bluuebunny/crossref_metadata_2025 huggingface dataset:
Detailed delineation of the fetal brain in diffusion MRI via multi-task learning
Authors: Karimi Davood , Calixto Camilo , Snoussi Haykel , Cortes-Albornoz Maria Camila , Velasco-Annis Clemente , Rollins Caitlin , Jaimes Camilo , Gholipour Ali , Warfield Simon K.
Published: August 2024

Diffusion-weighted MRI is increasingly used to study the normal and abnormal development of fetal brain inutero. Recent studies have shown that dMRI can offer invaluable insights into the neurodevelopmental processes in the fetal stage. However, because of the low data quality and rapid brain development, reliable analysis of fetal dMRI data requires dedicated computational methods that are currently unavailable. The lack of automated methods for fast, accurate, and reproducible data analysis has seriously limited our ability to tap the potential of fetal brain dMRI for medical and scientific applications. In this work, we developed and validated a unified computational framework to (1) segment the brain tissue into white matter, cortical/subcortical gray matter, and cerebrospinal fluid, (2) segment 31 distinct white matter tracts, and (3) parcellate the brain’s cortex and delineate the deep gray nuclei and white matter structures into 96 anatomically meaningful regions. We utilized a set of manual, semi-automatic, and automatic approaches to annotate 97 fetal brains. Using these labels, we developed and validated a multi-task deep learning method to perform the three computations. Our evaluations show that the new method can accurately carry out all three tasks, achieving a mean Dice similarity coefficient of 0.865 on tissue segmentation, 0.825 on white matter tract segmentation, and 0.819 on parcellation. The proposed method can greatly advance the field of fetal neuroimaging as it can lead to substantial improvements in fetal brain tractography, tract-specific analysis, and structural connectivity assessment.
Molecular Insights into Single Chain Lipid Modulation of Acid-Sensing Ion Channel 3
Authors: Bandarupalli Ramya , Roth Rebecca , Klipp Robert C , Bankston John R , Li Jing
Published: August 2024

Polyunsaturated fatty acids (PUFAs) and their analogs play a significant role in modulating the activity of diverse ion channels, and recent studies show that these lipids potentiate acid-sensing ion channels (ASICs), leading to increased activity. The potentiation of the channel stems from multiple gating changes, but the exact mechanism of these effects remains uncertain. We posit a mechanistic explanation for one of these changes in channel function, the increase in the maximal current, by applying a combination of electrophysiology and all-atom molecular dynamics simulations on the open-state hASIC3. Microsecond-scale simulations were performed on open-state hASIC3 in the absence and presence of a PUFA, docosahexaenoic acid (DHA), and a PUFA analog, N-arachidonyl glycine (AG). Intriguingly, our simulations in the absence of PUFA or PUFA analogs reveal that a tail from the membrane phospholipid POPC inserts itself into the pore of the channel through lateral fenestrations on the sides of the transmembrane segments, obstructing ion permeation through the channel. The binding of either DHA or AG prevented POPC from accessing the pore in our simulations, relieving the block of ionic conduction by phospholipids. Finally, we use the single-channel recording to show that DHA increases the amplitude of the single-channel currents in ASIC3, which is consistent with our hypothesis that PUFAs relieve the pore block of the channel induced by POPCs. Together, these findings offer a potential mechanistic explanation of how PUFAs modulate ASIC maximal current, revealing a novel mechanism of action for PUFA-induced modulation of ion channels.
Erythropoietin-dependent Acquisition of CD71hiCD105hiPhenotype within CD235a−Early Erythroid Progenitors
Authors: Schippel Natascha , Wei Jing , Ma Xiaokuang , Kala Mrinalini , Qiu Shenfeng , Stoilov Peter , Sharma Shalini
Published: August 2024

The development of committed erythroid progenitors and their continued maturation into mature erythrocytes requires the cytokine erythropoietin (Epo). Here, we describe the immunophenotypic identification of a unique Epo-dependent colony-forming unit-erythroid (CFU-E) cell subtype that forms during early erythropoiesis (EE). This previously undescribed CFU-E subtype, termed late-CFU-E (lateC), lacks surface expression of the characteristic erythroid marker CD235a (glycophorin A) but has high levels of CD71 and CD105. LateCs could be prospectively detected in human bone marrow (BM) cells and, upon isolation and reculture, exhibited the potential to form CFU-E colonies in medium containing only Epo (no other cytokines) and continued differentiation along the erythroid trajectory. Analysis ofex vivocultures of BM CD34+cells showed that acquisition of the CD7hiCD105hiphenotype in lateCs is gradual and occurs through the formation of four EE cell subtypes. Of these, two are CD34+burst-forming unit-erythroid (BFU-E) cells, distinguishable as CD7loCD105loearly BFU-E and CD7hiCD105lolate BFU-E, and two are CD34−CFU-Es, also distinguishable as CD71loCD105loearly CFU-E and CD7hiCD105lomid-CFU-E. The transition of these EE populations is accompanied by a rise in CD36 expression, such that all lateCs are CD36+. Single cell RNA-sequencing analysis confirmed Epo-dependent formation of a CFU-E cluster that exhibits high coexpression of CD71, CD105, and CD36 transcripts. Gene set enrichment analysis revealed the involvement of genes specific to fatty acid and cholesterol metabolism in lateC formation. Overall, in addition to identifying a key Epo-dependent EE cell stage, this study provides a framework for investigation into mechanisms underlying other erythropoiesis-stimulating agents.
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

The 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 & NOTEWORTHY

The 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

The 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

Humans 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

The 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.

This 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

Contextual 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

Background

Stratified 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.

Method

Antibiotic 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.

Results

When 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.

Conclusion

Using 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.

Using 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.
paraCell: A novel software tool for the interactive analysis and visualization of standard and dual host-parasite single cell RNA-Seq data
Authors: Agboraw Edward , Haese-Hill William , Hentzschel Franziska , Briggs Emma Marie , Aghabi Dana , Heawood Anna , Harding Clare R , Schiels Brian , Crouch Kathryn R , Somma Domenico , Otto Thomas D
Published: August 2024

Advances in sequencing technology have led to a dramatic increase in the number of single-cell transcriptomic datasets available. In the field of parasitology, these datasets typically describe the gene expression patterns of a given parasite species under specific experimental conditions, in specific hosts or tissues, or at different life-cycle stages. However, while this wealth of available data represents a significant resource for further research, the analysis of these datasets often requires significant computational skills, preventing a considerable proportion of the parasitology community from meaningfully incorporating existing single-cell data into their work. Here, we present paraCell, a novel software tool that automates the advanced analysis of published single-cell data without requiring any programming ability. On our free web server, we demonstrated how to visualise data, re-analyse published Plasmodium and Trypanosoma datasets, and present novel Toxoplasma-mouse and Theileria-cow atlases to study the impact of IFN-γ and host genetic susceptibility.
Highly dynamic mechanical transitions in embryonic cell populations duringDrosophilagastrulation
Authors: Gomez Juan Manuel , Bevilacqua Carlo , Thayambath Abhisha , Leptin Maria , Belmonte Julio M , Prevedel Robert
Published: August 2024

During animal development, the acquisition of three-dimensional morphology is a direct consequence of the dynamic interaction between cellular forces and the mechanical properties of cells and their environment. While the generation and transmission of cellular forces has been widely explored, less is known about the dynamic changes in cell mechanical properties during morphogenesis. Here, we characterise and spatially map in three dimensions the dynamics of cell mechanical properties duringDrosophilagastrulation utilising line-scan Brillouin microscopy. We find that cells in the embryo undergo rapid and spatially varying changes in their mechanical properties and that these differ in cell populations with different fates and behaviours. We identify microtubules as potential effectors of cell mechanics in this system, and corroborate our experimental findings with a physical model that underscores the role of localised and dynamic changes in mechanical properties to facilitate tissue folding. Our work provides the first spatio-temporal description of the evolving mechanical properties of cell populations during morphogenesis, and highlights the potential of Brillouin microscopy in studying the dynamic changes in cell shape behaviours and cell mechanical properties simultaneously in different cell populations in an intact organism.
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

Quantitative 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.

Methods

The 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.

Results

18F-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.

Conclusions

Total-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

1

Animal 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

Diffusion 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

Purpose

Studies 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.

Methods

In-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.

Results

Analysis 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.

Conclusion

We 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

A 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

Purpose

The 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.

Methods

NCS 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.

Results

No 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.

Conclusions

NCS 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.
Mast cells are not essential for pubertal mammary gland branching.
Authors: Kapoor Simran , Marsden Jimmy , Munz Clara M , Carvalho Cyril , Magalhaes Pinto Marlene , Malengier-Devlies Bert , Becker Solvig , Seuzaret Guillaume , Patatsos Katelyn , Akyol Ramazan , DALOD Marc , Pedersen Amy B , Wilson Gillian J , Gentek Rebecca
Published: August 2024

Mast cells are long-lived, tissue-resident immune cells of the myeloid lineage with cardinal functions in allergy and atopic disease. They are now increasingly recognized also for protective roles e.g. against infections and venoms. Other functions originally assigned to mast cells in development and physiology, however, have been refuted, and for yet others, their true contribution remains uncertain. Mast cells have been implicated in promoting ductal branching in the pubertal mammary gland, the organ that produces and secretes milk in mammals, but these findings are based on mouse models that are not mast cell-specific. In this study, we therefore re-addressed the impact of mast cells on mammary gland branching using several complementary genetic models, including a new transgenic line. We report that neither constitutive deficiency of mast cells, nor their conditional ablation induced at puberty affected mammary gland branching. Our results thus dispute that mast cells promote this process in mice, at least in a unique and non-redundant manner. This study adds to a growing body of work clarifying the biological roles of mast cells, and further expands the toolbox available to the field of mast cell research.
Anatomical Abnormalities Suggest a Compensatory Role of the Cerebellum in Early Parkinson’s Disease
Authors: Yun Juyoung Jenna , Gailly de Taurines Anastasia , Tai Yen F , Haar Shlomi
Published: August 2024

Brain atrophy is detected in early Parkinson’s disease (PD) and accelerates over the first few years post-diagnosis. This was captured by multiple cross-sectional studies and a few longitudinal studies in early PD. Yet only a longitudinal study with a control group can capture accelerated atrophy in early PD and differentiate it from healthy ageing. Accordingly, we performed a multicohort longitudinal analysis between PD and healthy ageing, examining subcortical regions implicated in PD pathology, including the basal ganglia, thalamus, corpus callosum (CC), and cerebellum. Longitudinal volumetric analysis was performed on 56 early PD patients and 53 matched controls, with scans collected 2-3 years apart. At baseline, the PD group showed a greater volume in the pallidum, thalamus, and cerebellar white matter (WM), suggesting potential compensatory mechanisms in prodromal and early PD. After 2-3 years, accelerated atrophy in PD was observed in the putamen and cerebellar WM. Interestingly, healthy controls – but not PD patients – demonstrated a significant decline in Total Intracranial Volume (TIV), and atrophy in the thalamus and mid-CC. Between-group analysis revealed more severe atrophy in the right striatum and cerebellar WM in PD, and in the mid-posterior CC in controls. Using CEREbellum Segmentation (CERES) for lobule segmentation on the longitudinal PD cohort, we found a significant decline in the WM of non-motor regions in the cerebellum, specifically Crus I and lobule IX. Our results highlight an initial increase in cerebellar WM volume during prodromal PD, followed by significant degeneration over the first few years post-diagnosis.
Multimodal brain imaging of insomnia, depression and anxiety symptoms: transdiagnostic commonalities and differences
Authors: de Lange Siemon C. , Tissink Elleke , Bresser Tom , Savage Jeanne E. , Posthuma Danielle , van den Heuvel Martijn P. , van Someren Eus J.W.
Published: August 2024

Insomnia disorder, major depressive disorder and anxiety disorders are the most common mental health conditions, with high comorbidity and genetic overlap suggesting shared brain mechanisms. Studies on brain correlates of these disorders have not fully addressed this overlap. Aiming to distinguish shared from specific brain structural and functional properties associated with symptoms of these disorders, this study analyzed multimodal brain imaging data from over 40,000 UK Biobank participants. Functional enrichment analyses were conducted to understand the cognitive-emotional and neurotransmission implications of the identified brain regions and connections. Results showed that smaller cortical surfaces, smaller thalamic volumes, and weaker functional connectivity were linked to more severe symptoms across all symptom types. Several symptom-specific associations were revealed, most commonly in different parts of the amygdala-hippocampal-medial prefrontal circuit. These findings revealed both transdiagnostically shared and unique brain properties that could lead to more directed treatment targets for insomnia, depression, and anxiety.
Distinct metabolite profiles in tissues and exudates of a monocot and dicot shaped by the environment
Authors: Siffert Alexandra , McLaughlin Sarah , Sasse Joëlle
Published: August 2024

Plants exhibit remarkable plasticity in response to environmental changes. Understanding how plants adapt to diverse environmental conditions through changes in their metabolite profiles can provide insights into their adaptive strategies under suboptimal climate conditions. For this, metabolite profiles of tissues and root-derived, exuded compounds in various environmental conditions need to be characterized. Here, we compare the shoot, root, and root exudate metabolite profiles of the monocotBrachypodium distachyonand the dicotArabidopsis thalianagrown in sterile, non-sterile, and sucrose-supplied basal salt medium or soil extract to represent natural and various standard laboratory conditions. We report unique metabolite fingerprints in shoots and roots for each species and environmental condition. Exuded compounds of Arabidopsis displayed higher sensitivity to soil extract conditions, whereas Brachypodium showed significant changes in response to non-sterile conditions. Organic acids, lipids, organic oxygen compounds, and phenylpropanoids were major contributors to the observed differences. Our results highlight the importance of considering environmental aspects when investigating plant metabolism and point towards crucial chemical classes involved in plant-microbe-environment interactions.
Human deep sleep facilitates faster cerebrospinal fluid dynamics linked to brain oscillations for sleep homeostasis and memory
Authors: Uji Makoto , Li Xuemei , Saotome An , Katsumata Ryosuke , Waggoner R. Allen , Suzuki Chisato , Ueno Kenichi , Aritake Sayaka , Tamaki Masako
Published: August 2024

While cerebrospinal fluid (CSF) dynamics during sleep have been implicated in metabolic waste reduction in animals, how CSF dynamics are driven in the human brain remains elusive. Here, by leveraging a simultaneous sparse-fMRI and polysomnography method designed specifically for acquiring deep stable sleep data, we present the first evidence of deep sleep-specific faster CSF dynamics in healthy young human participants. Slow waves and sleep spindles during slow-wave sleep and rapid eye movements and sawtooth waves during rapid eye movement (REM) sleep induce frequent low-amplitude CSF fluctuations, contributing to faster CSF dynamics during deep sleep. In contrast, arousal-related brain activities during light sleep produced infrequent large CSF changes. Furthermore, these brain oscillations during light and deep sleep recruited essentially different brain networks, with deep sleep emphasizing memory and homeostatic circuits. Thus, human deep sleep has a unique way of enabling faster CSF dynamics that are distinctive from arousal mechanisms.
Plasma membrane H+-ATPase activation increases global transcript levels and promotes the shoot growth of light-grown Arabidopsis seedlings
Authors: Kinoshita Satoru Naganawa , Taki Kyomi , Okamoto Fumika , Nomoto Mika , Takahashi Koji , Hayashi Yuki , Ohkanda Junko , Tada Yasuomi , Finkemeier Iris , Kinoshita Toshinori
Published: August 2024

(1)

Plant cell growth require the elongation of cells mediated by cell wall remodelling and turgor pressure changes. The plasma membrane (PM) H+-ATPase facilitates both cell wall remodelling and turgor pressure changes, by acidifying the apoplast of cells, referred to as acid growth. The acid growth theory is mostly established on the auxin-induced activation of PM H+-ATPase in non-photosynthetic tissues. However, how PM H+-ATPase affect the growth in photosynthetic tissues of Arabidopsis remains unclear.

(2)

Here, a combination of transcriptomics and cis-regulatory element analysis was conducted to identify the impact of PM H+-ATPase on global transcript levels and the molecular mechanism downstream of the PM H+-ATPase.

(3)

The PM H+-ATPase activation increased transcript levels globally, especially cell wall modification-related genes. The transcript level changes were in PM H+-ATPase-dependent manner. Involvement of Ca2+was suggested as CAMTA motif was enriched in the promoter of PM H+-ATPase-induced genes and cytosolic Ca2+elevated upon PM H+-ATPase activation.

(4)

PM H+-ATPase activation in photosynthetic tissues promote the expression of cell wall modification enzymes and shoot growth, adding a novel perspective of photosynthesis-dependent PM H+-ATPase activation in photosynthetic tissues to the acid growth theory that has primarily based on findings from non-photosynthetic tissues.
Antimicrobial nanolayers of thymol and carvacrol on titanium surfaces: the crucial role of interfacial properties in thymol’s superior osteogenic response
Authors: Gonzalez Ariel , Miñán Alejandro , Prieto Eduardo , Schilardi Patricia , Fagali Natalia S. , Fernández Lorenzo de Mele Mónica
Published: August 2024

“Green’’ nanotechnologies have emerged as environmentally friendly alternatives against microbial multidrug-resistant biofilms. In this study, bactericidal “green” nanolayers (NL) were developed on Ti surfaces using two isomeric phytocompounds, carvacrol (Carv-Ti-NL) and thymol (TOH-Ti-NL). These NLs were fabricated using a one-step immersion treatment method based on a simple and spontaneous self-assembly process. Both NLs revealed strong antimicrobial activity, displaying anti-biofilm and biocidal effects. Notably, TOH-Ti-NL exhibited superior osteogenic performance compared to Carv-Ti-NL, as evidenced by enhanced pre-osteoblast cell attachment and growth, and the production of ALP, collagen type I and Ca2+deposition. In contrast, fibroblastic cells exhibited reduced attachment on TOH-Ti-NL and enhanced proliferation on Carv-Ti-NL. Considering the biological differential effects, the physicochemical properties of these conformational isomers’ NLs were studied to elucidate potential differences that could impact on cell response. Although the ATR-FTIR spectra of the NLs were similar and indicated the spontaneous oxidation of Carv and TOH leading to ketonic structures, distinct contributions were observed after the electrooxidation of each NL. Slight differences in hydrophilicity were found for both nanostructures, but higher roughness was found for TOH-Ti-NL. Furthermore, the release curves of Carv and TOH from the NLs revealed distinct profiles over time. Overall, Carv and TOH formed self-assembled layers on Ti able to eradicateStaphylococcus aureusbiofilms. Their different physical and chemical characteristics induced distinct responses from eukaryotic cells attached to the NLs. Given these characteristics one might envisage the use of either Carv-Ti-NL or TOH-Ti-NL in order to fine-tune specific chemical physical properties of Ti-based implants.

Graphical abstract
Novel iGluSnFR3 variants with improved kinetics and dynamic range for tracking high frequency firing at glutamatergic synapses
Authors: Tran Oanh , Bertelli Sara , Hughes Holly J. , Lozo Luka , Plested Andrew , Török Katalin
Published: August 2024

The first genetically encoded single fluorescent protein-based glutamate sensor, iGluSnFR opened a new era of imaging neuronal activity at the level of circuits as well as at synapses. With slowoff-kinetics, iGluSnFR could only resolve low frequency glutamate release. A binding site variant of iGluSnFR, iGluuwith significantly fasteroff-kinetics, enabled the resolution of high (100 Hz) frequency glutamate release in hippocampal slices at individual CA3-CA1 synapses. Moreover, iGluurevealed impairment of glutamate retrieval in HD mice models pointing to defective glutamate transport. Recently, the iGluSnFR3 generation (SF-Venus-iGluSnFR. v857) has been developed with increased dynamic range and rapidon-kinetics, making it attractive forin vivoimaging. However, similarly to iGluSnFR, glutamateoff-kinetics of iGluSnFR3 were predicted to limit it to resolving low frequency release only. We undertook to improve the kinetic properties of iGluSnFR3 for resolving high (100 Hz) frequency glutamate release. We generated and characterized iGlu3fast, an ultrafast decay variant of iGluSnFR3. For iGlu3Fast we obtained a decay rate constant of 340 ± 48 s-1, ∼5-fold faster than iGluSnFR3 at 71 ± 3 s-1, at 20°C. Furthermore, iGlu3Fast superseded iGluSnFR3 with a 42-fold glutamate-induced fluorescence increase compared to 26 for iGluSnFR3. Thus, with rapidoff-kinetics comparable to that of iGluuas well as significantly increased fluorescence dynamic range and preserved rapidon-kinetics, iGlu3fast represents an excellent novel sensor for imaging high frequency glutamate release at all levels of organisation. Two novel variants with superslowoff-kinetics are also reported, expanding the range of applications in neurobiology.
Chromatin Remodelling in Damaged Intestinal Crypts Orchestrates Redundant TGFβ and Hippo Signalling to Drive Regeneration
Authors: Fink Mardi , Njah Kizito , Patel Shyam J. , Cook David P. , Man Vanessa , Ruso Francesco , Rajan Arsheen , Narimatsu Masahiro , Obersterescu Andreea , Pye Melanie J. , Trcka Daniel , Chan Kin , Ayyaz Arshad , Wrana Jeffrey L.
Published: August 2024

Cell state dynamics underlying regeneration are under-characterized. Intestinal damage prompts reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Single nuclei multiomics of chromatin accessibility and transcriptomes during regeneration from irradition showed revSCs display epigenetic profiles shared with ISCs and differentiated lineages. Furthermore, while revSC genes are accessible throughout homeostatic epithelia, damage-induced global alterations in crypt and revSC chromatin converge on TGFβ, as well as Hippo pathways. We show TGFβ directly induces functional revSCs and demonstrate individual revSCs form organoids with reconstituted Lgr5+ ISCs. Despite this, loss of TGFβ signalling yielded mild regenerative defects. In contrast, interference in both Hippo and TGFβ abolished revSCs, precluded generation of new ISCs and led to rapid intestinal collapse. Thus, the epithelium is poised to engage the revSC regenerative program that relies on crypt-localized, transient morphogen cues that function in a compensatory manner to support intestinal regeneration.