bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Subtypes of Apert Syndrome Are Associated With Differences in Airway Morphology and Early Upper Airway Obstruction
Authors: Wagner Connor S. , Wietlisbach Larissa E. , Kota Anchith , Villavisanis Dillan F. , Pontell Matthew E. , Barrero Carlos E. , Salinero Lauren K. , Swanson Jordan W. , Taylor Jesse A. , Bartlett Scott P. 
Published: August 2023

Background:
Apert syndrome is predominantly caused by 2 paternally inherited gain-of-function mutations in the FGFR2 gene, Pro253Arg, and Ser252Trp. Studies comparing phenotypic features between these 2 mutations have established differences in syndactyly severity and incidence of cleft palate. Obstructive sleep apnea can be debilitating in a subset of patients with Apert syndrome, yet is not well understood. This study aims to determine whether FGFR2 mutations impart differential effects on airway physiology and morphology.

Methods:
Patients with Apert syndrome and confirmatory molecular testing were reviewed for polysomnography, nasal endoscopy, microlaryngoscopy and bronchoscopy, and computed tomography imaging. Obstructive apnea-hypopnea index and oxygen saturation nadir, nasal airway volumes, choanal cross-sectional area, and midfacial cephalometric dimensions were compared across mutation types.

Results:
Twenty-four patients (13 Ser252Trp, 11 Pro253Arg) were included. Severe obstructive sleep apnea (obstructive apnea-hypopnea index>10) occurred in 8 (62%) patients with Ser252Trp mutations compared with 1 (9%) patient with Pro253Arg mutations (P=0.009). Computed tomography imaging at 1 year of age demonstrated that nasopharyngeal airway volumes were 5302±1076 mm3 in the Ser252Trp group and 6832±1414 mm3 in the Pro253Arg group (P=0.041). Maxillary length (anterior nasal spine-posterior nasal spine, P=0.026) and basion-anterior nasal spine (P=0.007) were shorter in patients with Ser252Trp mutations.

Conclusions:
The findings suggest that the Ser252Trp mutation in Apert syndrome is associated with higher severity obstructive sleep apnea and decreased nasopharyngeal airway volume. Heightened clinical awareness of these associations may inform treatment planning and family counseling.
Outcomes of Apert Syndrome Hand Reconstruction With Tilapia Skin: A prospective study
Authors: Monte Thais Miguel , Lima Júnior Edmar Maciel , de Moraes Filho Manoel Odorico , Koscky Paier Carlos Roberto , Rocha Rodrigues Felipe Augusto , Nunes Alves Ana Paula Negreiros , Mathor Mônica Beatriz , Raposo-Amaral Cassio Eduardo 
Published: August 2023

Background:
Tilapia skin has already been used in various medical scenarios, but there are no studies showing the use of tilapia skin for hand reconstruction in Apert syndrome. The objective of this study is to determine whether the use of tilapia skin during graft bed preparation for children with Apert syndrome can shorten wound reepithelialization intervals, reduce the number of dressing changes, and decrease patient discomfort.

Methods:
This is a prospective study on consecutive patients with Apert syndrome who underwent hand reconstruction at our Hospital. Patients were divided into 2 groups: (1) a control group consisting of patients who underwent conventional digit separation hand reconstruction surgery (2) an experimental group consisting of patients who underwent similar digit separation hand reconstruction surgery that commenced with the placement of a thin layer of tilapia skin at the raw commissures during a first operation, which was subsequently replaced by an autologous skin graft during a second operation staged 10 days postoperatively. Pain assessment was performed using the Visual Analog Scale. The number of dressing changes was also assessed. A T test compared the total number of dressings changes and pain data.

Results:
Experimental group patients (n = 8) required an average of 9.4 days of daily dressing changes, and control group patients (n = 5) required an average of 20.8 days of daily dressing changes (P < 0.05) and tended to experience significantly less pain when compared with patients in the control group (P = 0.079).

Conclusion:
Tilapia skin can shorten wound reepithelialization intervals by reducing the total number of dressing changes.
LOX-1 and MMP-9 inhibition attenuates the detrimental effects of delayed rt-PA therapy and improves outcomes after acute ischemic stroke
Authors: Arkelius Kajsa , Wendt Trevor S , Andersson Henrik , Arnou Anaële , Gottschalk Michael , Gonzales Rayna J , Ansar Saema 
Published: August 2023

AbstractBackgroundAcute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. Recombinant-tissue plasminogen activator (rt-PA) is an effective treatment; however, its use is limited due to a restricted time window and high risk for hemorrhagic transformation, which in part may involve activation of metalloproteinases (MMPs) mediated through lectin-like oxidized LDL receptor 1 (LOX-1). This study’s overall aim was to evaluate the therapeutic potential of novel MMP-9 and LOX-1 inhibitors in combination with rt-PA to improve stroke outcomes.MethodsThromboembolic rat stroke model was utilized to investigate the impact of rt-PA delivered 4h post-stroke onset as well as selective LOX-1 (BI-0115) and/or MMP-9 (JNJ0966) inhibitors given prior to rt-PA administration. Infarct size, perfusion, and hemorrhagic transformation were evaluated by MRI. Neurological function was assessed using sensorimotor functioning testing. Using anin vitro, human brain microvascular endothelial cell (HBMEC) model, cells were exposed to hypoxia plus glucose deprivation (3h)/reperfusion (12h) (HGD/R) and treated with rt-PA ± an MMP-9 and LOX-1 inhibition cocktail. MMP-9 activity was determined with zymography, and endothelial barrier marker gene expression and LOX-1 levels were evaluated via qRT-PCR and western blot respectively.ResultsRt-PA treatment increased edema, hemorrhage, and worsened neurological outcomes post stroke. LOX-1 inhibition significantly improved neurological function and reduced edema after delayed rt-PA treatment. Hemorrhagic transformation, edema, and increased MMP-9 activity were attenuated by the MMP-9 inhibitor. Stroke induced increases in cerebrovascular LOX-1 expression correlated with increased MMP-9 activity and elevated activity correlated with increased edema, infarct volume, and decreased neurological function. In cultured HBMECs, LOX-1/MMP-9 inhibition differentially attenuated rt-PA-mediated increases in endothelial derived MMP-9 levels and activity, inflammation, and activation following HGD/R.ConclusionHere, we conclude that MMP-9/LOX-1 inhibition attenuates negative aspects of delayed rt-PA therapy leading to improved neurological function.
Parental effects provide an opportunity for coral resilience following major bleaching events
Authors: Lenz Elizabeth A. , Donahue Megan J. , Gates Ruth D. , Putnam Hollie M. , van der Steeg Eveline , Padilla-Gamiño Jacqueline L. 
Published: August 2023

ABSTRACTIdentifying processes that promote coral reef recovery and resilience is crucial as ocean warming becomes more frequent and severe. Sexual reproduction is essential for the replenishment of coral populations and maintenance of genetic diversity; however, the ability for corals to reproduce may be impaired by marine heatwaves that cause coral bleaching. In 2014 and 2015, the Hawaiian Islands experienced coral bleaching with differential bleaching susceptibility in the speciesMontipora capitata, a dominant reef-building coral in the region. We tested the hypothesis that coral bleaching resistance enhances reproductive capacity and offspring performance by examining the reproductive biology of colonies that bleached and recovered (B) and colonies that did not bleach (NB) in 2015 in the subsequent spawning seasons. The proportion of colonies that spawned was higher in 2016 than in 2017. Regardless of parental bleaching history, we found eggs with higher abnormality and bundles with fewer eggs in 2016 than 2017. While reproductive output was similar between B and NB colonies in 2016, survivorship of offspring that year were significantly influenced by the parental bleaching history (egg donor × sperm donor: B × B, B × NB, NB × B, and NB × NB). Offspring produced by NB egg donors had the highest survivorship, while offspring from previously bleached colonies had the lowest survivorship, highlighting the negative effects of bleaching on parental investment and offspring performance. While sexual reproduction continues inM. capitatapost-bleaching, gametes are differentially impacted by recovery time following a bleaching event and by parental bleaching resistance. Our results demonstrate the importance of identifying bleaching resistant individuals during and after heating events. This study further highlights the significance of maternal effects through potential egg provisioning for offspring survivorship and provides a baseline for human-assisted intervention (i.e., selective breeding) to mitigate the effects of climate change on coral reefs.
Identification of inter- and intra-tumoral molecular phenotypes steering temozolomide resistance in patient-derived glioblastoma cells
Authors: Fabro Federica , Kers Trisha V. , Feller Kate J. , Beerens Cecile , Ntafoulis Ioannis , Idbaih Ahmed , Verreault Maite , Connor Kate , Biswas Archita , Salvucci Manuela , Prehn Jochen H.M. , Byrne Annette T. , O’Farrell Alice C. , Lambrechts Diether , Dilcan Gonca , Lodi Francesca , Arijs Ingrid , Kremer Andreas , Tching Chi Yen Romain , Chien Miao-Ping , Lamfers Martine L. M. , Leenstra Sieger 
Published: August 2023

AbstractBackgroundRadiation therapy and chemotherapy using Temozolomide are the standard adjuvant treatments for patients with glioblastoma. Despite maximal treatment prognosis is still poor largely due to the emergence of Temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. This study aims to investigate the diverse molecular mechanisms involved in temozolomide resistance.MethodsTo induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells’ molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell sequencing on four of the cell cultures to track the evolution of temozolomide resistance.ResultsThe induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as “adaptive” (ADA) or “non-adaptive” (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable.ConclusionsThe adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor’s ability to survive. Depending on the tumor’s adaptability potential, subpopulations with acquired resistance mechanisms may arise. Further research is necessary to deepen our understanding of these mechanisms and develop strategies to overcome them.
Effects of nicotine compared to placebo gum on sensitivity to pain and mediating effects of peak alpha frequency
Authors: Millard Samantha K. , Chiang Alan K. I. , Humburg Peter , Chowdhury Nahian , Rehan Raafay , Furman Andrew J. , Mazaheri Ali , Schabrun Siobhan M. , Seminowicz David A. 
Published: August 2023

AbstractRecent research has linked individual peak alpha frequency (PAF) to pain sensitivity, but whether PAF alterations can influence pain remains unclear. Our study investigated the effects of nicotine on pain sensitivity and whether pain changes are mediated by PAF changes. In a randomised, double-blind, placebo-controlled experiment, 62 healthy adults (18–44 years) received either 4 mg nicotine gum (n=29) or placebo (n=33). Resting state EEG and pain ratings during prolonged heat and pressure models were collected before and after nicotine intake. The nicotine group had a decrease in heat pain ratings compared to the placebo group and increased PAF speed across the scalp from pre to post-gum, driven by changes at central-parietal and right-frontal regions. However, mediation analysis did not support the notion that PAF changes mediate nicotine’s effects on pain sensitivity. While a growing body of literature supports a link between PAF and both acute and chronic pain, further work is needed to understand the mechanisms of this link.
Myelin ensheathment and drug response of oligodendrocytes are modulated by stiffness of artificial axons
Authors: Yang Mingyu , Martin Calliope J.L. , Kowsari Kavin , Jagielska Anna , Van Vliet Krystyn J. 
Published: August 2023

AbstractMyelination is a key biological process wherein glial cells such as oligodendrocytes wrap myelin around neuronal axons, forming an insulative sheath that accelerates signal propagation down the axon. A major obstacle to understanding myelination is the challenge of visualizing and reproducibly quantifying this inherently three-dimensional processin vitro. To this end, we previously developed Artificial Axons (AAs), a biocompatible platform consisting of 3D-printed hydrogel-based axon mimics designed to more closely recapitulate the micrometer-scale diameter and sub-kilopascal mechanical stiffness of biological axons. First, we present our platform for fabricating AAs with tunable axon diameter, stiffness, and inter-axonal spacing. Second, we demonstrate that increasing the Young’s modulusEor stiffness of polymer comprising the AAs increases the extent of myelin ensheathment by rat oligodendrocytes. Third, we demonstrate that the responses of oligodendrocytes to pro-myelinating compounds are also dependent on axon stiffness, which can affect compounds efficacy and the relative ranking. These results reinforce the importance of studying myelination in mechanically representative environments, and highlight the importance of considering biophysical cues when conducting drug screening studies.
17-Oxime ethers of oxidized ecdysteroid derivatives modulate oxidative stress in human brain endothelial cells and dose-dependently might protect or damage the blood-brain barrier
Authors: Vágvölgyi Máté , Laczkó Dávid , Santa-Maria Ana Raquel , Walter Fruzsina R. , Berkecz Róbert , Deli Mária , Tóth Gábor , Hunyadi Attila 
Published: August 2023

Abstract20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including ans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechainmodified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative2and fully characterized by comprehensive NMR techniques revealing their complete1H and13C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells totert-butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound8, containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect in a higher, 10 μM dose, while at lower (10 μM – 1 μM) doses it promoted tBHP-induced cellular damage. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role.
Unveiling the Role of Endoplasmic Reticulum Stress Pathways in Canine Demodicosis
Authors: Kelly Pamela A , McHugo Gillian P. , Scaife Caitriona , Peters Susan , Lynn Stevenson M. , McKay Jennifer S , MacHugh David E. , Saez Irene Lara , Breathnach Rory 
Published: August 2023

AbstractCanine demodicosis is a prevalent skin disease caused by overpopulation of a commensal species ofDemodexmite, yet its precise cause remains unknown. Research suggests that T cell exhaustion, increased immunosuppressive cytokines, induction of regulatory T cells, and increased expression of immune checkpoint inhibitors may contribute to its pathogenesis. This study aimed to gain a deeper understanding of the molecular changes occurring in canine demodicosis using mass spectrometry and pathway enrichment analysis. The results indicate that endoplasmic reticulum stress is promoting canine demodicosis through regulation of three linked signalling pathways: eIF2, mTOR, and eIF4 and p70S6K. These pathways are involved in the modulation of Toll-like receptors, most notably TLR2, and have been shown to play a role in the pathogenesis of skin diseases in both dogs and humans. Moreover, these pathways are also implicated in the promotion of immunosuppressive M2 phenotype macrophages. Immunohistochemical analysis, utilizing common markers of dendritic cells and macrophages, verified the presence of M2 macrophages in canine demodicosis. The proteomic analysis also identified immunological disease, organismal injury and abnormalities, and inflammatory response as the most significant underlying diseases and disorders associated with canine demodicosis. This study demonstrates thatDemodexmites, through ER stress, unfolded protein response and M2 macrophages contribute to an immunosuppressive microenvironment thereby assisting in their proliferation.
Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies
Authors: Hong Lisa , Braden Dennis C. , Zhao Yaoning , Skoko John J. , Chang Fei , Woodcock Steven R. , Uvalle Crystall , Casey Allison , Wood Katherine , Salvatore Sonia R. , Asan Alparslan , Harkness Trey , Fagunloye Adeola , Razzaghi Mortezaali , Straub Adam , Spies Maria , Brown Daniel D. , Lee Adrian V. , Schopfer Francisco , Freeman Bruce A. , Neumann Carola A 
Published: August 2023

ABSTRACTNitro fatty acids (NO2-FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO2-FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB). CP-6 specifically targets Cys319, essential in RAD51-controlled HR-mediated DNA DSB repair in cells. A nitroalkene library screen identified two structurally different nitroalkenes, a non-natural fatty acid [(E) 8-nitro- nonadec-7-enoic acid (CP-8)] and a dicarboxylate ester [dimethyl (E)nitro-oct-4-enedioate (CP- 23)] superior to CP-6 in TNBC cells killing, synergism with three different inhibitors of the poly ADP-ribose polymerase (PARP) and γ-IR. CP-8 and CP-23 effectively inhibited γ-IR-induced RAD51 foci formation and HR in a GFP-reported assay but did not affect benign human epithelial cells or cell cycle phases. In vivo, CP-8 and CP-23’s efficacies diverged as only CP-8 showed promising anticancer activities alone and combined with the PARP inhibitor talazoparib in an HR-proficient TNBC mouse model. As preliminary preclinical toxicology analysis also suggests CP-8 as safe, our data endorse CP-8 as a novel anticancer molecule for treating cancers sensitive to homologous recombination-mediated DNA repair inhibitors.Graphical Abstract
An Adaptive H-Refinement Method for the Boundary Element Fast Multipole Method for Quasi-static Electromagnetic Modeling
Authors: Wartman William A , Weise Konstantin , Rachh Manas , Morales Leah , Deng Zhi-De , Nummenmaa Aapo , Makaroff Sergey N 
Published: August 2023

AbstractObjectiveIn our recent work pertinent to modeling of brain stimulation and neurophysiological recordings, substantial modeling errors in the computed electric field and potential have sometimes been observed for standard multi-compartment head models. The goal of this study is to quantify those errors and, further, eliminate them through an adaptive mesh refinement (AMR) algorithm. The study concentrates on transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), and electroencephalography (EEG) forward problems.ApproachWe propose, describe, and systematically investigate an AMR method using the Boundary Element Method with Fast Multipole Acceleration (BEM-FMM) as the base numerical solver. The goal is to efficiently allocate additional unknowns to critical areas of the model, where they will best improve solution accuracy.The implemented AMR method’s accuracy improvement is measured on head models constructed from 16 Human Connectome Project subjects under problem classes of TES, TMS, and EEG. Errors are computed between three solutions: an initial non-adaptive solution, a solution found after applying AMR with a conservative refinement rate, and a “silver-standard” solution found by subsequent 4:1 global refinement of the adaptively-refined model.Main ResultsExcellent agreement is shown between the adaptively-refined and silver-standard solutions for standard head models. AMR is found to be vital for accurate modeling of TES and EEG forward problems for standard models: an increase of less than 25% (on average) in number of mesh elements for these problems, efficiently allocated by AMR, exposes electric field/potential errors exceeding 60% (on average) in the solution for the unrefined models.SignificanceThis error has especially important implications for TES dosing prediction – where the stimula t ion strength plays a central role – and for EEG lead fields. Though the specific form of the AMR method described here is implemented for the BEM-FMM, we expect that AMR is applicable and even required for accurate electromagnetic simulations by other numerical modeling packages as well.
A simplified and rapid in situ hybridization protocol for planarians
Authors: Gaetano Andrew J. , King Ryan S. 
Published: August 2023

AbstractWhole mount in situ hybridization is a critical technique for analyzing gene expression in planarians. While robust in situ protocols have been developed, these protocols are laborious, making them challenging to incorporate in an academic setting, reducing throughput, and increasing time to results. We systematically tested modifications to all phases of the protocol with the goal of eliminating steps and reducing time without impacting quality. Our modified protocol allows for whole mount colorimetric in situ hybridization and multicolor fluorescence in situ hybridization to be completed in two days with a significant reduction in steps and hands on processing time.Method summaryA planarian in situ hybridization protocol was optimized for time and simplicity. Modifications to the fixation, bleaching, and blocking solutions were tested to identify conditions that reduced time and number of steps without impacting staining quality.