Authors: Gansevoort Ron T , Wheeler David C , Debén Francisco Martínez , Speeckaert Marijn , Thomas Dirk , Berger Mario , Klein Stefan , Friedrichs Frauke , Paraschin Karen , Schmieder Roland E
Published: December 2024

Background and hypothesis

In chronic kidney disease (CKD) the nitric oxide (NO)−soluble guanylate cyclase (sGC)−cyclic guanosine monophosphate (cGMP) pathway is impaired. Runcaciguat, an sGC activator, activates heme-free sGC, restoring cGMP production. This phase 2a trial studied the efficacy, safety, and tolerability of runcaciguat in CKD patients with or without sodium-glucose co-transporter-2 inhibitor (SGLT2i).

Methods

Patients with CKD and established atherosclerotic cardiovascular disease or heart failure, plus type 2 diabetes (T2D) and/or hypertension, were enrolled. All were receiving stable maximum tolerated renin−angiotensin system inhibitors with or without SGLT2i. They were randomized 3:1 to runcaciguat once daily, titrated weekly (30–120 mg if tolerated), or placebo for 8 weeks. The primary efficacy endpoint was urine albumin-to-creatinine ratio (UACR) (average of post-randomization Days 22, 29, and 57 vs baseline). CONCORD was separately powered for CKD and T2D with stable SGLT2i comedication, CKD and T2D without SGLT2i, and non-diabetic CKD.

Results

Of 243 patients randomized, 229 were included in the full analysis set (FAS) and 170 in the per-protocol set (PPS). In the PPS, UACR decreased by −45.2% versus placebo with runcaciguat in patients with CKD without SGLT2i (P < 0.001) and by −48.1% versus placebo in patients with CKD taking SGLT2i (P = 0.02) In the FAS, the relative reductions were −46.9% (P < 0.001) and −44.8% (P = 0.01), respectively. No significant difference was observed between patients with or without SGLT2i. In non-diabetic CKD, UACR was reduced versus baseline with runcaciguat, but the change was not statistically significant (P = 0.10). Serious treatment-emergent adverse events were reported in 7% of patients receiving runcaciguat and 8% receiving placebo.

Conclusion

Runcaciguat improved albuminuria in patients with CKD, irrespective of concomitant SGLT2i. Runcaciguat was well tolerated. sGC activation may represent a novel kidney-protective treatment in CKD patients (funded by Bayer AG; ClinicalTrials.gov number, NCT04507061).
Prognostic factors for overall survival in elderly patients with glioblastoma: Analysis of the pooled NOA-08 and Nordic trials with the CCTG-EORTC (CE.6) trial
Authors: Malmström Annika , Oppong Felix B , O`Callaghan Christopher J , Wick Wolfgang , Laperriere Normand , Gorlia Thierry , Weller Michael , Henriksson Roger , Mason Warren , Platten Michael , Cantagallo Eva , Grønberg Bjørn H , Reifenberger Guido , Marosi Christine , Perry James R ,   NCBTSG, NOA, CCTG and EORTC Brain Tumor Group, Stupp Roger , Frappaz Didier , Schultz Henrik , Abacioglu Ufuk , Tavelin Björn , Lhermitte Benoit , Hegi Monika E , Rosell Johan , Platten Michael , Meisner Christoph , Felsberg Jörg , Tabatabai Ghazaleh , Simon Matthias , Nikkhah Guido , Papsdorf Kirsten , Steinbach Joachim P , Sabel Michael , Combs Stephanie E , Vesper Jan , Braun Christian , Meixensberger Jürgen , Ketter Ralf , Mayer-Steinacker Regine , Brandes Alba A , Menten Johan , Phillips Claire , Fay Michael , Nishikawa Ryo , Gregory Cairncross J , Roa Wilson , Osoba David , Rossiter John P , Sahgal Arjun , Hirte Hal , Laigle-Donadey Florence , Franceschi Enrico , Chinot Olivier , Golfinopoulos Vassilis , Fariselli Laura , Wick Antje , Feuvret Loic , Back Michael , Tills Michael , Winch Chad , Baumert Brigitta G
Published: December 2024

Background

The majority of patients diagnosed with glioblastoma are >60 years. Three randomized trials addressed the roles of radiotherapy (RT) and temozolomide (TMZ) for elderly patients. NORDIC and NOA-08 compared RT versus TMZ, while CE.6 randomized between hypofractionated RT and RT + TMZ. All showed significant benefits for the TMZ arms, especially for those patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. This pooled analysis aimed at identifying additional factors that could improve individualized treatment recommendations.

Methods

Analyses were performed separately in the RT and TMZ arms of the pooled NORDIC and NOA-08 data, and in the RT and TMZ/RT arms of CE.6. The prognostic value of baseline clinical factors, comorbidities, and quality of life (QoL) scores were assessed.

Results

NORDIC + NOA-08 (NN) included 715 patients and CE.6 included 562 patients. Median age for NN was 71 and 73 years for CE.6. In NN and CE.6 respectively, 66.2% versus 70.5% underwent resection and 50.9% and 75.3% were on steroids. In NN, 401 patients received RT alone and 281 in CE.6, while 314 were randomized to TMZ alone in NN and 281 to concomitant RT + TMZ in CE.6. Known clinical prognostic factors, such as extent of resection and WHO performance status were confirmed, as was MGMT promoter methylation status for TMZ-treated patients. TMZ-treated patients with 2 or 3 comorbidities; hypertension, diabetes, and/or stroke had worse survival, both in NN (P = .022) and CE.6 (P = .022). Baseline QoL had a minor association with outcome.

Conclusion

Consideration of comorbidities allows improved personalized treatment decisions for elderly glioblastoma patients.
Role of the tumor board when prescribing mutant isocitrate dehydrogenase inhibitors to patients with isocitrate dehydrogenase-mutant glioma
Authors: Roth Patrick , Capper David , Calabrese Evan , Halasz Lia M , Jakola Asgeir S
Published: December 2024

Isocitrate dehydrogenase (IDH)-mutant gliomas, comprising both astrocytomas and oligodendrogliomas, represent a distinct group of tumors that pose an interdisciplinary challenge. Addressing the needs of affected patients requires close collaboration among various disciplines, including neuropathology, neuroradiology, neurosurgery, radiation oncology, neurology, medical oncology, and other relevant specialties when necessary. Interdisciplinary tumor boards are central in determining the ideal diagnostic and therapeutic strategies for these patients. The key tasks of a tumor board include the evaluation of imaging findings, selecting the appropriate surgical approach, discussing additional treatment options, and identification/determination of tumor recurrence and progression. In addition to established treatments such as radiotherapy and alkylating chemotherapy, patients with an isocitrate dehydrogenase (IDH)-mutant glioma for whom additional treatment is indicated may now also have the option of receiving treatment with an mutant isocitrate dehydrogenase inhibitor such as vorasidenib or ivosidenib. In this regard, the collaborative nature of tumor boards becomes even more crucial for evaluating comprehensively the needs of these patients. Through interdisciplinary discussions, tumor boards aim to develop personalized treatment strategies that maximize therapeutic efficacy while minimizing potential side effects and preserving patients’ quality of life.
Histoplasmosis Associated With Bat Guano Exposure in Cannabis Growers: 2 Cases
Authors: Sudnik Paulina , Passarelli Patrick , Branche Angela , Giampoli Ellen , Louie Ted
Published: December 2024

Histoplasma capsulatum is a pathogenic dimorphic fungus with evolving epidemiology. Initially described as endemic to the Ohio and Mississippi river valleys, the infection now regularly occurs in central and eastern United States, with cases reported across the entire country. Transmission happens via inhalation of conidia during activities that disturb fungal hyphae. Sporadic cases related to individual exposures now outnumber work-related outbreak cases in the United States. We describe 2 fatal cases of histoplasmosis in Rochester, New York, associated with exposure to bat guano as a fertilizer for cannabis cultivation, including 1 case in which it was commercially obtained.
The Atmosphere in Spatial History: Digital Evidence and Visual Argument
Authors: Scholz Luca
Published: December 2024

Taking its cue from the weather wars that unfolded around the Alps in the eighteenth century — conflicts between neighbouring towns and polities attempting to divert storms by firing cannons at clouds — this article studies the representation of an environment rarely seen in spatial history: earth’s atmosphere. A survey of maps in different historiographical traditions, climate history foremost, reveals a visual repertoire that is effective for determining the physical properties of weather and climate but detaches the atmosphere from its human and non-human environments. A more recent genre of historical maps employs algorithmic methods of layering data to represent the atmosphere at local scales and in close connection with the human environment yet remains committed to a physicalist vision of weather and society. Returning to the Alpine weather wars, the article introduces a sequence of maps that attempt to represent past storms as they were understood and confronted by the armed farmers at the foot of the Alps: steerable entities trapped in an atmo-terrestrial force field where physical, political and religious influences collided to determine the ways of weather. The wider proposition is for historians of atmospheric environment to craft cartographic arguments that complement the range and ambition of their prose.
Fibrosis mechanisms in systemic sclerosis and new potential therapies
Authors: Barile Raffaele , Rotondo Cinzia , Rella Valeria , Trotta Antonello , Cantatore Francesco Paolo , Corrado Addolorata
Published: December 2024

Systemic sclerosis is a rare rheumatic disease characterized by immune cell activation, tissue fibrosis, and endothelial dysfunction. Extracellular matrix synthesis disorder causes widespread fibrosis, primarily in skin and internal organs. Various factors such as TGFβ, VEGF, Galectin-3, and signaling pathways like Wnt/β-catenin are involved in pathophysiological processes. Treatment lacks a unified approach but combines diverse modalities tailored to disease subtype and progression. Current therapeutic strategies include biologics, JAK inhibitors, and IL-6 pathway modulators. Monoclonal antibodies and hypomethylating agents demonstrate potential in fibrosis inhibition. This review focuses on emerging therapeutic evidence regarding drugs targeting collagen, cytokines, and cell surface molecules in systemic sclerosis, aiming to provide insight into potential innovative treatment strategies.
Constitutivism's plight: inescapability, normativity, and relativism
Authors: Leffler Olof
Published: December 2024

Constitutivists often argue that agency is inescapable. This is supposed to, among other things, explain why norms that are constitutive of agency are forceful. But can some form of inescapability do that? I consider four types of inescapability—psychological, further factor, standpoint, and plight—and evaluate whether they manage to explain four necessary features of normative force: that it does not vary with desire change, that ought-implies-can and can-fail, and that we are criticizable for failing to live up to forceful norms. The former three all fail to explain some of these features, but a version of plight inescapability does, in fact, appear able to explain them all. This is good news for constitutivists. The catch? The plight inescapability explanation generates relativism. This leaves constitutivists at a choice point: accept the plight inescapability explanation of normative force and relativism—or give up the plight inescapability explanation.
Photon Frequency Conversion in High-Q Superconducting Resonators: Axion Electrodynamics, QED, and Nonlinear Meissner Radiation
Authors: Ueki Hikaru , Sauls J A
Published: December 2024

High-Q superconducting resonators have been proposed and developed as detectors of light-by-light scattering mediated by the hypothesized axion or virtual electron–positron pairs in quantum electrodynamics: the Euler–Heisenberg (EH) interaction. Photon frequency and mode conversion is central to the scheme for detecting such rare events. Superconducting resonators are nonlinear devices. The Meissner screening currents that confine the electromagnetic fields to the vacuum region of a superconducting RF cavity are nonlinear functions of the EM field at the vacuum–superconducting interface, and as a result can generate source currents and frequency conversion of microwave photons in the cavity. In this report we consider photon frequency and mode conversion in superconducting resonators with high quality factors from Meissner currents in single- and dual-cavity setups proposed for axion and QED searches based on light-by-light scattering. In a single cavity with two pump modes, photon frequency conversion by the Meissner screening current dominates photon generation by the EH interaction for cavities with $Q \lesssim 10^{12}$. The Meissner currents also generate background photons that limit the operation of the resonator for axion detection in three-mode, single-cavity setups. We also consider the leakage of photons from pump modes into the signal mode for both axion- and EH-mediated light-by-light scattering. Photon frequency conversion by the EH interaction can compete with Meissner and leakage radiation in ultra-high-Q cavities that are beyond the current state of the art. Meissner radiation and leakage backgrounds can be suppressed in dual-cavity setups with appropriate choices for pump and spectator modes, as well as the single-cavity setup proposed for heterodyne detection of galactic axion dark matter.
On Stability of Metric Spaces and Kalton’s Property Q
Authors: Baudier F , Schlumprecht Th , ZSÁK A
Published: December 2024

The first named author introduced the notion of upper stability for metric spaces in F. Baudier, Barycentric gluing and geometry of stable metrics, Rev. R. Acad. Cienc. Exactas Fís. Nat. Ser. A Mat. RACSAM  116 no. 1, (2022), 48 as a relaxation of stability. The motivation was a search for a new invariant to distinguish the class of reflexive Banach spaces from stable metric spaces in the coarse and uniform category. In this paper we show that property Q does in fact imply upper stability. We also provide a direct proof of the fact that reflexive spaces are upper stable by relating the latter notion to the asymptotic structure of Banach spaces.
Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in systemic lupus erythematosus
Authors: Ai Minji , Zhou Xian , Carrer Michele , Jafar-nejad Paymaan , Li Yanfeng , Gades Naomi , Alexander Mariam , Bautista-Vargas Mario , Duarte-García Alí , Zeng Hu
Published: December 2024

Objective

We aimed to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in SLE development, and the in vivo regulation of mTORC2 by type I IFN signalling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro co-culture model using human peripheral blood mononuclear cells (PBMCs).

Method

We first induced lupus-like disease in T-cell-specific Rictor, a key component of mTORC2-deficient mice, by topical application of imiquimod (IMQ), and monitored disease development. Next, we investigated the changes in mTORC2 signalling and immunological phenotypes in type I IFNAR-deficient Lpr mice. We then tested the beneficial effects of anti-Rictor antisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lpr mice. Finally, we examined the beneficial effects of RICTOR-ASO on SLE patients’ PBMCs using an in vitro T–B co-culture assay.

Results

T-cell-specific Rictor-deficient mice have reduced age-associated B cells, plasma cells and germinal centre B cells, and less autoantibody production than WT mice, following IMQ treatment. IFNAR1-deficient Lpr mice have reduced mTORC2 activity in CD4+ T cells, accompanied by restored CD4+ T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. Rictor-ASO treatment improved renal function and pathology in MRL/lpr mice, and improved immunopathology. In a human SLE (N = 5) PBMCs derived T–B co-culture assay, RICTOR-ASO significantly reduced the production of immunoglobulin (Ig) and autoantibodies (P < 0.05).

Conclusion

Targeting mTORC2 could be a promising therapeutic strategy for SLE.
P029 High-definition neurostimulation to enhance slow oscillations during sleep in obstructive sleep apnea: A randomised, single-blind, sham-controlled, crossover proof-of-concept protocol
Authors: Riccardiello A , Tang J , Wassing R , Phillips C , Kao T , Cotta Ramusino G , Gordon C , Yee B , Grunstein R , Marshall N , D’Rozario A
Published: December 2024

Global and regional deficits in slow frequency EEG oscillations during non-rapid eye movement sleep, which have been reported in people with obstructive sleep apnea (OSA) may have detrimental consequences on cognitive performance. Current OSA treatments have variable effects on restoring slow waves and improving cognition, and some treatments are poorly tolerated. Previous studies using non-invasive transcranial direct current stimulation (tDCS) applied to frontal brain regions enhanced slow wave oscillations in healthy adults and may have utility in an OSA population. This protocol will assess the feasibility of using tDCS to enhance slow oscillations in middle to late aged people with OSA.

A randomised, crossover design will test two active (maximum current density 0.522mA/cm2) and one sham (<0.1mA) slow oscillation tDCS conditions. In this proof-of-concept study, 5 participants aged 40-65 years with mild-moderate OSA will attend three in laboratory visits with high-density EEG, with a 1-week washout. Active or sham stimulation in frontal or parietal regions will be applied in 5 x 5-minute blocks during the first NREM period of a 90-minute nap. EEG data will be measured for 60 seconds after each stimulation block. Memory and attention tasks and a perception questionnaire will be completed before and after the nap. The primary outcome is technical feasibility. Secondary outcomes include protocol acceptability, blinding and perceived effectiveness and delta EEG power. Tertiary outcomes include visuo-spatial recognition, vigilance, sigma power, and sleep macro-architecture. Preliminary feasibility data on this novel intervention to target sleep and cognition in OSA will inform a larger clinical trial.
P082 Actigraphic Assessment of Sleep Patterns in Women with Menopausal Symptoms
Authors: Li X , Chow C , Halaki M
Published: December 2024

Introduction

Approximately 40%-60% of menopausal women suffer from sleep disturbances, commonly linked to vasomotor symptoms of hot flashes and night sweats. This study aims to evaluate sleep patterns and quality in peri- and post-menopausal women using actigraphy.

Methods

Thirty-nine participants (45 to 65y, BMI 25.62±3.02 kg/m², Insomnia Severity Index (ISI) score 10.98±4.10) experiencing menopausal symptoms underwent actigraphy recordings of sleep onset/offset, duration, and mid-sleep times over at least three consecutive nights with 357 nights of data analysed.

Results

The vasomotor subscales (hot flash and night sweat, Greene Climacterics questionnaire) yielded a score of 2.43±1.15 (compared to general population: 1.79±1.12 and menopause clinic: 4.41±1.70). Sleep onset times ranged from 19:06-03:16 with the most common time at 22:00-22:59 (31.1%) followed by 23:00-23:59 (27.5%). Sleep offset times ranged from 03:39-11:28 with the most common time at 06:00-06:59 (34.5%). The average sleep duration ranged from 231 to 819 minutes with the most common duration 470-529 min (33.6%) with 43.1% of nights with <8h of sleep. The mid-sleep times ranged from 23:50-05:19 with the most common mid-sleep time at 02:30-02:59(19%), followed by 02:00-02:29 (17.9%) and 03:00-03:29 (17.4%).

Discussion

In consideration of demographic factors, moderate vasomotor symptoms and some irregularities in sleep-wake timing, the menopausal women in this study largely have adequate sleep duration of around eight or more hours. It is likely that their symptoms were not as severe as the clinic sample. However, it is not clear if better sleep in this group is linked to increased awareness of sleep as a health behaviour.
Malone v. Government of the United Kingdom of Great Britain and Northern Ireland and Another (2024) and State Immunity in South Africa in Extradition Proceedings: Interpreting the Foreign States Immunities Act in Light of Its Drafting History and International Law
Authors: Mujuzi Jamil Ddamulira
Published: December 2024

The Foreign States Immunities Act (the Act) provides for circumstances in which a state enjoys jurisdictional immunity for any act or omission that takes place in South Africa (sovereign acts under section 2) and for circumstances in which it loses that immunity (private/commercial acts under sections 4, 5, and 6). The Constitutional Court held that extradition is a sovereign act. Thus, the requesting state enjoys jurisdictional immunity. In Malone v. UK and Another, the United Kingdom requested South Africa to arrest and detain the applicant pending his extradition and to oppose his bail application. He spent several days in detention before the United Kingdom withdrew the extradition request. He argued that the United Kingdom was responsible for the violation of his rights. The United Kingdom argued that extradition was a sovereign act and the court did not have jurisdiction over the matter. Although the High Court recognized that extradition is a sovereign act, it invoked section 6 of the Act and held that the United Kingdom was liable for the violation of the applicant’s rights. It is argued that the Court’s reliance on section 6 is contrary to the drafting history of the Act and potentially to the jurisprudence of the International Court of Justice.
Effect of a dietary nutraceutical “STRUCTURE-Joint” on response of horses to intra-articular challenge with IL-1: implications for tissue adaptation to stress
Authors: Korac Lindsay , Golestani Nadia , MacNicol Jennifer , Souccar-Young Jamie , Witherspoon Sophie , Wildish Arayih , Topfer Sydney , Pearson Wendy
Published: December 2024

The purpose was to determine local (articular) and systemic effects of intra-articular interleukin-1 in horses supplemented with a dietary PUFA supplement [STRUCTURE-Joint (ST-J)]. Sixteen (16) healthy, mature, light breed horses were randomly assigned to diets containing 0 or 120 mL (n = 8 per group) of ST-J for 30 d. On days 0 (prior to beginning supplementation) and 27, recombinant equine interleukin-1β (reIL-1 β) (75 ng) was injected into the left or right intercarpal joint to induce mild, transient synovitis. Synovial fluid was obtained by aseptic arthrocentesis at postinjection hour 0 (immediately prior to IL-1 injection), 6, 12, and 72. ST-J supplementation for 30 d significantly increased synovial fluid nitric oxide, and resolvin D1 compared with the unsupplemented control group and significantly increased PGE2 levels and reduced joint circumference in the ST-J treated horses on day 30 compared to the same group of horses on day 0. There was also a significant increase in plasma hemoglobin, free and total bilirubin, and decrease in plasma glucose. These data provide evidence for the usefulness of ST-J to modulate physiological variables with importance in exercise performance and tissue adaptation to exercise stress and further research on this product is warranted.
Origin, spread, and interspecies transmission of a dominant genotype of BJ/94 lineage H9N2 avian influenza viruses with increased threat
Authors: Zhou Yong , Li Yudong , Chen Hongzhuang , Shu Sicheng , Li Zhixin , Sun Honglei , Sun Yipeng , Liu Jinhua , Lu Lu , Pu Juan
Published: December 2024

The H9N2 subtype of avian influenza viruses (AIVs) is widely prevalent in poultry and wild birds globally, with occasional transmission to humans. In comparison to other H9N2 lineages, the BJ/94 lineage has raised more public health concerns; however, its evolutionary dynamics and transmission patterns remain poorly understood. In this study, we demonstrate that over three decades (1994–2023), BJ/94 lineage has undergone substantial expansion in its geographical distribution, interspecies transmission, and viral reassortment with other AIV subtypes, increasing associated public health risks. These changes were primarily driven by the emergence of a dominant genotype G57. In the first decade, G57 emerged in East China and rapidly adapted to chickens and spread across China. Since 2013, the G57 genotype has expanded beyond China into eight other countries and reassorted with various AIV subtypes to form new zoonotic reassortants. Chickens have played a key role in the generation and circulation of the G57 viruses, with ducks and other poultry species likely assuming an increasingly importantly role. Over the past decade, G57 has been more frequently detected in wild birds, mammals, and humans. Additionally, Vietnam has emerged as a new hotspot for the international spread of G57. Our results suggest that the BJ/94 lineage H9N2 virus may continue to overcome geographical and species barriers, with potentially more severe consequences.
Supporting Women-Led Businesses: Narrative Review of Recent Causal Evidence
Authors: Ubfal Diego
Published: December 2024

Innovative women entrepreneurs can be agents of change and offer novel solutions to global challenges. However, they face multiple barriers to growing their businesses. I review the literature on strategies to support women entrepreneurs in improving their business outcomes. I focus on interventions designed to address four areas of constraints that influence their decisions and can impact their business performance: gaps in human capital, access to finance, access to technology and markets, and contextual factors such as legal and regulatory constraints, social norms, access to care, and gender-based violence. I conclude that evidence of modest average treatment effects and heterogeneity in treatment effects across various interventions suggests the need for more precise targeting. The multiple constraints faced by women entrepreneurs necessitates testing different packages of interventions. Moreover, the successful implementation and adoption of proposed solutions require consideration of the contextual constraints that differentially affect women-led businesses. While I highlight several interventions that show promise in supporting women entrepreneurs, significant gaps remain in the evidence concerning the most effective strategies.
Evolutionary, taxonomical, and ecological traits of the Late Neogene armadillo Macrochorobates Scillato-Yané (Xenarthra: Cingulata)
Authors: Barasoain Daniel , Tomassini Rodrigo L , Quiñones Sofía I , González-Ruiz Laureano R , Bonini Ricardo A , Zurita Alfredo E
Published: December 2024

Within armadillos, two clades are currently recognized: Chlamyphoridae and Dasypodidae. Major evolutionary processes of Chlamyphoridae are linked to the main environmental and climatic events that occurred in South America in the Cenozoic. More precisely, the Euphractinae reached a high diversity concomitant with the cooling period of the Late Miocene–Pliocene. One of the largest euphractines is Macrochorobates, which includes the species M. scalabrinii and M. chapalmalensis, differentiated by minor details on the osteoderms of the dorsal carapace. This genus had a wide distribution, with records in Late Miocene–Pliocene deposits of different regions of Argentina. Here we describe and compare new specimens of M. scalabrinii, which represent the most complete material known so far. Our comparative analysis strongly suggests that M. chapalmalensis represents a junior synonym of M. scalabrinii. This way, the biochron of M. scalabrinii would range from the Late Miocene to the Late Pliocene. Additionally, anatomical comparisons and cladistic analysis show that Macrochorobates and Macroeuphractus (another Late Neogene large euphractine) share some cranial characters, not observable in other armadillos; therefore, we propose that Macrochorobates scalabrinii could have had intermediate carnivorous diets between more generalist taxa such as Euphractus and the specialized carnivory proposed for Macroeuphractus.
The long-eared freshwater planarians of Madagascar form a separate phylogenetic clade within the genus Dugesia (Platyhelminthes: Tricladida), with the description of two new species
Authors: Stocchino Giacinta Angela , Sluys Ronald , Solà Eduard , Riutort Marta , Manconi Renata
Published: December 2024

Madagascar and the Comoros Archipelago are inhabited by freshwater planarians of the genus Dugesia characterized by a unique morphotype with long and pointed auricles, which were traditionally ascribed to only one species, Dugesia milloti. Collections of new specimens of these long-eared freshwater triclads enabled us to examine these worms in more detail than previously had been possible and, thus, we were able to study the animals from an integrative perspective, including morphological, karyological, and molecular data. In addition, we re-examined D. milloti specimens that were available from natural history collections. In contrast to previous notions, we found that at least seven species of long-eared planarians inhabit the Malagasy inland waters, two of which are here newly described, viz., Dugesia crassimentula Sluys & Stocchino, sp. nov., and Dugesia insolita Stocchino & Sluys, sp. nov. Molecularly, the long-eared planarians form a separate phylogenetic clade that is not closely related to the other distinct morphotypes of Malagasy congeners. Furthermore, our karyological analyses revealed a new haploid (n = 5) chromosome number for the genus Dugesia, being the lowest chromosome number presently known for this genus. In addition, a previously unknown autotomy-like behaviour in freshwater triclads is reported here for the first time.
Perioperative Hypotension in Chronic Kidney Disease Patients with Dialysis Undergoing Noncardiac Surgery: A Retrospective Cohort Study
Authors: Tok Cekmecelioglu Busra , Tire Yasin , Sertcakacilar Gokhan , Ekrami Elyad , Pu Xuan , Kopac Orkun , Chu Jeffrey , Roshanov Pavel S. , Argalious Maged , Ruetzler Kurt , Turan Alparslan
Published: December 2024

Background:

Patients with chronic kidney disease who require maintenance dialysis suffer excess morbidity and mortality for reasons that are not clearly elucidated. There are few targets for intervention to improve their outcomes. The authors hypothesized that perioperative hypotension is more common in patients receiving dialysis.

Methodology:

A retrospective cohort study was conducted of adult patients who had inpatient noncardiac surgery lasting greater than 2 h with general anesthesia between January 2012 and December 2021 at the Cleveland Clinic (Cleveland, Ohio). Using International Classification of Diseases codes and dialysis documentation in the electronic medical record, was derived age, American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status, surgery type, and propensity score (predicting dialysis dependence) matched groups of patients (1) with dialysis-dependent chronic kidney disease, (2) with nondialysis chronic kidney disease, and (3) without kidney disease. The primary outcomes were total area under the curve of mean arterial pressure (MAP) less than 65 mmHg during the surgery and postoperative MAP less than 70 mmHg during 48 h after surgery.

Results:

Three 1:1:1 matched groups of 1,886 patients (total, 5,658 patients) from an overall cohort of 123,761 were derived. Cases with dialysis-dependent kidney disease had a greater intraoperative area under the curve of MAP less than 65 mmHg (difference in medians, 18.4 mmHg-min 98.75% CI, 11.3 to 25.6; P < 0.001) when compared to patients who had nondialysis kidney disease and when compared to patients without kidney disease (difference in medians, 15.5 mmHg-min; 98.75% CI, 6.6 to 24.4; P < 0.001). Patients receiving preoperative dialysis were also more likely to have postoperative MAP less than 70 mmHg compared to patients with nondialysis kidney disease (rate ratio, 1.52; 98.75% CI, 1.48 to 1.57; P < 0.0001) and compared to patients without kidney disease (rate ratio, 1.43; 98.75% CI, 1.38 to 1.47; P < 0.0001).

Conclusions:

Perioperative hypotension is more severe and common among patients who undergo chronic maintenance dialysis compared to similar patients without dialysis dependence. The management of hemodynamics in this population comes with unique considerations that warrant further systematic evaluation.
ResNet-Vision Transformer based MRI-endoscopy fusion model for predicting treatment response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: A multicenter study
Authors: Zhang Junhao , Liu Ruiqing , Hao Di , Tian Guangye , Zhang Shiwei , Zhang Sen , Zang Yitong , Pang Kai , Hu Xuhua , Ren Keyu , Cui Mingjuan , Liu Shuhao , Wu Jinhui , Wang Quan , Feng Bo , Tong Weidong , Yang Yingchi , Wang Guiying , Lu Yun
Published: December 2024

Background:

Neoadjuvant chemoradiotherapy followed by radical surgery has been a common practice for patients with locally advanced rectal cancer, but the response rate varies among patients. This study aimed to develop a ResNet-Vision Transformer based magnetic resonance imaging (MRI)-endoscopy fusion model to precisely predict treatment response and provide personalized treatment.

Methods:

In this multicenter study, 366 eligible patients who had undergone neoadjuvant chemoradiotherapy followed by radical surgery at eight Chinese tertiary hospitals between January 2017 and June 2024 were recruited, with 2928 pretreatment colonic endoscopic images and 366 pelvic MRI images. An MRI-endoscopy fusion model was constructed based on the ResNet backbone and Transformer network using pretreatment MRI and endoscopic images. Treatment response was defined as good response or non-good response based on the tumor regression grade. The Delong test and the Hanley–McNeil test were utilized to compare prediction performance among different models and different subgroups, respectively. The predictive performance of the MRI-endoscopy fusion model was comprehensively validated in the test sets and was further compared to that of the single-modal MRI model and single-modal endoscopy model.

Results:

The MRI-endoscopy fusion model demonstrated favorable prediction performance. In the internal validation set, the area under the curve (AUC) and accuracy were 0.852 (95% confidence interval [CI]: 0.744–0.940) and 0.737 (95% CI: 0.712–0.844), respectively. Moreover, the AUC and accuracy reached 0.769 (95% CI: 0.678–0.861) and 0.729 (95% CI: 0.628–0.821), respectively, in the external test set. In addition, the MRI-endoscopy fusion model outperformed the single-modal MRI model (AUC: 0.692 [95% CI: 0.609–0.783], accuracy: 0.659 [95% CI: 0.565–0.775]) and the single-modal endoscopy model (AUC: 0.720 [95% CI: 0.617–0.823], accuracy: 0.713 [95% CI: 0.612–0.809]) in the external test set.

Conclusion:

The MRI-endoscopy fusion model based on ResNet-Vision Transformer achieved favorable performance in predicting treatment response to neoadjuvant chemoradiotherapy and holds tremendous potential for enabling personalized treatment regimens for locally advanced rectal cancer patients.