bluuebunny/crossref_metadata_2025 huggingface dataset:
H2CN/H2NC abundance ratio: a new potential temperature tracer for the interstellar medium
Authors: San Andrés D , Colzi L , Rivilla V M , García de la Concepción J , Melosso M , Martín-Pintado J , Jiménez-Serra I , Zeng S , Martín S , Requena-Torres M A
Published: May 2023

The H2NC radical is the high-energy metastable isomer of H2CN radical, which has been recently detected for the first time in the interstellar medium towards a handful of cold galactic sources, besides a warm galaxy in front of the PKS 1830−211 quasar. These detections have shown that the H2CN/H2NC isomeric ratio, likewise the HCN/HNC ratio, might increase with the kinetic temperature (Tkin), but the shortage of them in warm sources still prevents us from confirming this hypothesis and shedding light on their chemistry. In this work, we present the first detection of H2CN and H2NC towards a warm galactic source, the G+0.693−0.027 molecular cloud (with Tkin > 70 K), using IRAM 30-m telescope observations. We have detected multiple hyperfine components of the $N_{K_\text{a}K_\text{c}} =$ 101–000 and 202–101 transitions. We derived molecular abundances with respect to H2 of (6.8 ± 1.3) × 10−11 for H2CN and of (3.1 ± 0.7) × 10−11 for H2NC, and an H2CN/H2NC abundance ratio of 2.2 ± 0.5. These detections confirm that the H2CN/H2NC ratio is ≳2 for sources with Tkin > 70 K, larger than the ∼1 ratios previously found in colder cores (Tkin ∼ 10 K). This isomeric ratio dependence on temperature cannot be fully explained with the currently proposed gas-phase formation and destruction pathways. Grain surface reactions, including the H2NC → H2CN isomerization, deserve consideration to explain the higher isomeric ratios and H2CN abundances observed in warm sources, where the molecules can be desorbed into the gas phase through thermal and/or shock-induced mechanisms.
Early excess emission in Type Ia supernovae from the interaction between supernova ejecta and their circumstellar wind
Authors: Moriya Takashi J , Mazzali Paolo A , Ashall Chris , Pian Elena
Published: May 2023

The effects of the interaction between Type Ia supernova ejecta and their circumstellar wind on the photometric properties of Type Ia supernovae are investigated. We assume that a hydrogen-rich, dense, and extended circumstellar matter (CSM) is formed by the steady mass-loss of their progenitor systems. The CSM density is assumed to be proportional to r−2. When the mass-loss rate is above 10−4 M⊙ yr−1 with a wind velocity of 100 km s−1, CSM interaction results in an early flux excess in optical light curves within 4 d of explosion. In these cases, the optical colour quickly evolves to the blue. The ultraviolet flux below 3000 Å is found to have a persistent flux excess compared to Type Ia supernovae as long as CSM interaction continues. Type Ia supernovae with progenitor mass-loss rates between 10−4 and 10−3 M⊙ yr−1 may not have a CSM that is dense enough to affect spectra to make them Type Ia CSM, but they may still result in Type Ia supernovae with an early optical flux excess. Because they have a persistent ultraviolet flux excess, ultraviolet light curves around the luminosity peak would be significantly different from those with a low-density CSM.
Population Genomics Provide Insights into the Evolution and Adaptation of the Asia Corn Borer
Authors: Peng Yan , Jin Minghui , Li Zhimin , Li Hongran , Zhang Lei , Yu Songmiao , Zhang Zhuting , Fan Ruyi , Liu Jimin , Xu Qi , Wilson Kenneth , Xiao Yutao
Published: May 2023

Understanding the genetic basis of pest adaptive evolution and the risk of adaptation in response to climate change is essential for the development of sustainable agricultural practices. However, the genetic basis of climatic adaptation for the Asian corn borer (ACB), Ostrinia furnacalis, the main pest of corn in Asia and Oceania, is poorly understood. Here, we revealed the genomic loci underlying the climatic adaptation and evolution in ACB by integrating population genomic and environmental factors. We assembled a 471-Mb chromosome-scale reference genome of ACB and resequenced 423 individuals covering 27 representative geographic areas. We inferred that the ACB effective population size changes tracked with the global temperature and followed by a recent decline. Based on an integrated analysis of whole-genome selection scans and genome-wide genotype–environment association studies, we revealed the genetic basis of ACB adaption to diverse climates. For diapause traits, we identified a major effect association locus containing a circadian clock gene (period) by analyzing a diapause-segregating population. Moreover, our predictions indicated that the northern populations were more ecologically resilient to climate change than the southern populations. Together, our results revealed the genomic basis for ACB environmental adaptation and provided potential candidate genes for future evolutionary studies and genetic adaptation to climate change, intending to maintain the efficacy and sustainability of novel control techniques.
The Trolley Problem in the Ethics of Autonomous Vehicles
Authors: Paulo Norbert
Published: May 2023

In 2021, Germany passed the first law worldwide that regulates dilemma situations with autonomous cars. Against this background, this article investigates the permissibility of trade-offs between human lives in the context of self-driving cars. It does so by drawing on the debate about the traditional trolley problem. In contrast to most authors in the relevant literature, it argues that the debate about the trolley problem is both directly and indirectly relevant for the ethics of crashes with self-driving cars. Drawing on its direct normative relevance, the article shows that trade-offs are permissible in situations with self-driving cars that are similar to paradigmatic trolley cases. In scenarios that are unlike paradigmatic trolley cases, the debate about the trolley problem can have indirect normative relevance because it provides reasons against the use of moral theories and principles that cannot account for the trolley problem.
The differential crosstalk of the skin–gut microbiome axis as a new emerging actor in systemic sclerosis
Authors: Russo Edda , Bellando-Randone Silvia , Carboni Davide , Fioretto Bianca Saveria , Romano Eloisa , Baldi Simone , El Aoufy Khadija , Ramazzotti Matteo , Rosa Irene , Lepri Gemma , Di Gloria Leandro , Pallecchi Marco , Bruni Cosimo , Melchiorre Daniela , Guiducci Serena , Manetti Mirko , Bartolucci Gian Luca , Matucci-Cerinic Marco , Amedei Amedeo
Published: May 2023

Objectives

We characterized the microbiota in SSc, focusing on the skin–oral–gut axis and the serum and faecal free fatty acid (FFA) profile.

Methods

Twenty-five SSc patients with ACA or anti-Scl70 autoantibodies were enrolled. The microbiota of faecal, saliva and superficial epidermal samples was assessed through next-generation sequencing analysis. GC-MS was used to quantify faecal and serum FFAs. Gastrointestinal symptoms were investigated with the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA GIT-2.0) questionnaire.

Results

The ACA+ and anti-Scl70+ groups displayed different cutaneous and faecal microbiota profiles. The classes of cutaneous Sphingobacteriia and Alphaproteobacteria, the faecal phylum Lentisphaerae, the levels of the classes Lentisphaeria and Opitutae, and the genus NA-Acidaminococcaceae were significantly higher in faecal samples from the ACA+ patients than in samples from the anti-Scl70+ patients. The cutaneous Sphingobacteria and the faecal Lentisphaerae were significantly correlated (rho = 0.42; P = 0.03). A significant increase in faecal propionic acid was observed in ACA+ patients. Moreover, all levels of faecal medium-chain FFAs and hexanoic acids were significantly higher in the ACA+ group than in the anti-Scl70+ group (P < 0.05 and P < 0.001, respectively). In the ACA+ group, the analysis of the serum FFA levels showed an increasing trend in valeric acid.

Conclusion

Different microbiota signatures and FFA profiles were found for the two groups of patients. Despite being in different body districts, the cutaneous Sphingobacteria and faecal Lentisphaerae appear interdependent.
Within, Between, and Beyond: A New Approach to Examining World Income Inequality
Authors: Clark Rob
Published: May 2023

World income inequality is comprised of uneven development between states and unequal distribution within states. Recent work shows that the “between-country” component still accounts for a majority of the total, but that attention is shifting to the “within-country” portion, which is growing in both absolute and relative terms. What is less appreciated, though, is that the way income is distributed within countries also plays an indirect role in how income differences are recognized between them. When a nation’s income distribution is highly unequal, its mean income is substantially larger than the income of its average person, thereby masking a depreciation in living standards for those residing in the middle. The practical effect of this distortion is that poor, unequal countries seem wealthier than they really are when using mean incomes to represent country averages, as is typically done. I address this shortcoming in prior work by estimating between-country inequality using median incomes. My analysis covers the 1990–2017 period for 123 countries that represent over 90 percent of the world’s population. According to Theil’s T, I find that (a) inequality in median incomes is almost 15 percent higher than inequality in mean incomes, and that (b) median incomes are converging about 7.5 percent more slowly than mean incomes. This translates to a higher level of world income inequality, which is likewise converging at a slower rate. Overall, I find that the direct and indirect effects of national inequality are now responsible for about half of the world’s income inequality.
2Animal Studies
Authors: O’Key Dominic
Published: May 2023

In this chapter I survey, highlight, and critically reflect on recent work in animal studies, a field that continues to yield deeply researched scholarship and incisive works of critical and cultural theory, all in spite of its relative lack of institutional footholds. This is my first outing as a YWCCT reviewer, and so my ambition for this initial venture is modest. I wish, quite straightforwardly, to explore a handful of publications that caught my attention in 2022. I do not pretend to have a robust rationale for my criteria for inclusion. Instead, let me say that these are all publications that excited me in some way, that excited something in me, and that I believe will excite others too. I have divided the chapter into four sections: 1. ‘Living Machines of Imperialism’ examines two postcolonial animal histories, Saheed Aderinto’s Animality and Colonial Subjecthood in Africa and Jonathan Saha’s Colonizing Animals; 2. ‘I Dream of Dogs’ briefly considers Lydia Pyne’s Endlings before focusing on Margret Grebowicz’s short book of cultural critique on dog ownership, Rescue Me; 3. ‘The Gay Frog Is the Opposite of the Gay Penguin’ turns to recent issues of Humanimalia and Green Letters, and a special section of Environmental Humanities, co-edited by Sarah Bezan and Ina Linge; and 4. ‘Inside the Slaughterhouse’ looks at recent publications in the Palgrave Studies in Animals and Literature series, concentrating mostly on Sune Borkfelt’s Reading Slaughter. I end the chapter by reflecting on the links between these publications; I introduce my own monograph, Creaturely Forms in Contemporary Literature, to tie together the review’s key ideas. In all of this I have tried not to impose a grand narrative on the books reviewed, nor isolate them as symptoms of broader ideological tendencies. Yet if there is an argument here it is this: animal studies continues to remind us that human–animal relations are not natural, timeless, or inevitable. They are historical. They can be transformed.
Inverse Probability of Treatment Weighting and Confounder Missingness in Electronic Health Record-based Analyses: A Comparison of Approaches Using Plasmode Simulation
Authors: Vader Daniel T. , Mamtani Ronac , Li Yun , Griffith Sandra D. , Calip Gregory S. , Hubbard Rebecca A.
Published: May 2023

Background:

Electronic health record (EHR) data represent a critical resource for comparative effectiveness research, allowing investigators to study intervention effects in real-world settings with large patient samples. However, high levels of missingness in confounder variables is common, challenging the perceived validity of EHR-based investigations.

Methods:

We investigated performance of multiple imputation and propensity score (PS) calibration when conducting inverse probability of treatment weights (IPTW)-based comparative effectiveness research using EHR data with missingness in confounder variables and outcome misclassification. Our motivating example compared effectiveness of immunotherapy versus chemotherapy treatment of advanced bladder cancer with missingness in a key prognostic variable. We captured complexity in EHR data structures using a plasmode simulation approach to spike investigator-defined effects into resamples of a cohort of 4361 patients from a nationwide deidentified EHR-derived database. We characterized statistical properties of IPTW hazard ratio estimates when using multiple imputation or PS calibration missingness approaches.

Results:

Multiple imputation and PS calibration performed similarly, maintaining ≤0.05 absolute bias in the marginal hazard ratio even when ≥50% of subjects had missing at random or missing not at random confounder data. Multiple imputation required greater computational resources, taking nearly 40 times as long as PS calibration to complete. Outcome misclassification minimally increased bias of both methods.

Conclusion:

Our results support multiple imputation and PS calibration approaches to missingness in missing completely at random or missing at random confounder variables in EHR-based IPTW comparative effectiveness analyses, even with missingness ≥50%. PS calibration represents a computationally efficient alternative to multiple imputation.
Sensitivity Analyses for Means or Proportions with Missing Outcome Data
Authors: Cole Stephen R. , Zivich Paul N. , Edwards Jessie K. , Shook-Sa Bonnie E. , Hudgens Michael G.
Published: May 2023

We describe an approach to sensitivity analysis introduced by Robins et al (1999), for the setting where the outcome is missing for some observations. This flexible approach focuses on the relationship between the outcomes and missingness, where data can be missing completely at random, missing at random given observed data, or missing not at random. We provide examples from HIV that include the sensitivity of the estimation of a mean and proportion under different missingness mechanisms. The approach illustrated provides a method for examining how the results of epidemiologic studies might shift as a function of bias due to missing data.
Novel technique for intraocular foreign body removal: Magnetized disposable microforceps. A systematic approach and first clinical result
Authors: Werner Jens Ulrich , Wolf Armin , Parlak Melih
Published: May 2023

Purpose:

To verify whether disposable microforceps can be magnetized to atraumatically attract and then grasp intraocular foreign bodies. An effective magnetization protocol was developed. The clinical relevance was tested and a first practical application performed.

Methods:

The magnetic flux density (MFD) of a bar magnet and an electromagnet was measured. Steel screws were used to determine the magnetization protocol. Disposable microforceps was magnetized, MFD generated at the tip measured and the weight that can be lifted was tested. Foreign body removal with such forceps was performed.

Results:

The electromagnet MFD was much higher than the bar magnet. The most effective magnetization protocol was to pass the screw from the end along the shaft and back over the electromagnet. Magnetized microforceps had a 7.12 mT change in MFD at the tip. Steel balls up to 87 mg could be lifted in BSS. In clinical use, the intraocular foreign body could be attracted and grasped safely.

Conclusions:

Disposable microforceps can be easily and inexpensively magnetized. The achievable MFD is clinically relevant to attract typical intraocular foreign bodies. An electromagnet is best suited for this purpose. With such prepared forceps, foreign bodies can be attracted atraumatically and grasped securely.
The Re-emergence of Syphilis Among Females of Reproductive Age and Congenital Syphilis in Victoria, Australia, 2010-2020: A Public Health Priority
Authors: Borg Sarah , Tenneti Naveen , Lee Alvin , Drewett George , Ivan Mihaela , Giles Michelle L.
Published: May 2023

Background

Syphilis notifications in Victoria, Australia have been increasing over the past decade, with an increase in infectious syphilis (syphilis of less than two years duration) cases in females of reproductive age, and an associated re-emergence of congenital syphilis (CS). Prior to 2017 there had been two CS cases in the preceding 26 years. This study describes the epidemiology of infectious syphilis among females of reproductive age and CS in Victoria.

Methods

Routine surveillance data provided by mandatory Victorian syphilis case notifications were extracted and grouped into a descriptive analysis of infectious syphilis and CS incidence data from 2010-20.

Results

In 2020, infectious syphilis notifications in Victoria were approximately five times more than 2010 (n = 289 in 2010 to n = 1440 in 2020), with a more than seven-fold rise among females (n = 25 in 2010 to n = 186 in 2020). Females made up 29% (n = 60/209) of Aboriginal and Torres Strait Islander notifications occurring between 2010-2020. Between 2017-2020, 67% of notifications in females (n = 456/678) were diagnosed in low-caseload clinics, at least 13% (n = 87/678) of all female notifications were known to be pregnant at diagnosis, and there were nine CS notifications.

Conclusions

Cases of infectious syphilis in females of reproductive age and CS are on the rise in Victoria, necessitating sustained public health action. Increasing awareness among individuals and clinicians, and health system strengthening, particularly targeting primary care where most females are diagnosed prior to pregnancy, is required. Treating infections before or promptly during pregnancy and undertaking partner notification and treatment to reduce risk of reinfection is critical to reducing CS cases.
Association of Pregnancy and HIV Status With Molecular-Bacterial Vaginosis in Indian Women
Authors: Tuddenham Susan , Shafiq Mehr , Mathad Jyoti S. , Alexander Mallika , Naik Shilpa , Kulkarni Vandana , Deshpande Prasad , Humphrys Mike S. , Holm Johanna B. , Khan Nawshaba , Yadana Su , Cheedalla Aneesha , Bhosale Ramesh , Ghanem Khalil G. , Wang Tian , Wang Shuang , Ma Bing , Ravel Jacques , Gupta Amita , Shivakoti Rupak
Published: May 2023

Background:

Bacterial vaginosis (BV) is a highly prevalent disorder of the cervicovaginal microbiota. Molecular-BV may put women at increased risk for adverse reproductive and obstetric outcomes. We investigated the association of HIV and pregnancy on the vaginal microbiota and associations with molecular-BV in women of reproductive age from Pune, India.

Setting:

We studied vaginal samples from N = 170 women, including N = 44 nonpregnant HIV seronegative, N = 56 pregnant seronegative, N = 47 nonpregnant women with HIV (WWH), and N = 23 pregnant WWH, and collected data on clinical, behavioral, and demographic factors.

Methods:

We used 16S rRNA gene amplicon sequencing to characterize the composition of the vaginal microbiota. We classified the vaginal microbiota of these women into community state types based on bacterial composition and relative abundance and further categorized them into molecular-BV versus Lactobacillus-dominated states. To determine associations between pregnancy and HIV status with outcome of molecular-BV, logistic regression models were used.

Results:

There was a high prevalence of molecular-BV (30%) in this cohort. We found that pregnancy was associated with decreased odds of molecular-BV (adjusted OR = 0.35, 95% CI: 0.14 to 0.87), while HIV was associated with increased odds of molecular-BV (adjusted OR = 2.76, 95% CI: 1.33 to 5.73), even when controlling for multiple relevant factors such as age, number of sexual partners, condom use, and douching.

Conclusion:

Larger and longitudinal studies are needed to further characterize molecular-BV and the vaginal microbiota in pregnant women and WWH and relate these factors to infectious, reproductive, and obstetric outcomes. In the long term, these studies may lead to novel microbiota-based therapeutics to improve women's reproductive and obstetric health.
Machine Learning Classifier Models for Predicting Sarcopenia in the Elderly Based on Physical Factors
Authors: Kim Jun-hee
Published: May 2023

Background

As the elderly population gradually increases, musculoskeletal disorders such as sarcopenia are increasing. Diagnostic techniques such as X-ray, CT, and MRI imaging are used to predict and diagnose sarcopenia, and methods using machine learning are gradually increasing.

Purpose

The purpose of this study was to create a model that can predict sarcopenia using physical characteristics and activity-related variables without medical diagnostic equipment such as imaging equipment for the elderly aged 60 years or older.

Method

A sarcopenia prediction model was constructed using public data obtained from the Korea National Health and Nutrition Examination Survey. Models were built using the multi-layer perceptron, XGBoost, LightGBM, and RandomForest algorithms, and the feature importance of the model with the highest accuracy was analyzed through evaluation metrics.

Result

The sarcopenia prediction model built with the LightGBM algorithm showed the highest test accuracy at 0.852. In constructing the LightGBM model, physical characteristics variables such as BMI showed high importance, and activity-related variables were also used in constructing the model.

Conclusion

The sarcopenia prediction model composed only of physical characteristics and activity-related factors showed excellent performance, and the use of this model will help predict sarcopenia in the elderly living in communities with insufficient medical resources or difficult access to medical facilities.
Effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients
Authors: Lohia Sonnal , Siwy Justyna , Mavrogeorgis Emmanouil , Eder Susanne , Thoeni Stefanie , Mayer Gert , Mischak Harald , Vlahou Antonia , Jankowski Vera
Published: May 2023

Aim

Type II Diabetes mellitus (T2DM) accounts for approximately 90% of all DM cases in the world; and is diagnosed with increased levels of blood glucose or hyperglycemia. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while, the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients.

Material and Methods

Urine samples of thirty-two T2DM patients from the PROVALID study (A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers) were collected at pre- and post-treatment with GLP-1R agonist drugs, and analyzed by capillary electrophoresis coupled to mass spectrometry (CE-MS).

Results

In total, 329 urinary peptides were identified, of which 70 were significantly affected by the GLP-1R agonist treatment; fragmenting from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides with GLP-1R agonist treatment was highlighted in the study. Treatment also resulted in the downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR and TTR, many of which were previously found associated with increased kidney and/or vascular damage, indicating beneficial effect of GLP-1R agonists.

Conclusions

The novel findings in this study, indicate potential molecular mechanisms of GLP-1R agonists in the context of management of T2DM and prevention or delaying the progression of its associated diseases.
CREID – A ChemoReceptor-Effector Interaction Database
Authors: Peta Vincent , Hartman Timothy , Aryal Shiva , Gurung Bichar Shrestha , Singh Ram , Hass Samuel , Bomgni Alain , Do Tuyen , Dhiman Saurabh Sudha , Gadhamshetty Venkataramana , Gnimpieba Etienne Z.
Published: May 2023

The ChemoReceptor-Effector Interaction Database (CREID) is a collection of bacterial chemoreceptor and effector protein and interaction data to understand the process that chemoreceptors and effectors play in various environments. Our website includes terms associated with chemosensory pathways to educate users and those involved in collaborative research to help them understand this complex biological network. It includes 2,440 proteins involved in chemoreceptor and effector systems from 7 different bacterial families with 1,996 chemoeffector interactions. It is available athttps://react-creid.bicbioeng.org.

Key Highlights

CREID links bacterial chemoreceptors with their associated effectors.

Researchers interested in what attracts or repels bacteria can use CREID as a comprehensive source for information.

Biosensor developers can leverage CREID to discover better interactions for their applications.

CREID reveals knowledge gaps in chemoreceptor-effector interactions for both model and non-model organisms.
UV reflectance in crop remote sensing: Assessing the current state of knowledge and extending research with strawberry cultivars
Authors: Heath Megan , St-Onge David , Hausler Robert
Published: May 2023

Remote sensing of spectral reflectance is a crucial parameter in precision agriculture. In particular, the visual color produced from reflected light can be used to determine plant health (VIS-IR) or attract pollinators (Near-UV). However, the UV spectral reflectance studies largely focus on non-crop plants, even though they provide essential information for plant-pollinator interactions.

This literature review presents an overview of UV-reflectance in crops, identifies gaps in the literature, and contributes new data based on strawberry cultivars. The study found that most crop spectral reflectance studies relied on lab-based methodologies and examined a wide spectral range (Near UV to IR). Moreover, the plant family distribution largely mirrored global food market trends.

Through a spectral comparison of white flowering strawberry cultivars, this study discovered visual differences for pollinators in the Near UV and Blue ranges. The variation in pollinator visibility within strawberry cultivars underscores the importance of considering UV spectral reflectance when developing new crop breeding lines and managing pollinator preferences in agricultural fields.
Diving dinosaurs? Caveats on the use of bone compactness and pFDA for inferring lifestyle
Authors: Myhrvold Nathan P. , Sereno Paul C. , Baumgart Stephanie L. , Vidal Daniel , Fish Frank E. , Henderson Donald M. , Saitta Evan T.
Published: May 2023

Measures of bone compactness in amniote tetrapods of varying lifestyle were used to infer that two spinosaurid dinosaurs (Spinosaurus aegyptiacus,Baryonyx walkeri) were diving “subaqueous foragers,” whereas a third spinosaurid (Suchomimus tenerensis) and other sampled nonavian dinosaurs were non-diving terrestrial feeders entering water only as waders. We outline shortcomings in this analysis that involve bone compactness sampling and measurement, lifestyle categorization, the inclusion and exclusion of taxa in the dataset, and flawed statistical methods and inferences. These many shortcomings undermine the evidence used to conclude that two spinosaurid taxa were avid divers. Bone compactness indices remain a valuable tool for interpretation of lifestyle in extinct species when based on sound dataset composition, robust statistical analysis, and consilience with evidence from functional, biomechanical, or paleoenvironmental considerations.
Cardiological parameters predict mortality and cardiotoxicity in oncological patients
Authors: Romann Sebastian W. , Finke Daniel , Heckmann Markus B. , Hund Hauke , Giannitsis Evangelos , Katus Hugo A. , Frey Norbert , Lehmann Lorenz H.
Published: May 2023

Aims

Oncological patients suspected to have the risk for cardiotoxicity, are recommended to be under intensified cardiological surveillance. We aimed to investigate the value of cardiac biomarker and patient-related risk factors (age, cardiovascular risk factors (CRF), cardiac function) for the prediction of all-cause mortality (ACM) and development of cardiotoxicity.

Methods

Between 01/2016 to 12/2020, patients with oncological diseases, admitted to the cardio-oncology unit at the University Hospital Heidelberg were included. They were examined by medical history, physical examination, 12-lead-ECG, 2D-echocardiography and cardiac biomarkers (high sensitive Troponin T (hs-cTnT); N-terminal brain natriuretic peptide (NT-proBNP)). Primary endpoint was defined as ACM, secondary endpoint was defined as cardiotoxicity as defined by the European Society of Cardiology.

Results

From 1971 included patients, primary endpoint was reached by 490 patients (25.7%) with a median of 363.5 [IQR 121.8, 522.5] days after presentation. Hs-cTnT of ≥7 ng/L (OR 1.82, p < 0.001) and NT-proBNP (OR 1.98, p < 0.001) were independent predictors of ACM, while reduced LVEF was not associated with increased ACM (p=0.85). Secondary endpoint was reached by 182 patients (9.2%) within a median of 793.5 days [IQR 411.2, 1165.0]. Patients with multiple CRF (defined as high-risk, n=886) had an increased risk for cardiotoxicity (n=100/886, 11.3%; HR 1.57, p=0.004). They showed increased baseline values of hs-cTnT (OR 1.60; p=0.006) and NT-proBNP (OR 4.00, p<0.001) and had an increased risk for ACM (OR 1.43; p=0.031).

Conclusions

In cancer patients, accumulation of CRF predetermines cardiotoxicity while increased hs-cTnT levels and NT-proBNP associate with ACM. Therefore, less intense surveillance protocols might be justified in patients with low values of cardiac biomarker and absence of CRF.
Computer Modeling of Bevacizumab Drug Distribution After Intravitreal Injection in Rabbit and Human Eyes
Authors: Chowdhury Jabia M. , Ruiz Eduardo A. Chacin , Ohr Matthew P. , Swindle-Reilly Katelyn E. , Ford Versypt Ashlee N.
Published: May 2023

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action in the vitreous. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.
Synthesis of water-soluble and gastrointestinal transit-resistant FA-FOS conjugate for targeted delivery to the colon: pharmacokinetics, pharmacodynamics, efficacy
Authors: Johnson Eldin M , Suh Joo-Won
Published: May 2023

Ferulic acid is known to be a water-insoluble compound present in many fruits and vegetables and is known to possess antioxidant, anti-cancer, and anti-inflammatory properties. They are quickly absorbed in the stomach and metabolized in the liver. Their colonic exposure is found to be low due to their quick absorption and metabolism in the upper gastrointestinal tract, and due to this reason, only a small fraction of FA found in a bound form is associated with the insoluble and soluble fiber of the food matrix reaching the colon. Here we describe the synthesis and characterization of ferulic acid (FA) bound to fructo oligosaccharide (FOS) rendering the resultant FA-FOS conjugate water soluble, resistant to gastrointestinal digestion and absorption, along with the capability to deliver a therapeutically meaningful dose of FA to the large intestine. Free FA is released from FA-FOS conjugate by the digestive action of gut microflora, and the pharmacokinetic profile and pharmacodynamics are evaluated in a rat model. The efficacy of FA-FOS conjugate in the delivery of FA to the large intestine and its accumulation in tumours were evaluated in colitis induced colon cancer model and their efficacy through plasma bioavailability is determined in xenograft mice model carrying tumour from human colon cancer cells. The accumulation of FA derived from FA-FOS conjugate in the tumour was demonstrated by the MALDI imaging technique. The major metabolites of FA-FOS conjugate in plasma were determined through a data-dependent MS/MS experiment of precursor ion scan, utilizing triple quad (QTRAP) equipped LC-MS.
Species-level identification of the critically endangered European sturgeonAcipencer sturiousing DNA-based approaches
Authors: Chancerel Emilie , Acolas Marie-Laure , Lepais Olivier
Published: May 2023

The native European sturgeonAcipenser sturiois the focus of restoration programs. However,A. sturioidentification by direct observation is not always obvious for non-specialists. We aimed to develop a quick and easy genetic tool applicable to identify the species at risk in case of incidental capture or monitoring either at sea or in the watershed. We showed that primers and probe developed allow specific amplification forA. sturioby PCR, qPCR and Real-Time Loop-mediated isothermal amplification (LAMP) techniques. We determine benefits and limits of each method and highlight perspectives for field applications within the frame of conservation programs.
Integrative processing in artificial and biological vision predicts the perceived beauty of natural images
Authors: Nara Sanjeev , Kaiser Daniel
Published: May 2023

Previous research indicates that the beauty of natural images is already determined during perceptual analysis. However, it is still largely unclear which perceptual computations give rise to the perception of beauty. Theories of processing fluency suggest that the ease of processing for an image determines its perceived beauty. Here, we tested whether perceived beauty is related to the amount of spatial integration across an image, a perceptual computation that reduces processing demands by aggregating image elements into more efficient representations of the whole. We hypothesized that higher degrees of integration reduce processing demands in the visual system and thereby predispose the perception of beauty. We quantified integrative processing in an artificial deep neural network model of vision: We compared activations between parts of the image and the whole image, where the degree of integration was determined by the amount of deviation between activations for the whole image and its constituent parts. This quantification of integration predicted the beauty ratings for natural images across four studies, which featured different stimuli and task demands. In a complementary fMRI study, we show that integrative processing in human visual cortex predicts perceived beauty in a similar way as in artificial neural networks. Together, our results establish integration as a computational principle that facilitates perceptual analysis and thereby mediates the perception of beauty.
The CD4 transmembrane GGXXG and juxtamembrane (C/F)CV+C motifs mediate pMHCII-specific signaling independently of CD4-LCK interactions
Authors: Lee Mark S. , Tuohy Peter J. , Kim Caleb Y. , Yost Philip , Lichauco Katrina , Parrish Heather L. , Doorslaer Koenraad Van , Kuhns Michael S.
Published: May 2023

CD4+T cell activation is driven by 5-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee, et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
Structural polymorphisms within a common powdery mildew effector scaffold as a driver of co-evolution with cereal immune receptors
Authors: Cao Yu , Kümmel Florian , Logemann Elke , Gebauer Jan M. , Lawson Aaron W. , Yu Dongli , Uthoff Matthias , Keller Beat , Jirschitzka Jan , Baumann Ulrich , Tsuda Kenichi , Chai Jijie , Schulze-Lefert Paul
Published: May 2023

In plants, host–pathogen coevolution often manifests in reciprocal, adaptive genetic changes through variations in host nucleotide-binding leucine-rich repeat immune receptors (NLR) and virulence-promoting pathogen effectors. In grass powdery mildew (PM) fungi, an extreme expansion of a RNase-like effector family, termed RALPH, dominates the effector repertoire, with some members recognized as avirulence (AVR) effectors by cereal NLR receptors. We report the structures of the sequence-unrelated barley PM effectors AVRA6, AVRA7and allelic AVRA10/AVRA22variants, which are detected by highly sequence-related barley NLRs MLA6, MLA7, MLA10, and MLA22, and of wheat PM AVRPM2detected by the unrelated wheat NLR PM2. The AVR effectors adopt a common scaffold, which is shared with the ribonuclease (RNase) T1/F1-family. We found striking variations in the number, position, and length of individual structural elements between RALPH AVRs, which is associated with a differentiation of RALPH effector subfamilies. We show that all RALPH AVRs tested have lost nuclease and synthetase activities of the RNase T1/F1- family and lack significant binding to RNA, implying that their virulence activities are associated with neo-functionalization events. Structure-guided mutagenesis identified six AVRA6residues that are sufficient to turn a sequence-diverged member of the same RALPH subfamily into an effector specifically detected by MLA6. Similar structure-guided information for AVRA10and AVRA22indicates that MLA receptors detect largely distinct effector surface patches. Thus, coupling of sequence and structural polymorphisms within the RALPH scaffold of PMs facilitated escape from NLR recognition and potential acquisition of diverse virulence functions.
Pharmacological Studies on the Efficacy of Polyherbal Formulation Dawa ul kurkum in DEN-Induced 2-AAF-Promoted Hepatocellular Carcinoma in Male Wistar Rats
Authors: Gupta Meenakshi , Nimesh Hemlata , Sarwat Maryam
Published: May 2023

The purpose of this study was to explore the anti-cancer activity and the possible mechanism of Dawa-ul kurkum (Duk) against diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in male Wistar rats. We administered Duk at 3 doses, viz., 75, 150, and 300 mg/kg/day, 2 weeks before the DEN and continued it for 16 weeks. We found that Duk significantly reduced the DEN and 2-AAF induced phenotypical changes in rats and restored the activities of serum markers. Furthermore, Duk counteracted the oxidative stress induced by carcinogens as observed by restoration in the levels of superoxide dismutase (SOD) and catalase (CAT). Duk significantly diminished the levels of malondialdehyde (MDA) in a dose dependent manner and restored the liver microarchitecture as assessed by histopathological studies. The results of immunohistochemical staining showed that Duk inhibited the DEN-induced decrease in the number of cells positive for Bid and Caspase-9. It also reduces the number of cells positive for Cyclin D. This study shows that Duk significantly protects rat liver from hepatocarcinogenesis by regulating oxidative damage and restoring serum markers. The chemopreventive effect of Duk might be through induction of apoptosis.
eIF2B Activator Rescues Neonatal Lethality of an eIF2Bα Sugar Phosphate Binding Mutation Associated with Vanishing White Matter Disease
Authors: Lee James J. , Ly Nina , Kunjamma Rejani B. , Robb Holly M. , Mohler Eric G. , Sridar Janani , Hao Qi , Zavala-Solorio José , Zhang Chunlian , Kolumam Ganesh , Bruggen Nick van , Connelly Caitlin F. , Sidrauski Carmela
Published: May 2023

eIF2B is a decameric guanine nucleotide exchange factor (GEF) that is essential for protein synthesis and a key effector of the integrated stress response (ISR). Hypomorphic mutations in any of the eIF2B subunits are associated with Vanishing White Matter Disease (VWM), a leukodystrophy characterized by ISR activation and white matter loss. Here, we showed that the VWM-associated N208Y eIF2Bα mutation, which abolishes sugar phosphate binding, led to a drastic reduction in its level in cells and concomitant ISR activation. We found that N208Y homozygous mice are small and die shortly after birth. Remarkably, continuous availability of 2BAct, a small molecule eIF2B activator, in food rescued the lethality and significantly extended their lifespan. 2BAct-maintained N208Y homozygous mice, however, developed motor deficits and loss of myelin with age. As is the case for milder VWM models, ISR induction was restricted to the central nervous system in treated animals. Upon 2BAct withdrawal, adult mutant mice deteriorated quickly, the ISR was induced in all peripheral tissues tested and resulted in high levels of circulating FGF21 and GDF15. This model provides a novel platform to study the impact of ISR activation across tissues with temporal control.
Leveraging RAS-mSIN1 Interaction to Selectively Inhibit mTORC2 Employing Competitive RAS Binding Peptide: Implications in Breast Cancer Metastasis
Authors: Miyan Javed , Kumar Narayan , Malik Showkat Ahmad , Moinuddin  , Akif Usmani Mohammed , Kumar Jay , Hameed Rohil , Dubey Parul , Singh Maninder , Vishwakarma Jyoti , Tripathi Sarita , Ramachandran Ravishankar , Siddiqi Mohammad Imran , Kumar Vijay , Bhatt Madan Lal Brahma , Nazir Aamir , Arora Ashish , Bhadauria Smrati
Published: May 2023

Statement

The authors have withdrawn their manuscript owing to the authors decision of withdrawing of the manuscript until all experiments are completed. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Transplanted Autologous Neural Stem Cells Show Promise in Restoring Motor Function in Monkey Spinal Cord Injury
Authors: Jaberi Razieh , Jabbari Reza , Hajinasrollah Mostafa , Mirsadeghi Sara , Rahmani Saeid , Zarei-Khairabadi Masoumeh , Rezaei Omidvar , Nabavi Seyed-Masoud , Kiani Sahar
Published: May 2023

Spinal cord injury (SCI) is a devastating condition that can result in permanent loss of motor and sensory function. In recent years, transplantation of neural stem cells (NSCs) has emerged as a promising therapeutic approach for SCI. However, adult NSCs residing in the central nervous system (CNS) show promise for cell-replacement therapy in neurodegenerative disorders. In this study, we aimed to investigate the efficacy of transplanting autologous NSCs isolated from the subventricular zone (SVZ-NSCs) into a spinal cord injury model in Rhesus monkeys. We induced SCI in eight Rhesus monkeys and then transplanted SVZ-NSCs into the injury site. Behavioral assessments and magnetic resonance imaging (MRI) were performed to evaluate the functional and structural recovery of the spinal cord. Histological analyses were also performed to assess the survival and differentiation of the transplanted cells. SVZ-NSCs were capable of expressing SOX2, Nestin, and GFAP in addition to self-renewing and spontaneous differentiationin vitro. The monkeys showed sensory and motor function recovery, spinal tract regeneration, and partial reconstruction of the spinal cord. Positive Reinforcement Training confirmed no adverse effects from the isolation procedure. Our findings suggest that NSCs transplantation could be a promising therapeutic approach for SCI in humans, and further studies are warranted to investigate its potential for clinical translation.

Graphical abstract
NF-κB c-REL-OTUD4 axis regulates B-cell receptor in B-cell lymphoma
Authors: Katab Eslam , Kumar Anushree Jai , Steiger Katja , Mergner Julia , Azkargorta Mikel , Yeroslaviz Assa , Elortza Felix , Fernández-Sáiz Vanesa
Published: May 2023

The B-cell receptor (BCR) is essential for B-cell development and a crucial clinical target in immuno-oncology. However, therapeutic success against the BCR and downstream signaling pathways is hampered by enhanced NF-κB activation as a resistance mechanism. Using a multiomic approach, we discover the c-REL proto-oncogenic subunit of the NF-κB family as a key transcription factor regulating BCR subunit levels in B-cell lymphoma. Subsequent ChIP- seq, cell biology experiments, and patient data analysis reveal that OTUD4 is a critical deubiquitinase for inhibiting proteasomal degradation of c-REL and for stabilizing a multi-loop positive feedback of NF-κB to the BCR pathway. Remarkably,OTUD4downregulation destabilizes c-REL and BCR levels and inhibits cell growth of B cell lymphoma. Thus, we shed light on the malignant potential of c-REL abundance, identify a positive feedback from c-REL to upstream BCR and present OTUD4 as a vulnerability to synergistically target NF-κB and BCR pathways in B-cell lymphoid malignancies.