bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo
Authors: Aubert Martine , Haick Anoria K. , Strongin Daniel E. , Klouser Lindsay M. , Loprieno Michelle A. , Stensland Laurence , Santo Tracy K. , Huang Meei-Li , Hyrien Ollivier , Stone Daniel , Jerome Keith R.
Published: May 2024

Abstract

Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.
Mammographic density mediates the protective effect of early-life body size on breast cancer risk
Authors: Vabistsevits Marina , Davey Smith George , Richardson Tom G. , Richmond Rebecca C. , Sieh Weiva , Rothstein Joseph H. , Habel Laurel A. , Alexeeff Stacey E. , Lloyd-Lewis Bethan , Sanderson Eleanor
Published: May 2024

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%–79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.
Optical vectorial-mode parity Hall effect: a case study with cylindrical vector beams
Authors: Zhou Changyu , Liang Weili , Xie Zhenwei , Ma Jia , Yang Hui , Yang Xing , Hu Yueqiang , Duan Huigao , Yuan Xiaocong
Published: May 2024

The vectorial optical field (VOF) assumes a pivotal role in light-matter interactions. Beyond its inherent polarization topology, the VOF also encompasses an intrinsic degree of freedom associated with parity (even or odd), corresponding to a pair of degenerate orthogonal modes. However, previous research has not delved into the simultaneous manipulation of both even and odd parities. In this study, we introduce and validate the previously unexplored parity Hall effect for vectorial modes using a metasurface design. Our focus lies on a cylindrical vector beam (CVB) as a representative case. Through the tailored metasurface, we effectively separate two degenerate CVBs with distinct parities in divergent directions, akin to the observed spin states split in the spin Hall effect. Additionally, we provide experimental evidence showcasing the capabilities of this effect in multi-order CVB demultiplexing and parity-demultiplexed CVB-encoded holography. This effect unveils promising opportunities for various applications, including optical communication and imaging.
Rapid and scalable photocatalytic C(sp2)–C(sp3) Suzuki−Miyaura cross-coupling of aryl bromides with alkyl boranes
Authors: Wan Ting , Capaldo Luca , Djossou Jonas , Staffa Angela , de Zwart Felix J. , de Bruin Bas , Noël Timothy
Published: May 2024

In recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp3-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a powerful approach for the light-mediated B-alkyl Suzuki−Miyaura cross-coupling between alkyl boranes and aryl bromides. Alkyl boranes were easily generated via hydroboration from readily available alkenes, exhibiting excellent regioselectivity and enabling the selective transfer of a diverse range of primary alkyl fragments onto the arene ring under photocatalytic conditions. This methodology eliminates the need for expensive catalytic systems and sensitive organometallic compounds, operating efficiently at room temperature within just 30 min. We further demonstrate the translation of the present protocol to continuous-flow conditions, enhancing scalability, safety, and overall efficiency of the method. This versatile approach offers significant potential for accelerating drug discovery efforts by enabling the introduction of complex aliphatic fragments in a straightforward and reliable manner.
Analysis of early intermediate states of the nitrogenase reaction by regularization of EPR spectra
Authors: Heidinger Lorenz , Perez Kathryn , Spatzal Thomas , Einsle Oliver , Weber Stefan , Rees Douglas C. , Schleicher Erik
Published: May 2024

Due to the complexity of the catalytic FeMo cofactor site in nitrogenases that mediates the reduction of molecular nitrogen to ammonium, mechanistic details of this reaction remain under debate. In this study, selenium- and sulfur-incorporated FeMo cofactors of the catalytic MoFe protein component from Azotobacter vinelandii are prepared under turnover conditions and investigated by using different EPR methods. Complex signal patterns are observed in the continuous wave EPR spectra of selenium-incorporated samples, which are analyzed by Tikhonov regularization, a method that has not yet been applied to high spin systems of transition metal cofactors, and by an already established grid-of-error approach. Both methods yield similar probability distributions that reveal the presence of at least four other species with different electronic structures in addition to the ground state E0. Two of these species were preliminary assigned to hydrogenated E2 states. In addition, advanced pulsed-EPR experiments are utilized to verify the incorporation of sulfur and selenium into the FeMo cofactor, and to assign hyperfine couplings of 33S and 77Se that directly couple to the FeMo cluster. With this analysis, we report selenium incorporation under turnover conditions as a straightforward approach to stabilize and analyze early intermediate states of the FeMo cofactor.
Snail-inspired water-enhanced soft sliding suction for climbing robots
Authors: Yue Tianqi , Bloomfield-Gadêlha Hermes , Rossiter Jonathan
Published: May 2024

Snails can stably slide across a surface with only a single high-payload sucker, offering an efficient adhesive locomotion mechanism for next-generation climbing robots. The critical factor for snails’ sliding suction behaviour is mucus secretion, which reduces friction and enhances suction. Inspired by this, we proposed an artificial sliding suction mechanism. The sliding suction utilizes water as an artificial mucus, which is widely available and evaporates with no residue. The sliding suction allows a lightweight robot (96 g) to slide vertically and upside down, achieving high speeds (rotation of 53°/s and translation of 19 mm/s) and high payload (1 kg as tested and 5.03 kg in theory), and does not require energy during adhesion. Here, we show that the sliding suction is a low-cost, energy-efficient, high-payload and clean adhesive locomotion strategy, which has high potential for use in climbing robots, outdoor inspection robots and robotic transportation.
Tuning instability in suspended monolayer 2D materials
Authors: Hou Yuan , Zhou Jingzhuo , He Zezhou , Chen Juzheng , Zhu Mengya , Wu HengAn , Lu Yang
Published: May 2024

Monolayer two-dimensional (2D) materials possess excellent in-plane mechanical strength yet extremely low bending stiffness, making them particularly susceptible to instability, which is anticipated to have a substantial impact on their physical functionalities such as 2D-based Micro/Nanoelectromechanical systems (M/NEMS), nanochannels, and proton transport membrane. In this work, we achieve quantitatively tuning instability in suspended 2D materials including monolayer graphene and MoS2 by employing a push-to-shear strategy. We comprehensively examine the dynamic wrinkling-splitting-smoothing process and find that monolayer 2D materials experience stepwise instabilities along with different recovery processes. These stepwise instabilities are governed by the materials’ geometry, pretension, and the elastic nonlinearity. We attribute the different instability and recovery paths to the local stress redistribution in monolayer 2D materials. The tunable instability behavior of suspended monolayer 2D materials not only allows measuring their bending stiffness but also opens up new opportunities for programming the nanoscale instability pattern and even physical properties of atomically thin films.
Single-site iron-anchored amyloid hydrogels as catalytic platforms for alcohol detoxification
Authors: Su Jiaqi , Wang Pengjie , Zhou Wei , Peydayesh Mohammad , Zhou Jiangtao , Jin Tonghui , Donat Felix , Jin Cuiyuan , Xia Lu , Wang Kaiwen , Ren Fazheng , Van der Meeren Paul , García de Arquer F. Pelayo , Mezzenga Raffaele
Published: May 2024

Constructing effective antidotes to reduce global health impacts induced by alcohol prevalence is a challenging topic. Despite the positive effects observed with intravenous applications of natural enzyme complexes, their insufficient activities and complicated usage often result in the accumulation of toxic acetaldehyde, which raises important clinical concerns, highlighting the pressing need for stable oral strategies. Here we present an effective solution for alcohol detoxification by employing a biomimetic-nanozyme amyloid hydrogel as an orally administered catalytic platform. We exploit amyloid fibrils derived from β-lactoglobulin, a readily accessible milk protein that is rich in coordinable nitrogen atoms, as a nanocarrier to stabilize atomically dispersed iron (ferrous-dominated). By emulating the coordination structure of the horseradish peroxidase enzyme, the single-site iron nanozyme demonstrates the capability to selectively catalyse alcohol oxidation into acetic acid, as opposed to the more toxic acetaldehyde. Administering the gelatinous nanozyme to mice suffering from alcohol intoxication significantly reduced their blood-alcohol levels (decreased by 55.8% 300 min post-alcohol intake) without causing additional acetaldehyde build-up. Our hydrogel further demonstrates a protective effect on the liver, while simultaneously mitigating intestinal damage and dysbiosis associated with chronic alcohol consumption, introducing a promising strategy in effective alcohol detoxification.
Polarity-driven three-dimensional spontaneous rotation of a cell doublet
Authors: Lu Linjie , Guyomar Tristan , Vagne Quentin , Berthoz Rémi , Torres-Sánchez Alejandro , Lieb Michèle , Martin-Lemaitre Cecilie , van Unen Kobus , Honigmann Alf , Pertz Olivier , Riveline Daniel , Salbreux Guillaume
Published: May 2024

Mechanical interactions between cells play a fundamental role in the self-organization of organisms. How these interactions drive coordinated cell movement in three dimensions remains unclear. Here we report that cell doublets embedded in a three-dimensional extracellular matrix undergo spontaneous rotations. We investigate the rotation mechanism and find that it is driven by a polarized distribution of myosin within cell cortices. The mismatched orientation of this polarized distribution breaks the doublet mirror symmetry. In addition, cells adhere at their interface through adherens junctions and with the extracellular matrix through focal contacts near myosin clusters. We use a physical theory describing the doublet as two interacting active surfaces to show that rotation is driven by myosin-generated gradients of active tension whose profiles are dictated by interacting cell polarity axes. We also show that three-dimensional shape symmetries are related to broken symmetries of the myosin distribution in cortices. To test for the rotation mechanism, we suppress myosin clusters using laser ablation and generate new myosin clusters by optogenetics. Our work clarifies how polarity-oriented active mechanical forces drive collective cell motion in three dimensions.
Laser-driven high-energy proton beams from cascaded acceleration regimes
Authors: Ziegler Tim , Göthel Ilja , Assenbaum Stefan , Bernert Constantin , Brack Florian-Emanuel , Cowan Thomas E. , Dover Nicholas P. , Gaus Lennart , Kluge Thomas , Kraft Stephan , Kroll Florian , Metzkes-Ng Josefine , Nishiuchi Mamiko , Prencipe Irene , Püschel Thomas , Rehwald Martin , Reimold Marvin , Schlenvoigt Hans-Peter , Umlandt Marvin E. P. , Vescovi Milenko , Schramm Ulrich , Zeil Karl
Published: May 2024

Laser-driven ion accelerators can deliver high-energy, high-peak current beams and are thus attracting attention as a compact alternative to conventional accelerators. However, achieving sufficiently high energy levels suitable for applications such as radiation therapy remains a challenge for laser-driven ion accelerators. Here we generate proton beams with a spectrally separated high-energy component of up to 150 MeV by irradiating solid-density plastic foil targets with ultrashort laser pulses from a repetitive petawatt laser. The preceding laser light heats the target, leading to the onset of relativistically induced transparency upon main pulse arrival. The laser peak then penetrates the initially opaque target and triggers proton acceleration through a cascade of different mechanisms, as revealed by three-dimensional particle-in-cell simulations. The transparency of the target can be used to identify the high-performance domain, making it a suitable feedback parameter for automated laser and target optimization to enhance stability of plasma accelerators in the future.
Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes
Authors: Kim Minsoo , Gorelick Alexander N. , Vàzquez-García Ignacio , Williams Marc J. , Salehi Sohrab , Shi Hongyu , Weiner Adam C. , Ceglia Nick , Funnell Tyler , Park Tricia , Boscenco Sonia , O’Flanagan Ciara H. , Jiang Hui , Grewal Diljot , Tang Cerise , Rusk Nicole , Gammage Payam A. , McPherson Andrew , Aparicio Sam , Shah Sohrab P. , Reznik Ed
Published: May 2024

The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.
Investigating the growth promotion potential of biochar on pea (Pisum sativum) plants under saline conditions
Authors: Fareed Shahid , Haider Arslan , Ramzan Tahrim , Ahmad Muhammad , Younis Aqsa , Zulfiqar Usman , Rehman Hafeez ur , Waraich Ejaz Ahmad , Abbas Adeel , Chaudhary Talha , Soufan Walid
Published: May 2024

Pea, member of the plant family Leguminosae, play a pivotal role in global food security as essential legumes. However, their production faces challenges stemming from the detrimental impacts of abiotic stressors, leading to a concerning decline in output. Salinity stress is one of the major factors that limiting the growth and productivity of pea. However, biochar amendment in soil has a potential role in alleviating the oxidative damage caused by salinity stress. The purpose of the study was to evaluate the potential role of biochar amendment in soil that may mitigate the adverse effect of salinity stress on pea. The treatments of this study were, (a) Pea varieties; (i) V1 = Meteor and V2 = Green Grass, Salinity Stress, (b) Control (0 mM) and (ii) Salinity (80 mM) (c) Biochar applications; (i) Control, (ii) 8 g/kg soil (56 g) and (iii) 16 g/kg soil (112 g). Salinity stress demonstrated a considerable reduction in morphological parameters as Shoot and root length decreased by (29% and 47%), fresh weight and dry weight of shoot and root by (85, 63%) and (49, 68%), as well as area of leaf reduced by (71%) among both varieties. Photosynthetic pigments (chlorophyll a, b, and carotenoid contents decreased under 80 mM salinity up to (41, 63, 55 and 76%) in both varieties as compared to control. Exposure of pea plants to salinity stress increased the oxidative damage by enhancing hydrogen peroxide and malondialdehyde content by (79 and 89%), while amendment of biochar reduced their activities as, (56% and 59%) in both varieties. The activities of catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) were increased by biochar applications under salinity stress as, (49, 59, and 86%) as well as non-enzymatic antioxidants as, anthocyanin and flavonoids improved by (112 and 67%). Organic osmolytes such as total soluble proteins, sugars, and glycine betaine were increased up to (57, 83, and 140%) by biochar amendment. Among uptake of mineral ions, shoot and root Na+ uptake was greater (144 and 73%) in saline-stressed plants as compared to control, while shoot and root Ca2+ and K+ were greater up to (175, 119%) and (77, 146%) in biochar-treated plants. Overall findings revealed that 16 g/kg soil (112 g) biochar was found to be effective in reducing salinity toxicity by causing reduction in reactive oxygen species and root and shoot Na+ ions uptake and improving growth, physiological and anti-oxidative activities in pea plants (Fig. 1).
Statistical analysis on the incidence and predictors of death among second-line ART patients in public hospitals of North Wollo and Waghemira Zones, Ethiopia, 2021
Authors: Kidie Atitegeb Abera , Masresha Seteamlak Adane , Bizuneh Fassikaw Kebede
Published: May 2024

Acquired immune deficiency virus, caused by the human immunodeficiency virus, is a significant global health concern. Sub-Saharan Africa particularly Ethiopia faces a high prevalence of human immunodeficiency virus. In low-income settings like Ethiopia, early mortality rates are elevated due to severe opportunistic infections and advanced disease at Anti-retroviral treatment initiation. Despite available treatments, delayed treatment initiation among Human Immunodeficiency Virus -infected individuals in Africa, including Ethiopia, leads to disease progression and increased mortality risk. This study aimed to identify the factors contributing to the death of HIV patients under treatment at second line regimen in public hospitals of North Wollo and Waghemira Zones. A retrospective cohort study with 474 patients was conducted in selected hospitals of North Wollo and Waghemira Zones. A parametric Weibull regression model was employed, and the adjusted hazard ratio served as the measure of association. Variables significantly affected the outcome of the study was determined at a p-value < 0.05, along with a 95% confidence interval for the variables. The patients were within the average age of 38.6(standard deviation ± 12.5) years and majority (45.57%) had no formal education. The overall death incidence rate among second-line anti-retroviral treatment patients was 1.98 per 100-person years [95% CI 1.4—2.9%]. Poor adherence to antiretroviral treatment, male gender, and being underweight significantly increased the hazard of death. Conversely, increased anti-retroviral treatment duration had a significant and negative impact, reducing the hazard of death among patients. The study reveals a high incidence of death among second line anti-retroviral treatment users. Independent predictors include poor adherence, male gender, and underweight status, all significantly increasing the risk of death. On the positive side, the hazard of death decreases with longer anti-retroviral treatment duration. A critical concern and counseling should be given for better ART adherence, to change their nutritional status and for males.
Long-lasting negativity in the left motoric brain structures during word memory inhibition in the Think/No-Think paradigm
Authors: Vitkova Viktoriya , Ristori Dominique , Cheron Guy , Bazan Ariane , Cebolla Ana Maria
Published: May 2024

In this study, we investigated the electrical brain responses in a high-density EEG array (64 electrodes) elicited specifically by the word memory cue in the Think/No-Think paradigm in 46 participants. In a first step, we corroborated previous findings demonstrating sustained and reduced brain electrical frontal and parietal late potentials elicited by memory cues following the No-Think (NT) instructions as compared to the Think (T) instructions. The topographical analysis revealed that such reduction was significant 1000 ms after memory cue onset and that it was long-lasting for 1000 ms. In a second step, we estimated the underlying brain generators with a distributed method (swLORETA) which does not preconceive any localization in the gray matter. This method revealed that the cognitive process related to the inhibition of memory retrieval involved classical motoric cerebral structures with the left primary motor cortex (M1, BA4), thalamus, and premotor cortex (BA6). Also, the right frontal-polar cortex was involved in the T condition which we interpreted as an indication of its role in the maintaining of a cognitive set during remembering, by the selection of one cognitive mode of processing, Think, over the other, No-Think, across extended periods of time, as it might be necessary for the successful execution of the Think/No-Think task.
The value of linear and non-linear quantitative EEG analysis in paediatric epilepsy surgery: a machine learning approach
Authors: Mercier Mattia , Pepi Chiara , Carfi-Pavia Giusy , De Benedictis Alessandro , Espagnet Maria Camilla Rossi , Pirani Greta , Vigevano Federico , Marras Carlo Efisio , Specchio Nicola , De Palma Luca
Published: May 2024

Epilepsy surgery is effective for patients with medication-resistant seizures, however 20–40% of them are not seizure free after surgery. Aim of this study is to evaluate the role of linear and non-linear EEG features to predict post-surgical outcome. We included 123 paediatric patients who underwent epilepsy surgery at Bambino Gesù Children Hospital (January 2009–April 2020). All patients had long term video-EEG monitoring. We analysed 1-min scalp interictal EEG (wakefulness and sleep) and extracted 13 linear and non-linear EEG features (power spectral density (PSD), Hjorth, approximate entropy, permutation entropy, Lyapunov and Hurst value). We used a logistic regression (LR) as feature selection process. To quantify the correlation between EEG features and surgical outcome we used an artificial neural network (ANN) model with 18 architectures. LR revealed a significant correlation between PSD of alpha band (sleep), Mobility index (sleep) and the Hurst value (sleep and awake) with outcome. The fifty-four ANN models gave a range of accuracy (46–65%) in predicting outcome. Within the fifty-four ANN models, we found a higher accuracy (64.8% ± 7.6%) in seizure outcome prediction, using features selected by LR. The combination of PSD of alpha band, mobility and the Hurst value positively correlate with good surgical outcome.
The effect of diversity on disease reverses from dilution to amplification in a 22-year biodiversity × N × CO2 experiment
Authors: Strauss Alexander T. , Hobbie Sarah E. , Reich Peter B. , Seabloom Eric W. , Borer Elizabeth T.
Published: May 2024

Plant disease often increases with N, decreases with CO2, and increases as biodiversity is lost (i.e., the dilution effect). Additionally, all these factors can indirectly alter disease by changing host biomass and hence density-dependent disease transmission. Yet over long periods of time as communities undergo compositional changes, these biomass-mediated pathways might fade, intensify, or even reverse in direction. Using a field experiment that has manipulated N, CO2, and species richness for over 20 years, we compared severity of a specialist rust fungus (Puccinia andropogonis) on its grass host (Andropogon gerardii) shortly after the experiment began (1999) and twenty years later (2019). Between these two sampling periods, two decades apart, we found that disease severity consistently increased with N and decreased with CO2. However, the relationship between diversity and disease reversed from a dilution effect in 1999 (more severe disease in monocultures) to an amplification effect in 2019 (more severe disease in mixtures). The best explanation for this reversal centered on host density (i.e., aboveground biomass), which was initially highest in monoculture, but became highest in mixtures two decades later. Thus, the diversity-disease pattern reversed, but disease consistently increased with host biomass. These results highlight the consistency of N and CO2 as drivers of plant disease in the Anthropocene and emphasize the critical role of host biomass—despite potentially variable effects of diversity—for relationships between biodiversity and disease.
Different association of atherogenic index of plasma with the risk of high platelet reactivity according to the presentation of acute myocardial infarction
Authors: Won Ki-Bum , Kim Hyeon Jeong , Cho Jun Hwan , Lee Sang Yup , Her Ae-Young , Kim Byeong-Keuk , Joo Hyung Joon , Park Yongwhi , Chang Kiyuk , Song Young Bin , Ahn Sung Gyun , Suh Jung-Won , Cho Jung Rae , Kim Hyo-Soo , Kim Moo Hyun , Lim Do-Sun , Kim Sang-Wook , Jeong Young-Hoon , Shin Eun-Seok
Published: May 2024

This study evaluated the association of atherogenic index of plasma (AIP) with platelet reactivity and clinical outcomes according to acute myocardial infarction (AMI). The composite of 3-year adverse outcomes of all-cause death, myocardial infarction, and cerebrovascular accident was evaluated in 10,735 patients after successful percutaneous coronary intervention with drug-eluting stents. AIP was defined as the base 10 logarithm of the ratio of triglyceride to high-density lipoprotein cholesterol concentration. High platelet reactivity (HPR) was defined as ≥ 252 P2Y12 reactivity unit. An increase of AIP (per-0.1 unit) was related to the decreased risk of HPR [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.96–0.99; P = 0.001] in non-AMI patients, not in AMI patients (OR 0.98, 95% CI 0.96–1.01; P = 0.138). The HPR was associated with the increased risk of composite outcomes in both non-AMI and AMI patients (all-P < 0.05). AIP levels were not independently associated with the risk of composite outcomes in both patients with non-AMI and AMI. In conclusion, an inverse association between AIP and the risk of HPR was observed in patients with non-AMI. This suggests that the association between plasma atherogenicity and platelet reactivity may play a substantial role in the development of AMI.

Trial registration: NCT04734028.
Scaling of damage mechanism for additively manufactured alloys at very high cycle fatigue
Authors: Voloskov B. S. , Bannikov M. V. , Bayandin Y. V. , Naimark O. B. , Sergeichev I. V.
Published: May 2024

A comparative analysis of fracture mechanisms in high- and very high- cycle fatigue (HCF, VHCF) regimes was carried out based on the results of multifractal analysis of the fracture surfaces of additively manufactured 316L stainless steel samples. In terms of scale invariants, the morphology of fracture surfaces in HCF and VHCF regimes inside and outside the fine granular area is shown. The analysis demonstrated that chaotic patterns of relief formation prevail in the crack initiation zone of VHCF samples. However, there is a self-similar relief with a pronounced correlation in the crack propagation area. The relief of the crack growth areas for HCF and VHCF samples are similar to each other.
An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin
Authors: Piersanti Agnese , Pacini Giovanni , Tura Andrea , D’Argenio David Z. , Morettini Micaela
Published: May 2024

The aim of this study was to develop a dynamic model-based approach to separately quantify the exogenous and endogenous contributions to total plasma insulin concentration and to apply it to assess the effects of inhaled-insulin administration on endogenous insulin secretion during a meal test. A three-step dynamic in-silico modeling approach was developed to estimate the two insulin contributions of total plasma insulin in a group of 21 healthy subjects who underwent two equivalent standardized meal tests on separate days, one of which preceded by inhalation of a Technosphere® Insulin dose (22U or 20U). In the 30–120 min test interval, the calculated endogenous insulin component showed a divergence in the time course between the test with and without inhaled insulin. Moreover, the supra-basal area-under-the-curve of endogenous insulin in the test with inhaled insulin was significantly lower than that in the test without (2.1 ± 1.7 × 104 pmol·min/L vs 4.2 ± 1.8 × 104 pmol·min/L, p < 0.01). The percentage of exogenous insulin reaching the plasma, relative to the inhaled dose, was 42 ± 21%. The proposed in-silico approach separates exogenous and endogenous insulin contributions to total plasma insulin, provides individual bioavailability estimates, and can be used to assess the effect of inhaled insulin on endogenous insulin secretion during a meal.
Cell type specific long non-coding RNA targets identified by integrative analysis of single-cell and bulk colorectal cancer transcriptomes
Authors: Mihaljevic Ante , Rubin Philip D. , Chouvardas Panagiotis , Esposito Roberta
Published: May 2024

Long non-coding RNAs (lncRNAs) represent an emerging class of genes which play significant and diverse roles in human cancers. Nevertheless, the functional repertoires of lncRNAs in cancer cell subtypes remains unknown since most studies are focused on protein coding genes. Here, we explored the contribution of lncRNAs in Colorectal Cancer (CRC) heterogeneity. We analyzed 49′436 single-cells from 29 CRC patients and showed that lncRNAs are significantly more cell type specific compared to protein-coding genes. We identified 996 lncRNAs strongly enriched in epithelial cells. Among these, 98 were found to be differentially expressed in tumor samples compared to normal controls, when integrating 270 bulk CRC profiles. We validated the upregulation of two of them (CASC19 and LINC00460) in CRC cell lines and showed their involvement in CRC proliferation by CRISPR-Cas9 knock down experiments. This study highlights a list of novel RNA targets for potential CRC therapeutics, substantiated through experimental validation.
Association between serum vitamin A and body mass index in adolescents from NHANES 1999 to 2006
Authors: Su Xiaoqi , Patel Nishant , Zhu Shanliang , Zhou Xin , Chen Ye , Chen Jun , Mo Xuming
Published: May 2024

Vitamin A plays a pivotal role in health, particularly in regulating fat metabolism. Despite its significance, research into the direct relationship between vitamin A levels and obesity, especially among adolescents, is sparse. This study aims to explore this association within the adolescent population in the United States. This cross-sectional study analyzed the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2006, with 8218 participants. The levels of vitamin A in the serum were determined based on utilizing high-performance liquid chromatography with photodiode array detection. The relationship between serum vitamin A concentrations and body mass index (BMI) was evaluated using weighted multiple linear regression models, incorporating subgroup analyses by sex and race/ethnicity to provide nuanced insights. A positive correlation was observed between serum vitamin A levels and BMI, with BMI increasing progressively across vitamin A quartiles (P < 0.001). Using the lowest quartile of serum vitamin A as a reference, the BMI of the highest quartile of serum vitamin A was 1.236 times higher (95% CI 0.888, 1.585). Subgroup analyses revealed that this positive association persisted across different genders and racial/ethnic groups (P < 0.001). Notably, smooth curve fitting and saturation threshold analysis unveiled an inverted U-shaped relationship between serum vitamin A and BMI among female adolescents, non-Hispanic Whites, Mexican Americans, and other races/ethnicities groups. Our study substantiates the association between serum vitamin A levels and the risk of obesity/overweight status in adolescents. The findings suggest the potential serum vitamin A is an early biomarker for identifying obesity risk, although further studies are needed to determine to clarify its role as a contributing factor to obesity. This study contributes to the understanding of nutritional influences on adolescent obesity, highlighting the need for targeted interventions based on serum biomarkers.
Multiple paths to rumination within a network analytical framework
Authors: Tamm Gerly , Koster Ernst H. W. , Hoorelbeke Kristof
Published: May 2024

Theories of rumination have proposed different psychological factors to place one at risk for repetitive negative thinking. A comprehensive empirical test that captures the most relevant contributors to rumination is lacking. Building on influential self-regulatory and metacognitive frameworks, we modeled how key constructs in this context relate to ruminative thinking. 498 participants completed online questionnaires including indicators of rumination, metacognition, promotion goal orientation, effortful control, and depression. We estimated regularized partial correlation networks to investigate unique associations between the different constructs and followed these analyses up with directed acyclic graphs to identify potential pathways towards rumination. Results demonstrated that: (1) both self-regulatory and metacognitive factors were directly linked to rumination, amongst these were (2) positive beliefs, negative beliefs about uncontrollability and harm, cognitive self-consciousness, depression, effortful control, perfectionism, and (lack of) cognitive confidence, and (3) we identified multiple directed pathways, suggesting three direct contributors to rumination while controlling for the influence of all other variables: diminished effortful control, positive beliefs, and cognitive self-consciousness. This study is the first to comprehensively assess metacognitive and self-regulatory frameworks of rumination in a data-driven manner. Our findings suggest that there are multiple pathways towards rumination, which should be incorporated in clinical case conceptualization of rumination and related disorders.
RNA-Seq transcriptome profiling of immature grain wheat is a technique for understanding comparative modeling of baking quality
Authors: Ahmadi-Ochtapeh Hossein , Soltanloo Hassan , Ramezanpour Seyyede Sanaz , Yamchi Ahad , Shariati Vahid
Published: May 2024

Improving the baking quality is a primary challenge in the wheat flour production value chain, as baking quality represents a crucial factor in determining its overall value. In the present study, we conducted a comparative RNA-Seq analysis on the high baking quality mutant “O-64.1.10” genotype and its low baking quality wild type "Omid" cultivar to recognize potential genes associated with bread quality. The cDNA libraries were constructed from immature grains that were 15 days post-anthesis, with an average of 16.24 and 18.97 million paired-end short-read sequences in the mutant and wild-type, respectively. A total number of 733 transcripts with differential expression were identified, 585 genes up-regulated and 188 genes down-regulated in the “O-64.1.10” genotype compared to the “Omid”. In addition, the families of HSF, bZIP, C2C2-Dof, B3-ARF, BES1, C3H, GRF, HB-HD-ZIP, PLATZ, MADS-MIKC, GARP-G2-like, NAC, OFP and TUB were appeared as the key transcription factors with specific expression in the “O-64.1.10” genotype. At the same time, pathways related to baking quality were identified through Kyoto Encyclopedia of Genes and Genomes. Collectively, we found that the endoplasmic network, metabolic pathways, secondary metabolite biosynthesis, hormone signaling pathway, B group vitamins, protein pathways, pathways associated with carbohydrate and fat metabolism, as well as the biosynthesis and metabolism of various amino acids, have a great deal of potential to play a significant role in the baking quality. Ultimately, the RNA-seq results were confirmed using quantitative Reverse Transcription PCR for some hub genes such as alpha-gliadin, low molecular weight glutenin subunit and terpene synthase (gibberellin) and as a resource for future study, 127 EST-SSR primers were generated using RNA-seq data.
Dynamic changes in extracellular vesicle-associated miRNAs elicited by ultrasound in inflammatory bowel disease patients
Authors: Tran Florian , Scharmacher Alena , Baran Nathan , Mishra Neha , Wozny Marek , Chavez Samuel Pineda , Bhardwaj Archana , Hinz Sophia , Juzenas Simonas , Bernardes Joana P. , Sievers Laura Katharina , Lessing Matthias , Aden Konrad , Lassen Arne , Bergfeld Arne , Weber Hauke Jann , Neas Lennart , Vetrano Stefania , Schreiber Stefan , Rosenstiel Philip
Published: May 2024

Blood-based biomarkers that reliably indicate disease activity in the intestinal tract are an important unmet need in the management of patients with IBD. Extracellular vesicles (EVs) are cell-derived membranous microparticles, which reflect the cellular and functional state of their site of site of origin. As ultrasound waves may lead to molecular shifts of EV contents, we hypothesized that application of ultrasound waves on inflamed intestinal tissue in IBD may amplify the inflammation-specific molecular shifts in EVs like altered EV-miRNA expression, which in turn can be detected in the peripheral blood. 26 patients with IBD were included in the prospective clinical study. Serum samples were collected before and 30 min after diagnostic transabdominal ultrasound. Differential miRNA expression was analyzed by sequencing. Candidate inducible EV-miRNAs were functionally assessed in vitro by transfection of miRNA mimics and qPCR of predicted target genes. Serum EV-miRNA concentration at baseline correlated with disease severity, as determined by clinical activity scores and sonographic findings. Three miRNAs (miR-942-5p, mir-5588, mir-3195) were significantly induced by sonography. Among the significantly regulated EV-miRNAs, miR-942-5p was strongly induced in higher grade intestinal inflammation and correlated with clinical activity in Crohn’s disease. Prediction of target regulation and transfection of miRNA mimics inferred a role of this EV-miRNA in regulating barrier function in inflammation. Induction of mir-5588 and mir-3195 did not correlate with inflammation grade. This proof-of-concept trial highlights the principle of induced molecular shifts in EVs from inflamed tissue through transabdominal ultrasound. These inducible EVs and their molecular cargo like miRNA could become novel biomarkers for intestinal inflammation in IBD.
Exploring the geometry of the bifurcation sets in parameter space
Authors: Barrio Roberto , Ibáñez Santiago , Pérez Lucía
Published: May 2024

By studying a nonlinear model by inspecting a p-dimensional parameter space through $$(p-1)$$

(
p
-
1
)

-dimensional cuts, one can detect changes that are only determined by the geometry of the manifolds that make up the bifurcation set. We refer to these changes as geometric bifurcations. They can be understood within the framework of the theory of singularities for differentiable mappings and, in particular, of the Morse Theory. Working with a three-dimensional parameter space, geometric bifurcations are illustrated in two models of neuron activity: the Hindmarsh–Rose and the FitzHugh–Nagumo systems. Both are fast-slow systems with a small parameter that controls the time scale of a slow variable. Geometric bifurcations are observed on slices corresponding to fixed values of this distinguished small parameter, but they should be of interest to anyone studying bifurcation diagrams in the context of nonlinear phenomena.
Mortality among extrapulmonary tuberculosis patients in the HIV endemic setting: lessons from a tertiary level hospital in Mbeya, Tanzania
Authors: Grønningen Erlend , Nanyaro Marywinnie , Blomberg Bjørn , Hassan Shoaib , Ngadaya Esther , Mustafa Tehmina
Published: May 2024

Extrapulmonary tuberculosis (EPTB) has received less attention than pulmonary tuberculosis due to its non-contagious nature. EPTB can affect any organ and is more prevalent in people living with HIV. Low- and middle-income countries are now facing the double burden of non-communicable diseases (NCDs) and HIV, complicating the management of patients with symptoms that could be compatible with both EPTB and NCDs. Little is known about the risk of death of patients presenting with symptoms compatible with EPTB. We included patients with a clinical suspicion of EPTB from a tertiary level hospital in Mbeya, Tanzania, to assess their risk of dying. A total of 113 (61%) patients were classified as having EPTB, and 72 (39%) as having non-TB, with corresponding mortality rates of 40% and 41%. Associated factors for mortality in the TB groups was hospitalization and male sex. Risk factors for hospitalization was having disease manifestation at any site other than lymph nodes, and comorbidities. Our results imply that NCDs serve as significant comorbidities amplifying the mortality risk in EPTB. To strive towards universal health coverage, focus should be on building robust health systems that can tackle both infectious diseases, such as EPTB, and NCDs.
Integrated single-cell and bulk RNA-Seq analysis enhances prognostic accuracy of PD-1/PD-L1 immunotherapy response in lung adenocarcinoma through necroptotic anoikis gene signatures
Authors: Sui Ping , Liu Xueping , Zhong Cheng , Sha Zhanming
Published: May 2024

In addition to presenting significant diagnostic and treatment challenges, lung adenocarcinoma (LUAD) is the most common form of lung cancer. Using scRNA-Seq and bulk RNA-Seq data, we identify three genes referred to as HMR, FAM83A, and KRT6A these genes are related to necroptotic anoikis-related gene expression. Initial validation, conducted on the GSE50081 dataset, demonstrated the model's ability to categorize LUAD patients into high-risk and low-risk groups with significant survival differences. This model was further applied to predict responses to PD-1/PD-L1 blockade therapies, utilizing the IMvigor210 and GSE78220 cohorts, and showed strong correlation with patient outcomes, highlighting its potential in personalized immunotherapy. Further, LUAD cell lines were analyzed using quantitative PCR (qPCR) and Western blot analysis to confirm their expression levels, further corroborating the model's relevance in LUAD pathophysiology. The mutation landscape of these genes was also explored, revealing their broad implication in various cancer types through a pan-cancer analysis. The study also delved into molecular subclustering, revealing distinct expression profiles and associations with different survival outcomes, emphasizing the model’s utility in precision oncology. Moreover, the diversity of immune cell infiltration, analyzed in relation to the necroptotic anoikis signature, suggested significant implications for immune evasion mechanisms in LUAD. While the findings present a promising stride towards personalized LUAD treatment, especially in immunotherapy, limitations such as the retrospective nature of the datasets and the need for larger sample sizes are acknowledged. Prospective clinical trials and further experimental research are essential to validate these findings and enhance the clinical applicability of our prognostic model.
SNPs in microRNA seed region and impact of miR-375 in concurrent regulation of multiple lipid accumulation-related genes
Authors: Lee Jiyeon , Hong Inpyo , Lee Chanwoo , Kim Daehyun , Kim Sunghak , Lee Yoonseok
Published: May 2024

Bovine intramuscular fat (IMF), commonly referred to as marbling, is regulated by lipid metabolism, which includes adipogenesis, lipogenesis, glycerolipid synthesis, and lipolysis. In recent years, breeding researchers have identified single nucleotide polymorphisms (SNPs) as useful marker-assisted selection tools for improving marbling scores in national breeding programs. These included causal SNPs that induce phenotypic variation. MicroRNAs (miRNAs) are small highly conserved non-coding RNA molecules that bind to multiple non-coding regions. They are involved in post-transcriptional regulation. Multiple miRNAs may regulate a given target. Previously, three SNPs in the GPAM 3ʹ UTR and four miRNAs were identified through in silico assays. The aim of this study is to verify the binding ability of the four miRNAs to the SNPs within the 3ʹUTR of GPAM, and to identify the regulatory function of miR-375 in the expression of genes related to lipid metabolism in mammalian adipocytes. It was verified that the four miRNAs bind to the GPAM 3ʹUTR, and identified that the miR-375 sequence is highly conserved. Furthermore, it was founded that miR-375 upregulated the GPAM gene, C/EBPα, PPARγ and lipid metabolism-related genes and promoted lipid droplet accumulation in 3T3-L1 cells. In conclusion, these results suggest that miR-375 is a multifunctional regulator of multiple lipid metabolism-related genes and may aid in obesity research as a biomarker.