bluuebunny/crossref_metadata_2025 huggingface dataset:
An environment-dependent halo mass function as a driver for the early quenching of z ≥ 1.5 cluster galaxies
Authors: Ahad Syeda Lammim , Muzzin Adam , Bahé Yannick M , Hoekstra Henk
Published: February 2024

Many z ≈1.5 galaxies with a stellar mass (M⋆) $\ge 10^{10}\, \mathrm{M}_\odot$ are already quenched in both galaxy clusters (>50 per cent) and the field (>20 per cent), with clusters having a higher quenched fraction at all stellar masses compared to the field. A puzzling issue is that these massive quenched galaxies have stellar populations of similar age in both clusters and the field. This suggests that, despite the higher quenched fraction in clusters, the dominant quenching mechanism for massive galaxies is similar in both environments. In this work, we use data from the cosmological hydrodynamic simulations Hydrangea and EAGLE to test whether the excess quenched fraction of massive galaxies in z=1.5 clusters results from fundamental differences in their halo properties compared to the field. We find that (i) at $10^{10}\le \, M_{\star }/\mathrm{M}_\odot \, \le 10^{11}$, quenched fractions at 1.5<z<3.5 are consistently higher for galaxies with higher peak maximum circular velocity of the dark matter halo (vmax, peak), and (ii) the distribution of vmax, peak is strongly biased towards higher values for cluster satellites compared to the field centrals. Due to this difference in the halo properties of cluster and field galaxies, secular processes alone may account for (most of) the environmental excess of massive quenched galaxies in high-redshift (proto-)clusters. Taken at face value, our results challenge a fundamental assumption of popular quenching models that clusters are assembled from an unbiased subset of infalling field galaxies. If confirmed, this would imply that such models must necessarily fail at high redshift, as indicated by recent observations.
Cyclotron line evolution revealed with pulse-to-pulse analysis in the 2020 outburst of 1A 0535+262
Authors: Shui Qing C , Zhang S , Wang Peng J , Mushtukov Alexander A , Santangelo A , Zhang Shuang N , Kong Ling D , Ji L , Chen Yu P , Doroshenko V , Frontera F , Chang Z , Peng Jing Q , Yin Hong X , Qu Jin L , Tao L , Ge Ming Y , Li J , Ye Wen T , Li Pan P
Published: February 2024

We present a detailed analysis of the X-ray luminosity (LX) dependence of the cyclotron absorption line energy (Ecyc) for the X-ray binary pulsar 1A 0535+262 during its 2020 giant outburst based on pulse-to-pulse analysis. By applying this technique to high cadence observations of Insight-Hard X-ray Modulation Telescope, we reveal the most comprehensive Ecyc–LX correlation across a broad luminosity range of ∼(0.03–1.3) × 1038 erg s−1. Apart from the positive and negative correlations between cyclotron line energy and luminosity at LX ∼ (1–3) × 1037 erg s−1 and ∼(7–13) × 1037 erg s−1, which are expected from the typical subcritical and supercritical accretion regimes, respectively, a plateau in the correlation is also detected at ∼(3–7) × 1037 erg s−1. Moreover, at the lowest luminosity level (LX ≲ 1037 erg s−1), the positive Ecyc–LX correlation seems to be broken, and the pulse profile also occurs a significant transition. These discoveries provide the first complete view on the correlation between luminosity and the centriod energy of the cyclotron line, and therefore are relevant for understanding how accretion on to magnetized neutron stars depends on luminosity.
The dynamic surface evolution of halide perovskites induced by external energy stimulation
Authors: Cheng Feiyu , Wang Pengdong , Xu Chenzhe , Liao Qingliang , Zhang Suicai , Sun Haochun , Fan Wenqiang , Liu Guodong , Li Zhiyun , Kong Yaping , Wang Li , Li Fangsen , Kang Zhuo , Zhang Yue
Published: February 2024

Tracking the dynamic surface evolution of metal halide perovskite is crucial for understanding the corresponding fundamental principles of photoelectric properties and intrinsic instability. However, due to the volatility elements and soft lattice nature of perovskites, several important dynamic behaviors remain unclear. Here, an ultra-high vacuum (UHV) interconnection system integrated by surface-sensitive probing techniques has been developed to investigate the freshly cleaved surface of CH3NH3PbBr3  in situ under given energy stimulation. On this basis, the detailed three-step chemical decomposition pathway of perovskites has been clarified. Meanwhile, the evolution of crystal structure from cubic phase to tetragonal phase on the perovskite surface has been revealed under energy stimulation. Accompanied by chemical composition and crystal structure evolution, electronic structure changes including energy level position, hole effective mass, and Rashba splitting have also been accurately determined. These findings provide a clear perspective on the physical origin of optoelectronic properties and the decomposition mechanism of perovskites.
Occurrence of larval fishes sampled by drifting light traps in the lower reaches of a South African estuary
Authors: Kisten Yanasivan , Kruger Michelle , Strydom Nadine A
Published: February 2024

The tidal occurrence of larval fishes was investigated in the permanently open Kowie Estuary on the warm-temperate coast of South Africa. Larval fishes were sampled in the mouth region using two drifting light traps deployed on the ebb and flood tides every second night for two consecutive 14-day periods, coinciding with the dark moon phase. A total of 553 larval fishes were caught, representing nine families and 26 species, of which Blenniidae and Clupeidae dominated. The prevalence of different estuarine association fish guilds was also tide-specific. Marine and estuarine species, such as Omobranchus woodi, were more dominant during flood tides, while marine straggler species, such as Sardinops sagax, which are not dependent on estuaries, were dominant on the ebb tide. Marine estuarine-dependents were only present during flood tides, potentially indicating ingress and entrainment within the estuary. The results confirm that light trap catches yield a different composition of species compared to towed ichthyoplankton net studies. Additionally, drifting light traps allow for better targeting of species with a phototactic response and reduction of incidental catch. Consequently, a mixture of gear is encouraged for more comprehensive surveys of larval fish occurrence.
Storm and tidal interactions control sediment exchange in mixed-energy coastal systems
Authors: Georgiou Ioannis Y , FitzGerald Duncan M , Hanegan Kevin C
Published: February 2024

Storms can have devasting effects on shorelines, causing flooding and the destruction of property and infrastructure. As global warming and the frequency and magnitude of tropical storms increase, barrier islands comprising 10% of the world's coast may undergo significant change caused by beach erosion, loss of dunes, and formation of washovers and tidal inlets. Understanding how storms affect sediment transport at tidal inlets is an understudied subject that directly influences barrier island erosional-depositional processes and long-term sediment budgets. This study models hydrodynamics and sediment transport at a conceptualized mixed-energy, mesotidal inlet system using 10 synthetic storm tracks. We investigate the provenance and the role of various storm characteristics and timing between the peak storm surge and high tide on sediment fluxes for different grain sizes. We find that most storms (38 of 40) cause a net import of sediment into the basin that is sourced primarily from the updrift and downdrift nearshore and secondly from the ebb-delta. Very little sediment comes from inlet channel scour. Cumulative (net) transport correlates well with peak significant wave height because wave height influences bottom shear stresses and sediment suspension on the ebb-tidal delta and in the nearshore. The duration of the storm surge also correlates with net transport because it controls the period of flood-directed currents. Our findings help explain the formation of flood deltas inside tidal inlets and the formation of sand shoals in backbarrier regions. Storm-induced enlargement of these deposits represents a permanent long-term loss of sand from barrier islands that will lead to erosion.
Season of drought affects growth, but not nonstructural carbohydrates dynamics, in Pinus taeda saplings
Authors: Oswald Scott W , Aubrey Doug P
Published: February 2024

In temperate evergreen conifers, growth occurs mostly in summer but photosynthesis proceeds year-round; thus, nonstructural carbohydrates (NSCs) increase in winter but decrease in summer. Given that mild drought reduces growth but not photosynthesis, a drought in summer should increase NSCs more than one in winter. However, the active regulation hypothesis suggests that to increase future drought resilience, plants might downregulate growth to increase NSCs after a winter drought even if NSCs do not increase during the drought. To test whether this is so, potted Pinus taeda saplings (age $<\kern-3pt1$ year) were subjected to 6-month droughts in a greenhouse with one treatment receiving drought during winter (September–March), and another during summer (March–September). Both treatments were compared with a control. To measure dry biomass and NSCs, we harvested plants monthly following each drought, while to assess changes in growth rates, we measured height and diameter monthly. While we observed seasonal variation and an overall increase during the study, we found no drought-related changes in NSC dynamics; however, drought did reduce growth. Furthermore, drought in winter did reduce growth during the following summer, but the reduction was less than for a drought in summer. We conclude that the effect of drought on NSCs was too small to detect in our plants. While better control of soil water would have reduced a major source of uncertainty, plants with larger NSC reserves or more intense stress would also yield easier-to-detect effects. Although not definitive, our results suggest that water stress does not lead to dramatic changes in seasonal NSC dynamics in its aftermath, despite what one might expect under the active regulation hypothesis.
Imaging and clinical features of pulsatile polypoidal choroidal vasculopathy
Authors: Choi Kwang-Eon , Lee Young Joo , Bae So Hyeon
Published: February 2024

Purpose:

To investigate the imaging and clinical features of polypoidal choroidal vasculopathy (PCV) with the pulsation.

Methods:

The PCV eyes were classified into pulsatile and non-pulsatile PCV groups according to the pulsation on indocyanine green angiography (ICGA). Imaging features including the dye filling time of the polyp and clinical features were compared.

Results:

A total of 75 eyes were classified into the pulsatile PCV (30 eyes) or the non-pulsatile PCV (45 eyes) groups. The initial and complete filling time of the polyp of the pulsatile PCV group (2.59 ± 0.93 and 8.33 ± 3.42 seconds) were shorter than those of the non-pulsatile PCV group (4.11 ± 1.87 and 10.63 ± 3.81 seconds, p < 0.001 and p = 0.010, respectively). Pigment epithelial detachment (PED) height of the pulsatile PCV group (414.90 ± 377.15 µm) was greater than that of the non-pulsatile PCV group (247.81 ± 164.07 µm, p = 0.030). Pulsatile PCV group showed a higher prevalence of subretinal hemorrhage (43.33%) after intravitreal injection than non-pulsatile PCV group (13.95%, p = 0.005) during 12 months. The mean number of injections during 12 months of the pulsatile PCV group (5.48 ± 1.46) was greater than that of the non-pulsatile PCV group (4.09 ± 1.21, p < 0.001).

Conclusion:

Eyes with pulsatile PCV showed shorter filling time of the polyp, greater PED height, higher prevalence of subretinal hemorrhage, and more intravitreal injection numbers during 12 months. These might suggest that PCV has distinct imaging and clinical features according to the polyp pulsation.
Resting-state Functional Connectivity Predicts Cochlear-Implant Speech Outcomes
Authors: Esmaelpoor Jamal , Peng Tommy , Jelfs Beth , Mao Darren , Shader Maureen J. , McKay Colette M.
Published: February 2024

Background

Cochlear implants (CIs) have revolutionized hearing restoration for individuals with severe or profound hearing loss. However, a substantial and unexplained variability persists in CI outcomes, even when considering subject-specific factors such as age and the duration of deafness. In this study, we explore the utility of resting-state functional near-infrared spectroscopy (fNIRS) recordings to predict speech understanding outcomes before and after CI implantation. Our hypothesis revolves around resting-state functional connectivity (FC) as a reflection of brain plasticity post-hearing loss and implantation. Specifically, we hypothesized that the average clustering coefficient in resting FC networks can capture this variation among CI users.

Methods

Twenty-two cochlear implant candidates participated in this study. Resting-state fNIRS data were collected pre-implantation and at one month, three months, and one year post-implantation. Speech understanding performance was assessed using CNC words in quiet and BKB sentences in noise one year post-implantation. Resting-state functional connectivity networks were constructed using regularized partial correlation, and the average clustering coefficient was measured in the signed weighted networks as a predictive measure for implantation outcomes.

Results

Our findings demonstrate a significant correlation between the average clustering coefficient in resting-state functional networks and speech understanding outcomes. Importantly, our analysis reveals that this measure provides unique information not accounted for by subject-specific factors such as age and duration of deafness.

Conclusion

This approach utilizes an easily deployable resting-state functional brain imaging metric to predict speech understanding outcomes in implant recipients. The results indicate that the average clustering coefficient, both pre and post implantation, correlates with speech understanding outcomes.
Renal Profile of Herbal Medicine Users versus Non-users: an Exploratory Cross-sectional Study in a Family Medicine Clinic in Nigeria
Authors: Maiyegun Afisulahi Abiodun , Akangoziri Mark Divine , Grema Bukar Alhaji , Mutalub Yahkub Babatunde , Ibrahim Farida Buhari
Published: February 2024

Background

A major risk of herbal medicine is the potential for toxicity and serious side effects. Unlike orthodox medicine, herbs are usually consumed without prior safety assessment via clinical studies. This means the clinical effects of herbs may be detected only through an assessment of health parameters of consumers.

Objective

To evaluate participants’ renal profile, comparing that of herb users with non-users, thereby identifying any differences between the two groups.

Design

Cross-sectional study.

Setting

Primary care clinic of a teaching hospital in Nigeria

Participants

341 patients participated in the study. Of these, 60% were female and 80 % were of Hausa/Fulani ethnicity. All adult patients attending the clinic were eligible. Very sick patients were excluded from the research.

Primary outcome

estimated glomerular filtration rate, microalbuminuria and proteinuria among patients who reported using herbs and those who did not report any use.

Secondary outcome

electrolyte, urea, and creatinine levels among study participants.

Results

The mean eGFR for participants who used herbs was 87.47 ± 25.44 ml/min/1.73m2and 84.76 ± 25.49 ml/min/1.73m2for those who never used herbs (P value 0.48). Proteinuria ≥0.3g/l was present in 29(8.50%) of participants, and microalbuminuria ≥30mg/l in 138 (40.47%). There was no statistically significant difference in the renal parameters of both groups.

Conclusion

The study could not establish harmful effect of the herbs reported on kidney function. Further studies in human subjects of the effect of herbal medicine on the kidney and other systems are suggested.

Article Summary

Strengths and Limitations

This study provides empiric evidence to compare renal function among users of herbal medicine and others.

The study provides a detailed evaluation of renal function in the participants using estimated glomerular filtration rate, as well as urine protein and microalbumin estimation.

It identifies the common herbs used in a primary care clinic in the most populous black nation.

A major limitation of the study is that the quantity and frequency of herbal medicine use were not measured.
Mechanical confinement governs phenotypic plasticity in melanoma
Authors: Hunter Miranda V. , Montal Emily , Ma Yilun , Moncada Reuben , Yanai Itai , Koche Richard P. , White Richard M.
Published: February 2024

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes - proliferative versus invasive states. While it has long been hypothesised that such switching is triggered by external cues, the identity of these cues has remained elusive. Here, we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumor cells at the interface between the tumor and surrounding microenvironment. Morphological analysis of these rare cells showed flattened, elliptical nuclei suggestive of mechanical confinement by adjacent tissue. Spatial and single-cell transcriptomics demonstrated that the interface cells adopted a gene program of neuronal invasion, including acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favor the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2hightumor cells are less proliferative but more drug resistant. Our results implicate the mechanical microenvironment as a mechanism driving phenotype switching in melanoma.
Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance
Authors: Storey Claire M , Altai Mohamed , Lückerath Katharina , Zedan Wahed , Zhu Henan , Trajkovic-Arsic Marija , Park Julie , Peekhaus Norbert , Siveke Jens , Lilljebjörn Henrik , Abou Diane , Marks Haley , Ulmert Enna , Lilja Hans , Ridley Alexander , Safi Marcella , Yuen Constance , Geres Susanne , Mao Liqun , Cheng Michael , Czernin Johannes , Herrmann Ken , Bentolila Laurent , Yang Xia , Fioretos Thoas , Graeber Thomas , Sjöström Kjell , Damoiseaux Robert , Thorek Daniel , Ulmert David
Published: February 2024

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. We have developed a humanized monoclonal antibody (mAb), DUNP19, that specifically binds to a phylogenetically conserved LRRC15 epitope and is internalized by target-expressing cancer and stromal cells. In xenograft mouse models, Lutetium-177 labeled DUNP19 ([177Lu]-DUNP19) enables non-invasive imaging and precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts (CAFs), halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [177Lu]-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a transforming growth factor beta (TGFβ)-driven and LRRC15+ signature associated with immunotherapy resistance. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and aggressive disease.

SIGNIFICANCE

We introduce a pioneering LRRC15-guided radio-theranostic approach integrating clinical imaging and radioimmunotherapy. Our strategy utilizes a mAb, DUNP19, to target LRRC15-expressing cancer cells and fibroblasts, demonstrating significant tumor reduction, prolonged survival, and reversal of TGFβ-driven treatment resistance. This approach offers a promising strategy for improving outcomes in aggressive cancers.
CELL CYCLE STATE PREDICTION USING GRAPH NEURAL NETWORKS
Authors: Acharya Sayan , Ganguly Aditya , Sarkar Ram , Jose Abin
Published: February 2024

Mitosis is a crucial process ensuring the faithful transmission of the genetic information stored in the cell nucleus. Aberrations in this intricate process pose a significant threat to an organism’s health, leading to conditions like cancer and various diseases. Hence, the study of mitosis holds paramount importance. Recent investigations have involved manual and semiautomated analyses of time-lapse microscopy images to understand mitosis better. This paper introduces an approach for predicting mitosis stages, employing a Convolutional Neural Network (CNN) as the initial feature extractor, followed by a Graph Neural Network (GNN) for predicting cell cycle states. A distinctive timestamp is incorporated into the feature vectors, treating this information as a graph to leverage internal interactions for predicting the subsequent cell state. To assess performance, experiments were conducted on three datasets, demonstrating that our method exhibits comparable efficacy to state-of-the-art techniques.
Integrated Closed-loop Control of Bio-actuation for Proprioceptive Bio-hybrid Robots
Authors: Filippi Miriam , Balciunaite Aiste , Georgopoulou Antonia , Paniagua Pablo , Drescher Felix , Nie Minghao , Takeuchi Shoji , Clemens Frank , Katzschmann Robert
Published: February 2024

Biohybrid robots are emergent soft robots that combine engineered artificial structures and living biosystems to exploit unique characteristics of biological cells and tissues. Skeletal muscle tissue-based bio-actuators can respond to externally applied stimuli, such as electrical fields. However, current bio-actuation systems rely on open-loop control strategies that lack knowledge of the actuator’s state. The regulation of output force and position of bio-hybrid robots requires self-sensing control systems that combine bio-actuators with sensors and control paradigms. Here, we propose a soft, fiber-shaped mechanical sensor based on a composite with piezoresistive properties that efficiently integrates with engineered skeletal muscle tissue and senses its contracting states in a cell culture environment in the presence of applied electrical fields. After testing the sensor’s insulation and biocompatibility, we characterized its sensitivity for typical strains (<1%) and proved its ability to detect motions from contractile skeletal muscle tissue constructs. Finally, we showed that the sensor response can feed an autonomous control system, thus demonstrating the first proprioceptive bio-hybrid robot that can sense and respond to its contraction state. In addition to inspiring intelligent implantable systems, informative biomedical models, and other bioelectronic systems, the proposed technology will encourage strategies to exceed the durability, design, and portability limitations of biohybrid robots and confer them decisional autonomy, thus driving the paradigm shift between bio-actuators and intelligent bio-hybrid robots.

One Sentence Summary

Integrating soft mechanical sensors into engineered skeletal muscle tissue enables bio-hybrid robots with proprioception.
miR-210 is essential to retinal homeostasis in fruit flies and mice
Authors: Colaianni Davide , Virga Federico , Tisi Annamaria , Stefanelli Chiara , Zaccagnini Germana , Cusumano Paola , Sales Gabriele , Ivan Mircea , Martelli Fabio , Taverna Daniela , Mazzone Massimiliano , Bertolucci Cristiano , Maccarone Rita , De Pittà Cristiano
Published: February 2024

miR-210 is one of the most evolutionarily conserved microRNAs. Recent studies inDrosophila melanogasterhave unveiled that the absence of miR-210 leads to a progressive retinal degeneration characterized by the accumulation of lipid droplets and disruptions in lipid metabolism. Further investigation into lipid anabolism and catabolism revealed significant alterations in gene expression within these pathways. We provide the first morphological characterization of miR-210 KO mice retinas, highlighting a significant photoreceptor degeneration. While exploring potential parallels between miR-210 KO models in flies and mice, we examined mice lipid metabolism, circadian behaviour, and retinal transcriptome yet found no resemblances, suggesting divergent mechanisms of retinal degeneration between the two species. Simultaneously, analysis of the transcriptome in the brains of miR-210 KO flies revealed the potential existence of a shared upstream mechanism contributing to retinal degeneration in both fruit flies and mammals.
A mutant ASXL1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia
Authors: Dong Zhen , Sepulveda Hugo , Arteaga-Vazquez Leo J. , Blouin Chad , Fernandez Jenna , Binder Moritz , Chou Wen-Chien , Tien Hwei-Fang , Patnaik Mrinal , Faulkner Geoffrey J , Myers Samuel A , Rao Anjana
Published: February 2024

ASXL1is one of the three most frequently mutated genes in age-related clonal hematopoiesis (CH), alongsideDNMT3AandTET2. CH can progress to myeloid malignancies including chronic monomyelocytic leukemia (CMML), and is also strongly associated with inflammatory cardiovascular disease and all-cause mortality in humans. DNMT3A and TET2 regulate DNA methylation and demethylation pathways respectively, and loss-of-function mutations in these genes reduce DNA methylation in heterochromatin, allowing de-repression of silenced elements in heterochromatin. In contrast, the mechanisms that connect mutant ASXL1 and CH are not yet fully understood. CH/CMML-associatedASXL1mutations encode C-terminally truncated proteins that enhance the deubiquitinase activity of the ASXL-BAP1 “PR-DUB” deubiquitinase complex, which removes mono-ubiquitin from H2AK119Ub. Here we show that ASXL1 mutant proteins interact with the EHMT1-EHMT2 methyltransferase complex, which generates H3K9me1 and me2, the latter a repressive modification in constitutive heterochromatin. Compared to cells from age-matched wildtype mice, we found that expanded myeloid cells from old (≥18-month-old)Asxl1tm/+mice, a heterozygous knock-in mouse model of CH, display genome-wide decreases of H3K9me2, H3K9me3 and H2AK119Ub as well as an associated increase in expression of transposable elements (TEs) and satellite repeats. Increased TE expression was also observed in monocytes fromASXL1-mutant CMML patients compared to monocytes from healthy controls. Our data suggest that mutant ASXL1 proteins compromise the integrity of both constitutive and facultative heterochromatin in an age-dependent manner, by reducing the levels of H3K9me2/3 and H2AK119Ub. This increase in TE expression correlated with increased expression of nearby genes, including many interferon-inducible (inflammation-associated) genes (ISGs).

Significance Statement

Age-related clonal hematopoiesis (CH) is a premalignant condition associated with inflammatory cardiovascular disease.ASXL1mutations are very frequent in CH. We show that ASXL1 interacts with EHMT1 and EHMT2, H3K9 methyltransferases that deposit H3K9me1 and me2. Using a mouse model of mutantASXL1to recapitulate CH, we found that old ASXL1-mutant mice showed marked expansion of myeloid cells in bone marrow, with decreased H3K9me2/3 and increased expression of transposable elements (TEs) in heterochromatin. In humans, ASXL1-mutant CH progresses to chronic monomyelocytic leukemia (CMML); CMML patient samples showed striking upregulation of many TE families, suggesting that ASXL1 mutations compromise heterochromatin integrity, hence causing derepression of TEs. Targeting heterochromatin-associated proteins and TEs might counter the progression of CH, CMML and other myeloid malignancies.
Identifying compositional and density changes across the Murine and Human Dentin-enamel Junction
Authors: Truhlar Michael , Rosenberg Bradley , Katebifar Sobhan , Kroger Roland , Deymier Alix
Published: February 2024

Human and mouse incisors are both primarily composed of dentin and enamel which meet at an interface called the dentin-enamel junction (DEJ). However, incisors in the two species have very different growth patterns, structures, and loading requirements. Since the DEJ is responsible for minimizing cracking at this at-risk interface between mechanically dissimilar dentin and enamel, its structure is expected to be significantly different between humans and mice. Here, strucutral and compositional gradients across human and murine incisors DEJs were measured via microcomputed tomography and Raman spectroscopy. Density gradients across the DEJ were significantly larger in humans compared to murine teeth likely due to the larger size of the mantle dentin. Multiple gradients in mineral content and crystallinity were found at the murine DEJ while the human DEJ only exhibited gradients in mineral content. Models predicting the modulus across the DEJ according to compositional results show that mineral crystallinity is critical in regulating the mechanical gradient across the murine DEJ. Together these results show the multiple ways in which the DEJ can adapt to variations in loading environment.
Single-Cell Peripheral Immunoprofiling of Lewy Body Disease in a Multi-site Cohort
Authors: Phongpreecha Thanaphong , Mathi Kavita , Cholerton Brenna , Fox Eddie J. , Sigal Natalia , Espinosa Camilo , Reincke Momsen , Chung Philip , Hwang Ling-Jen , Gajera Chandresh R. , Berson Eloise , Perna Amalia , Xie Feng , Shu Chi-Hung , Hazra Debapriya , Channappa Divya , Dunn Jeffrey E. , Kipp Lucas B. , Poston Kathleen L. , Montine Kathleen S. , Maecker Holden T. , Aghaeepour Nima , Montine Thomas J.
Published: February 2024

Studies implicated peripheral organs involvement in the development of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson’s Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). This study characterized peripheral immune responses unique to LBD at single-cell resolution. Peripheral mononuclear cell (PBMC) samples were collected from sites across the U.S. The diagnosis groups comprise healthy controls (HC, n=164), LBD (n=132), Alzheimer’s disease dementia (ADD, n=98), other neurodegenerative disease controls (NDC, n=21), and immune disease controls (IDC, n=14). PBMCs were activated with three stimulants, stained by surface and intracellular signal markers, and analyzed by flow cytometry, generating 1,184 immune features. Our model classified LBD from HC with an AUROC of 0.90±0.06. The same model distinguished LBD from ADD, NDC, IDC, or other common conditions associated with LBD. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations and activations.
Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy
Authors: Khetarpal Sumeet A. , Li Haobo , Vitale Tevis , Rhee James , Grauvogel Louisa , Castro Claire , Mittenbühler Melanie J. , Houstis Nicholas E. , Vargas-Castillo Ariana , Smythers Amanda L. , Liu Jing , Curtin Casie , Sprenger Hans-Georg , Blackmore Katherine A. , Kuznetsov Alexandra , Freeman Rebecca , Bogoslavski Dina , Ellinor Patrick T. , Asnani Aarti , Dumesic Phillip A. , Puigserver Pere , Roh Jason D. , Spiegelman Bruce M. , Rosenzweig Anthony
Published: February 2024

Exercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1α is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1α, but it is unclear whether cardiomyocyte PGC-1α is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1α is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1α, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1α as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1α-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1α-deficient mice during endurance training. Finally, we show that cardiomyocytePPARGC1Aexpression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1α as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.
Chronic Pod-Mod E-Cigarette Aerosol Exposure Induces Aortic Dysfunction in Hypercholesterolemic Mice: Role of Oxidative Stress and Inflammation
Authors: Farra Yasmeen M. , Matz Jacqueline , Wilker Hannah , Kim Hannah , Rivera Cristobal , Vlahos John , Ramkhelawon Bhama , Oakes Jessica M. , Bellini Chiara
Published: February 2024

Objective

Electronic (e-)cigarettes are the most used tobacco product amongst youth, and adult smokers favor e-cigarettes over approved cessations aids. Despite the lower perceived harm of vaping compared to smoking, inhalation of e-cigarette aerosol elicits cardiovascular responses that may lead to permanent injury when repeated over time. We thus aimed to infer the long-term outcomes of vaping on the function and structure of the aorta and shed light on the underlying cellular and molecular mechanisms.

Approach and Results

We exposed female hypercholesterolemic mice to either pod-mod e-cigarette aerosol or room air daily for 24 weeks. Chronic inhalation of e-cigarette aerosol triggered accumulation of inflam-matory signals systemically and within aortic tissues, as well as T lymphocyte accrual in the aortic wall. Reduced eNOS expression and enhanced ROS production following eNOS uncoupling and NADPH oxi-dase activation curbed nitric oxide availability in the aorta of mice exposed to e-cigarette aerosol, impairing the endothelium-dependent vasodilatation that regulates blood flow distribution. Inhalation of e-cigarette aerosol thickened and stiffened aortic tissues via collagen deposition and remodeling, hindering the storage of elastic energy and limiting the cyclic distensibility that enables the aorta to function as a pressure reservoir. These effects combined contributed to raising systolic and pulse pressure above control levels.

Conclusions

Chronic inhalation of aerosol from pod-mod e-cigarettes promotes oxidative stress, inflammation, and fibrosis within aortic tissues, significantly impairing passive and vasoactive aortic functions. This evidence provides new insights on the biological processes that increase the risk for adverse cardio-vascular events as a result of pod-mod e-cigarette vaping.
Population-based analysis of knee joint loading in a knee osteoarthritis cohort: the impact of PCA-derived gait kinematic variations on estimated medial knee contact forces
Authors: Di Raimondo Giacomo , Willems Miel , Killen Bryce Adrian , Havashinezhadian Sara , Turcot Katia , Vanwanseele Benedicte , Jonkers Ilse
Published: February 2024

Osteoarthritis (OA) is a prevalent musculoskeletal condition leading to functional limitations, especially among the elderly. Current treatments focus on pain relief and functional improvement, however there is a lack of approaches which slow disease progression. A promising approach focusses on reducing knee joint loading, as excessive loading contributes to knee OA progression. This study explores kinematic variations in the knee OA population, utilizing principal component analysis (PCA) to examine gait variations (primitives) in both healthy individuals and those with knee osteoarthritis (KOA) and their implications for knee joint loading. The KOA population exhibited 14 modes of variation representing 95% of the cumulative variance, compared to 20 in the healthy population, indicating lower variability with KOA. The relation between identified gait primitives and knee loading parameters, revealed complex relationships. Surprisingly, modes with the largest kinematic variations did not consistently correspond to the highest variations in knee loading parameters revealing degrees of freedom which may have a larger role in determining joint loading. Moreover, potential gait-retraining strategies for KOA, associating specific kinematic combinations with altered knee loading were identified. The results showed a good agreement with previously applied strategies. However, this study highlights the importance of analyzing whole-body kinematics for effective gait retraining, as opposed to focusing on one single joint variation. The study’s insights contribute to understanding the intricate interplay between gait pattern variations and knee joint loading changes in healthy and KOA populations, offering practical applications for guiding interventions and estimating loading parameters.
A Stacking Framework for Polygenic Risk Prediction in Admixed Individuals
Authors: Liao Kevin , Zöllner Sebastian
Published: February 2024

1.1

Polygenic risk scores (PRS) are summaries of an individual’s personalized genetic risk for a trait or disease. However, PRS often perform poorly for phenotype prediction when the ancestry of the target population does not match the population in which GWAS effect sizes were estimated. For many populations this can be addressed by performing GWAS in the target population. However, admixed individuals (whose genomes can be traced to multiple ancestral populations) lie on an ancestry continuum and are not easily represented as a discrete population.

Here, we propose slaPRS (stackinglocalancestryPRS), which incorporates multiple ancestry GWAS to alleviate the ancestry dependence of PRS in admixed samples. slaPRS uses ensemble learning (stacking) to combine local population specific PRS in regions across the genome. We compare slaPRS to single population PRS and a method that combines single population PRS globally. In simulations, slaPRS outperformed existing approaches and reduced the ancestry dependence of PRS in African Americans. In lipid traits from African British individuals (UK Biobank), slaPRS again improved on single population PRS while performing comparably to the globally combined PRS. slaPRS provides a data-driven and flexible framework to incorporate multiple population-specific GWAS and local ancestry in samples of admixed ancestry.
Socioeconomic correlates of urban mobility trends in two Australian cities during transitional periods of the COVID-19 pandemic
Authors: Kollepara Pratyush , Dey Subhrasankha , Tomko Martin , Martino Erika , Bentley Rebecca , Tizzoni Michele , Geard Nicholas , Zachreson Cameron
Published: February 2024

During the COVID-19 pandemic, both government-mandated lockdowns and discretionary changes in behaviour combined to produce dramatic and abrupt changes to human mobility patterns. To understand the socioeconomic determinants of intervention compliance and discretionary behavioural responses to epidemic threats, we investigate whether changes in human mobility showed a systematic variation with socioeconomic status during two distinct periods of the COVID-19 pandemic in Australia. We analyse mobility data from two major urban centres and compare the trends during mandated stay-at-home policies and after the full relaxation of NPIs, which coincided with a large surge of COVID-19 cases. We analyse data aggregated from de-identified GPS trajectories, collated from providers of mobile phone applications and aggregated to small spatial regions. Our results demonstrate systematic decreases in mobility relative to pre-pandemic baseline with the Index of Education and Occupation, for both pandemic periods. On the other hand, the Index of Economic Resources was not correlated with mobility changes. This result contrasts with observations from other national contexts, where reductions in mobility typically increased strongly with indicators of wealth. We interpret these findings in the context of the economic policies put in place by Australian authorities to subsidise household incomes and maintain the essential workforce.
Automated Deep Learning Segmentation of Cardiac Inflammatory FDG PET
Authors: Poitrasson-Rivière Alexis , Vanderver Michael D. , Hagio Tomoe , Arida-Moody Liliana , Moody Jonathan B. , Renaud Jennifer M. , Ficaro Edward P. , Murthy Venkatesh L.
Published: February 2024

Background

Fluorodeoxyglucose positron emission tomography (FDG PET) with glycolytic metabolism suppression plays a pivotal role in diagnosing cardiac sarcoidosis. Reorientation of images to match perfusion datasets is critical and myocardial segmentation enables consistent image scaling and quantification. However, both are challenging and labor intensive. We developed a 3D U-Net deep learning (DL) algorithm for automated myocardial segmentation in cardiac sarcoidosis FDG PET.

Methods

The DL model was trained on 316 patients’ FDG PET scans, and left ventricular contours derived from perfusion datasets. Qualitative analysis of clinical readability was performed to compare DL segmentation with the current automated method on a 50-patient test subset. Additionally, left ventricle displacement and angulation, as well as SUVmax sampling were compared to inter-user reproducibility results.

Results

DL segmentation enhanced readability scores in over 90% of cases compared to the standard segmentation currently used in the software. DL segmentation performed similarly to a trained technologist, surpassing standard segmentation for left ventricle displacement and angulation, as well as correlation of SUVmax.

Conclusion

The DL-based automated segmentation tool presents a marked improvement in the processing of cardiac sarcoidosis FDG PET, promising enhanced clinical workflow. This tool holds significant potential for accelerating clinical practice and improving consistency and quality. Further research with varied datasets is warranted to broaden its applicability.
Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
Authors: Touvier Thierry , Veneri Francesca A. , Claessens Anke , Ferri Cinzia , Mastrangelo Rosa , Sorgiati Noémie , Bianchi Francesca , Valenzano Serena , Del Carro Ubaldo , Rivellini Cristina , Duong Phu , Shy Michael E. , Kelly Jeffery W. , Svaren John , Wiseman R. Luke , D’Antonio Maurizio
Published: February 2024

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing ofXbp1mRNA to generate splicedXbp1(Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models whereXbp1is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed thatXbp1is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However,Xbp1deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy inXbp1deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
The Effect of Adrenalectomy on Bleomycin-Induced Pulmonary Fibrosis in Mice
Authors: McGovern John , Perry Carrighan , Ghincea Alexander , Shao Shuai , Herzog Erica L. , Sun Huanxing
Published: February 2024

Progressive lung fibrosis is often fatal and has limited treatment options. Though the mechanisms are poorly understood, fibrosis is increasingly linked with catecholamines such as adrenaline (AD) and noradrenaline (NA), and hormones such as aldosterone (ALD). The essential functions of adrenal glands include the production of catecholamines and numerous hormones, but the contribution of adrenal glands to lung fibrosis remains less well studied. Here, we characterized the impact of surgical adrenal ablation in the bleomycin model of lung fibrosis. Wild type mice underwent surgical adrenalectomy or sham surgery followed by bleomycin administration. We found that the bleomycin induced collagen over deposition in the lung was not affected by adrenalectomy. However, histologic indices of lung remodeling were ameliorated by adrenalectomy. These findings were accompanied by a decrease in bronchoalveolar lavage (BAL) cell count along with concomitant reductions in alpha smooth muscle actin (⍺SMA) and fibronectin. Surgical adrenalectomy completely abrogated AD detection in all compartments, but only reduced NA in the BAL of uninjured mice. Systemic ALD levels were reduced after adrenalectomy. Taken together, these results support the presence of pulmonary-adrenal axis in lung fibrosis and suggest that adrenalectomy is protective in this disease. Further investigation will be needed to better understand this observation and aid in the development of novel therapeutic strategies.