bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipose tissue protein kinase D (PKD): regulation of signalling networks and its sex-dependent effects on metabolism
Authors: Renton Mark C. , Humphrey Sean J. , Connor Tim , Martin Sheree D. , Kremerer Krystal , Fernando Hilary , Shaw Christopher S. , James David E. , Howlett Kirsten F. , McGee Sean L. 
Published: August 2024

ABSTRACTThe protein kinase D (PKD) family of three highly homologous isoforms (PKD1, PKD2, and PKD3) are implicated as nutrient sensing signalling kinases that regulate the response of adipose and other tissues to the nutrient environment. However, the physiological role of adipose tissue PKD and its downstream cellular signalling targets are not well characterised. Phosphoproteomics was performed to elucidate signalling events downstream of PKD activation in differentiated 3T3L1 adipocytes using a triple isoform siRNA knockdown model. This revealed PKD-regulated pathways including insulin and cAMP signalling, which control metabolic responses in adipose tissue. An adipose tissue-specific and inducible dominant negative PKD (atDNPKD) mouse model that achieves functional inhibition of all three PKD isoforms was generated to assess the function of adipose PKD on whole-body metabolismin vivoin both male and female mice. Insulin-stimulated suppression of lipolysis was blunted in male, but not female, atDNPKD mice compared to control mice. Female, but not male, atDNPKD mice had higher fasting insulin but normal insulin action. Male atDNPKD mice showed greater sensitivity to the β3-adrenergic receptor agonist CL316,243 on measures of lipolysis and energy expenditure, and displayed greater fat oxidation during fasting. During refeeding, male atDNPKD mice consumed less food and took longer to regain body weight lost during fasting. These effects were not observed in female mice. These findings indicate that PKD provides sex-dependent fine-tuning control of cAMP signalling in adipose tissue that is important for the coordination of energy balance during fasting and refeeding.NEW & NOTEWORTHYThe protein kinase D (PKD) family is a target for the treatment of obesity-related disorders. However, the physiological role of PKD in adipose tissue remains to be resolved. Using phosphoproteomics and an adipose tissue PKD loss-of-function mouse model, results demonstrate that PKD provides fine tuning of metabolic signalling in adipose tissue and metabolic responses to fasting and refeeding challenges, via coordination of feeding behaviour and regulation of body weight.
Systematic Optimization of Activity-Based Protein Profiling for Identification of Polysorbate-Degradative Enzymes in Biotherapeutic Drug Substance Down to 10 ppb
Authors: Tsukidate Taku , Liu Anita P. , Rivera Shannon , Stiving Alyssa Q. , Welch Jonathan , Li Xuanwen 
Published: August 2024

ABSTRACTThe identification and control of high-risk host cell proteins (HCPs) in biotherapeutics development is crucial for ensuring product quality and shelf life. Specifically, HCPs with hydrolase activity can cause degradation of excipient polysorbates (PS), leading to a decrease in the shelf life of the drug product. In this study, we systematically optimized every step of an activity-based protein profiling (ABPP) workflow to identify trace amounts of active polysorbate-degradative enzymes (PSDEs) in biotherapeutics process intermediates. Evaluation of various parameters during sample preparation pinpointed optimal pH level and fluorophosphonate (FP)-biotin concentration. Moreover, the combined use of a short liquid chromatography gradient and the fast-scanning Parallel Accumulation Serial Fragmentation (PASEF) methodology increased sample throughput without compromising identification coverage. Tuning Trapped Ion Mobility Spectrometry (TIMS) parameters further enhanced sensitivity. In addition, we evaluated various data acquisition modes including PASEF combined with data-dependent acquisition (DDA PASEF), data-independent acquisition (diaPASEF), or parallel reaction monitoring (prm-PASEF). By employing the newly optimized ABPP workflow, we successfully identified PSDEs at a concentration as low as 10 parts per billion (ppb) in a drug substance sample. Finally, the new workflow enabled us to detect a PSDE that could not be detected with the original workflow during a PS degradation root-cause investigation.
Numerosity adaptation suppresses early visual responses
Authors: Zhang Liangyou , Hendrikx Evi , Wang Yizhen , Gayet Surya , Dumoulin Serge O. , Harvey Ben M. 
Published: August 2024

ABSTRACTHumans and many animals rapidly and accurately perceive numerosity, the number of objects, in a visual image. The numerosity of recently viewed images influences our perception of the current image’s numerosity: numerosity adaptation. How does numerosity adaptation affect responses to numerosity in the brain? Recent studies show both early visual responses that monotonically increase with numerosity, and later numerosity-tuned responses that peak at different (preferred) numerosities in different neural populations. We have recently shown that numerosity adaptation affects the preferred numerosity of numerosity-tuned neural populations. We have also shown that early visual monotonic responses reflect image contrast, which follows numerosity closely. Here we ask how monotonic responses in the early visual cortex are affected by adaptation to different numerosities, using ultra-high field (7T) fMRI and neural model-based analyses. FMRI response amplitudes increased monotonically with numerosity throughout the early visual field maps (V1-V3, hV4, LO1-LO2 & V3A/B). This increase in response amplitudes becomes less steep after adaptation to higher numerosities, with this effect becoming stronger through the early visual hierarchy. This suppression of responses to numerosity is consistent with perceptual effects where adaptation to high numerosities reduces the perceived numerosity. These results imply that numerosity adaptation effects in later numerosity-tuned neural populations may originate in early visual areas that respond to image contrast in the adapting image.
Integrated Dual-Channel Retrograde Signaling Directs Stress Responses by Degrading the HAT1/TPL/IMPα-9 Suppressor Complex and Activating CAMTA3
Authors: Zeng Liping , Guo Jingzhe , Palayam Malathy , Rodriguez Carlos , Gomez Mendez Maria Fernanda , Wang Yaqi , van de Ven Wilhelmina , Pruneda-Paz Jose , Shabek Nitzan , Dehesh Katayoon 
Published: August 2024

AbstractThe intricate communication between plastids and the nucleus, shaping stress-responsive gene expression, has long intrigued researchers. This study combines genetics, biochemical analysis, cellular biology, and protein modeling to uncover how the plastidial metabolite MEcPP activates the stress-response regulatory hub known as the Rapid Stress Response Element (RSRE). Specifically, we identify the HAT1/TPL/IMPα- 9 suppressor complex, where HAT1 directly binds to RSRE and its activator, CAMTA3, masking RSRE and sequestering the activator. Stress-induced MEcPP disrupts this complex, exposing RSRE and releasing CAMTA3, while enhancing Ca2+influx and raising nuclear Ca2+levels crucial for CAMTA3 activation and the initiation of RSRE- containing gene transcription. This coordinated breakdown of the suppressor complex and activation of the activator highlights the dual-channel role of MEcPP in plastid-to- nucleus signaling. It further signifies how this metabolite transcends its expected biochemical role, emerging as a crucial initiator of harmonious signaling cascades essential for maintaining cellular homeostasis under stress.SummaryThis study uncovers how the stress-induced signaling metabolite MEcPP disrupts the HAT1/TPL/IMPα-9 suppressor complex, liberating the activator CAMTA3 and enabling Ca2+influx essential for CAMTA3 activation, thus orchestrating stress responses via repressor degradation and activator induction.
Learning-Induced Effects of Practice Schedule Variability on Stimuli Discrimination Efficiency: High-Density EEG Multi-scale Analyses of Contextual Interference Effect
Authors: Cretton Alexandre , Schipper Kate , Hassan Mahmoud , Ruggeri Paolo , Barral Jérôme 
Published: August 2024

ABSTRACTContextual interference (CI) enhances motor learning by practicing skill variations in a random rather than blocked order. It has been demonstrated that performing aiming distances in a random order increased electrophysiological (EEG) markers of perceptual, attentional, and working memory processes. However, only the effect of CI on these markers before training was assessed, without evaluating whether they would decrease with learning in participants trained under the random compared to the blocked condition, indicating enhanced neural efficiency. To address this, 35 participants practiced an aiming task involving three distances over nine sessions across three weeks. They were divided into two groups: one trained with distances in a random order (HCI group) and the other in a blocked order (LCI group). Electrophysiological activity was recorded for all participants in the random condition before and after the training program using a high-density EEG multiscale approach, including topographical, source estimation, and source connectivity analyses. EEG analyses revealed post-training neural dynamic differences between groups. The HCI group showed reduced and shorter P3a-like activity, while the LCI group displayed greater occipito-temporal-frontal gamma-band synchronization. These findings suggest that random practice enhances the efficiency of perceptual and attentional processes, particularly of stimuli discrimination, compared to blocked practice.
An Analysis of the Value-Added of Antibiogram Subgroup Stratification
Authors: Xie Connie T. Y. , Martinez Samantha , Simon Ceylon V. , Poutanen Susan M. 
Published: August 2024

AbstractBackgroundStratified antibiograms are recommended to guide empiric clinical treatment. However, which strata to focus on, the limited number of isolates in identified strata, and the heavy associated workload all pose challenges. This study compares differences in antibiotic susceptibility between a hospital-wide, all-specimens antibiogram and stratified antibiograms in order to identify the value-added of antibiogram stratification.MethodAntibiotic susceptibility of bacterial isolates from 2021 at a quaternary-care academic hospital was obtained from published hospital-wide and unit- and specimen-specific stratified antibiograms. Differences in percent susceptibility by organism and drug between the hospital-wide and stratified antibiograms were calculated. Weighted averages of the difference in percent susceptibility were calculated for each stratified antibiogram compared to the hospital-wide antibiogram and unit-wide antibiograms. Differences were shown through heat maps.ResultsWhen compared to a hospital-wide, all-specimens antibiogram, the emergency department (ED) antibiogram showed higher susceptibility, whereas intensive care unit (ICU) and, particularly, transplant unit (TR) antibiograms exhibited reduced susceptibility. Compared to ward level antibiograms, further stratification within each ward to specimen-specific (syndromic) antibiograms revealed additional differences. In ED, urine and respiratory-stratified antibiograms had lower susceptibility and blood had higher susceptibility. Compared to ward-specific antibiograms, in ICU, all specimen-stratified antibiograms had lower susceptibility and in transplant, antibiograms for all specimens but urine had lower susceptibility.ConclusionUsing a hospital-wide all-specimens antibiogram may both overcall and under call susceptibility leading to poor empiric antimicrobial choices. Specimen-specific antibiograms stratified by unit best inform empiric therapy for specific populations.SummaryUsing a hospital-wide all-specimens antibiogram may both overcall and under call susceptibility leading to poor empiric antimicrobial choices. There is value-added to providing combined unit-specific and specimen-specific antibiograms to help best inform empiric therapy for specific populations.
Quantitative Total-Body Imaging of Blood Flow with High Temporal Resolution Early Dynamic18F-Fluorodeoxyglucose PET Kinetic Modeling
Authors: Chung Kevin J. , Chaudhari Abhijit J. , Nardo Lorenzo , Jones Terry , Chen Moon S. , Badawi Ramsey D. , Cherry Simon R. , Wang Guobao 
Published: August 2024

AbstractQuantitative total-body PET imaging of blood flow can be performed with freely diffusible flow radiotracers such as15O-water and11C-butanol, but their short half-lives necessitate close access to a cyclotron. Past efforts to measure blood flow with the widely available radiotracer18F-fluorodeoxyglucose (FDG) were limited to tissues with high18F-FDG extraction fraction. In this study, we developed an early-dynamic18F-FDG PET method with high temporal resolution kinetic modeling to assess total-body blood flow based on deriving the vascular transit time of18F-FDG and conducted a pilot comparison study against a11C-butanol reference.MethodsThe first two minutes of dynamic PET scans were reconstructed at high temporal resolution (60×1 s, 30×2 s) to resolve the rapid passage of the radiotracer through blood vessels. In contrast to existing methods that use blood-to-tissue transport rate (K1) as a surrogate of blood flow, our method directly estimates blood flow using a distributed kinetic model (adiabatic approximation to the tissue homogeneity model; AATH). To validate our18F-FDG measurements of blood flow against a flow radiotracer, we analyzed total-body dynamic PET images of six human participants scanned with both18F-FDG and11C-butanol. An additional thirty-four total-body dynamic18F-FDG PET scans of healthy participants were analyzed for comparison against literature blood flow ranges. Regional blood flow was estimated across the body and total-body parametric imaging of blood flow was conducted for visual assessment. AATH and standard compartment model fitting was compared by the Akaike Information Criterion at different temporal resolutions.Results18F-FDG blood flow was in quantitative agreement with flow measured from11C-butanol across same-subject regional measurements (Pearson R=0.955, p<0.001; linear regression y=0.973x–0.012), which was visually corroborated by total-body blood flow parametric imaging. Our method resolved a wide range of blood flow values across the body in broad agreement with literature ranges (e.g., healthy cohort average: 0.51±0.12 ml/min/cm3in the cerebral cortex and 2.03±0.64 ml/min/cm3in the lungs, respectively). High temporal resolution (1 to 2 s) was critical to enabling AATH modeling over standard compartment modeling.ConclusionsTotal-body blood flow imaging was feasible using early-dynamic18F-FDG PET with high-temporal resolution kinetic modeling. Combined with standard18F-FDG PET methods, this method may enable efficient single-tracer flow-metabolism imaging, with numerous research and clinical applications in oncology, cardiovascular disease, pain medicine, and neuroscience.
Enhancement of network architecture alignment in comparative single-cell studies
Authors: Schächter Clemens , Treppner Martin , Hackenberg Maren , Raum Hanne , Bödecker Joschka , Binder Harald 
Published: August 2024

1AbstractAnimal data can provide meaningful context for human gene expression at the single-cell level. This context can improve cell-type or cell-state detection and clarify how well the animal models human biological processes. To achieve this, we propose a deep learning approach that identifies a unified latent space to map complex patterns between datasets. Specifically, we combine variational autoencoders with a data-level nearest neighbor search to align neural network architectures across species. We visualize commonalities by mapping cell samples into the latent space. The aligned latent representation facilitates information transfer in applications of liver, white adipose tissue, and glioblastoma cells from various animal models. We also identify genes that exhibit systematic differences and commonalities between species. The results are robust for small datasets and with large differences in the observed gene sets. Thus, we reliably uncover and exploit similarities between species to provide context for human single-cell data.
Implicit Neural Representation of Multi-shell Constrained Spherical Deconvolution for Continuous Modeling of Diffusion MRI
Authors: Hendriks Tom , Vilanova Anna , Chamberland Maxime 
Published: August 2024

AbstractDiffusion magnetic resonance imaging (dMRI) provides insight into the micro and macro-structure of the brain. Multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD) models the underlying local fiber orientation distributions (FODs) using the dMRI signal. While generally producing high-quality FODs, MSMT-CSD is a voxel-wise method that can be impacted by noise and produce erroneous FODs. Local models also do not use the spatial correlation between neighboring voxels to increase parameter estimating power. Additionally, voxel-wise methods require interpolation at arbitrary locations outside of voxel centers. These interpolations can be computationally costly or inaccurate, depending on the method of choice. Expanding upon previous work, we apply the implicit neural representation (INR) methodology to the MSMT-CSD model. This results in an unsupervised machine learning framework that generates a continuous representation of a given dMRI dataset. The input of the INR consists of coordinates in the volume, which produce the spherical harmonics coefficients parameterizing an FOD at any desired location. A key characteristic of our model is its ability to leverage spatial correlations in the volume, which acts as a form of regularization. We evaluate the output FODs quantitatively and qualitatively in synthetic and real dMRI datasets and compare them to existing methods.
Aerosol delivery of immunotherapy and Hesperetin-loaded nanoparticles increases survival in a murine lung cancer model
Authors: Yasmin-Karim Sayeda , Richards Geraud , Fam Amanda , Ogurek Alina-Marissa , Sridhar Srinivas , Makrigiorgos G. Mike 
Published: August 2024

ABSTRACTPurposeStudies have shown that flavonoids like Hesperetin, an ACE2 receptor agonist with antioxidant and pro-apoptotic activity, can induce apoptosis in cancer cells. ACE2 receptors are abundant in lung cancer cells. Here, we explored the application of Hesperetin bound to PLGA-coated nanoparticles (Hesperetin-nanoparticles, HNPs), and anti-CD40 antibody as an aerosol treatment for lung tumor-bearing mice.MethodsIn-vitroand in-vivo studies were performed in human A549 (ATCC) and murine LLC1 (ATCC) lung cancer cell lines. Hesperetin Nanoparticles (HNP) of about 60nm diameter were engineered using a nano-formulation microfluidic technique. A syngeneic orthotopic murine model of lung adenoma was generated in wild (+/+) C57/BL6 background mice with luciferase-positive cell line LLC1 cells. Lung tumor-bearing mice were treated via aerosol inhalation with HNP, anti-CD40 antibody, or both. Survival was used to analyze the efficacy of aerosol treatment. Cohorts were also analyzed for body condition score, weight, and liver and kidney function.ResultsAnalysis of an orthotopic murine lung cancer model demonstrates a differential uptake of the HNP and anti-CD40 by cancer cells relative to normal cells. A higher survival rate, relative to untreated controls, was observed when aerosol treatment with HNP was added to treatment via anti-CD40 (p<0.001), as compared to CD40 alone (p<0.01). Moreover, 2 out of 9 tumor-bearing mice survived long term, and their tumors diminished. These 2 mice were shown to be refractory to subsequent development of subcutaneous tumors, indicating systemic resilience to tumor formation.ConclusionWe successfully established increased therapeutic efficacy of anti-CD40 and HNP in an orthotopic murine lung cancer model using inhalation-based administration. Our findings open the possibility of improved lung cancer treatment using flavonoids and immuno-adjuvants.
Membrane transporter Progressive Ankylosis Protein Homolog (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation and ageing
Authors: James Emma Naomi , Teh Muy-Teck , Li Yufeng , Wagner-Bock Christine , Al-Khateeb Zahra Falah , Karen-Ng Lee Peng , Roberts Terry , Synchyshyn Linnea , Lewis Amy , O’Loghlen Ana , Silver Andrew , Michael-Titus Adina Teodora , Bennett Mark , Bundy Jacob Guy , Mycielska Maria Elzbieta , Parkinson Eric Kenneth 
Published: August 2024

AbstractA considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cellsin vitroandin vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear. We show here that EC is partially mediated by a newly described plasma membrane citrate transporterANKH/SLC62A1(progressive human ankylosis -ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/orANKHare regulated by telomere dysfunction, the p38 mitogen-activated kinase axis, transforming growth factor beta and p53, but in contrast not by steroids, sodium butyrate, or Ataxia Telangiectasia Mutated (ATM).ANKHwas upregulated in other senescent cell types relevant to ageing but not keratinocytes. In contrast, EC andANKHwere inhibited in dividing and senescent fibroblasts by interleukin 1α (IL-1α) in parallel with increased IL-6 secretion. Loss- and gain of function mutations ofANKH/Ankare associated with disease and interestingly,Ankis also downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and several cytokines, suggesting that inflammatory cytokines could inhibit EC productionin vivo. These data identifyANKH/Ankas a novel regulator of senescence-derived EC in both humans and mice.
Neural contrast sensitivity is not affected by myopic blur
Authors: Domdei Niklas , Müller Jonas , Renner Lisa , Ameln Julius , Breher Katharina , Harmening Wolf , Wahl Siegfried 
Published: August 2024

AbstractPurposeThe prevalence of myopia is increasing worldwide, accompanied by an increase of potentially under-corrected myopes. Because the neural pathways processing the retinal image are prone to adaptation in relation to the retinal image quality, we wondered to what extent neural contrast sensitivity (NCS) is altered in the presence of myopic blur. Additionally, the impact of retinal abnormalities like foveal hypoplasia with albinism on NCS was tested.MethodsNCS was psychophysically determined for 11 emmetropic, 23 myopic well-corrected and 15 myopic under-corrected otherwise healthy young (27 ± 6 years) participants and 1 albinism patient. Aberration-free stimulation, independent of the eye’s refractive state, was achieved by using a unique spatial light modulator-based interferometric system to bypass the eye’s optics.ResultsNo significant differences in NCS were observed between the three groups (Median area-under-curve: 61.9, 62.1, and 62.9 for emmetropes, well-corrected, and under-corrected myopes, respectively; all p > 0.1) but were significantly equivalent between emmetropes and myopes (all p < 0.001). However, the NCS function of the albinism patient differed significantly from the here defined “normal” NCS function.ConclusionsNCS is unaffected by myopic blur and remains stable even for under-correction of up to 1.5 D. This means, that long-term under-corrected myopes still can achieve normal visual acuity as soon as their refractive errors are sufficiently corrected. Furthermore, NCS testing can relate visual deficits to an underlying neurological disorder.