bluuebunny/crossref_metadata_2025 huggingface dataset:
A Japanese case of VEXAS syndrome after COVID-19 vaccination: Comparison with previously reported cases
Authors: Miyagi Yui , Kobayashi Hiroshi , Umebayashi Yoshihiro , Okimura Akira , Nakatsugawa Munehide , Maeda Ayaka , Kirino Yohei , Aoki Akiko
Published: September 2024

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome is a novel adult-onset autoinflammatory disorder caused by variants in the UBA1 gene. Here, we report a Japanese case of VEXAS syndrome in which symptoms began 1 day after the second booster dose of a coronavirus disease 2019 (COVID-19) messenger ribonucleic acid vaccine, and a UBA1 variant was subsequently confirmed. Combined with the three cases reported thus far, this suggests that the COVID-19 vaccine may be one of the triggers for development of VEXAS syndrome in Asian populations. Since COVID-19 vaccines have been reported to be associated with various autoinflammatory and autoimmune diseases, it is important to continue to pay close attention to the relationship between COVID-19 vaccines and VEXAS syndrome.
“Because That is the Right Thing to do”: A Focus Group Study of Australian Expert Perspectives on Offering Smoking Cessation Support in Lung Cancer Screening
Authors: Harrison Nathan J , Dodd Rachael H , Sharman Ashleigh R , Marshall Henry M , Stone Emily , Rhee Joel J , Yap Mei Ling , McCullough Sue , Paul Christine , Bowden Jacqueline A , Bonevski Billie , Rankin Nicole M
Published: September 2024

Introduction

Lung cancer screening (LCS) trials, targeting people with a smoking history, have demonstrated reduced mortality. How to optimally embed evidence-based smoking cessation support in LCS, including in Australia, needs to be better understood. We sought experts’ perspectives to identify potential barriers and effective implementation strategies.

Aims and Methods

Perceptions of providing smoking cessation support in LCS were elicited in 24 focus groups and three individual interviews with clinicians, cancer screening program managers/policymakers, and researchers during 2021. We conducted framework analysis and mapped key topics to the updated Consolidated Framework for Implementation Research (CFIR).

Results

Experts (N = 84 participants) strongly supported capitalizing on an “opportune time” for smoking cessation and new LCS participant contact opportunities throughout the screening and assessment pathway. Many advocated for adapting existing cessation resources to the LCS setting and providing support without participant costs. Experts generally considered referral alone to established programs (eg, telephone Quitline) as insufficient, but likely helpful in follow-up, and dedicated cessation specialist roles as essential. Broader cessation messaging (via mass media/community channels) was also suggested to reinforce individualized support. Experts described inherent alignment, and an ethical responsibility, to deliver smoking cessation as a core LCS component. It was suggested that LCS-eligible participants’ varied experiences of stigma, health literacy, and motivation, be considered in cessation support. Primary care support and individualized interventions were suggested to facilitate implementation.

Conclusions

Experts considered smoking cessation support essential in LCS. The expert-identified and multi-level implementation strategies described here can directly inform smoking cessation-specific planning for Australia’s forthcoming National LCS Program.

Implications

The international literature includes few examples considering how best to provide smoking cessation support within a LCS program in advance of program commencement. Our analysis, using the updated CFIR, is one of the first to explore experts’ perspectives within this context. Experts identified multiple implementation barriers to providing smoking cessation support within and outside of an Australian LCS program, including key work infrastructure barriers, and advocated for providing tailored interventions within this program. Our foundational work in a new targeted screening program’s preimplementation phase will allow international comparisons to be made.
Characteristics Associated With Ice Flavor Use Among Middle and High School Students Currently Using E-cigarettes: National Youth Tobacco Survey, 2023
Authors: Park-Lee Eunice , Cowan Hannah , Gaines-Harris Mo’Nique , Cooper Maria R , Sawdey Michael D , Cullen Karen A
Published: September 2024

Purpose

To examine ice flavor use and its correlates among middle and high school students who currently (any past 30 days) used e-cigarettes.

Methods

The 2023 National Youth Tobacco Survey (NYTS) assessed for the first time the use of e-cigarette flavors that included the word “ice” or “iced” in the name. Using logistic regression, data from the 2023 NYTS were used to examine differences in sociodemographic characteristics and tobacco use behaviors by ice flavor use among students who currently used e-cigarettes (n = 1,565).

Results

Among middle and high school students who currently used e-cigarettes, an estimated 1.1 million or 57.9% reported ice flavor use. Youth who currently used e-cigarettes were more likely to use ice flavors if they used e-cigarettes on ≥20 of the past 30 days compared to 1–5 days (adjusted odds ratio [aOR] = 2.31, 95% confidence interval [CI] = 1.36 to 3.94); used fruit (aOR = 2.27, 95% CI = 1.36 to 3.80), candy (aOR = 2.73, 95% CI = 1.54 to 4.82), or mint flavors (aOR = 3.63, 95% CI = 1.98 to 6.65) compared to those who did not use the respective flavor type; reported any nicotine dependence compared to those who did not (aOR = 1.71, 95% CI = 1.04 to 2.80); or had mild/moderate (aOR = 1.97, 95% CI = 1.01 to 3.83) or severe psychological distress (aOR = 2.41, 95% CI = 1.25 to 4.62) compared to those without psychological distress.

Conclusions

The present study found that ice-flavored e-cigarette use among youth was associated with the use of e-cigarettes for ≥20 days, the use of fruit, candy, or mint flavors, any symptoms of nicotine dependence, and psychological distress (mild/moderate, severe). The emergence of novel flavor categories and features of e-cigarettes warrant continued surveillance to provide an understanding of associated use patterns, especially among youth.

Implications

This study examined ice flavor use and its correlates among middle and high school students who currently use e-cigarettes. Ice-flavored e-cigarette use among youth was positively associated with frequent e-cigarette use, use of fruit, candy, or mint flavors, and any symptoms of nicotine dependence. Additionally, the likelihood of ice-flavored e-cigarette use was associated with the severity of psychological distress.
A Systematic Review of Nirmatrelvir/Ritonavir and Molnupiravir for the Treatment of Coronavirus Disease 2019
Authors: Haslam Alyson , Prasad Vinay
Published: September 2024

Background

To address the need for treatments for patients with coronavirus disease 2019 (COVID-19), 3 therapies have been given either full approval or Emergency Use Authorization. These were based on randomized data showing a reduction in deaths/hospitalization, but since then, circulating viral strains and population immunity have changed.

Methods

We searched PubMed, Web of Science, Embase, and ClinicalTrials.gov for clinical trials testing nirmatrelvir/ritonavir and molnupiravir for COVID-19. We identified all trials testing nirmatrelvir/ritonavir and molnupiravir in patients with COVID-19 and assessed the pooled efficacy in a meta-analysis. We calculated pooled estimates of hospitalization and death in patients with COVID-19 and the number of studies with published/reported data.

Results

Of the 23 studies found, 11 tested nirmatrelvir/ritonavir, 10 tested molnupiravir, and 2 tested both agents. The pooled estimate in reducing deaths and hospitalization for molnupiravir was 0.62 (95% confidence interval [CI], 0.15–2.53), and the pooled estimate for nirmatrelvir/ritonavir was 0.33 (95% CI, 0.03–3.35). The 1 nirmatrelvir/ritonavir trial that reported significant improvements tested people who were predominantly infected with earlier COVID-19 variants, whereas the 2 null trials were tested in people infected with more recent variants. The 2 positive molnupiravir trials included participants primarily with the Delta variant, whereas the null trials were tested later, against more recent variants.

Conclusions

While early trial data show effectiveness of these therapies, the overall pooled effects are nonsignificant, suggesting that recommendations and use of approved oral COVID-19 treatment therapies need to be reevaluated in the context of current viral strains and population immunity.
Thymoma with recurrent opportunistic infections—a case report
Authors: Karjala Sri Lasya , Namala Satya Prasad , Machiraju Phani Krishna , Pandurangan Prabu
Published: September 2024

Good’s syndrome (GS) is a rare adult-onset thymoma associated with acquired combined B-cell and T-cell immunodeficiency. It has similarities with Common variable immunodeficiency (CVID) in terms of hypogammaglobulinemia and significant risk of invasive bacterial and opportunistic infections. We still have a long way to go in understanding the pathogenesis of Good’s syndrome. Here, we describe a case of a middle-aged female with thymoma and recurrent opportunistic infections. Clinico-laboratory evaluation led to a diagnosis of GS and she showed good response to intravenous immunoglobulin. Clinicians should be aware that thymoma can precede the onset of immunodeficiency.
Ventricular Tachyarrhythmia in a Newborn Baby
Authors: Maclennan Alexander Paul Henning , Sitner-Medvedovsky Emily , Varon Daryelle , Parikh Abhinav , Shah Ankur , Chhabra Manoj
Published: September 2024

Supraventricular tachycardia (SVT) is a narrow QRS complex tachyarrhythmia with a heart rate above 220 beats per minute in infants and children. Ventricular tachycardia can be due to electrolyte abnormalities, cardiomyopathies, congenital heart disease, myocarditis or drug toxicity. Incidence has been estimated to be 1 in 250 to 1 in 1000 with spontaneous resolution in infants by one year of life. We present a full-term neonate who started experiencing a tachyarrhythmia on day zero of life until she reverted to sinus rhythm on day nine of life. The rhythm was most likely a ventricular tachyarrhythmia rather than supraventricular tachycardia due to its unresponsiveness to adenosine, wide QRS complexes, and lack of association with hemodynamic instability. This is a unique case presentation of a ventricular tachyarrhythmia for its diagnostic and therapeutic challenges, it’s idiopathic nature and lack of association with any cardiac compromise, congenital heart disease or electrolyte imbalance.
Secondary corneal keloid: a report of two cases
Authors: Sharifi Ali , Mirshekari Touraj-Reza , Azh Milad , Sadeghi Hamid , Akbari Zahra , Zand Amin
Published: September 2024

We conducted clinical and histological evaluations on two male patients who presented with corneal keloid. One patient had a history of corneal trauma due to contact with boiling sunflower oil, while the other had undergone pterygium removal. Upon slit lamp examination, the corneal lesions were identified as single, well-circumscribed, pearly white nodules with a smooth surface. We successfully removed these nodules using a combination of superficial keratectomy and the application of mitomycin C. Light microscopy analysis of the excised nodules revealed hyperplastic epithelium, disrupted Bowman’s layer, and irregularly arranged abundant collagen fibers within the stroma. Notably, there was no recurrence of the lesions in either case within six months following the surgical excision. Secondary corneal keloids should be considered as a potential diagnosis in patients with elevated corneal nodules, especially when there is a history of ocular surface trauma or surgery.
Strengthening the evidence base on the use of digital health technologies to accelerate progress towards universal health coverage
Authors: Forslund Mathilde , Mathieson Kirsten , Djibo Yacine , Mbindyo Caroline , Lugangira Neema , Balasubramaniam Priya
Published: September 2024

Digital health and the digital transformation of health systems are an enabler and accelerator to achieving Universal Health Coverage (UHC) in low- and middle-income countries. This can help close equity gaps, enhance primary healthcare, and improve efficiency and health outcomes. However, the digital health landscape is characterized by fragmented initiatives and investments, insufficient political will, and inadequate governance of health data. This special collection of Oxford Open Digital Health showcases impacts of digital health interventions and approaches towards expanded healthcare access and improved health outcomes. This commentary makes the case for policy innovation and leadership, improved investments, robust health data governance and a people-centred approach to leverage the benefits of digital health transformation. Prioritizing these areas can enhance the accessibility, affordability, and quality of care, towards UHC goals.
Climate change impacts on dengue transmission areas in Espírito Santo state, Brazil
Authors: Barcellos Madeira Rosa Yasmim , Tamanini Silva Moschen Henrique , Loss Ana Carolina , Cardoso da Silva Theresa Cristina , Brioschi dos Santos Ana Paula , Caetano Pimenta Bruna , Nunes Zordan Julia Sthefany , Cerutti Junior Crispim , Espinosa Barbosa Miranda Angelica , Drumond Louro Iuri , Dummer Meira Débora , Vicente Creuza Rachel
Published: September 2024

Espírito Santo state, in Brazil, is a dengue-endemic region predicted to suffer from an increase in temperature and drought due to climate change, which could affect the areas with active dengue virus transmission. The study objective was modeling climatic factors and climate change effects in zones suitable for dengue virus transmission in Espírito Santo state, Brazil. Data on dengue reports from 2022 were used to determine climatic variables related to spatial distribution. The climate change projections were generated for the 2030s, 2050s, 2070s, and 2090s for three distinct Shared Socioeconomic Pathways: SSP1-2.6, SSP2-4.5 and SSP5-8.5. A maximum entropy algorithm was used to construct the three models and projections, and the results were used to calculate the ensemble mean. Isothermality, the maximum temperature of the warmest month, precipitation of the wettest month, precipitation of the warmest quarter, and annual precipitation impacted the model. Projections indicated a change in areas suitable for dengue virus transmission, varying from −30.44% in the 2070s (SSP1-2.6) to +13.07% in the 2070s (SSP5-8.5) compared to 2022. The coastal regions were consistently suitable in all scenarios. Urbanized and highly populated areas were predicted to persist with active dengue transmission in Espírito Santo state, posing challenges for public health response.
Phosphorylation of auxin signaling repressor IAA8 by heat-responsive MPKs causes defective flower development
Authors: Kim Sun Ho , Hussain Shah , Pham Huyen Trang Thi , Kadam Ulhas Sopanrao , Bahk Sunghwa , Ramadany Zakiyah , Lee Jeongwoo , Song Young Hun , Lee Kyun Oh , Hong Jong Chan , Chung Woo Sik
Published: September 2024

Heat stress is a substantial and imminent threat to plant growth and development. Understanding its adverse effects on plant development at the molecular level is crucial for sustainable agriculture. However, the molecular mechanism underlying how heat stress causes developmental defects in flowers remains poorly understood. Here, we identified Indole-3-Acetic Acid 8 (IAA8), a repressor of auxin signaling, as a substrate of mitogen-activated protein kinases (MPKs) in Arabidopsis thaliana, and found that MPK-mediated phosphorylation of IAA8 inhibits flower development. MPKs phosphorylated three residues of IAA8: S74, T77, and S135. Interestingly, transgenic plants overexpressing a phospho-mimicking mutant of IAA8 (IAA8DDD OX) exhibited defective flower development due to high IAA8 levels. Furthermore, MPK-mediated phosphorylation inhibited IAA8 polyubiquitination, thereby significantly increasing its stability. Additionally, the expression of key transcription factors involved in flower development, such as bZIP and MYB genes, was significantly perturbed in the IAA8DDD OX plants. Collectively, our study demonstrates that heat stress inhibits flower development by perturbing the expression of flower development genes through the MPK-mediated phosphorylation of IAA8, suggesting that Aux/IAA phosphorylation enables plants to fine-tune their development in response to environmental stress.
Stealthy and hyperuniform isotropic photonic band gap structure in 3D
Authors: Siedentop Lukas , Lui Gianluc , Maret Georg , Chaikin Paul M , Steinhardt Paul J , Torquato Salvatore , Keim Peter , Florescu Marian
Published: September 2024

In photonic crystals, the propagation of light is governed by their photonic band structure, an ensemble of propagating states grouped into bands, separated by photonic band gaps. Due to discrete symmetries in spatially strictly periodic dielectric structures their photonic band structure is intrinsically anisotropic. However, for many applications, such as manufacturing artificial structural color materials or developing photonic computing devices, but also for the fundamental understanding of light-matter interactions, it is of major interest to seek materials with long range nonperiodic dielectric structures which allow the formation of isotropic photonic band gaps. Here, we report the first ever 3D isotropic photonic band gap for an optimized disordered stealthy hyperuniform structure for microwaves. The transmission spectra are directly compared to a diamond pattern and an amorphous structure with similar node density. The band structure is measured experimentally for all three microwave structures, manufactured by 3D laser printing for metamaterials with refractive index up to n=2.1. Results agree well with finite-difference-time-domain numerical investigations and a priori calculations of the band gap for the hyperuniform structure: the diamond structure shows gaps but being anisotropic as expected, the stealthy hyperuniform pattern shows an isotropic gap of very similar magnitude, while the amorphous structure does not show a gap at all. Since they are more easily manufactured, prototyping centimeter scaled microwave structures may help optimizing structures in the technologically very interesting region of infrared.
The unintended consequences of improving police recording of rape in England and Wales
Authors: Lovett Jo , Kelly Liz , Vera-Gray Fiona
Published: September 2024

A strong focus in recent policy and media coverage has been the increase in reporting of rape coupled with an associated fall in the charge rate, often attributed to victim withdrawal. Drawing on an analysis of 741 police case files as part of Operation Soteria we question each of these positions. We argue that changes to the Home Office Counting Rules since 2014 have resulted in the recording of a significant proportion of cases which are not reports from victim-survivors and which they did not consent to. Closing such cases at outcomes which make victim-survivors responsible is both inaccurate and leads to misperceptions of where the problems lie in rape investigations.
High risk of misclassification of acute Parvovirus B19 infection into a systemic rheumatic disease
Authors: D’Onofrio Bernardo , Virelli Giulia , Pedrollo Elisa , Caprioli Marta , Riva Marta , Renna Daniela , Tonutti Antonio , Luciano Nicoletta , Ceribelli Angela , Gremese Elisa , De Santis Maria , Selmi Carlo
Published: September 2024

Objectives

Parvovirus B19 most frequently causes epidemics of erythema infectiosum in children but also affects adults often leading to rheumatologic manifestations. While the serum profile allows the diagnosis, manifestations may mimic autoimmune conditions. The aim was to evaluate the proportion of patients with acute Parvovirus B19 infection fulfilling classification criteria for rheumatic diseases (RA and SLE).

Methods

We evaluated the clinical and serological features of 54 patients diagnosed with acute Parvovirus B19 infection seeking rheumatological attention between March and June 2024.

Results

The majority of patients were females (78%), with a mean (s.d.) age of 45 (13) years and 54% could not recall any known exposure. Fifty-one/54 (94%) had arthralgia, 27 (50%) arthritis (oligoarthritis in 67% of them), 24 (44%) fever, 19 (35%) skin rash and 7 (13%) purpura. Symptoms resolution generally occurred within 6 weeks. Complement levels were low in 14/33 (42%) tested patients, while the presence of serum ANA, anti-dsDNA, anti-phospholipids and rheumatoid factor was detected in 21/38 (55%), 10/26 (38%), 6/12 (50%) and 5/37 (13%) patients, respectively. Classification criteria for SLE were fulfilled in 93% of ANA-positive patients and RA criteria in 38% of patients with arthritis.

Conclusions

Parvovirus B19 infection manifestations may vary and nearly all patients with positive serum ANA fulfil the classification criteria for SLE. The risk of misclassification in patients with viral infection should not be overlooked.
Engineered liver-derived decellularized extracellular matrix-based three-dimensional tumor constructs for enhanced drug screening efficiency
Authors: Luo Shengchang , Wang Qingqing , Li Miaoting , Xu Peiyao , Wang Yicheng , Wang Ying , Kankala Ranjith Kumar , Wang Shibin , Chen Aizheng
Published: September 2024

The decellularized extracellular matrix (dECM) has emerged as an effective medium for replicating the in vivo-like conditions of the tumor microenvironment (TME), thus enhancing the screening accuracy of chemotherapeutic agents. However, recent dECM-based tumor models have exhibited challenges such as uncontrollable morphology and diminished cell viability, hindering the precise evaluation of chemotherapeutic efficacy. Herein, we utilized a tailor-made microfluidic approach to encapsulate dECM from porcine liver in highly poly(lactic-co-glycolic acid) (PLGA) porous microspheres (dECM-PLGA PMs) to engineer a three-dimensional (3D) tumor model. These dECM-PLGA PMs-based microtumors exhibited significant promotion of hepatoma carcinoma cells (HepG2) proliferation compared to PLGA PMs alone, since the infusion of extracellular matrix (ECM) microfibers and biomolecular constituents within the PMs. Proteomic analysis of the dECM further revealed the potential effects of these bioactive fragments embedded in the PMs. Notably, dECM-PLGA PMs-based microtissues effectively replicated the drug resistance traits of tumors, showing pronounced disparities in half-maximal inhibitory concentration (IC50) values, which could correspond with certain aspects of the TME. Collectively, these dECM-PLGA PMs substantially surmounted the prevalent challenges of unregulated microstructure and suboptimal cell viability in conventional 3D tumor models. They also offer a sustainable and scalable platform for drug testing, holding promise for future pharmaceutical evaluations.
Optimal investment and equilibrium pricing under ambiguity
Authors: Anthropelos Michail , Schneider Paul
Published: September 2024

We study a model for portfolio selection under uncertainty along with market equilibria that are associated with the optimal positions. Allowing for both ambiguity-seeking and ambiguity-averse market participants, model-implied demand functions resemble observed bid–ask spreads, and are consistent with extant limited-participation results based on more specialized ambiguity settings. A Pareto-efficient second-best equilibrium arises from constraining the portfolio allocations of ambiguity seekers. It implies that heterogeneity in ambiguity preferences is sufficient for mutually beneficial transactions even among all else homogeneous traders. Our results reconcile many observed phenomena in liquid high-information financial markets, such as portfolio inertia and negative risk premia.
Securities financing and asset markets: new evidence
Authors: Breach Tomas , King Thomas B
Published: September 2024

Using survey data on secured funding arrangements provided by broker–dealers for their clients—a class of contracts that includes bilateral repo—we document that financing rates, collateral haircuts, lending maturities, and position limits move strongly together over time and across asset classes. Liquidity of the underlying securities, as opposed to their volatility or credit risk, is the main driver of this behavior, with dealer balance-sheet constraints also playing a role in the funding of less-liquid security types. A simple model of dealer–client interaction rationalizes these findings. Instrumenting with changes in market conventions, we find that funding conditions had little effect on cash securities markets between 2011 and 2019, but the tightening of terms during the market stress of early 2020 likely impaired liquidity and reduced asset returns to some degree.
Modeling Decision-Making in Schizophrenia: Associations Between Computationally Derived Risk Propensity and Self-Reported Risk Perception
Authors: Herms Emma N , Brown Joshua W , Wisner Krista M , Hetrick William P , Zald David H , Purcell John R
Published: September 2024

Background and Hypothesis

Schizophrenia is associated with a decreased pursuit of risky rewards during uncertain-risk decision-making. However, putative mechanisms subserving this disadvantageous risky reward pursuit, such as contributions of cognition and relevant traits, remain poorly understood.

Study Design

Participants (30 schizophrenia/schizoaffective disorder [SZ]; 30 comparison participants [CP]) completed the Balloon Analogue Risk Task (BART). Computational modeling captured subprocesses of uncertain-risk decision-making: Risk Propensity, Prior Belief of Success, Learning Rate, and Behavioral Consistency. IQ, self-reported risk-specific processes (ie, Perceived Risks and Expected Benefit of Risks), and non-risk-specific traits (ie, defeatist beliefs; hedonic tone) were examined for relationships with Risk Propensity to determine what contributed to differences in risky reward pursuit.

Study Results

On the BART, the SZ group exhibited lower Risk Propensity, higher Prior Beliefs of Success, and comparable Learning Rates. Furthermore, Risk Propensity was positively associated with IQ across groups. Linear models predicting Risk Propensity revealed 2 interactions: 1 between group and Perceived Risk, and 1 between IQ and Perceived Risk. Specifically, in both the SZ group and individuals with below median IQ, lower Perceived Risks was related to lower Risk Propensity. Thus, lower perception of financial risks was associated with a less advantageous pursuit of uncertain-risk rewards.

Conclusions

Findings suggest consistently decreased risk-taking on the BART in SZ may reflect risk imperception, the failure to accurately perceive and leverage relevant information to guide the advantageous pursuit of risky rewards. Additionally, our results highlight the importance of cognition in uncertain-risk decision-making.
The herbicide acetochlor causes lipid peroxidation by inhibition of glutathione peroxidase activity
Authors: Mesmar Fahmi , Muhsen Maram , Mirchandani Rachna , Tourigny Jason P , Tennessen Jason M , Bondesson Maria
Published: September 2024

Metabolic syndrome is increasing worldwide, particularly in rural communities, where residents have a higher risk of exposure to pesticides. We investigated whether six commonly used agricultural pesticides on corn and soy fields possess adipogenic and metabolic disruption activity. Exposure to two of these pesticides, the herbicides acetochlor and metolachlor, induced adipogenesis in vitro in mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure induced morphological malformations and lethality in zebrafish larvae with an EC50 of 7.8 µM and LC50 of 12 µM. Acetochlor exposure at 10 nM resulted in lipid accumulation in zebrafish larvae when simultaneously fed a high-cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we performed transcriptomic and lipidomic analyses of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consistent with this prediction, Gpx activity was efficiently repressed by acetochlor in zebrafish, whereas lipid peroxidation was increased. We propose that acetochlor disrupts lipid homeostasis by inhibiting GPX activity, resulting in the accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contains the chloroacetamide group, inhibition of GPX activity may represent a novel, common molecular initiating event of metabolic disruption.
In Silico Target Identification Reveals IL12B as a Candidate for Small Molecule Drug Development
Authors: Tanner Trevor J.
Published: September 2024

Drug discovery’s rising costs and complexities require innovative strategies to identify viable therapeutic targets. We developed a computational pipeline to pinpoint protein targets lacking known small molecule probes, focusing on sites traditionally considered challenging for small molecule intervention but validated by FDA-approved biologics. Our approach, which integrates machine learning, public databases, and structural analysis, targeted autoimmune diseases. This method identified IL12B as a promising candidate, uncovering a potential small molecule binding site involved in dimer formation. Inhibitors targeting this site could offer benefits such as shorter half-lives and more precise tissue distribution compared to existing biologics. These findings present a new opportunity to develop small molecule therapeutics for IL12B, potentially improving the safety and efficacy of treatments for conditions like inflammatory bowel disease (IBD).
Estimating soil mineral nitrogen from data-sparse field experiments using crop model-guided machine learning approach
Authors: Gupta Rishabh , Pothapragada Satya Krishna , Xu Weihuang , Goel Prateek Kumar , Barrera Miguel , Saldanha Mira , Harley Joel , Morgan Kelly T. , Zare Alina , Zotarelli Lincoln
Published: September 2024

Sandy soils are susceptible to excessive nitrogen (N) leaching under intensive crop production which is linked with the soil's low nutrient holding capacity and high-water infiltration rate. Estimating soil mineral nitrogen (SMN) at the daily time-step is crucial in providing fertilizer recommendations balancing plant nitrogen use efficiency (NUE) and N losses to the environment. Crop models [e.g., Decision Support System for Agrotechnology Transfer (DSSAT)] can simulate the trend of SMN in varied fertilizer rates and timing of application but are unable to replicate its magnitude due to the inability to capture high-water table conditions in a sub-irrigated soil. As an alternative to such physics-based model, time-series deep learning (DL) models based on a long short-term memory (LSTM) are promising in understanding nonlinearity among complex variables. Yet, purely data-driven DL models for crops are difficult to obtain due to the insufficient amount of data available and the excessive costs with producing more data. To address this challenge, a hybrid model (hybrid-LSTM) was developed by leveraging both the DSSAT andLSTM models to estimate daily SMN primarily using daily weather, applied fertilizer rates- timings, and the SMN sparse observations. This study used the observations from field trials conducted between 2010-2014 in Hastings, FL. The first step was to calibrate the DSSAT-SUBSTOR-Potato model to produce reliable SMN of the topsoil for treatments with varied N applied fertilizer rates split among the pre-planting, emergence, and tuber-initiation stages of the potato crop. Thereafter, the hybrid-LSTM model was trained on the calibrated DSSAT simulated SMN time-series and fine-tuned its predictions using the observed SMN to improve DSSAT simulated SMN. The hybrid-LSTM model was then tested on both calibrated and uncalibrated DSSAT SMN simulations where it outperformed the DSSAT model (range of improvement ranged ~18-30% on comparing the normalized root mean squared error) in providing reliable estimates of SMN across most of the farms and years. This novel hybrid modeling approach could guide stakeholders and farmers to build sustainable N management with improved crop NUE and yield and help in minimizing environmental losses.
Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma
Authors: Li Annie , Gonda Bianca L , Paternos Adam von , Codd Elizabeth M , Mitchell Dawn R , Herrmann Markus D , Dzu Thuc Q , Kalyan Prinjali , Gao Chengzhuo , Zhang Edwin , Mendel Julia J , Thierauf Julia C , Sadow Peter M , Denize Thomas , Yang Diane , Park Jong C , Fintelmann Florian J , Gao Xin , Merkin Ross D , Bhan Atul K , Faquin William C , Wirth Lori J , Faden Daniel L , Kaluziak Stefan T , Iafrate A John
Published: September 2024

Purpose

Adenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs.

Experimental Design

We leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-ψ or a STING agonist.

Results

mIF demonstrated that ACC tumors are immunologically ‘cold’, with few tumor- infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-ψ or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression.

Conclusions

Low/absent HLA/B2M expression may explain ACC tumors’ immunologically cold status and lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.
Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade
Authors: Ruiz-Torres Daniel A. , Wise Jillian , Zhao Brian Yinge , Oliveira-Costa Joao Paulo , Cavallaro Sara , Sadow Peter , Fang Jacy , Yilmaz Osman , Patel Amar , Loosbroock Christopher , Sade-Feldman Moshe , Faden Daniel L. , Stott Shannon L.
Published: September 2024

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increasedCLEC9A+dendritic cell andCLEC7A/SYKexpression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study.

Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8+T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+T- cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.
T cell correction pipeline for Inborn Errors of Immunity
Authors: Mamia Katariina , Kolbeinsdottir Solrun , Li Zhuokun , Labun Kornel , Komisarczuk Anna , Keskitalo Salla , Reint Ganna , Haugen Frida Hosoien , Lindestad Britt Olaug , Gjerdingen Thea Johanne , Tuhkala Antti , Ervik Carolina Wieczorek , Kopcil Pavel , Fatkhutdinov Nail , Szymanska Monika , Tolo Eero , Glumoff Virpi , Saarela Janna , Michelsen Trond Melbye , Schalin-Jantti Camilla , Olweus Johanna , Leinonen Eira , Varjosalo Markku , Valen Eivind , Hautala Timo , Enge Martin , Martelius Timi , Dahal-Koirala Shiva , Haapaniemi Emma
Published: September 2024

CRISPR/Cas9 gene editing technology is a promising tool for correcting pathogenic variants for autologous cell therapies for Inborn Errors of Immunity (IEI). The present IEI correction strategies mainly focus on the knock-in of therapeutic cDNAs, or knockout of the disease-causing gene when feasible. These strategies address many single-gene defects but may disrupt gene expression and require significant optimization for each newly discovered IEI-causing gene, highlighting the need for complementary platforms that can precisely correct diverse pathogenic variants. Here, we present a safe and efficient T cell single nucleotide variant (SNV) correction pipeline based on homology-directed repair (HDR), suitable for diverse monogenic mutations. By using founder mutations of Deficiency of ADA2 (DADA2), Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and Cartilage Hair Hypoplasia (CHH) as IEI models, we show that our pipeline can achieve up to 80% bi-allelic editing, with resultant functional correction of the disease phenotype in patient T cells. We do not find detectable pre-malignant off-target effects or karyotypic, transcriptomic or proteomic aberrations upon profiling patient T cells with GUIDE-seq, single cell RNA sequencing, PacBio based long-read whole genome sequencing, and high-throughput proteomics. This study demonstrates that HDR-based SNV editing is a safe and effective option for IEI T cell correction and that it could be developed to an autologous T cell therapy, as the presented protocol is scalable for a GMP-compatible workflow. This study is a step towards the development of gene correction platform that targets a broad number of monogenic mutations.
Generating virtual patient data for in silico clinical trials of medical devices during extracorporeal membrane oxygenation treatment
Authors: Landoll Micha , Huang Yifei , Follegot Filippo , Strassmann Stephan , Steinseifer Ulrich , Karagiannidis Christian , Neidlin Michael
Published: September 2024

This study introduces a virtual patient generation model as online tool through the generation of high-quality synthetic data, addressing challenges like privacy cocerns and limited dataset sizes. Using a Conditional Tabular Generative Adversarial Network (CTGAN), we generated synthetic data from the Electronic Health Records (EHR) of 767 veno-venous extracorporeal membrane oxygenation (ECMO) patients, focusing on 55 critical therapy parameters. Rigorous preprocessing, imputation, and model tuning ensured that the synthetic data closely mirrored real patient records, achieving a 86.6% coverage score and minimal deviations in data correlations. The tool is integrated into a web platform -https://cve-sim.de/ecmo-vpg, allowing researchers to generate and visualize virtual patient cohorts, potentially enhancing ECMO research and reducing the need for extensive clinical trials.
The Multiple Roles of Gamma Interferon in Intraepithelial T Cell-Villous Enterocyte Interactions in Active Celiac Disease
Authors: Johnson JE , Agrawal K , Al-Lamki RS , Zhang F , Wang Xi , Liburd S , Tobiasova Z , Rodriguez L , Martins AJ , Sefik E , Flavell RA , Robert ME , Pober JS
Published: September 2024

We identified molecular interactions between duodenal enterocytes and intraepithelial T cells in celiac disease (CeD) vs normal controls. We observed an expected increased ratio of T cells [bearing either T cell receptor (TCR) αβ or γδ and mostly activated cytotoxic T lymphocytes (CTLs) expressing granzyme B, CD45RO, Ki67 and Nur 77 proteins as well as IFNγ mRNA] to villous enterocytes. Few T cells (<5%) express NKG2C or DAP12 proteins. CeD villous enterocytes express an IFNγ signature (by single cell RNA sequencing and nuclear phopho-STAT1 and HLA-DR protein staining). CeD enterocytes express increased IFNγ-inducible chemokines CCL3, CCL4, CXCL10 and CXCL11 mRNA while CeD intraepithelial T cells express reduced levels of CCR5 and CXCR3 chemokine receptors, suggesting ligand-induced downregulation. CeD enterocyte HLA-E mRNA and protein are upregulated whereas HLA-B mRNA but not protein increases. Proximity ligation detected frequent interactions of αβ and γδ TCRs with HLA-E and HLA-B but not with HLA-DR and fewer NKG2C interactions with HLA-E. We suggest that CeD IFNγ-producing TCR αβ and γδ CTLs are recruited into villous epithelium by IFNγ-induced enterocyte production of CCR5 and CXCR3-binding chemokines and kill villous enterocytes primarily by TCR engagement with class I HLA molecules, including HLA-E, likely presenting gluten peptides. The IFN-γ signature of CeD villous enterocytes is a potential biomarker of active disease and a therapeutic target.
Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis
Authors: Luan Yaqi , He Weiwei , Jiang Kunmao , Qiu Shenghui , Jin Lan , Mao Xinrui , Huang Ying , Liu Wentao , Cao Jingyuan , Jin Lai , Wang Rong
Published: September 2024

Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora
Effect of Genotype and Age on a Defined Microbiota in Gnotobiotic SCID Piglets
Authors: Widmer Katherine M. , Rahic-Seggerman Faith , Forster Ahlea , Ahrens-Kress Amanda , Sauer Mary , Mooyottu Shankumar , Vinithakumari Akhil , Dunkerson-Kurzhumov Aaron , Sponseller Brett , Kiupel Matti , Schmitz-Esser Stephan , Tuggle Christopher K.
Published: September 2024

Severe combined immunodeficient (SCID) individuals lack functional T and B lymphocytes, leading to a deficient adaptive immune system. SCID pigs are a unique large animal biomedical model as they possess many similarities to humans, allowing for the collection of translatable data in regenerative medicine, cancer, and other biomedical research topics. While many studies suggest early gut microbiota development is necessary for developing the intestinal barrier and immune system, these animals are often cesarian section derived, leaving them uncolonized for normal intestinal microflora. The hypothesis was that an increase in complexity of microbiota inoculum will allow for more stability in the composition of the gut microbiota of SCID piglets. This was tested across multiple litters of SCID piglets with three different defined microbiota consortium (2-strain, 6-strain, 7-strain). All piglets received their designated defined microbiota by oral gavage immediately after birth and again 24 hours later. There was no effect of SCID genotype on the composition of the gut microbiota, but there was a significant effect due to piglet age. Additionally, all three defined microbiota consortia were deemed safe to use in SCID piglets, and the 7-strain microbiota was the most stable over time. Based on these results, the 7-strain defined microbiota will be added to the SCID pig husbandry protocol, allowing for a more reproducible model.
Chamaeleo calyptratus(veiled chameleon) chromosome-scale genome assembly and annotation provides insights into the evolution of reptiles and developmental mechanisms.
Authors: Shylo Natalia , Price Andrew , Robb Sofia , Kupronis Richard , Guzmán Méndez Irán Andira , DeGraffenreid Dustin , Gamble Tony , Trainor Paul
Published: September 2024

The family Chamaeleonidae comprises 228 species, boasting an extensive geographic spread and an array of evolutionary novelties and adaptations, but a paucity of genetic and molecular analyses. Veiled chameleon (Chamaeleo calyptratus) has emerged as a tractable research organism for the study of squamate early development and evolution. Here we report a chromosomal-level assembly and annotation of the veiled chameleon genome. We note a remarkable chromosomal conservation across squamates, but comparisons to more distant genomes reveal GC peaks correlating with ancestral chromosome fusion events. We subsequently identified the XX/XY region on chromosome 5, confirming environmental-independent sex determination in veiled chameleons. Furthermore, our analysis of theHoxgene family indicates that veiled chameleons possess the most complete set of 41Hoxgenes, retained from an amniote ancestor. Lastly, the veiled chameleon genome has retained both ancestral paralogs of theNodalgene, but is missingDand5and several other genes, recently associated with the loss of motile cilia during the establishment of left-right patterning. Thus, a complete veiled chameleon genome provides opportunities for novel insights into the evolution of reptilian genomes and the molecular mechanisms driving phenotypic variation and ecological adaptation.