bluuebunny/crossref_metadata_2025 huggingface dataset:
Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFκB
Authors: Mishra Saurabh , Welch Nicole , Singh Shashi Shekhar , Singh Khuraijam Dhanachandra , Bellar Annette , Kumar Avinash , Deutz Lars N. , Hanlon Maxmillian D. , Kant Sashi , Dastidar Sumitava , Patel Hailee , Agrawal Vandana , Attaway Amy H. , Musich Ryan , Stark George R. , Tedesco Francesco Saverio , Truskey George A. , Weiner I. David , Karnik Sadashiva S. , Dasarathy Srinivasan
Published: July 2024

Transceptors, solute transporters that facilitate intracellular entry of molecules and also initiate intracellular signaling events, have been primarily studied in lower-order species. Ammonia, a cytotoxic endogenous metabolite, is converted to urea in hepatocytes for urinary excretion in mammals. During hyperammonemia, when hepatic metabolism is impaired, nonureagenic ammonia disposal occurs primarily in skeletal muscle. Increased ammonia uptake in skeletal muscle is mediated by a membrane-bound, 12 transmembrane domain solute transporter, Rhesus blood group-associated B glycoprotein (RhBG). We show that in addition to its transport function, RhBG interacts with myeloid differentiation primary response-88 (MyD88) to initiate an intracellular signaling cascade that culminates in activation of NFκB. We also show that ammonia-induced MyD88 signaling is independent of the canonical toll-like receptor-initiated mechanism of MyD88-dependent NFκB activation. In silico, in vitro, and in situ experiments show that the conserved cytosolic J-domain of the RhBG protein interacts with the Toll-interleukin-1 receptor (TIR) domain of MyD88. In skeletal muscle from human patients, human-induced pluripotent stem cell-derived myotubes, and myobundles show an interaction of RhBG–MyD88 during hyperammonemia. Using complementary experimental and multiomics analyses in murine myotubes and mice with muscle-specific RhBG or MyD88 deletion, we show that the RhBG–MyD88 interaction is essential for the activation of NFkB but not ammonia transport. Our studies show a paradigm of substrate-dependent regulation of transceptor function with the potential for modulation of cellular responses in mammalian systems by decoupling transport and signaling functions of transceptors.
Shot noise-mitigated secondary electron imaging with ion count-aided microscopy
Authors: Agarwal Akshay , Kasaei Leila , He Xinglin , Kitichotkul Ruangrawee , Hitit Oğuz Kağan , Peng Minxu , Schultz J. Albert , Feldman Leonard C. , Goyal Vivek K
Published: July 2024

Modern science is dependent on imaging on the nanoscale, often achieved through processes that detect secondary electrons created by a highly focused incident charged particle beam. Multiple types of measurement noise limit the ultimate trade-off between the image quality and the incident particle dose, which can preclude useful imaging of dose-sensitive samples. Existing methods to improve image quality do not fundamentally mitigate the noise sources. Furthermore, barriers to assigning a physically meaningful scale make the images qualitative. Here, we introduce ion count-aided microscopy (ICAM), which is a quantitative imaging technique that uses statistically principled estimation of the secondary electron yield. With a readily implemented change in data collection, ICAM substantially reduces source shot noise. In helium ion microscopy, we demonstrate 3

×

dose reduction and a good match between these empirical results and theoretical performance predictions. ICAM facilitates imaging of fragile samples and may make imaging with heavier particles more attractive.
Lack of evidence for direct ligand-gated ion channel activity of GluD receptors
Authors: Itoh Masayuki , Piot Laura , Mony Laetitia , Paoletti Pierre , Yuzaki Michisuke
Published: July 2024

Delta receptors (GluD1 and GluD2), members of the large ionotropic glutamate receptor (iGluR) family, play a central role in numerous neurodevelopmental and psychiatric disorders. The amino-terminal domain (ATD) of GluD orchestrates synapse formation and maturation processes through its interaction with the Cbln family of synaptic organizers and neurexin (Nrxn). The transsynaptic triad of Nrxn–Cbln–GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. Despite these recognized functions, there is still debate as to whether GluD functions as a "canonical" ion channel, similar to other iGluRs. A recent report proposes that the ATD of GluD2 imposes conformational constraints on channel activity; removal of this constraint by binding to Cbln1 and Nrxn, or removal of the ATD, reveals channel activity in GluD2 upon administration of glycine (Gly) and
d
-serine (
d
-Ser), two GluD ligands. We were able to reproduce currents when Gly or
d
-Ser was administered to clusters of heterologous human embryonic kidney 293 (HEK293) cells expressing Cbln1, GluD2 (or GluD1), and Nrxn. However, Gly or
d
-Ser, but also
l
-glutamate (
l
-Glu), evoked similar currents in naive (i.e., untransfected) HEK293 cells and in GluD2-null Purkinje neurons. Furthermore, no current was detected in isolated HEK293 cells expressing GluD2 lacking the ATD upon administration of Gly. Taken together, these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels.
Determination of dark matter distribution in Ursa Major III and constraints on dark matter annihilation*
Authors: Zhao 赵 Yi 熠 , Bi 毕 Xiao-Jun 效军 , Lin 林 Su-Jie 苏杰 , Yin 殷 Peng-Fei 鹏飞
Published: July 2024

The recently discovered satellite dwarf galaxy Ursa Major III provides a promising opportunity to explore the signatures resulting from dark matter (DM) annihilation owing to its proximity and large J-factor. Given the absence of an excess of γ-ray signatures originating from Ursa Major III, observations of γ-rays, such as those from Fermi-LAT, can be utilized to set constraints on the DM annihilation cross-section. In this study, we determined the DM density profile and considered the relationship between DM density and velocity dispersion at different locations within Ursa Major III through Jeans analysis. We calculated the J-factor of Ursa Major III for s-wave annihilation along with the effective J-factors for p-wave and Sommerfeld enhanced annihilation scenarios. Employing these derived J-factors, we set stringent constraints on DM annihilation cross-sections in three scenarios. Given the substantial impact of member star identification on the J-factor of Ursa Major III, we further calculated J-factors under the exclusion of the largest velocity outlier. Our analysis reveals a notable reduction in the median value and an increase in the deviation of J-factors, thereby leading to considerably weaker constraints.
On the positive solutions for some diffusive logistic equations
Authors: Sun Jian-Wen
Published: July 2024

In this paper, we study the positive solutions of the diffusive logistic equations. It is shown that the asymptotic profiles of the positive solutions display differences between nonlocal dispersal equation and semilinear elliptic equation. When the degeneracy domain becomes small, we find that the positive solution of semilinear elliptic equation admits a blow-up profile. However, when the non-degeneracy domain becomes large, the positive solution of nonlocal equation exhibits a blow-up profile.
The minimal projective bundle dimension and toric 2-Fano manifolds
Authors: Araujo Carolina , Beheshti Roya , Castravet Ana-Maria , Jabbusch Kelly , Makarova Svetlana , Mazzon Enrica , Viswanathan Nivedita
Published: July 2024

Motivated by the problem of classifying toric

2
2

-Fano manifolds, we introduce a new invariant for smooth projective toric varieties, the minimal projective bundle dimension. This invariant

m
(
X
)
∈
{
1
,
…
,
dim
⁡
(
X
)
}

m(X)\in \{1, \dots ,\dim (X)\}

captures the minimal degree of a dominating family of rational curves on

X
X

or, equivalently, the minimal length of a centered primitive relation for the fan of

X
X

. We classify smooth projective toric varieties with

m
(
X
)
≥
dim
⁡
(
X
)
−
2

m(X)\geq \dim (X)-2

, and show that projective spaces are the only

2
2

-Fano manifolds among smooth projective toric varieties with
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="m left-parenthesis upper X right-parenthesis element-of StartSet 1 comma dimension left-parenthesis upper X right-parenthesis minus 2 comma dimension left-parenthesis upper X right-parenthesis minus 1 comma dimension left-parenthesis upper X right-parenthesis EndSet">

m
(
X
)
∈
{
1
,
dim
⁡
(
X
)
−
2
,
dim
⁡
(
X
)
−
1
,
dim
⁡
(
X
)
}

m(X)\in \{1, \dim (X)-2,\dim (X)-1,\dim (X)\}

.
Faith and diversity
Authors: Trigg Roger
Published: July 2024

Religious beliefs in many forms have been universal features of human life, as recent research in cognitive science of religion indicates. Religious faith, for good or ill, is deep-rooted in the way humans are. There may be common strands between its different forms, but we must be wary of interpreting everything in terms familiar to our own society. Faith needs reason and understanding, and belief in God needs further special revelation. This gives rise to diversity between religions, and divergent claims within religion, including Christianity. Claims to religious revelation have to be tested. If reason plays a part in faith, we must face the fact of disagreement within and between religions, and about all religion.
survivalContour: visualizing predicted survival via colored contour plots
Authors: Shi Yushu , Zhang Liangliang , Do Kim-Anh , Jenq Robert R , Peterson Christine B
Published: July 2024

Advances in survival analysis have facilitated unprecedented flexibility in data modeling, yet there remains a lack of tools for illustrating the influence of continuous covariates on predicted survival outcomes. We propose the utilization of a colored contour plot to depict the predicted survival probabilities over time. Our approach is capable of supporting conventional models, including the Cox and Fine–Gray models. However, its capability shines when coupled with cutting-edge machine learning models such as random survival forests and deep neural networks.

Availability and implementation

We provide a Shiny app at https://biostatistics.mdanderson.org/shinyapps/survivalContour/ and an R package available at https://github.com/YushuShi/survivalContour as implementations of this tool.
ZMPY3D: accelerating protein structure volume analysis through vectorized 3D Zernike moments and Python-based GPU integration
Authors: Lai Jhih-Siang , Burley Stephen K , Duarte Jose M
Published: July 2024

Motivation

Volumetric 3D object analyses are being applied in research fields such as structural bioinformatics, biophysics, and structural biology, with potential integration of artificial intelligence/machine learning (AI/ML) techniques. One such method, 3D Zernike moments, has proven valuable in analyzing protein structures (e.g., protein fold classification, protein–protein interaction analysis, and molecular dynamics simulations). Their compactness and efficiency make them amenable to large-scale analyses. Established methods for deriving 3D Zernike moments, however, can be inefficient, particularly when higher order terms are required, hindering broader applications. As the volume of experimental and computationally-predicted protein structure information continues to increase, structural biology has become a “big data” science requiring more efficient analysis tools.

Results

This application note presents a Python-based software package, ZMPY3D, to accelerate computation of 3D Zernike moments by vectorizing the mathematical formulae and using graphical processing units (GPUs). The package offers popular GPU-supported libraries such as CuPy and TensorFlow together with NumPy implementations, aiming to improve computational efficiency, adaptability, and flexibility in future algorithm development. The ZMPY3D package can be installed via PyPI, and the source code is available from GitHub. Volumetric-based protein 3D structural similarity scores and transform matrix of superposition functionalities have both been implemented, creating a powerful computational tool that will allow the research community to amalgamate 3D Zernike moments with existing AI/ML tools, to advance research and education in protein structure bioinformatics.

Availability and implementation

ZMPY3D, implemented in Python, is available on GitHub (https://github.com/tawssie/ZMPY3D) and PyPI, released under the GPL License.
SpatialQC: automated quality control for spatial transcriptome data
Authors: Mao Guangyao , Yang Yi , Luo Zhuojuan , Lin Chengqi , Xie Peng
Published: July 2024

The advent of spatial transcriptomics has revolutionized our understanding of the spatial heterogeneity in tissues, providing unprecedented insights into the cellular and molecular mechanisms underlying biological processes. Although quality control (QC) critical for downstream data analyses, there is currently a lack of specialized tools for one-stop spatial transcriptome QC. Here, we introduce SpatialQC, a one-stop QC pipeline, which generates comprehensive QC reports and produces clean data in an interactive fashion. SpatialQC is widely applicable to spatial transcriptomic techniques.

Availability and implementation

source code and user manuals are available via https://github.com/mgy520/spatialQC, and deposited on Zenodo (https://doi.org/10.5281/zenodo.12634669).
GUANIN: an all-in-one GUi-driven analyzer for NanoString interactive normalization
Authors: Montoto-Louzao Julián , Gómez-Carballa Alberto , Bello Xabier , Pardo-Seco Jacobo , Camino-Mera Alba , Viz-Lasheras Sandra , Martín María J , Martinón-Torres Federico , Salas Antonio
Published: July 2024

Most tools for normalizing NanoString gene expression data, apart from the default NanoString nCounter software, are R packages that focus on technical normalization and lack configurable parameters. However, content normalization is the most sensitive, experiment-specific, and relevant step to preprocess NanoString data. Currently this step requires the use of multiple tools and a deep understanding of data management by the researcher. We present GUANIN, a comprehensive normalization tool that integrates both new and well-established methods, offering a wide variety of options to introduce, filter, choose, and evaluate reference genes for content normalization. GUANIN allows the introduction of genes from an endogenous subset as reference genes, addressing housekeeping-related selection problems. It performs a specific and straightforward normalization approach for each experiment, using a wide variety of parameters with suggested default values. GUANIN provides a large number of informative output files that enable the iterative refinement of the normalization process. In terms of normalization, GUANIN matches or outperforms other available methods. Importantly, it allows researchers to interact comprehensively with the data preprocessing step without programming knowledge, thanks to its easy-to-use Graphical User Interface (GUI).

Availability and implementation

GUANIN can be installed with pip install GUANIN and it is available at https://pypi.org/project/guanin/. Source code, documentation, and case studies are available at https://github.com/julimontoto/guanin under the GPLv3 license.
Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy
Authors: Li Yan , Uhelski Megan L , North Robert Y , Mwirigi Juliet M , Tatsui Claudio E , McDonough Kathleen E , Cata Juan P , Corrales German , Dussor Greg , Price Theodore J , Dougherty Patrick M
Published: July 2024

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors.

Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment.

Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
Decoding the muscle transcriptome of patients with late-onset Pompe disease reveals markers of disease progression
Authors: Monceau Alexandra , Nath Rasya Gokul , Suárez-Calvet Xavier , Musumeci Olimpia , Toscano Antonio , Kierdaszuk Biruta , Kostera-Pruszczyk Anna , Domínguez-González Cristina , Hernández-Lain Aurelio , Paradas Carmen , Rivas Eloy , Papadimas George , Papadopoulos Constantinos , Chrysanthou-Piterou Margarita , Gallardo Eduard , Olivé Montse , Lilleker James , Roberts Mark E , Marchese Domenica , Lunazzi Giulia , Heyn Holger , Fernández-Simón Esther , Villalobos Elisa , Clark James , Katsikis Panos , Collins Catherine , Mehra Priyanka , Laidler Zoe , Vincent Amy , Tasca Giorgio , Marini-Bettolo Chiara , Guglieri Michela , Straub Volker , Raben Nina , Díaz-Manera Jordi
Published: July 2024

Late-onset Pompe disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction owing to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage (a classic manifestation of the disease) has been studied extensively by analysing the whole-muscle tissue; however, little, if anything, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single-nucleus RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age- and sex-matched healthy controls. We matched these changes with histological findings using GeoMx spatial transcriptomics to compare the transcriptome of control myofibres from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibres of LODP patients.

We observed an increase in the proportion of slow and regenerative muscle fibres and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibres, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. Upregulation of genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibres. Notably, enzyme replacement therapy (the only available therapy for the disease) showed a tendency to restore dysregulated metabolism, particularly within slow fibres. A combination of single-nucleus RNA sequencing and spatial transcriptomics revealed the landscape of the normal and diseased muscle and highlighted the early abnormalities associated with disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.
Absence of lung tumor promotion with reduced tumor size in mice after inhalation of copper welding fumes
Authors: Zeidler-Erdely Patti C , Kodali Vamsi , Falcone Lauryn M , Mercer Robert , Leonard Stephen S , Stefaniak Aleksandr B , Grose Lindsay , Salmen Rebecca , Trainor-DeArmitt Taylor , Battelli Lori A , McKinney Walter , Stone Samuel , Meighan Terence G , Betler Ella , Friend Sherri , Hobbie Kristen R , Service Samantha , Kashon Michael , Antonini James M , Erdely Aaron
Published: July 2024

Welding fumes are a Group 1 (carcinogenic to humans) carcinogen as classified by the International Agency for Research on Cancer. The process of welding creates inhalable fumes rich in iron (Fe) that may also contain known carcinogenic metals such as chromium (Cr) and nickel (Ni). Epidemiological evidence has shown that both mild steel (Fe-rich) and stainless steel (Fe-rich + Cr + Ni) welding fume exposure increases lung cancer risk, and experimental animal data support these findings. Copper-nickel (CuNi) welding processes have not been investigated in the context of lung cancer. Cu is intriguing, however, given the role of Cu in carcinogenesis and cancer therapeutics. This study examines the potential for a CuNi fume to induce mechanistic key characteristics of carcinogenesis in vitro and to promote lung tumorigenesis, using a two-stage mouse bioassay, in vivo. Male A/J mice, initiated with 3-methylcholanthrene (MCA; 10 µg/g), were exposed to CuNi fumes or air by whole-body inhalation for 9 weeks (low deposition-LD and high deposition-HD) and then sacrificed at 30 weeks. In BEAS-2B cells, the CuNi fume-induced micronuclei and caused DNA damage as measured by γ-H2AX. The fume exhibited high reactivity and a dose–response in cytotoxicity and oxidative stress. In vivo, MCA/CuNi HD and LD significantly decreased lung tumor size and adenomas. MCA/CuNi HD exposure significantly decreased gross-evaluated tumor number. In summary, the CuNi fume in vitro exhibited characteristics of a carcinogen, but in vivo, the exposure resulted in smaller tumors, fewer adenomas, less hyperplasia severity, and with HD exposure, less overall lung lesions/tumors.
Treatment of Behçet disease with oral roflumilast: an observational study
Authors: Peñuelas Leal Rodrigo , Labrandero Hoyos Carolina , Peñuelas Ruiz Jose Amancio , Bagán Leticia , Zaragoza Ninet Violeta , Sánchez Carazo Jose Luis , Pérez Pastor Gemma , Grau Echevarría Andrés , Esteve Martínez Altea , Finello Malena , Blaya Imbernon Daniel , Dios Guillán Víctor , Aguilar González Lucía , Bagán José , Alegre De Miquel Victor
Published: July 2024

Background

Mucocutaneous Behçet disease often presents a therapeutic challenge. Roflumilast has shown promise in the treatment of other inflammatory dermatological conditions.

Objectives

The objective of this study was to evaluate the characteristics, effectiveness and safety of roflumilast in the treatment of Behçet disease-associated aphthosis in routine clinical practice.

Methods

We performed a single-cohort ambispective observational study. Eleven patients with Behçet disease treated with roflumilast participated. Data collection included demographic, clinical and outcome variables. Statistical analysis compared 12 weeks of treatment with roflumilast with a previous period without treatment and with a period when the previous treatment was used.

Results

During treatment with roflumilast, a reduction in flare-ups and oral ulcers was observed compared with the untreated period and the previous treatment period. A reduction in genital ulcers, pain and ulcer duration was observed between the without treatment period and the roflumilast treatment period. Adverse effects occurred in 54% of patients, most of which were self-limiting or manageable with dose adjustment. No patients withdrew treatment.

Conclusions

Roflumilast appears to be a potential option in the treatment of Behçet disease with favourable effectiveness, safety and tolerability profiles. Although further research is needed, roflumilast offers a promising treatment option for Behçet disease-associated aphthosis, which could improve the patients’ quality of life and address unmet therapeutic needs.
Structural and functional abnormalities and cognitive profiles in older adults with early-onset and late-onset focal epilepsy
Authors: Wan Xinyue , Zeng Yanwei , Wang Jianhong , Tian Mei , Yin Xuyang , Zhang Jun
Published: July 2024

This study aimed to determine the patterns of changes in structure, function, and cognitive ability in early-onset and late-onset older adults with focal epilepsy (OFE). This study first utilized the deformation-based morphometry analysis to identify structural abnormalities, which were used as the seed region to investigate the functional connectivity with the whole brain. Next, a correlation analysis was performed between the altered imaging findings and neuropsychiatry assessments. Finally, the potential role of structural-functional abnormalities in the diagnosis of epilepsy was further explored by using mediation analysis. Compared with healthy controls (n = 28), the area of reduced structural volume was concentrated in the bilateral cerebellum, right thalamus, and right middle cingulate cortex, with frontal, temporal, and occipital lobes also affected in early-onset focal epilepsy (n = 26), while late-onset patients (n = 31) displayed cerebellar, thalamic, and cingulate atrophy. Furthermore, correlation analyses suggest an association between structural abnormalities and cognitive assessments. Dysfunctional connectivity in the cerebellum, cingulate cortex, and frontal gyrus partially mediates the relationship between structural abnormalities and the diagnosis of early-onset focal epilepsy. This study identified structural and functional abnormalities in early-onset and late-onset focal epilepsy and explored characters in cognitive performance. Structural-functional coupling may play a potential role in the diagnosis of epilepsy.
Economic growth and the foreign sector: Peru 1821–2020
Authors: Varona Luis , Gonzales Jorge R , García Benjamín , Gismera Laura
Published: July 2024

Thirlwall Model shows evidence in Latin American countries, as well as for the Peruvian economy, with an economic growth rate of balance of payments equilibrium, which is explained by causal variables that present a long-term cointegration relationship. These variables are exports with little added value, imports that reinforce technological dependence, external income, relative prices or the real exchange rate, the institutions, and the volatility of exports. Investment policies are prescribed in innovative, physical, financial, natural, and social human capital that tend to reduce the restriction of foreign exchange, technological dependence and the international market. Therefore, endogenous, dynamic, sustained, inclusive economic growth is generated, low in carbon as a means for sustainable human development, within the framework of a new growth and development strategy that involves balancing the participation of the market, state and civil society.
Immune-related adverse event-myocarditis with marked ST-segment elevation requiring differentiation from COVID-19-induced myocarditis: a case report
Authors: Fujita Kana , Ohashi Yoshitaka , Nagasawa Yoshinori , Otani Tomoyuki , Hatakeyama Kinta
Published: July 2024

Background

Immunotherapy with immune checkpoint inhibitors (ICIs) enhances the host immune reaction against tumour cells by inhibiting intrinsic down-regulators of the T cell-mediated immune response. Although the advent of ICIs has dramatically changed oncology, ICIs may also trigger an overactivation of T cells against non-cancerous tissues, leading to off-target immune-related adverse events (irAEs).

Case summary

A 64-year-old man with a history of seven courses of atezolizumab, an ICI, for small-cell lung cancer and coronavirus disease 2019 (COVID-19) was admitted to the hospital complaining of acute chest pain. Transthoracic echocardiography showed preserved ejection fraction (EF), but electrocardiography indicated precordial ST-elevations and marked increases in biomarkers for myocardial injury were observed. Emergent cardiac catheterization showed no significant coronary stenosis. On the fifth hospital day, EF decreased to 25% and pericardial effusion occurred. Endomyocardial biopsy was immediately performed, and prednisolone (60 mg/day) was administered. Troponin I level rapidly reduced, ST changed, and EF improved. Histological examinations demonstrated CD8-predominant T lymphocytic infiltration with myocardial cell injury, consistent with irAE-myocarditis.

Discussion

In irAEs, myocarditis is the most common and severe cardiac manifestation with a high mortality. Even at 20 weeks after the initial ICI treatment, irAE-myocarditis occurs and the clinical presentation may mimic ST-elevation myocardial infarction. The histopathological findings suggested the high possibility of irAE-myocarditis rather than COVID-19-induced myocarditis, but COVID-19 has possibly played a role in the development of late-onset irAE-myocarditis. This educational case implies the importance of immediate recognition of irAE even after stable ICI treatment.
Ventricular volume asymmetry as a novel imaging biomarker for disease discrimination and outcome prediction
Authors: McCracken Celeste , Szabo Liliana , Abdulelah Zaid A , Condurache Dorina-Gabriela , Vago Hajnalka , Nichols Thomas E , Petersen Steffen E , Neubauer Stefan , Raisi-Estabragh Zahra
Published: July 2024

Aims

Disruption of the predictable symmetry of the healthy heart may be an indicator of cardiovascular risk. This study defines the population distribution of ventricular asymmetry and its relationships across a range of prevalent and incident cardiorespiratory diseases.

Methods and results

The analysis includes 44 796 UK Biobank participants (average age 64.1 ± 7.7 years; 51.9% women). Cardiovascular magnetic resonance (CMR) metrics were derived using previously validated automated pipelines. Ventricular asymmetry was expressed as the ratio of left and right ventricular (LV and RV) end-diastolic volumes. Clinical outcomes were defined through linked health records. Incident events were those occurring for the first time after imaging, longitudinally tracked over an average follow-up time of 4.75 ± 1.52 years. The normal range for ventricular symmetry was defined in a healthy subset. Participants with values outside the 5th-95th percentiles of the healthy distribution were classed as either LV dominant (LV/RV > 112%) or RV dominant (LV/RV < 80%) asymmetry. Associations of LV and RV dominant asymmetry with vascular risk factors, CMR features, and prevalent and incident cardiovascular diseases (CVDs) were examined using regression models, adjusting for vascular risk factors, prevalent diseases, and conventional CMR measures. Left ventricular dominance was linked to an array of pre-existing vascular risk factors and CVDs, and a two-fold increased risk of incident heart failure, non-ischaemic cardiomyopathies, and left-sided valvular disorders. Right ventricular dominance was associated with an elevated risk of all-cause mortality.

Conclusion

Ventricular asymmetry has clinical utility for cardiovascular risk assessment, providing information that is incremental to traditional risk factors and conventional CMR metrics.
Role of myocardial microRNAs in the long-term ventricular remodelling of patients with aortic stenosis
Authors: Gabriel André F , Costa Marina C , Caldeira Daniel , Plácido Rui , Rigueira Joana , Carrilho-Ferreira Pedro , Gonçalves Susana , Ferreira Ricardo , Nobre Ângelo , Pinto Fausto J , Enguita Francisco J , Almeida Ana G
Published: July 2024

Aims

We hypothesize that miRs are key players in the dynamics of the hypertrophy phenotype in aortic stenosis (AS) patients. In our study, we aimed to identify the transcriptional patterns (protein-coding transcripts and miRs) from myocardial sample biopsies that could be associated with the absence of left ventricular (LV) mass regression after aortic valve replacement (AVR) in patients with severe AS and LV hypertrophy.

Methods and results

We prospectively included 40 patients with severe AS, LV hypertrophy, and preserved ejection fraction undergoing AVR. Myocardial biopsies obtained during surgery were analysed for transcriptomic analysis performed by next-generation sequencing. At a 1-year follow-up, no hypertrophy reversal was observed in about half of the patients in the absence of patient–prosthesis mismatch and prosthesis dysfunction of uncontrolled hypertension. Predictors of mass regression were assessed from clinical, echocardiographic, and biochemical variables as well as from 300 miRs obtained from myocardial specimens, allowing the identification 29 differentially expressed. miR-4709-3p was found as a positive independent predictor of hypertrophy regression together with high-sensitivity troponin T (cTNT-hs) as a negative predictor. Gene transcripts RFX1, SIX5, MAPK8IF3, and PKD1 were predicted as simultaneous targets of five upregulated miRs suggesting its importance in LV hypertrophy.

Conclusion

In our cohort, tissue miR-4709-3p and cTNT-hs were independent predictors of hypertrophy regression. The hypertrophy reversal process will likely depend from a complex network where miRNAs may have an important role, allowing a potential opportunity for therapy.
The Road to Crime: An Unintended Consequence of the Interstate Highway System
Authors: Calamunci Francesca , Lonsky Jakub
Published: July 2024

The necessity to overhaul national infrastructure has become one of the key issues of US domestic policy in recent years. While the benefits of infrastructure spending are often straightforward, its unintended consequences are less well understood. This paper studies the impact of transportation infrastructure on local crime, focusing on the construction of the Interstate Highway System, the largest public works project in US history. Using a staggered difference-in-differences design and a county-by-year panel dataset spanning all US counties between 1960 and 1993, we find that a highway opening in a county led to an 8% rise in total index crime. This effect is driven by property crime (burglary, larceny and motor vehicle theft), although some evidence suggests an increase in violent crime as well. Exploring potential mechanisms, we show that the positive effect of highways on crime is concentrated in counties with low pre-existing stock of police resources where increased connectivity may have raised the returns to crime. Moreover, we find that highway construction induced higher local employment, average firm size and the local population size, thus increasing the returns to criminal activity, and ultimately the risk of victimisation in the newly connected counties.
‘There was a star riding through clouds one night, and I said to the star, “Consume me”’: Post-human extinction in Virginia Woolf’s The Waves
Authors: Case Oliver
Published: July 2024

Human beings are now in a period of the Earth’s history during which their extinction seems ever more probable due to extreme climate change, global pandemics, international conflicts, and lack of long-term intergovernmental or transnational cooperation to tackle these threats to life. Concern for the future of humanity is not, however, a uniquely contemporary phenomenon. Several of Virginia Woolf’s late novels suggest an awareness of the potential for human extinction. Where this concern can be found in The Waves (1931), the text does not express nihilism or panic at the prospect. Instead, the idea of a world without humans is seized as the provocation to continue an experiment which runs throughout Woolf’s writing: to reimagine the relationship between the human and the non-human. By exploring this writerly concern in The Waves, this essay argues that Woolf also redefines human death by reconceptualizing the natural world in ways which undo anthropocentric understandings of the potential extinction of the human species. By re-reading Woolf’s seventh novel through ecocritical practices and alongside ideas from contemporary post-humanist critical theory, the analyses proposed herein suggest that The Waves encourages a reassessment of our position in and response to a human-made environmental crisis which threatens the future of existence, human and non-human, in the twenty-first century.
Furanocoumarin profiles and inhibitory effects on cytochrome P450 activity of whole citrus fruit
Authors: Sun Yujing , Wang Yihua , Zhang Le , Ye Xingqian , Guo Jingtong
Published: July 2024

Furanocoumarins in citrus fruit can cause adverse drug interactions; however, there are few reports on furanocoumarins and drug interactions in common edible citrus cultivars except grapefruit. An ultra-performance liquid chromatography (UPLC)–based method for ten furanocoumarins in citrus fruit was established, and the effects on cytochrome P450 activity were investigated. Furanocoumarins were more abundant (2–43 times) in the peel than in the pulp. The pulp of Xiyou, Hongyou, and Navel orange exhibited P450 inhibition, with 50% maximal inhibitory concentration (IC50) values of 0.63, 0.67, and 1.02 mg/mL, respectively. The peel of all the varieties except Huyou and Satsuma exhibited P450 inhibition. Xiyou, Baiyou, Huangjinyou, Hongyou, Ponkan, and Navel orange had IC50 values of 0.33, 0.76, 0.38, 0.35, 0.43, and 0.37 mg/mL, respectively. These findings indicate that, except for Xiyou, Hongyou, and Navel orange, the consumption of the pulp of popular Chinese varieties of citrus fruit has a low risk of drug interactions, and the use of citrus products including peel may carry a significant risk of adverse drug interactions.
Transposon-sequencing (Tn-seq) of the Candida glabrata reference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin
Authors: Nickels Timothy J , Gale Andrew N , Harrington Abigail A , Timp Winston , Cunningham Kyle W
Published: July 2024

Candida glabrata (also called Nakaseomyces glabratus) is an opportunistic pathogen that can resist common antifungals and rapidly acquire multidrug resistance. A large amount of genetic variation exists between isolates, which complicates generalizations. Portable transposon-sequencing (Tn-seq) methods can efficiently provide genome-wide information on strain differences and genetic mechanisms. Using the Hermes transposon, the CBS138 reference strain and a commonly studied derivative termed 2001 were subjected to Tn-seq in control conditions and after exposure to varying doses of the clinical antifungal micafungin. The approach revealed large differences between these strains, including a 131-kb tandem duplication and a variety of fitness differences. Additionally, both strains exhibited up to 1,000-fold increased transposon accessibility in subtelomeric regions relative to the BG2 strain, indicative of open subtelomeric chromatin in these isolates and large epigenetic variation within the species. Unexpectedly, the Pdr1 transcription factor conferred resistance to micafungin through targets other than CDR1. Other micafungin resistance pathways were also revealed including mannosyltransferase activity and biosynthesis of the lipid precursor sphingosine, the inhibition of which by SDZ 90–215 and myriocin enhanced the potency of micafungin in vitro. These findings provide insights into the complexity of the C. glabrata species as well as strategies for improving antifungal efficacy.
HLA-DQA1*05 correlates with increased risk of anti-drug antibody development and reduced response to infliximab in Chinese patients with Crohn’s disease
Authors: Wang Wei , Zhang Qi , Zhao Junzhang , Liu Tao , Yao Jiayin , Peng Xiang , Zhi Min , Zhang Min
Published: July 2024

Background

The efficacy of anti-TNF therapy in Crohn’s disease (CD), such as infliximab, is often compromised by the development of anti-drug antibodies (ADAs). The genetic variation HLA-DQA1*05 has been linked to the immunogenicity of biologics, influencing ADA formation. This study investigates the correlation between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab in a Chinese Han population and assesses clinical outcomes.

Methods

In this retrospective cohort study, 345 infliximab-exposed CD patients were genotyped for HLADQ A1*05A>G (rs2097432). We evaluated the risk of ADA development, loss of infliximab response, adverse events, and treatment discontinuation among variant and wild-type allele individuals.

Results

A higher percentage of patients with ADAs formation was observed in HLA-DQA1*05 G variant carriers compared with HLA-DQA1*05 wild-type carriers (58.5% vs 42.9%, P = 0.004). HLA-DQA1*05 carriage significantly increased the risk of ADAs development (adjusted hazard ratio = 1.65, 95% CI 1.18–2.30, P = 0.003) and was associated with a greater likelihood of infliximab response loss (adjusted HR = 2.55, 95% CI 1.78–3.68, P < 0.0001) and treatment discontinuation (adjusted HR = 2.21, 95% CI 1.59–3.06, P < 0.0001). Interestingly, combined therapy with immunomodulators increased the risk of response loss in HLA-DQA1*05 variant carriers.

Conclusions

HLA-DQA1*05 significantly predicts ADAs formation and impacts treatment outcomes in infliximab-treated CD patients. Pre-treatment screening for this genetic factor could therefore be instrumental in personalizing anti-TNF therapy strategies for these patients.
Interventional endoscopy in inflammatory bowel disease: a comprehensive review
Authors: Pal Partha , Reddy D Nageshwar
Published: July 2024

Interventional endoscopy can play a key role in the multidisciplinary management of complex inflammatory bowel disease (IBD) as an adjunct to medical and surgical therapy. The primary role of interventional IBD (IIBD) includes the treatment of Crohn’s disease-related stricture, fistula, and abscess. Endoscopic balloon dilation (EBD), endoscopic stricturotomy, and placement of endoscopic stents are different forms of endoscopic stricture therapy. EBD is the most widely used therapy whereas endoscopic stricturotomy has higher long-term efficacy than EBD. Fully covered and partially covered self-expanding metal stents are useful in long and refractory strictures whereas lumen-apposing metal stents can be used in short, and anastomotic strictures. Endoscopic fistula/abscess therapy includes endoscopic fistulotomy, seton placement, endoscopic ultrasound-guided drainage of rectal/pelvic abscess, and endoscopic injection of filling agents (fistula plug/glue/stem cell). Endoscopic seton placement and fistulotomy are mainly feasible in short, superficial, single tract fistula and in those with prior surgical seton placement. Similarly, endoscopic fistulotomy is usually feasible in short, superficial, single-tract fistula. Endoscopic closure therapies like over-the-scope clips, suturing, and self-expanding metal stent should be avoided for de novo/bowel to hollow organ fistulas. Other indications include management of postoperative complications in IBD such as management of surgical leaks and complications of pouchitis in ulcerative colitis. Additional indications include endoscopic resection of ulcerative colitis-associated neoplasia (by endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection), retrieval of retained capsule endoscope, and control of bleeding. IIBD therapies can potentially act as a bridge between medical and surgical therapy for properly selected IBD patients.
Power equipment image enhancement processing based on YOLO-v8 target detection model under MSRCR algorithm
Authors: Zhou Guoliang , Liu Min , Wang Hongxu , Zheng Yi
Published: July 2024

With the rapid development of the power industry, higher requirements have been put forward for real-time monitoring and fault identification of power equipment. However, images of power equipment in actual scenes are often affected by problems such as uneven illumination and color distortion, leading to a decrease in the performance of the target detection model. Hence, this paper suggests merging the Multi-Scale Retinex with Color Restoration (MSRCR) algorithm with the YOLO-v8 target detection model to enhance the visual quality of power equipment images and boost the accuracy and efficiency of target detection. Initially, the MSRCR algorithm enhances image brightness, contrast, and color restoration and preserves edge and detail features. Subsequently, the paper explores the architecture of YOLO-v8, incorporating the SE (Squeeze-and-Excitation) attention mechanism. This mechanism dynamically adjusts channel weights to optimize feature processing in input data. The final experimental results show that using the MSRCR algorithm to enhance the data and combining it with the SE attention mechanism have improved by about 3.2% compared to the original YOLO-v8 model. In comparative experiments with other algorithms, the method proposed in this article achieved an accuracy of 94.3% and a recall rate of 92.6%, which are both higher than other models. By enhancing power equipment images with the MSRCR algorithm, the YOLO-v8 model has significantly improved both target detection accuracy and recall rate. In summary, the MSRCR power equipment image enhancement processing method proposed in this article based on the YOLO-v8 target detection model can effectively improve the visual quality of power equipment images and improve the accuracy and efficiency of target detection.
Bayesian estimation of the prevalence of antimicrobial resistance: a mathematical modelling study
Authors: Howard Alex , Green Peter L , Velluva Anoop , Gerada Alessandro , Hughes David M , Brookfield Charlotte , Hope William , Buchan Iain
Published: July 2024

Background

Estimates of the prevalence of antimicrobial resistance (AMR) underpin effective antimicrobial stewardship, infection prevention and control, and optimal deployment of antimicrobial agents. Typically, the prevalence of AMR is determined from real-world antimicrobial susceptibility data that are time delimited, sparse, and often biased, potentially resulting in harmful and wasteful decision-making. Frequentist methods are resource intensive because they rely on large datasets.

Objectives

To determine whether a Bayesian approach could present a more reliable and more resource-efficient way to estimate population prevalence of AMR than traditional frequentist methods.

Methods

Retrospectively collected, open-source, real-world pseudonymized healthcare data were used to develop a Bayesian approach for estimating the prevalence of AMR by combination with prior AMR information from a contextualized review of literature. Iterative random sampling and cross-validation were used to assess the predictive accuracy and potential resource efficiency of the Bayesian approach compared with a standard frequentist approach.

Results

Bayesian estimation of AMR prevalence made fewer extreme estimation errors than a frequentist estimation approach [n = 74 (6.4%) versus n = 136 (11.8%)] and required fewer observed antimicrobial susceptibility results per pathogen on average [mean = 28.8 (SD = 22.1) versus mean = 34.4 (SD = 30.1)] to avoid any extreme estimation errors in 50 iterations of the cross-validation. The Bayesian approach was maximally effective and efficient for drug–pathogen combinations where the actual prevalence of resistance was not close to 0% or 100%.

Conclusions

Bayesian estimation of the prevalence of AMR could provide a simple, resource-efficient approach to better inform population infection management where uncertainty about AMR prevalence is high.