Depletion Model Research Articles

DOP112 Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis

Abstract Background ACOD1 is the ubiquitous source of the anti-inflammatory metabolite itaconate. We hypothesised monocyte ACOD1 expression is an inhibitory pathway that limits intestinal inflammation. Methods We performed single-cell RNA sequencing of colonoscopic biopsies from >120 Crohn’s disease (CD) patients and healthy controls, with complementary analysis of DSS treated C57BL/6J (WT) mice, validated using flow cytometry in independent cohorts. Acod1–/– mice received 2% DSS in acute and recovery models, complemented by competitive bone marrow chimeric mice, anti-IFN / itaconate-derivate treatment and transgenic cell depletion models. Results We profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of intestinal CXCL9/10+ cells that accumulate in IBD, which we term inflammation associated monocytes (IAMs). These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate specific expression of IBD susceptibility genes, including NOD2. By performing cross-species analysis in mice, we show an analogous population of IAMs accumulate during chemically induced colitis. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete MDP-precursor in the bone marrow and are locally imprinted to produce heightened IL-1β and TNF in mouse and humans. Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production. Conclusion Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health. Reduced itaconate production from IAMs in CD may predispose to chronic inflammation and disease progression.

Formation control for multiple nonholonomic wheeled mobile robots based on integrated sliding mode controller and force function

In this paper, we present a novel method to achieve collision-free formation control for multiple nonholonomic wheeled mobile robots. By utilizing the leader–follower strategy, an integrated controller that combines a sliding mode controller for formation control and a force function for obstacle avoidance is proposed. To address the common chattering issue associated with sliding mode control, a novel depletion model is developed, which constrains the controller input to vary smoothly within a small range and effectively eliminates chattering. Additionally, a dynamic-gain structure is introduced to reconcile the conflicting demands of formation control and obstacle avoidance, providing enhanced coordination between the two tasks. Simulation and experiments’ results are provided to illustrate the effectiveness of the proposed method.

Projecting Climate Change Impacts on Channel Depletion in the Sacramento–San Joaquin Delta of California in the 21st Century

The Sacramento–San Joaquin Delta (Delta) is a critical hub of California’s statewide water distribution system. Located at the confluence of California’s two largest rivers, the Sacramento River and the San Joaquin River, the Delta features a complex network of braided channels and over a hundred islands, most of which are located below sea level. The Delta’s complex nature and low-lying topography make it a unique hydrological area pertinent to climate change studies. This paper aims to estimate and explore the potential effects of climate change on the hydrological features of the Delta, especially Net Channel Depletion (NCD), which is one of the main contributors to the Net Delta Outflow (NDO). Downscaled CMIP6 General Circulation Model outputs are used to generate plausible future climate data. The Delta Channel Depletion model (DCD) is used to simulate daily hydrological processes for 61 plausible future climate scenarios. Simulation models are applied to the historical period (1930–2014) and projected future periods (2016–2100). A thorough water balance is computed in the DCD simulation model, offering insights into various elements in the hydrological cycle. Key hydrological features such as crop evapotranspiration, seepage, drainage, and runoff are simulated. Potential changes in NCD, calculated as the sum of diversions and seepage minus drainage, are also examined. The study identified a wide range of increases in NCD across all scenarios in the future period relative to the average of the historical period. These increases are projected to vary from 0.3% up to 20%. Moreover, a spatial analysis conducted across diverse regions of the Delta highlights notable variations in depletion across these areas. The results of this research indicate an anticipated increased stress on water resources, necessitating the adoption of innovative strategies to manage extreme events effectively and ensure the sustainability and resilience of water resource management.

MiR-199a-5p aggravates renal ischemia-reperfusion and transplant injury by targeting AKAP1 to disrupt mitochondrial dynamics.

Renal ischemia-reperfusion injury (IRI) is a complex pathophysiological process and a major cause of delayed graft function (DGF) after transplantation. MicroRNA (miRNA) has important roles in the pathogenesis of IRI and may represent promising therapeutic targets for mitigating renal IRI. miRNA sequencing was performed to profile microRNA expression in mouse kidneys after cold storage and transplantation (CST). Lentivirus incorporating a miR-199a-5p modulator was injected into mouse kidney in situ before syngenetic transplantation and unilateral IRI to determine the effect of miR-199a-5p in vivo. miR-199a-5p mimic or inhibitor was transfected cultured tubular cells before ATP depletion recovery treatment to examine the role of miR-199a-5p in vitro. Sequencing data and microarray showed upregulation of miR-199a-5p in mice CST and human DGF samples. Lentivirus incorporating a miR-199a-5p mimic aggravated renal IRI, and protective effects were obtained with a miR-199a-5p inhibitor. Treatment with the miR-199a-5p inhibitor ameliorated graft function loss, tubular injury, and immune response after CST. In vitro experiments revealed exacerbation of mitochondria dysfunction upon ATP depletion and repletion model in the presence of the miR-199a-5p mimic, whereas dysfunction was attenuated when the miR-199a-5p inhibitor was applied. miR-199a-5p was shown to target A-kinase anchoring protein 1 (AKAP1) by double luciferase assay and miR-199a-5p activation reduced dynamin-related protein 1 (Drp1)-s637 phosphorylation and mitochondrial length. Overexpression of AKAP1 preserved Drp1-s637 phosphorylation and reduced mitochondrial fission. miR-199a-5p activation reduced AKAP1 expression, promoted Drp1-s637 dephosphorylation, aggravated the disruption of mitochondrial dynamics, and contributed to renal IRI.NEW & NOTEWORTHY This study identifies miR-199a-5p as a key regulator in renal ischemia-reperfusion injury through microRNA sequencing in mouse models and human delayed graft function. miR-199a-5p worsens renal IRI by aggravating graft dysfunction, tubular injury, and immune response, while its inhibition shows protective effects. miR-199a-5p downregulates A-kinase anchoring protein 1 (AKAP1), reducing dynamin-related protein 1 (Drp1)-s637 phosphorylation, increasing mitochondrial fission, and causing dysfunction. Targeting the miR-199a-5p/AKAP1/Drp1 axis offers therapeutic potential for renal IRI, as AKAP1 overexpression preserves mitochondrial integrity by maintaining Drp1-s637 phosphorylation.

A Census of the β Pic Moving Group and Other Nearby Associations with Gaia* * Based on observations made with the Gaia mission, the Two Micron All Sky Survey, the Wide-field Infrared Survey Explorer, the NASA Infrared Telescope Facility, Cerro Tololo Inter-American Observatory, the Southern Astrophysical Research Telescope, Gemini Observatory, the Spitzer Space Telescope, and the eROSITA instrument on the

I have used the third data release of the Gaia mission to improve the reliability and completeness of membership samples in the β Pic moving group (BPMG) and other nearby associations with ages of 20–50 Myr (Sco Body, Carina, Columba, χ 1 For, Tuc-Hor, IC 2602, IC 2391, NGC 2547). I find that Carina, Columba, and χ 1 For are physically related and coeval, and that Carina is the closest fringe of a much larger association. Similarly, Tuc-Hor and IC 2602 form a coeval population that is spatially and kinematically continuous. Both results agree with hypotheses from Gagné et al. I have used the new catalogs to study the associations in terms of their initial mass functions, X-ray emission, ages, and circumstellar disks. For instance, using the model for Li depletion from Jeffries et al., I have derived an age of 24.7−0.6+0.9 Myr for BPMG, which is similar to estimates from previous studies. In addition, I have used infrared photometry from the Wide-field Infrared Survey Explorer to check for excess emission from circumstellar disks among the members of the associations, which has resulted in a dramatic increase in the number of known disks around M stars at ages of 30–50 Myr and a significant improvement in measurements of excess fractions for those spectral types and ages. Most notably, I find that the W3 excess fraction for M0–M6 initially declines with age to a minimum in BPMG (<0.015), increases to a maximum in Carina/Columba/χ 1 For ( 0.041−0.007+0.009 , 34 Myr), and declines again in the oldest two associations (40–50 Myr). The origin of that peak and the nature of the M dwarf disks at >20 Myr are unclear.

Using neural network models to estimate stellar ages from lithium equivalent widths: an eagles expansion

ABSTRACT We present an artificial neural network (ANN) model of photospheric lithium depletion in cool stars ($3000\lt T_{\rm eff}/{\rm K} \lt 6500$), producing estimates and probability distributions of age from $^7$Li 6708 Å equivalent width (LiEW) and effective temperature data inputs. The model is trained on the same sample of 6200 stars from 52 open clusters, observed in the Gaia-ESO spectroscopic survey, and used to calibrate the previously published analytical eagles model, with ages 2–6000 Myr and $-0.3 \lt $ [Fe/H] $\lt 0.2$. The additional flexibility of the ANN provides some improvements, including better modelling of the ‘lithium dip’ at ages $\lt 50$ Myr and $T_{\rm eff}\sim 3500$ K, and of the intrinsic dispersion in LiEW at all ages. Poor age discrimination is still an issue at ages &amp;gt;1 Gyr, confirming that additional modelling flexibility is not sufficient to fully represent the LiEW–age–T$_{\text{eff}}$ relationship, and suggesting the involvement of further astrophysical parameters. Expansion to include such parameters–rotation, accretion, and surface gravity–is discussed, and the use of an ANN means these can be more easily included in future iterations, alongside more flexible functional forms for the LiEW dispersion. Our methods and ANN model are provided in an updated version 2.0 of the eagles software.

229.1: A study of menopause effects on lung inflammation after brain death using a model of transitional follicular depletion with aging.

229.1: A study of menopause effects on lung inflammation after brain death using a model of transitional follicular depletion with aging.

A 187Re-187Os and highly siderophile element study of diamondiferous kimberlite melt-mantle interactions and the inferred age of continental lithosphere

The ∼ 1.15-billion-year-old (Ga) Premier kimberlite pipe (Cullinan diamond mine), South Africa, is composed of several distinct kimberlite facies (Grey, Brown, Pale Piebald, Dark Piebald, Black Coherent [Type 3C], Blue/Brown Transitional, and Fawn). We report bulk rock Re-Os isotope data for Premier kimberlite facies, as well as for a suite of entrained peridotite and mafic xenoliths. These data are complemented by bulk rock highly siderophile element (HSE: Re, Pd, Pt, Ru, Ir, Os), major- and trace-element abundances. Measured 187Os/188Os for the kimberlite facies range from 0.1223 to 0.1672 (γOsi of −2.5 to + 17.4), peridotite xenoliths range from 0.1096 to 0.1244 (γOsi of −13.3 to −1.1), and pyroxenite xenoliths range from 0.1796 to 0.938 (γOsi of + 27 to + 419). A single measured amphibolite xenolith has the most radiogenic measured 187Os/188Os of 2.86 (γOsi of + 43). Harzburgite xenoliths yield time of rhenium depletion model ages (TRD) of ∼ 1.5 to 2.8 Ga, consistent with average TRD ages for Premier peridotites (2.4 ± 0.4 Ga). With these and published data, we considered the relationships between kimberlite and mantle xenoliths, compare estimates of relative peridotite incorporation to sampled diamond grade, and explore recratonization versus refertilization arguments with regards to TRD model ages. Kimberlite melt infiltration into Premier peridotite xenoliths is evident from melt veins accounting for ∼ 2 and ∼ 14 modal % of samples, and has led to incompatible element enrichment, including elevated Re. In turn, kimberlites show geochemical evidence for addition of peridotite xenolith fragments, with Type 3C having > 30 % more peridotite contribution than the Brown volcaniclastic facies. Kimberlites and peridotites plot on a 187Re/188Os versus 187Os/188Os mixing line (R2 = 0.92), with kimberlites having older apparent ages than the true age of crystallization. This mixing line provides estimates of lithospheric incorporation into the kimberlites, where the units with higher peridotite incorporation do not correlate with diamond grade. This is likely due to lithological and post-emplacement alteration heterogeneity within the kimberlite units, perhaps also reflecting the eclogitic paragenesis of many Premier diamonds. The peridotites provide evidence for the nature of the lithosphere beneath Premier prior to ∼ 1.15 Ga. Metasomatism of the peridotites is possibly linked to the Bushveld Igneous Event at ∼ 2 Ga, as well as to other magmatic events that affected the Kaapvaal craton from the Archean to the Mesoproterozoic. Premier peridotites do not suggest that the cratonic lithosphere beneath the region was completely replaced. Samples with Proterozoic TRD eruption model ages may represent Archean lithosphere that experienced alteration by metasomatism and modification, such as during the Bushveld Igneous Event.

Induction of osteoblast apoptosis stimulates macrophage efferocytosis and paradoxical bone formation

Apoptosis is crucial for tissue homeostasis and organ development. In bone, apoptosis is recognized to be a main fate of osteoblasts, yet the relevance of this process remains underexplored. Using our murine model with inducible Caspase 9, the enzyme that initiates intrinsic apoptosis, we triggered apoptosis in a proportion of mature osteocalcin (OCN+) osteoblasts and investigated the impact on postnatal bone development. Osteoblast apoptosis stimulated efferocytosis by osteal macrophages. A five-week stimulation of OCN+ osteoblast apoptosis in 3-week-old male and female mice significantly enhanced vertebral bone formation while increasing osteoblast precursors. A similar treatment regimen to stimulate osterix+ cell apoptosis had no impact on bone volume or density. The vertebral bone accrual following stimulation of OCN+ osteoblast apoptosis did not translate in improved mechanical strength due to disruption of the lacunocanalicular network. The observed bone phenotype was not influenced by changes in osteoclasts but was associated with stimulation of macrophage efferocytosis and vasculature formation. Phenotyping of efferocytic macrophages revealed a unique transcriptomic signature and expression of factors including VEGFA. To examine whether macrophages participated in the osteoblast precursor increase following osteoblast apoptosis, macrophage depletion models were employed. Depletion of macrophages via clodronate-liposomes and the CD169-diphtheria toxin receptor mouse model resulted in marked reduction in leptin receptor+ and osterix+ osteoblast precursors. Collectively, this work demonstrates the significance of osteoblast turnover via apoptosis and efferocytosis in postnatal bone formation. Importantly, it exposes the potential of targeting this mechanism to promote bone anabolism in the clinical setting.

Mechanically induced M2 macrophages are involved in bone remodeling of the midpalatal suture during palatal expansion

BackgroundPalatal expansion is a common way of treating maxillary transverse deficiency. Under mechanical force, the midpalatal suture is expanded, causing local immune responses. This study aimed to determine whether macrophages participate in bone remodeling of the midpalatal suture during palatal expansion and the effects on bone remodeling.MethodsPalatal expansion model and macrophage depletion model were established. Micro-CT, histological staining, and immunohistochemical staining were used to investigate the changes in the number and phenotype of macrophages during palatal expansion as well as the effects on bone remodeling of the midpalatal suture. Additionally, the effect of mechanically induced M2 macrophages on palatal osteoblasts was also elucidated in vitro.ResultsThe number of macrophages increased significantly and polarized toward M2 phenotype with the increase of the expansion time, which was consistent with the trend of bone remodeling. After macrophage depletion, the function of osteoblasts and bone formation at the midpalatal suture were impaired during palatal expansion. In vitro, conditioned medium derived from M2 macrophages facilitated osteogenic differentiation of osteoblasts and decreased the RANKL/OPG ratio.ConclusionsMacrophages through polarizing toward M2 phenotype participated in midpalatal suture bone remodeling during palatal expansion, which may provide a new idea for promoting bone remodeling from the perspective of regulating macrophage polarization.

Abstract Tu023: The VEGF-A splice variants as a mechanism of impaired Inflammatory Angiogenesis in the context of advanced aging.

Background and Objectives: Aging and age-related diseases like peripheral artery disease (PAD) is associated with impairment of angiogenesis responses to injury. Critical ischemic limb and wound injury animal models have shown impact of monocytes/macrophages as a major source of angiogenic mediators leading to new arterial growth. Aging has also been associated with impairment of blood flow recovery and reduced VEGF-A expression in animals. However, recombinant VEGF-A administration or clinical trials involving VEGF-A have not fully overcome the foot perfusion and prevent limb/leg amputation. We sought to understand molecular mechanisms of reduced VEGF-A expression which remain incomplete in the context of advanced aging. Results: Firstly, in hindlimb ischemia mouse model, our data from liposomes containing-clodronate treated mice (12-weeks C57Bl6 with macrophage depletion model ) ( Fig. 1a ) demonstrate impairment of blood flow recovery compared to Control group. On day 3 post-surgery, VEGF-A and VEGF-A isoforms expression (VEGF-A 165 a and VEGF-A 165 b, respectively) were reduced in ischemic muscle. Fluorescence staining showed a reduction of macrophages (CD68 + ) was also associated with reduced endothelial cells (CD31 + ). Using a myeloid-specific and inducible deleted VEGF fl/fl mice, we then have shown a key role of early inflammatory macrophages stage as a major source of VEGF-A required for angiogenesis in young mice (Fig. 1b). Secondly, bone marrow-derived-macrophages (BMDMs) from C57Bl6 104-weeks mice also demonstrate reduced VEGF-A expression. Aged BMDMs demonstrate reduced VEGF-A 165 a while VEGF-A 165 b was highly increased. Polarized BMDMs from 12-weeks demonstrate increased VEGFR1 in “M2" macrophages while VEGFR2 was increased in “M1” macrophages. On the other hand, BMDMs from 104-weeks demonstrate reduced VEGFR2 expression while VEGFR1 was unaffected compared to young. Lastly, 104-weeks mice also demonstrate severe impairment of blood flow recovery ( Fig. 2 ) after surgery and reduced VEGF-A and VEGF-A 165 a in ischemic muscle tissue. VEGF-A 165 b was increased and both receptors, VEGF-R1/R2 levels ( Fig. 3 ) were also reduced. Fluorescence staining on day 3 post ligation demonstrates reduced endothelial cells recruitment in muscle tissue while macrophage (CD68+) number was similar. Conclusion: Our investigations will contribute to define mechanisms whereby vascular injury is associated with VEGF-A isoforms specific switch in the context of advanced aging.

Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues.

Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors Acvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent in vivo neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

Turing bifurcation in activator–inhibitor (depletion) models with cross‐diffusion and nonlocal terms

Turing bifurcation in activator–inhibitor (depletion) models with cross‐diffusion and nonlocal terms

Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments

This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper’s role in TME.

Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression

ObjectiveThe metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains...

Intestinal epithelial Cldn-7 regulates intestinal inflammation by altering the gut microbiota

Background and aimTight junctions maintain gut homeostasis by forming a physical barrier that protects the gut from invasion by microbiota. Cldn-7 is an important component involved in this protection, but the relationship between Cldn-7, intestinal inflammation, and gut microbiota has not been clarified. Here, we hypothesize that Cldn-7 depletion affects intestinal inflammation by altering the gut microbiota. MethodsBased on the induced intestinal condition of Cldn-7 knockout mice (Cldn7fl/fl;villin-CreaERT2), we established the intestinal flora depletion model and colitis model by antibiotic drinking and feeding with dextran sodium sulfate (DSS). The environment of Cldn-7 gene deletion mice was changed by co-housing experiment. AB-PAS staining and Muc2 were used to detect the effect of co-housing and Cldn-7 deficiency on the mucus layer after flora depletion. qRT-PCR was used to detect the expression of intestinal inflammatory factors and AMPs in mice. Feces were collected and proportions of microbiota were analyzed by 16 S rRNA amplicon sequencing. ResultsMice in the co-housing experiment had altered intestinal microbiota, including diversity, composition, and functional prediction, compared to controls. Intestinal inflammation was restored to some extent following altered intestinal microbiota. The intestinal inflammation caused by Cldn-7 deficiency and susceptibility to DSS could be reduced after antibiotic administration compared to controls, in terms of phenotype, pathological changes, inflammatory factors, mucus barrier, and expression of AMPs. ConclusionsIn analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal disruption of Cldn-7, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. Cldn-7might therefore be an important mediator of host–microbiome interactions. Our research has revealed that Cldn-7 plays an indispensable role in maintaining intestinal homeostasis by regulating the gut microbiota and impacting intestinal inflammation. These findings provide new insights into the pathogenesis of ulcerative colitis.

Multi-level Factors Associated with HIV Late Presentation with Advanced Disease and Delay Time of Diagnosis in South Carolina, 2005–2019

This study explored individual- and county-level risk factors of late presentation with advanced disease (LPAD) among people with HIV (PWH) and their longer delay time from infection to diagnosis in South Carolina (SC), using SC statewide Enhanced HIV/AIDS Reporting System (eHARS). LPAD was defined as having an AIDS diagnosis within three months of initial HIV diagnosis, and delay time from HIV infection to diagnosis was estimated using CD4 depletion model. 3,733 (41.88%) out of 8,913 adult PWH diagnosed from 2005 to 2019 in SC were LPAD, and the median delay time was 13.04 years. Based on the generalized estimating equations models, PWH who were male (adjusted prevalence ratio [aPR]: 1.22, 95% CI: 1.12 ∼ 1.33), aged 55+ (aPR: 1.76, 95% CI: 1.62 ∼ 1.92), were Black (aPR: 1.09, 95% CI: 1.03 ∼ 1.15) or Hispanic (aPR: 1.42, 95% CI: 1.26 ∼ 1.61), and living in counties with a larger proportion of unemployment individuals (aPR: 1.02, 95% CI: 1.01 ∼ 1.03) were more likely to be LPAD. Among PWH who were LPAD, Hispanic (adjusted beta: 1.17, 95% CI: 0.49 ∼ 1.85) instead of Black (adjusted beta: 0.11, 95% CI: -0.30 ∼ 0.52) individuals had significant longer delay time compared to White individuals. Targeted and sustained interventions are needed for older, male, Hispanic or Black individuals and those living in counties with a higher percentage of unemployment because of their higher risk of LPAD. Additionally, specific attention should be paid to Hispanic individuals due to their longer delay time to diagnosis.

Simultaneous dose and dose rate optimization via dose modifying factor modeling for FLASH effective dose.

Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV). This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED. SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method. SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10mm ring expansion of CTV). We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO.

The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program.

Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenograftsand controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2-activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small-molecule and PROTAC-mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2-activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.

Kinematic Age of the β-Pictoris Moving Group

Accurate age estimation of nearby young moving groups (NYMGs) is important as they serve as crucial testbeds in various fields of astrophysics, including the formation and evolution of stars and planets, as well as loose stellar associations. The β-Pictoris moving group (BPMG), being one of the closest and youngest NYMGs, has been extensively investigated, and its estimated ages have a wide range from ∼10–25 Myr, depending on the age estimation methods and data used. Unlike other age dating methods, kinematic traceback analysis offers a model-independent age assessment hence the merit in comparing many seemingly discordant age estimates. In this study, we determine the kinematic ages of the BPMG using three methods: probabilistic volume calculation, mean pairwise distance calculation, and covariance matrix analysis. These methods yield consistent results, with estimated ages in the range of 14–20 Myr. Implementing corrections to radial velocities due to gravitational redshift and convectional blueshift increases the ages by ∼2–4 Myr. Conversely, considering data uncertainties decreases the estimated ages by 1–2 Myr. Taken together, our analysis determined the kinematic age of the BPMG to be 16.3−2.1+3.4 Myr. This age is significantly younger than the commonly accepted age of the BPMG (∼24 Myr) determined primarily from the lithium depletion boundary analysis. This younger kinematic age may point to the discrepancy between the luminosity evolution and lithium depletion models or the presence of unaccounted systematic error in the method. This result underscores the necessity for systematic reevaluations of age-dating methods for nearby, young moving groups.