bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermo-hydro-mechanical coupling analysis of geothermal reservoirs: optimizing extraction capacities by revealing influential factors
Authors: Zhang Guolong , Liu Shiqi , Fei Yu , Li Yang , Guo Feng
Published: May 2024

Extraction of high-temperature geothermal resources from reservoirs is a challenge due to the complex interactions between temperature, permeability, and stress fields. Variations in physical fields are critical to thermal reservoir engineering. In this study, the coupling mechanism between temperature, permeability, and stress fields is systematically explored using theoretical analyses and numerical simulations, by using the three-field coupling model. This study models the changes in porosity and permeability evolution during geothermal extraction, emphasizing the importance of the coupling term. The effects of pressure differences between injection and production wells, reservoir temperature variations, and fluid property changes on the temperature distribution and output thermal power within the geothermal reservoir were modeled and analyzed. The results reveal the significant effect of pressure differences between wells, and show that the geothermal extraction capacity of supercritical carbon dioxide (SC-CO2) is 1.83 times higher than that of water. Based on the statistical characteristics of the distribution pattern of natural fractures within the geothermal reservoir, the study simulated the distribution of natural fractures and developed a coupled thermo-hydro-mechanical (THM) model containing natural fractures. The results show that increasing the porosity of hydraulic and natural fractures can effectively increase the geothermal production capacity, especially the increase in the porosity of natural fractures is significant. These findings provide a key theoretical basis for understanding the THM coupling mechanism during geothermal extraction, and provide substantial support for optimizing the development and use of geothermal resources.
A Pseudo-Deterministic Noisy Extremal Optimization algorithm for the pairwise connectivity Critical Node Detection Problem
Authors: Gaskó Noémi , Suciu Mihai-Alexandru , Ioana Lung Rodica , Képes Tamás
Published: May 2024

The critical node detection problem is a central task in computational graph theory due to its large applicability, consisting in deleting $k$ nodes to minimize a certain graph measure. In this article, we propose a new Extremal Optimization-based approach, the Pseudo-Deterministic Noisy Extremal Optimization (PDNEO) algorithm, to solve the Critical Node Detection variant in which the pairwise connectivity is minimized. PDNEO uses an adaptive pseudo-deterministic parameter to switch between random nodes and articulation points during the search, as well as other features, such as noise induction to preserve diversity, greedy search to better exploit the search space and a greater search space exploration mechanism. Numerical experiments on synthetic and real-world networks show the effectiveness of the proposed algorithm compared with existing methods.
Imaging polarimetry of comet 67 P/Churyumov–Gerasimenko: homogeneous distribution of polarization and its implications
Authors: Gray Zuri , Bagnulo Stefano , Boehnhardt Hermann , Borisov Galin , Jones Geraint H , Kolokolova Ludmilla , Kwon Yuna G , Moreno Fernando , Muñoz Olga , Nežič Rok , Snodgrass Colin
Published: May 2024

Comet 67P/Churyumov–Gerasimenko (67P) become observable for the first time in 2021 since the Rosetta rendezvous in 2014–2016. Here, we present pre-perihelion polarimetric measurements of 67P from 2021 performed with the Very Large Telescope (VLT), as well as post-perihelion polarimetric measurements from 2015 to 2016 obtained with the VLT and the William Herschel Telescope. This new data covers a phase angle range of ∼4○−50○ and presents polarimetric measurements of unprecedentedly high S/N ratio. Complementing previous measurements, the polarimetric phase curve of 67P resembles that of other Jupiter family comets and high-polarization, dusty comets. Comparing pre- and post-perihelion data sets, we find only a marginal difference between the polarimetric phase curves. In our imaging maps, we detect various linear structures produced by the dust in the inner coma of the comet. Despite this, we find a homogeneous spread of polarization around the photocentre throughout the coma and tail, in contrast to previous studies. Finally, we explore the consequences of image misalignments on both polarimetric maps and aperture polarimetric measurements.
Star formation exists in all early-type galaxies – evidence from ubiquitous structure in UV images
Authors: Pandey Divya , Kaviraj Sugata , Saha Kanak , Sharma Saurabh
Published: May 2024

Recent surveys have demonstrated the widespread presence of ultraviolet (UV) emission in early-type galaxies (ETGs), suggesting the existence of star formation in many of these systems. However, potential UV contributions from old and young stars, together with model uncertainties, makes it challenging to confirm the presence of young stars using integrated photometry alone. This is particularly true in ETGs that are fainter in the UV and have red UV-optical colours. An unambiguous way of disentangling the source of the UV is to look for structure in UV images. Optical images of ETGs, which are dominated by old stars, are smooth and devoid of structure. If the UV is also produced by these old stars, then the UV images will share this smoothness, while, if driven by young stars, they will exhibit significant structure. We compare the UV and optical morphologies of 32 ETGs (93 per cent of which are at z < 0.03) using quantitative parameters (concentration, asymmetry, clumpiness, and the Sérsic index), calculated via deep UV and optical images with similar resolution. Regardless of stellar mass, UV-optical colour or the presence of interactions, the asymmetry and clumpiness of ETGs is significantly larger (often by several orders of magnitudes) in the UV than in the optical, while the UV Sérsic indices are typically lower than their optical counterparts. The ubiquitous presence of structure demonstrates that the UV flux across our entire ETG sample is dominated by young stars and indicates that star formation exists in all ETGs in the nearby Universe.
Peering into the Wolf–Rayet phenomenon through [WO] and [WC] stars
Authors: Toalá Jesús A , Todt Helge , Sander Andreas A C
Published: May 2024

Spectroscopic observations have shown for decades that the Wolf–Rayet (WR) phenomenon is ubiquitous among stars with different initial masses. Although much effort to understand the winds from massive WR stars has been presented in the literature, not much has been done for such type of stars in the low-mass range. Here we present an attempt to understand the winds from [WR]-type stars using results from spectral analyses with the full non-local thermodynamic equilibrium stellar atmosphere code PoWR. These results are put into context with the properties of massive WR stars. We found that WC + [WC] stars and WO + [WO] stars create independent sequences in the mass-loss rate ($\dot{M}$) and modified wind momentum (Dmom) versus luminosity (L) diagrams. Our analysis indicates that even when the winds of WR and [WR] stars become optically thin, there is no breakdown of the general mass-loss trend, contrary to the observed ‘weak wind phenomenon’ in OB stars. We report that all WR-type stars studied here broadly define single sequences in the wind efficiency (η) versus transformed mass-loss rate ($\dot{M}_\mathrm{t}$), the $\dot{M}_\mathrm{t}$–Teff diagram, and the $(L, T_\mathrm{eff}, \dot{M})$ space, which suggest these to be fundamental properties of the WR phenomenon (regardless of the mass range), at least for WR-type stars of the O and C sequences. Our analytical estimations could drive computations of future stellar evolution models for WR-type stars.
Consensus review on strategies to improve delivery across the blood-brain barrier including focused ultrasound
Authors: Piper Keaton , Kumar Jay I , Domino Joseph , Tuchek Chad , Vogelbaum Michael A
Published: May 2024

Drug delivery to the central nervous system (CNS) has been a major challenge for CNS tumors due to the impermeability of the blood-brain barrier (BBB). There has been a multitude of techniques aimed at overcoming the BBB obstacle aimed at utilizing natural transport mechanisms or bypassing the BBB which we review here. Another approach that has generated recent interest in the recently published literature is to use new technologies (Laser Interstitial Thermal Therapy, LITT; or Low-Intensity Focused Ultrasound, LIFU) to temporarily increase BBB permeability. This review overviews the advantages, disadvantages, and major advances of each method. LIFU has been a major area of research to allow for chemotherapeutics to cross the BBB which has a particular emphasis in this review. While most of the advances remain in animal studies, there are an increasing number of translational clinical trials that will have results in the next few years.
Advancing collaborative social outcomes through place-based solutions—aligning policy and funding systems
Authors: Lata Lutfun Nahar , Reddel Tim , Head Brian W , Craven Luke
Published: May 2024

More collaborative and human-centered approaches to tackle social problems of entrenched disadvantage have been introduced in many countries, including Australia, but with mixed results. Traditional programs that reinforce existing political and bureaucratic processes have been seen as blockers to collaborative modes of policymaking, governance, and delivery. Drawing on collaborative governance perspectives, this paper reports new research undertaken in conjunction with a not-for-profit organization (Collaboration for Impact) involved in supporting place-based collaborative community change efforts. Research findings, based on stakeholder perspectives, highlight not only the potential benefits of a more collaborative model (i.e., placed-based and community driven) but also the significant unresolved challenges for “backbone” coordination bodies, which have recently been established to achieve more “joined-up” policy, funding, and service delivery arrangements. The paper concludes by proposing a practice-driven focus on policy and funding systems, together with implications for policy learning and program design.
Energy deprivation affects nitrogen assimilation and fatty acid biosynthesis leading to leaf chlorosis under waterlogging stress in the endangered Abies koreana
Authors: Chandrasekaran Umashankar , Park Sanghee , Kim Kunhyo , Byeon Siyeon , Han Ah Reum , Lee Young-Sang , Oh Neung-Hwan , Chung Haegeun , Choe Hyeyeong , Kim Hyun Seok
Published: May 2024

Energy deprivation triggers various physiological, biochemical and molecular changes in plants under abiotic stress. We investigated the oxidative damages in the high altitude grown conifer Korean fir (Abies koreana) exposed to waterlogging stress. Our experimental results showed that waterlogging stress led to leaf chlorosis, 35 days after treatment. A significant decrease in leaf fresh weight, chlorophyll and sugar content supported this phenotypic change. Biochemical analysis showed a significant increase in leaf proline, lipid peroxidase and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical content of waterlogged plants. To elucidate the molecular mechanisms, we conducted RNA-sequencing (RNA-seq) and de novo assembly. Using RNA-seq analysis approach and filtering (P < 0.05 and false discovery rate <0.001), we obtained 134 unigenes upregulated and 574 unigenes downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis placed the obtained differentially expressed unigenes in α-linoleic pathway, fatty acid degradation, glycosis, glycolipid metabolism and oligosaccharide biosynthesis process. Mapping of unigenes with Arabidopsis using basic local alignment search tool for nucleotides showed several critical genes in photosynthesis and carbon metabolism downregulated. Following this, we found the repression of multiple nitrogen (N) assimilation and nucleotide biosynthesis genes including purine metabolism. In addition, waterlogging stress reduced the levels of polyunsaturated fatty acids with a concomitant increase only in myristic acid. Together, our results indicate that the prolonged snowmelt may cause inability of A. koreana seedlings to lead the photosynthesis normally due to the lack of root intercellular oxygen and emphasizes a detrimental effect on the N metabolic pathway, compromising this endangered tree’s ability to be fully functional under waterlogging stress.
Effect of different lung recruitment strategies and airway device on oscillatory mechanics in children under general anaesthesia
Authors: Zannin Emanuela , Nguyen Julie , Vigevani Sara , Hauser Neil , Sommerfield David , Dellacà Raffaele , Khan R. Nazim , Sommerfield Aine , von Ungern-Sternberg Britta S.
Published: May 2024

BACKGROUND

Atelectasis has been reported in 68 to 100% of children undergoing general anaesthesia, a phenomenon that persists into the recovery period. Children receiving recruitment manoeuvres have less atelectasis and fewer episodes of oxygen desaturation during emergence. The optimal type of recruitment manoeuvre is unclear and may be influenced by the airway device chosen.

OBJECTIVE

We aimed to investigate the different effects on lung mechanics as assessed by the forced oscillation technique (FOT) utilising different recruitment strategies: repeated inflations vs. one sustained inflation and different airway devices, a supraglottic airway device vs. a cuffed tracheal tube.

DESIGN

Pragmatic enrolment with randomisation to the recruitment strategy.

SETTING

We conducted this single-centre trial between February 2020 and March 2022.

PARTICIPANTS

Seventy healthy patients (53 boys) aged between 2 and 16 years undergoing general anaesthesia were included.

INTERVENTIONS

Forced oscillations (5 Hz) were superimposed on the ventilator waveform using a customised system connected to the anaesthesia machine. Pressure and flow were measured at the inlet of the airway device and used to compute respiratory system resistance and reactance. Measurements were taken before and after recruitment, and again at the end of surgery.

MAIN OUTCOME MEASURES

The primary endpoint measured is the change in respiratory reactance.

RESULTS

Statistical analysis (linear model with recruitment strategy and airway device as factors) did not show any significant difference in resistance and reactance between before and after recruitment. Baseline reactance was the strongest predictor for a change in reactance after recruitment: prerecruitment Xrs decreased by mean (standard error) of 0.25 (0.068) cmH2O s l−1 per  1 cmH2O−1 s l−1 increase in baseline Xrs (P < 0.001). After correcting for baseline reactance, the change in reactance after recruitment was significantly lower for sustained inflation compared with repeated inflation by mean (standard error) 0.25 (0.101) cmH2O (P = 0.0166).

CONCLUSION

Although there was no significant difference between airway devices, this study demonstrated more effective recruitment via repeated inflations than sustained inflation in anaesthetised children.

TRIAL REGISTRATION

Australian New Zealand Clinical Trials Registry: ACTRN12619001434189.
Arthroscopic debridement, synovectomy, and thermal shrinkage for basal joint arthritis
Authors: Kuo Hsueh-Min , Lo I.-Ning , Yin Cheng-Yu , Wang Jung-Pan , Huang Yi-Chao
Published: May 2024

Background:

Ligamentous laxity, cartilage wear, and diffuse synovitis are frequently seen in thumb basal joint arthritis. Although these degenerative changes may be mild for the majority, they have the potential to cause discomfort during movement and compromised hand function. This study assesses the long-term outcomes of arthroscopic debridement, synovectomy, and thermal shrinkage in managing early-stage basal joint arthritis.

Methods:

We retrospectively reviewed patients with basal joint arthritis who underwent arthroscopic debridement, synovectomy, and thermal shrinkage between November 2010 and January 2021 by a single surgeon at our medical institute. We assessed functional outcomes, thumb range of motion, perioperative nonsteroidal anti-inflammatory drug (NSAID) use, return to work and satisfaction level.

Results:

A total of 12 patients (13 hands), with a mean follow-up of 72 months, were included in this study. Significant improvements were observed in pain scores and functional outcomes, along with a reduction in postoperative NSAID use. Patients also reported a relatively quick return to work and a high satisfaction level.

Conclusion:

The study highlights the benefits of arthroscopic intervention, providing a minimally invasive approach with favorable long-term outcomes for patients with symptomatic basal joint arthritis.
Quality-of-Life Instruments and Nutrition Screening Tools
Authors: Arensberg Mary Beth , Gahche Jaime J. , Pemau Raquel Clapes , Kerr Kirk W. , Dwyer Johanna T.
Published: May 2024

Background

Quality of life (QoL) is critical for healthy aging—both for older adults and for healthcare providers/health systems. Eating and nutritious food are essential for older adults to remain healthy/independent and maintain good nutrition status and also provide pleasure and enhance QoL. However, research on nutrition and QoL is limited, including for building understanding of the relationship between nutrition and QoL and of the instruments and tools used to help develop a research framework and evaluate the impact of United States community nutrition programs/services on QoL.

Objectives

The first objective is to review overlaps/gaps in previously identified/validated QoL instruments and nutrition screening tools used in research with community-living older adults and then, second, to use these findings to suggest opportunities for further research and implications for developing US health and nutrition policies/programs supporting healthy aging.

Methods

Twenty validated QoL instruments were reviewed to determine if they included nutrition-related items that corresponded to 8 QoL domains (physical health, emotional state, mental health, social connection, environment, personhood, autonomy, and spiritual feeling). Sixteen validated nutrition screening tools were reviewed to determine if any of their nutrition items corresponded with these same 8 QoL domains.

Results

Of the 20 QoL instruments reviewed, 75% included at least 1 nutrition-related item, most commonly fitting into the autonomy (n = 11), physical health (n = 7), social connection (n = 3), environment (n = 3), emotional state (n = 2), mental health (n = 2), and personhood (n = 1) domains, with none in the spiritual feeling domain. All 16 nutrition screening tools included at least 1 nutrition-related item corresponding to a QoL domain, most commonly the physical health (n = 16) domain. Other QoL domains represented by nutrition items in nutrition screening tools were autonomy (n = 9), emotional state (n = 5), social connection (n = 5), environment (n = 4), and mental health (n = 3). Commonalities existed between QoL instruments and nutrition screening tools in types of nutrition-related items included, but there were many inconsistencies/gaps.

Conclusions

Nutrition items corresponding to different QoL domains are found inconsistently among validated QoL instruments and nutrition screening tools. Nutrition can be potentially modified to benefit healthy aging and QoL outcomes; findings present opportunities for further research to help increase understanding of the relationship between QoL and nutrition and the effectiveness of nutrition interventions, as well as to help advance US policy development and programs supporting healthy aging.
Structural racism, residential segregation, and exposure to trauma: The persistent impact of redlining
Authors: Bradford James M. , Eldin Maya M. , Golestani Simin , Cardenas Tatiana C.P. , Trust Marc D. , Mery Marissa , Teixeira Pedro G. , DuBose Joseph , Brown Lawrence H. , Bach Michelle , Robert Michelle , Ali Sadia , Salvo Deborah , Brown Carlos V.R.
Published: May 2024

INTRODUCTION

As part of New Deal era federal housing policy, the Home Owners' Loan Corporation (HOLC) developed maps grading US neighborhoods by perceived financial security. Neighborhoods with high concentrations of racial and ethnic minorities were deemed financially unstable and denied federal investment, a practice colloquially known as redlining. The aim of this study was to assess the association of historical redlining within Austin, Texas, to spatial patterns of penetrating traumatic injury.

METHODS

A retrospective cross-sectional study was conducted using data from violent penetrating trauma admissions between January 1, 2014, and December 31, 2021, at the single Level 1 trauma center in Austin, Texas. Using ArcGIS, addresses where the injury took place were geocoded, and spatial joining was used to match them to their corresponding census tract, for which 1935 HOLC financial designations are classified as “Hazardous,” “Definitely Declining,” “Still Desirable,” “Best,” or “Non HOLC Graded.” Tracts with designations of “Hazardous” and “Definitely Declining” were categorized as “Redlined.” The adjusted incidence rate ratio comparing rates of penetrating trauma among historically “Redlined” versus “Not Redlined” and “Not Graded” census tracts was calculated.

RESULTS

A total of 1,404 violent penetrating trauma admissions were identified for the study period, of which 920 occurred within the county of interest. Among these, 5% occurred in census tracts that were Not Redlined, 13% occurred in Redlined tracts, and 82% occurred in non-HOLC graded tracts. When adjusting for differences in current census tract demographics and social vulnerability, historically Redlined areas experienced a higher rate of penetrating traumatic injury (Not Redlined injury rate ratio, 0.42; 95% confidence interval, 0.19–0.94; p = 0.03; Not Graded injury rate ratio, 0.15; 95% confidence interval, 0.07–0.29; p < 0.001).

CONCLUSION

Neighborhoods unfavorably classified by HOLC in 1935 continue to experience a higher incidence rate of violent penetrating trauma today. These results underscore the persistent impacts of structural racism and of historical residential segregation policies on exposure to trauma.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Genomic analysis of an outbreak of Shiga toxin-producing Escherichia coli O183:H18 in the United Kingdom, 2023
Authors: Greig David R. , Quinn Orlagh I. , Rodwell Ella V. , Olonade Israel , Swift Craig , Douglas Amy , Balasegram Sooria , Jenkins Claire
Published: May 2024

In June 2023, UKHSA surveillance systems detected an outbreak of severe gastrointestinal symptoms caused by a rare serotype of Shiga toxin-producing Escherichia coli, STEC O183:H18. There were 26 cases aged 6 months to 74 years (42 % cases were aged 0–9 years), distributed across the UK with onset dates range between 22 May 2023 and 4 July 2023. The epidemiological and food chain investigations were inconclusive, although meat products made from beef mince were implicated as a potential vehicle. The outbreak strain belonged to sequence type (ST) 657 and harboured a Shiga toxin (stx) subtype stx2a located on a prophage that was unique in the UKHSA stx-encoding bacteriophage database. Plasmid encoded, putative virulence genes subA, ehxA, saa, iha, lpfA and iss were detected, however, the established STEC virulence genes involved in attachment to the gut mucosa (eae and aggR) were absent. The acquisition of stx across the global population structure of ST657 appeared to correspond with the presence of subA, ehxA, saa, iha, lpfA and iss. During the outbreak investigation, we used long read sequencing to characterise the plasmid and prophage content of this atypical STEC, to look for evidence to explain its recent emergence. Although we were unable to determine source and transmission route of the outbreak strain, the genomic analysis revealed potential clues as to how novel strains for STEC evolve. With the implementation of PCR capable of detecting all STEC, and genome sequencing for typing and virulence profiling, we have the tools to enable us to monitor the changing landscape of STEC. Improvements in the standardised collection of epidemiological data and trace-back strategies within the food industry, will ensure we have a surveillance system capable of alerting us to emerging threats to public health.
Influence of temperature, time, and moisture content on rheology of
tomatoes and pepper purees
Authors: Fadeyibi Adeshina , Ayinla Zainab Ololamide , Ajiboye Rasaq A.
Published: May 2024

This study explored how temperature, time, and moisture content affect the
rheological properties (apparent viscosity, flow behavior index, and consistency
coefficient) of stored tomato and pepper purees. These purees were prepared with
moisture contents of 85%, 90%, and 95% (w/v) using the
hot-break method and tested over 6 days at 2-day intervals and temperatures of
5°C, 10°C, and 15°C. Results displayed distinct ranges for
apparent viscosity, consistency coefficient, and flow behavior indices: tomato
puree (2,519.9-4,324.6 mPa · s, 258.0-550.6 mPa · Sn, 1.80-0.48)
and pepper puree (2,105.6-4,562.0 mPa · s, 268.4-580.4 mPa · Sn,
0.22-0.48). The temperature and storage time had significant (p≤0.05)
effects, but moisture content did not affect these properties. Flow behavior and
consistency coefficients demonstrated relative variation with apparent
viscosity, indicating pseudoplastic behavior. Optimal processing and storage
conditions were identified within specific ranges: 13.21-14.42°C for 2
days with 92.22-94.23% (w/v) moisture content for pepper, and
8.42-11.77°C for 2-6 days with 85% (w/v) moisture for tomato.
Intracellular Retention of Estradiol is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells
Authors: Kim Hyung Bum , Kraus W. Lee
Published: May 2024

Abstract

Elevated blood levels of estrogens have been associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating hormone levels in the blood and intracellular hormone concentrations are not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. While circulating E2 is sequestered by sex hormone binding globulin (SHBG), the potential mechanisms of intracellular E2 retention are poorly understood. We found that a mislocalization of a steroid-binding GRAM-domain containing protein, ASTER-B, to the nucleus, which is observed in a subset of breast cancer patients, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2, and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B-mediated E2 retention is required for sustained hormone-induced ERα chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes.

Significance

This study demonstrates how E2 can be accumulated and retained intracellularly to drive a pro-proliferative gene expression program in ER+ breast cancer cells. Mechanistically, intracellular E2 retention is mediated in part by mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, including E2-mediated gene expression
Beyond the phloem: A general role of the ArabidopsisOCTOPUSgene family in controlling plant growth vigour
Authors: Crivelli Simona , Bartusch Kai , Ruiz-Sola M. Aguila , Coiro Mario , Schmidt Kjølner Hansen Signe , Truernit Elisabeth
Published: May 2024

OCTOPUS(OPS) andOCTOPUS-LIKE 2(OPL2), two homologous genes, were previously identified as important regulators of phloem differentiation in Arabidopsis roots, impacting root growth when their function is lost. Here, we investigated the roles of the other threeOPShomologs in Arabidopsis,OPL1,OPL3, andOPL4. We employed promoter activity analyses, protein localisation studies, functional complementation assays, analysis of single and multiple mutant combinations, and growth assays, including exposure to CLE45 and brassinosteroid pathway modulators. TheOPS/OPLgenes exhibit overlapping expression patterns and functions. Multiple mutant combinations revealed a high degree of redundancy, withOPSand the phloem domain playing a major role in controlling plant growth. While phloem phenotypes are not exacerbated in higher-order mutants, plant growth vigour is nevertheless more severely impacted than inops opl2. Our results suggest a novel role of theOPS/OPLgenes in broadly controlling plant growth and development, potentially through the modulation of meristematic activity via brassinosteroid pathways.
Investigation of the isomerization oftrans- andcis-cinnamic acid in Arabidopsis using stable-isotope-labeled cinnamic acid isomers
Authors: Tsuzuki Kei , Suzuki Taiki , Nishiyama Kotaro , Seto Yoshiya
Published: May 2024

Cinnamic acid (CA) is a widely distributed metabolite in plant species and is a precursor of many important plant molecules, including lignin, flavonoids, and coumarins. CA exists as bothtransandcisisomers; thetransisomer is more stable and common in nature. Previous reports have revealed that thecisisomer of CA (cis-CA) has auxin-like activity when exogenously applied. However, it has also been reported thatcis-CA does not function as an auxin but affects its transport. Although these reports suggest a crucial role forcis-CA as an endogenous signaling molecule, its exact function and mechanism of isomerization fromtrans-CA remain unclear. Here, we report the chemical synthesis of stable-isotope-labeledtrans- andcis-CA. Using these labeled compounds as internal standards, we developed a quantification method of CA using LC–MS/MS. Moreover, we monitored the endogenous conversion fromtrans-tocis-CA using the labeled compounds, demonstrating the UV-dependent and UV-independent CA isomerization in Arabidopsis. Additionally, we identifiedcis-CA in diverse plant species, including liverwort.
Experimental myositis: an optimised version of C-protein-induced myositis
Authors: Giannini M , Rovito D , Oulad-Abdelghani M , Messaddeq N , Debrut L , Kessler P , Charles AL , Geny B , Metzger D , Laverny G , Meyer A
Published: May 2024

Introduction

Inflammatory myopathies (IM) are a group of severe autoimmune diseases, sharing some similarities, whose cause is unknown and treatment is empirical. While C-protein-induced myositis (CIM), the most currently used model of IM, has removed some roadblock to understand and improve the treatment of IM, it has only been partially characterised and its generation limited by reproducibility issues. This study aimed at optimising the generation and the characterisation of CIM.

Methods

In silicoanalysis was run to identify the top-3 specific and immunogenic regions of C-protein. The cognate polypeptides were synthetised and used to immunise C57BL/6N mice. Grip strength, walking ability, serum creatine-kinase levels and muscle pathology (histological and electron microscopic features) were assessed. Immune cell proportions and interferon signature in muscles were also determined.

Results

Among the three C-protein polypeptides with the highest immunogenic score, amino acids 965-991 induced the most severe phenotype (i.e., 37% decrease in strength, 36% increase in hind base width, 45% increase in serum creatine-kinase level, 80% increase in histological inflammatory score) from day (D) 14 to at least D31 after immunisation [experimental myositis (EM)]. Optical and electron microscopy revealed mononuclear cell infiltrate, myofibre necrosis, atrophy, MHC-I expression as well as sarcolemmal, sarcomeric and mitochondrial abnormalities. Proinflammatory T-lymphocytes, macrophages, type-I and II interferon-stimulated transcripts were found within the muscle of EM mice.

Conclusion

EM recapitulates the common hallmarks of IM. This costless, high throughput, reproducible and stable model, generated in the most commonly used background for genetically engineered mice, may foster pre-clinical research in IM.

Key messages

What is already known on this topic

C-protein-induced myositis is currently the most used model of inflammatory myopathies but has been partially characterised and its generation is limited by reproducibility issues.

What this study adds.

Immunisation against the polypeptide encompassing C-protein amino acids 965-991 induces a costless, high throughput, reproducible and stable model of myositis (experimental myositis) that recapitulates the common hallmarks of inflammatory myopathies.

How this study might affect research, practice or policy

Experimental myositis, generated in the most used background for genetically engineered mice (C57BL/6N), might foster pre-clinical research in IM.
Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance
Authors: Liu Jianyong , He Qing-Li , Zhou Jianya , Chikarmane Roshan , Hauk Glenn , Rachakonda Archana , Vaghasia Ajay M. , Castagna Nicole , Steinberg Ruchama C. , Pham Minh-Tam , Anders Nicole M. , Wanjiku Teresia M. , Nuhn Philipp , Shim Joong Sup , Giovinazzo Hugh , Esopi David M. , Kim Kunhwa , Coulter Jonathan , Wang Rulin , Zhou Jianying , Rudek Michelle A. , Berger James M. , Liu Jun O. , Nelson William G. , Yegnasubramanian Srinivasan
Published: May 2024

While nucleoside DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome (MDS)/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identified that triptolide, a diterpenoid epoxide fromTripterygium wilfordii, or analogs significantly augmented the epigenetic and anti-cancer effects of decitabinein vitroandin vivo. These effects were attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced global DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression was associated with cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance.

SIGNIFICANCE

We screened a library of existing drugs to identify those capable of enhancing the anti-cancer effects of the nucleoside DNMTi decitabine. The combination of triptolide and decitabine synergistically inhibited cancer cell growth and survivalin vitro, and was highly effective in inhibiting xenograft growthin vivo. Biochemical, genetic and structural biology studies with triptolide and its analogs revealed that this synergy was due to their inhibition of DCTPP1-mediated pyrophosphate cleavage from 5-aza-deoxycytidine triphosphate, the active metabolite of DNMTi. The genomic incorporation and efficacy of decitabine in cancer cell lines were significantly correlated with DCTPP1 expression more so than those of other nucleoside metabolizing genes. Triptolide and its analogs comprise rational adjuncts to nucleoside DNMTi ripe for further pre-clinical/clinical translation.

HIGHLIGHTS

Triptolide synergistically sensitizes cancer cells to DNMTiin vitro.

Triptolide and decitabine combination shows favorable efficacy and safetyin vivo.

Synergy of triptolide and decitabine is mediated through inhibition of DCTPP1.

High DCTPP1 expression confers cell intrinsic resistance to DNMTi.
Novel and Efficient Plasmid Transfection Protocols for Functional Analysis of Genetic Elements in Human Cardiac Fibroblasts
Authors: Makoto MATSUYAMA , Takahiro IWAMIYA
Published: May 2024

Cardiac fibroblasts, have lower gene transfer efficiency compared to dermal fibroblasts, posing challenges for plasmid-based gene transfer methods. A higher transfer efficiency could enable improved insight into heart pathology and development of novel therapeutic targets.

In this study we compared eleven commercially available transfection reagents and eight plasmid purification methods. Finally, we systematically evaluated 150 unique transfection conditions (incubation times, addition of innate immune inhibitors, reagent to plasmid ratios etc) to optimize the methodology.

The aim was to develop an optimized plasmid transfection protocol specifically tailored for primary human cardiac fibroblasts with high efficiency and minimal toxicity. Leveraging our newly developed methodology, we could perform comprehensive profiling of nine viral and native enhancer/promoters, revealing regulatory sequences governing classical fibroblast marker (VIM) and resident cardiac fibroblast marker (TCF21) expression. We believe that these findings can help advance many aspects of cardiovascular research.

In conclusion, we here report for the first time a plasmid transfection protocol for cardiac fibroblasts with minimal cell toxicity.
Transcriptional control of central T cell tolerance by NR4A family nuclear receptors
Authors: Nielsen Hailyn V. , Mueller James L. , Hiwa Ryosuke , Yang Letitia , Proekt Irena , Rackaityte Elze , Aylard Dominik , Scharer Christopher D. , Anderson Mark , Au-Yeung Byron , Zikherman Julie
Published: May 2024

Although deletion of self-reactive thymocytes and their diversion into regulatory T cell (Treg) lineage are critical for immune tolerance and homeostasis, the molecular pathways that link antigen recognition to these fates are incompletely understood. The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to TCR signaling in the thymus and are implicated in both deletion and diversion, but the mechanisms by which they operate are not clear. Redundancy among the family members and their requirement for Treg generation and maintenance have obscured their role in negative selection. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to demonstrate thatNr4a1andNr4a3are essential for upregulation ofBcl2l11/BIM and negative selection by tissue-restricted model self-antigen (TRA). Moreover, we reveal that the Nr4a family is absolutely required for full induction of a broad transcriptional program triggered in self-reactive thymocytes by TRA recognition, and conserved across model systems and the natural repertoire. Importantly, both model self antigen-specific TCR Tg and polyclonal thymocytes lackingNr4a1/3that escape negative selection acquire an anergy-like program that persists in the periphery and is also evident among wild-type recent thymic emigrants (RTEs). We propose that the Nr4a family transduces TCR signals during thymic development to enforce the fates of highly self-reactive clones, mediating not only deletion and Treg diversion, but also contributing to a cell-intrinsic, persistent anergy-like program that may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.
Cholesterol Restriction Primes RIG-I Antiviral Responses Through a Noncanonical Type I IFN Pathway
Authors: Nishimura Tasuku , Kouwaki Takahisa , Takashima Ken , Ochi Akie , Mtali Yohana S , Oshiumi Hiroyuki
Published: May 2024

Cholesterol metabolism is associated with innate immune responses; however, the mechanisms underlying this have not been fully elucidated. Here, we performed a chemical screening to isolate small molecules affecting the activity of RIG-I, a cytoplasmic viral RNA sensor, and found that statins, which inhibit cholesterol synthesis, dramatically enhanced RIG-I-dependent antiviral responses in specific cell types. The restriction of cholesterol synthesis induced the expression of noncanonical type I interferons (IFNs), such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This noncanonical type I IFN expression pathway subsequently enhanced RIG-I-mediated signaling following viral infection. Administration of statins in mice augmented RIG-I-dependent cytokine expression in the lungs. Conversely, a mouse obesity model exhibited reduced RIG-I response in the lungs compared to wild-type mice. Single-cell transcriptome analyses revealed a subset of alveolar macrophages that increased the RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study revealed the noncanonical type I IFN pathway linking cholesterol metabolism and RIG-I signaling. Targeting this pathway could offer valuable insights for developing novel treatment approaches to address future viral pandemics.
Health Disparities and Reporting Gaps in Artificial Intelligence (AI) Enabled Medical Devices: A Scoping Review of 692 U.S. Food and Drug Administration (FDA) 510k Approvals
Authors: Muralidharan Vijaytha , Adewale Boluwatife Adeleye , Huang Caroline J , Nta Mfon Thelma , Ademiju Peter Oluwaduyilemi , Pathmarajah Pirunthan , Hang Man Kien , Adesanya Oluwafolajimi , Abdullateef Ridwanullah Olamide , Babatunde Abdulhammed Opeyemi , Ajibade Abdulquddus , Onyeka Sonia , Cai Zhou Ran , Daneshjou Roxana , Olatunji Tobi
Published: May 2024

Machine learning and artificial intelligence (AI/ML) models in healthcare may exacerbate health biases. Regulatory oversight is critical in evaluating the safety and effectiveness of AI/ML devices in clinical settings. We conducted a scoping review on the 692 FDA 510k-approved AI/ML-enabled medical devices to examine transparency, safety reporting, and sociodemographic representation. Only 3.6% of approvals reported race/ethnicity, 99.1% provided no socioeconomic data. 81.6% did not report the age of study subjects. Only 46.1% provided comprehensive detailed results of performance studies; only 1.9% included a link to a scientific publication with safety and efficacy data. Only 9.0% contained a prospective study for post-market surveillance. Despite the growing number of market-approved medical devices, our data shows that FDA reporting data remains inconsistent. Demographic and socioeconomic characteristics are underreported, exacerbating the risk of algorithmic bias and health disparity.
Genetic Variants and Therapeutic Approaches in Maturity-Onset Diabetes of the Young: A Retrospective Analysis
Authors: Deng Lily , Shah Amy S. , Krishnamurthy Mansa
Published: May 2024

Context

Identifying Maturity-Onset Diabetes of the Young (MODY) in patients with diabetes is essential because treatment differs significantly from other forms of diabetes. We identified patients with MODY gene variants and evaluated their clinical characteristics and responses to treatment.

Evidence Acquisition

We identified 106 patients with genetic MODY variants. Demographics, islet autoantibodies at diabetes diagnosis, co-morbidities, and response to treatment by genetic variant were evaluated.

Evidence Synthesis

Patients diagnosed with MODY variants comprised 4% of the total population with diabetes. Mean age and HbA1c of patients with MODY at diagnosis were 10.5 years and 8.2%, respectively. Surprisingly, diabetic ketoacidosis was a presenting feature for some (n=7, 6.8%), and others with MODY had positive islet cell autoantibodies (n= 7, 6.6%). Variants in HNF1A, GCK, and HNF1B were frequently observed (20%, 22%, and 17% respectively), while rare variants in PDX1, RFX6, BLK, and CNOT1 were uncovered. Initial and follow up treatment of patients with MODY were compared. For each medication (Insulin, Metformin, Sulfonylureas, and GLP-1 receptor agonists), a reduction in HbA1c was observed at follow-up (0.3-21%). Insulin and sulfonylureas were associated with an increase in average BMI (insulin: +8.23%, n=21, sulfonylurea: +0.63%, n=12) at follow-up, metformin was intermediate (−2.46%, n=4), and GLP-1 receptor agonists demonstrated the greatest decrease in BMI (−4.79%, n=4).

Conclusions

The presence of islet autoantibodies or diabetic ketoacidosis does not preclude the diagnosis of MODY. Given the observed improvements in BMI and HbA1c, further investigation into the use of GLP-1 receptor agonists as treatment for MODY should be considered.
A 3D-printed multi-compartment organ-on-chip platform with a tubing-free pump models communication with the lymph node
Authors: Cook Sophie R , Ball Alexander G , Mohammad Anwaruddin , Pompano Rebecca R.
Published: May 2024

Multi-organ-on-chip systems (MOOCs) have the potential to mimic communication between organ systems and reveal mechanisms of health and disease. However, many existing MOOCs are challenging for non-experts to implement, due to complex tubing, electronics, or pump mechanisms. In addition, few MOOCs have incorporated immune organs such as the lymph node (LN), limiting their applicability to critical events such as vaccination. Here we developed a 3D-printed, user-friendly device and companion tubing-free impeller pump with the capacity to co-culture two or more tissue samples, including a LN, under a recirculating common media. Native tissue structure and immune function were incorporated by maintaining slices of murine LN tissue ex vivo in 3D-printed mesh supports for at least 24 hr. In a two-compartment model of a LN and an upstream injection site in mock tissue, vaccination of the multi-compartment chip was similar to in vivo vaccination in terms of locations of antigen accumulation and acute changes in activation markers and gene expression in the LN. We anticipate that in the future, this flexible platform will enable models of multi-organ immune responses throughout the body.
Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs
Authors: Zhang Kejia , Manning Aidan C. , Lentini Jenna M. , Howard Jonathan , Dalwigk Felix , Maroofian Reza , Efthymiou Stephanie , Chan Patricia , Eliseev Sergei I. , Yang Zi , Chang Hayley , Karimiani Ehsan Ghayoor , Bakhshoodeh Behnoosh , Houlden Henry , Kaiser Stefanie M. , Lowe Todd M. , Fu Dragony
Published: May 2024

The tRNA methyltransferase 1 (TRMT1) enzyme catalyzes m2,2G modification in tRNAs. Intriguingly, vertebrates encode an additional tRNA methyltransferase 1-like (TRMT1L) paralog. Here, we use a comprehensive tRNA sequencing approach to decipher targets of human TRMT1 and TRMT1L. We find that TRMT1 methylates all known tRNAs containing guanosine at position 26 while TRMT1L represents the elusive enzyme catalyzing m2,2G at position 27 in tyrosine tRNAs. Surprisingly, TRMT1L is also necessary for maintaining acp3U modifications in a subset of tRNAs through a process that can be uncoupled from methyltransferase activity. We also demonstrate that tyrosine and serine tRNAs are dependent upon m2,2G modifications for their stability and function in translation. Notably, human patient cells with disease-associated TRMT1 variants exhibit reduced levels of tyrosine and serine tRNAs. These findings uncover unexpected roles for TRMT1 paralogs, decipher functions for m2,2G modifications, and pinpoint tRNAs dysregulated in human disorders caused by tRNA modification deficiency.