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Youth interpersonal firearm violence disproportionately affects Black youth, with residential racial segregation as a key determinant. Racially segregated neighborhoods, which are economically isolated (e.g., neighborhood disadvantage), are linked to increased exposure to violence. This exposure, in turn, is a determinant of youth firearm aggression (i.e., using a gun on someone else). Mechanisms from residential racial segregation to firearm aggression, however, have not been evaluated. Therefore, we tested neighborhood disadvantage and exposure to violence as mediators in the association between residential racial segregation and youth firearm aggression. Participants were 338 Black youth who had used drugs in the past 6 months and sought care in an urban emergency department. Using serial mediation analysis, residential racial segregation was indirectly associated with youth firearm aggression via neighborhood disadvantage and then exposure to violence. While researchers have documented the association between structural racism and firearm violence injury and incidents, our study assessed multiple socioecological mechanisms simultaneously. Identifying the downstream socioecological consequences of residential segregation can guide the development of firearm aggression prevention programs addressing the consequences of racism.

Abstract Ensuring sufficient gRNA transcript levels is critical for obtaining optimal CRISPR-Cas9 gene editing efficiency. The standard gRNA scaffold contains a sequence of four thymine nucleotides (4T), which is known to inhibit transcription from Pol III promoters such as the U6 promoter. Our study showed that using standard plasmid transfection protocols, the presence of these 4Ts did not significantly affect editing efficiency, as most of the gRNAs tested (55 gRNAs) achieved near-perfect editing outcomes. We observed that gRNAs with lower activity were T-rich and had reduced gRNA transcript levels. However, this issue can be effectively resolved by increasing transcript levels, which can be readily achieved by shortening the 4T sequences. In this study, we demonstrated this by modifying the sequences to 3TC. Although the 3TC scaffold modification did not improve editing efficiency for already efficient gRNAs when high vector quantities were available, it proved highly beneficial under conditions of limited vector availability, where the 3TC scaffold yielded higher editing efficiency. Additionally, we demonstrated that the 3TC scaffold is compatible with SpCas9 high-fidelity variants and ABEmax base editing, enhancing their editing efficiency. Another commonly used natural Cas9 variant, SaCas9, also benefited from the 3TC scaffold sequence modification, which increased gRNA transcription and subsequently improved editing activity. This modification was applied to the EDIT-101 therapeutic strategy, where it demonstrated marked improvements in performance. This study highlights the importance of shortening the 4T sequences in the gRNA scaffold to optimize gRNA transcript expression for enhanced CRISPR-Cas9 gene editing efficiency. This optimization is particularly important for therapeutic applications, where the quantity of vector is often limited, ensuring more effective and optimal outcomes.

Abstract The AMoRE collaboration searches for neutrinoless double beta decay of $$^{100}$$ 100 Mo using molybdate scintillating crystals via low temperature thermal calorimetric detection. The early phases of the experiment, AMoRE-pilot and AMoRE-I, have demonstrated competitive discovery potential. Presently, the AMoRE-II experiment, featuring a large detector array with about 90 kg of $$^{100}$$ 100 Mo isotope, is under construction. This paper discusses the baseline design and characterization of the lithium molybdate cryogenic calorimeters to be used in the AMoRE-II detector modules. The results from prototype setups that incorporate new housing structures and two different crystal masses (316 g and 517–521 g), operated at 10 mK temperature, show energy resolutions (FWHM) of 7.55–8.82 keV at the 2.615 MeV $$^{208}$$ 208 Tl $$\gamma $$ γ line and effective light detection of 0.79–0.96 keV/MeV. The simultaneous heat and light detection enables clear separation of alpha particles with a discrimination power of 12.37–19.50 at the energy region around $$^{6}$$ 6 Li $$(n,\alpha )^3$$ ( n , α ) 3 H with Q-value = 4.785 MeV. Promising detector performances were demonstrated at temperatures as high as 30 mK, which relaxes the temperature constraints for operating the large AMoRE-II array.

Abstract Background Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD), exhibiting spatial heterogeneity across various genetic subgroups, which may be driven by distinct biological mechanisms. Methods We employed an integrative imaging transcriptomics approach to identify both disparate and shared transcriptomic signatures associated with cortical thickness in bvFTD with C9orf72 repeat expansions or pathogenic variants in GRN or MAPT. Functional enrichment analyses were conducted on each gene list significantly associated with cortical thickness. Additionally, we mapped neurotransmitter receptor/transporter density maps to the cortical thickness maps, to uncover different correlation patterns for each genetic form. Furthermore, we examined whether the identified genes were enriched for pathology-related genes by using previously identified genes linked to TDP-43 positive neurons and genes associated with tau pathology. Results For each genetic form of bvFTD, we identified cortical thickness signatures and gene sets associated with them. The cortical thickness associated genes for GRN-bvFTD were significantly involved in neurotransmitter system and circadian entrainment. The different patterns of spatial correlations between synaptic density and cortical thinning, further confirmed the critical role of neurotransmission and synaptic signaling in shaping brain structure, especially in the GRN-bvFTD group. Furthermore, we observed significant overlap between genes linked to TDP-43 pathology and the gene sets associated with cortical thickness in C9orf72-bvFTD and GRN-bvFTD but not the MAPT-bvFTD group providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD also shared genes displaying consistent directionality, with those exhibiting either positive or negative correlations with cortical thickness in C9orf72-bvFTD showing the same direction (positive or negative) in GRN-bvFTD. MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures compared to the other two genetic forms. The genes that exhibited significantly positive or negative correlations with cortical thickness in MAPT-bvFTD showed opposing directionality in C9orf72-bvFTD and GRN-bvFTD. Conclusions Overall, this integrative transcriptomic approach identified several new shared and disparate genes associated with regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression. These findings illuminated the intricate molecular underpinnings contributing to the heterogeneous nature of disease distribution in bvFTD with distinct genetic backgrounds.

Abstract AMoRE-II aims to search for neutrinoless double beta decay ( $$0\nu \beta \beta $$ 0 ν β β ) with an array of 423 $$\hbox {Li}_2^{100}\hbox {MoO}_4$$ Li 2 100 MoO 4 crystals operating in the cryogenic system as the main phase of the Advanced Molybdenum-based Rare process Experiment (AMoRE). AMoRE has been planned to operate in three phases: AMoRE-pilot, AMoRE-I, and AMoRE-II. AMoRE-II is currently being installed at the Yemi Underground Laboratory, located approximately 1000 m deep in Jeongseon, Korea. The goal of the experiment is to reach an exclusion half-life sensitivity to the $$0\nu \beta \beta $$ 0 ν β β of $$^{100}$$ 100 Mo on the level of $$T^{0\nu \beta \beta }_{1/2} > 6 \times 10^{26}$$ T 1 / 2 0 ν β β > 6 × 10 26 year that covers completely the inverted Majorana neutrino mass hierarchy region of (15–46) meV. To achieve this, the background level of the experimental configurations and possible background sources of gamma and beta events should be well understood. We have intensively performed Monte Carlo simulations using the GEANT4 toolkit in all the experimental configurations with potential sources. We report the estimated background level that meets the $$10^{-4}$$ 10 - 4 counts/(keV $$\cdot $$ · kg $$\cdot $$ · year) requirement for AMoRE-II in the Region Of Interest (ROI) and show the projected half-life sensitivity based on the simulation study.

As the Earth's climate warms, the intensity and rain rate of tropical cyclones (TCs) is projected to increase. TCs intensify by extracting heat energy from the ocean; hence, a better understanding of upper-ocean changes with the TC passage is helpful to improve our understanding of air–sea interactions during and after the event. This work uses Argo float observations and the HYbrid Coordinate Ocean Model (HYCOM) ocean reanalysis to describe characteristics of upper-ocean changes with hurricane-strength wind events. We study the association of these changes with the vertical structure of the salinity profile before the event, i.e., increasing versus decreasing with depth. We also study the contribution of changes in salinity to upper-ocean density changes in each case. Results show that in regions where pre-event salinity increases with depth there is a corresponding statistically significant increase in upper-ocean salinity; vice versa, we observe a significant decrease in upper-ocean salinity in regions where pre-event salinity decreases with depth. Consistent with previous studies, temperature decreases in both regions. As near-surface temperature decreases, upper-ocean density increases, and the increase is larger where pre-event salinity increases with depth. Changes in upper-ocean properties from Argo and HYCOM are overall consistent with wind-driven vertical mixing of near-surface waters with colder and higher-salinity (or lower-salinity) waters below. Resulting changes in ocean stratification have implications for air–sea interactions during and after the event, with potential impacts on weather events that follow.

3D voxel models facilitate simulating 3D pedestrian motions within indoor environments with diverse furniture, equipment, and complex room layouts featuring stairs and ramps. Reasonable voxel sizes enable the effective identifications of indoor spaces, navigable surfaces, and vertical links from voxel models for the simulations. However, the performance of different voxel sizes on these identifications has yet to be thoroughly investigated. The choice of appropriate voxel sizes for various 3D evacuation scenarios has to be clarified to avoid unreliable simulation outcomes. Therefore, this paper aims to assess the performance of different voxel sizes on the identifications of the spaces, surfaces, and links. Firstly, we introduce three key metrics for the assessment: accuracy, robustness, and efficiency. Then, three IFC models are selected based on predefined criteria for the tests. Experimental procedures are elaborated to include data preparation, collection, and analysis. The primary findings of this investigation are: 1) with increasing voxel sizes, accuracy decreases, robustness changes, and efficiency increases; 2) larger indoor spaces exhibit smaller changes in accuracy across different voxel sizes, while smaller indoor spaces show more significant changes in accuracy. 3) when the voxel size is tiny, it becomes challenging to complete identifications. Conversely, with relatively larger voxel sizes, some indoor spaces and vertical links cannot be identified. 4) Indoor spaces with complex and non-orthogonal geometries require more identification time. This work is expected to advance the creation of 3D indoor model to facilitate 3D evacuation simulations.

Abstract In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we perform a systematic annotation of RBP combinatorial interactions via multimodal data integration. We build a large-scale map of RBP protein neighborhoods by generating in vivo proximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we use CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generate an integrated map of functional RBP interactions. We then use this map to match RBPs to their context-specific functions and validate the predicted functions biochemically for four RBPs. This study provides a detailed map of RBP interactions and deconvolves them into distinct regulatory modules with annotated functions and target regulons. This multimodal and integrative framework provides a principled approach for studying post-transcriptional regulatory processes and enriches our understanding of their underlying mechanisms.

This paper explores the epistemic agency of American trans students/youths by emphasizing the ordinary practices of life-making as they are enacted or rather reflected textually. It draws on Latina feminist María Lugones's scholarship on relationality to conceive of trans students/youths as 'streetwise theorists', or "callejer@." I illustrate how new knowledges about streetwise trans youth can be generated through employing what I call the 'trans*intramural protocol of reading'. I draw on texts retrieved from university archives and open access collections; resource guides and anthologies written by and for trans communities; as well as trans and queer zines published in the late twentieth and early twenty-first centuries to illustrate the epistemic significance of such a reading practice. I conclude with a meditation on how an aesthetic relation to a text can rekindle memories to our past as trans subjects and therefore contribute to a new relation to histories of our own embodiments.

Background: Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer’s disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration. We employ a MTL subregional segmentation strategy of T1-weighted (T1w) MRI in biomarker-supported or autopsy-confirmed LBD and LBD/AD+ to investigate the anatomic consequences of co-occurring LBD/AD+ pathology on neurodegeneration. Methods: We studied 167 individuals with clinical diagnoses of LBD (PD, n = 124 (74.3 %); PDD, n = 11 (6.6 %); DLB, n = 32 (19.2 %)) with available T1w MRI and AD biomarkers or autopsy evidence of ADNC. Individuals were further biologically classified as LBD/AD+ based on hierarchical evidence of ADNC pathology: 1) AD “intermediate” or “high” by ABC neuropathologic criteria (n = 39 (23.4 %)); 2) positive amyloid PET (n = 2 (1.2 %)); or 3) CSF β-amyloid1-42

This case is designed to provide students with real property appraisal experience, specifically in the determination of the impact on valuation due to a change in the flood zone maps by the Federal Emergency Management Association (FEMA) in Lee County, FL. It is designed in a modular format, so that instructors may assign individual valuation assignments requiring alternative appraisal techniques both before and after changes in federal land regulations that alter the indicated market value of existing commercial properties.

Objectives: Pulse oximetry screening of newborns detects critical congenital heart disease (CCHD). Rural birth location is known to affect timing and management of when infants with CHD undergo surgery, but its association with CCHD screening is unknown. We assess the relationship between rural location and postnatal CCHD diagnosis and describe lesion-specific modes of diagnosis. Study design: Data were abstracted from medical records at 2 cardiac surgery centers in Washington state. Infants with CCHD, defined as CHD requiring either cardiac intervention or resulting in death at

Abstract The strongest gamma-ray burst (GRB) of the century, GRB20221009A, has been detected by the Korean Pathfinder Lunar Orbiter Gamma-ray Spectrometer (KGRS) instrument onboard the Korean Pathfinder Lunar Orbiter (KPLO). KGRS uses a LaBr3 detector to measure GRB counts with five energy bins in the energy range from 30 keV to 12 MeV. KGRS detected GRB221009A at a distance of 1.508 million kilometers from the Earth. The full duration of the main burst was recorded between 13:20 and 13:26 on October 9, 2022 with peak counts of over 1000 times background. The dead time of KGRS reached as high as 50%, and the intrinsic gamma-ray spectrum of LaBr3 was significantly altered.

Abstract Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Tropical cyclones (TCs), driven by heat exchange between the air and sea, pose a substantial risk to many communities around the world. Accurate characterization of the subsurface ocean thermal response to TC passage is crucial for accurate TC intensity forecasts and an understanding of the role that TCs play in the global climate system. However, that characterization is complicated by the high-noise ocean environment, correlations inherent in spatiotemporal data, relative scarcity of in situ observations, and the entanglement of the TC-induced signal with seasonal signals. We present a general methodological framework that addresses these difficulties, integrating existing techniques in seasonal mean field estimation, Gaussian process modeling, and nonparametric regression into an ANOVA decomposition model. Importantly, we improve upon past work by properly handling seasonality, providing rigorous uncertainty quantification, and treating time as a continuous variable, rather than producing estimates that are binned in time. This ANOVA model is estimated using in situ subsurface temperature profiles from the Argo fleet of autonomous floats through a multistep procedure, which (1) characterizes the upper-ocean seasonal shift during the TC season, (2) models the variability in the temperature observations, and (3) fits a thin-plate spline using the variability estimates to account for heteroskedasticity and correlation between the observations. This spline fit reveals the ocean thermal response to the TC passage. Through this framework, we obtain new scientific insights into the interaction between TCs and the ocean on a global scale, including a three-dimensional characterization of the near-surface and subsurface cooling along the TC storm track and the mixing-induced subsurface warming on the track's right side.

Abstract Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

HER2 mutations have been identified as potential mechanisms of resistance to EGFR-directed therapies in patients with advanced or metastatic NSCLC. Here, we report the case of a 65-year-old female with metastatic, EGFR exon 19–mutant NSCLC initially treated with first-line osimertinib. After several subsequent lines of treatment including erlotinib and carboplatin+pemetrexed+osimertinib, repeat genetic sequencing identified a HER2 exon 20 insertion (A775_G776insYVMA) in both blood and tissue. She was treated using fam-trastuzumab-deruxtecan, which resulted in a disease response lasting for 8 months. This report represents the first published case detailing the safety and efficacy of a combination fam-trastuzumab-deruxtecan and osimertinib in a patient with NSCLC and HER2-mutated resistance after EGFR-targeted therapy. The findings from this report suggest that fam-trastuzumab-deruxtecan can be safely given in combination with osimertinib and should be considered as subsequent-line therapy for patients who progress on osimertinib and develop a HER2 resistance mutation.

Transcatheter embolization currently constitutes the primary treatment for lumbar artery injury due to blunt trauma. We present a case where a stent graft effectively treated a lumbar artery injury after coil embolization failed to achieve hemostasis. Aortic stent graft implantation is a safe procedure that can prevent surgical morbidity and has minimal complications. It may serve as an effective alternative for achieving hemostasis when coil embolization is not feasible or is unsuccessful.

Solid organ transplant recipients (SOTR) are at increased risk from COVID-19. Over time, the absolute risk of adverse outcomes after COVID-19 has decreased in both the non-immunosuppressed/immunocompromised (non-ISC) general population, and amongst SOTR. Using the N3C, we examined the absolute risk of mortality, major adverse renal or cardiac events, and hospitalization after COVID-19 diagnosis amongst non-ISC and SOTR populations over five waves of the pandemic (Wave 1: Ancestral COVID; Wave 2: Alpha; Wave 3: Delta; Wave 4: Omicron; Wave 5: Omicron). Within each wave, we determined the relative risk of each outcome for SOTR versus the non-ISC population based on crude event rates, and then used multivariable cox proportional hazards models and logistic regression to determine the adjusted risk of each outcome based on SOT status. Throughout the pandemic, including during the Omicron wave (Wave 5), SOTR were at greater absolute risk for each outcome than non-ISC patients (p-values all

Therapeutic Area: ASCVD/CVD Risk Factors Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), enhances atherosclerotic cardiovascular disease (ASCVD) risk. Previous studies have shown lower plasma lipoprotein (a) [Lp(a)] correlating with increased NAFLD severity by histology. Given emerging Lp(a)-lowering medications, the mechanisms and implications of this relationship are important. We investigated whether this observation persists utilizing new MASLD diagnostic criteria within the UK Biobank. Methods: Patients with pre-existing ASCVD, significant alcohol intake, or other chronic liver diseases were excluded. Those with plasma Lp(a) and liver magnetic resonance imaging data were stratified into Lp(a) concentration quartiles. MASLD was defined as at least 1 cardiometabolic derangement, per the recent multi-society Delphi consensus statement, with proton density fat-fraction >5%. Metabolic dysfunction-associated steatohepatitis (MASH) was defined as at least 1 cardiometabolic derangement with iron-corrected T1 >800 ms. Prevalence of MASLD and MASH across quartiles were compared using Pearsons’ chi-squared test. We then calculated odds of prevalent MASLD and MASH in the lowest quartile compared with the rest of the cohort. Results: The final cohort was 14,957 patients (51% women, median age 55 years). Plasma Lp(a) was measured using a molar (nmol/L) assay and the median concentration was 20.39 (IQR 9.5-62.30). Participants were stratified using Lp(a) quartiles: 62.3 (N=3,742). Their respective median Lp(a) concentrations were 6.30, 13.59, 34.33 and 118.18. The prevalence of MASLD in each quartile was 25%, 24%, 22% and 23% (p=0.025). The odds ratio (OR) of MASLD in the lowest Lp(a) quartile was 1.08 (95% CI 0.99-1.18, p=0.07). The prevalence of MASH in each was 5.7%, 5.0%, 4.0% and 4.9% (p=0.006). The OR of MASH in the lowest Lp(a) quartile was 1.26 (95% CI 1.07-1.48, p=0.006). Conclusions: In this novel population, very low plasma Lp(a) level is associated with prevalent MASH, but not MASLD overall, which corroborates prior investigations of non-alcoholic steatohepatitis and NAFLD. A similar relationship with insulin resistance and type 2 diabetes has also been reported. These findings raise important questions regarding hepatic safety of Lp(a)-lowering medications. It is unclear whether low Lp(a) precedes or follows MASH, necessitating further research.

Abstract The vertebrate stress response (SR) is mediated by the hypothalamic–pituitary–adrenal (HPA) axis and contributes to generating context appropriate physiological and behavioral changes. Although the HPA axis plays vital roles both in stressful and basal conditions, research has focused on the response under stress. To understand broader roles of the HPA axis in a changing environment, we characterized an adaptive behavior of larval zebrafish during ambient illumination changes. Genetic abrogation of glucocorticoid receptor (nr3c1) decreased basal locomotor activity in light and darkness. Some key HPI axis receptors (mc2r [ACTH receptor], nr3c1), but not nr3c2 (mineralocorticoid receptor), were required to adapt to light more efficiently but became dispensable when longer illumination was provided. Such light adaptation was more efficient in dimmer light. Our findings show that the HPI axis contributes to the SR, facilitating the phasic response and maintaining an adapted basal state, and that certain adaptations occur without HPI axis activity.

Abstract Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

Abstract The purpose of this study was to clarify sex differences in the inhibition of sympathetic vasomotor outflow which is caused by the loading of cardiopulmonary baroreceptors. Ten young males and ten age-matched females participated. The participants underwent a passive leg raising (PLR) test wherein they were positioned supine (baseline, 0º), and their lower limbs were lifted passively at 10º, 20º, 30º, and 40º. Each angle lasted for 3 min. Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. Baseline MSNA was lower in females compared to males. MSNA burst frequency was decreased during the PLR in both males (− 6.2 ± 0.4 bursts/min at 40º) and females (− 6.5 ± 0.4 bursts/min at 40º), but no significant difference was detected between the two groups (P = 0.61). These results suggest that sex has minimal influence on the inhibition of sympathetic vasomotor outflow during the loading of cardiopulmonary baroreceptors in young individuals.

Abstract Objective Alzheimer's disease neuropathologic change and alpha‐synucleinopathy commonly co‐exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta‐amyloid compared to alpha‐synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. Methods We used digital histology to measure percent area‐occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha‐synucleinopathy, and a co‐pathology group with both Alzheimer's and alpha‐synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. Results There were lower levels of tau pathology (β = 1.86–2.96, p

Abstract Ultrastructure of human brain tissue has traditionally been examined using electron microscopy (EM) following fixation, staining, and sectioning, which limit resolution and introduce artifacts. Alternatively, cryo-electron tomography (cryo-ET) allows higher resolution imaging of unfixed cellular samples while preserving architecture, but it requires samples to be vitreous and thin enough for transmission EM. Due to these requirements, cryo-ET has yet to be employed to investigate unfixed, never previously frozen human brain tissue. Here we present a method for generating lamellae in human brain tissue obtained at time of autopsy that can be imaged via cryo-ET. We vitrify the tissue via plunge-freezing and use xenon plasma focused ion beam (FIB) milling to generate lamellae directly on-grid at variable depth inside the tissue. Lamellae generated in Alzheimer’s disease brain tissue reveal intact subcellular structures including components of autophagy and potential pathologic tau fibrils. Furthermore, we reveal intact compact myelin and functional cytoplasmic expansions. These images indicate that plasma FIB milling with cryo-ET may be used to elucidate nanoscale structures within the human brain.

Two-particle response functions are a centerpiece of both experimental and theoretical quantum many-body physics. Yet, due to their size and discontinuity structure, they are challenging to handle numerically. Recently, two advances were made to tackle this problem: first, the overcomplete intermediate representation (OIR), which provides a highly efficient compression of Green's functions in imaginary frequency, and second, partial spectral functions (PSFs), which allow for an efficient evaluation in real frequency. We show that there is a two-to-one correspondence between PSFs and OIR coefficients and exploit this fact to construct the OIR for three-or-more-particle propagators. We then use OIR to fit and compress imaginary-frequency data obtained from the numerical renormalization group (NRG), reaching a compression ratio of more than 400. Finally, we attempt to match the OIR data to partial Green's functions from NRG. Due to the overcompleteness, we achieve only qualitative agreement.

Despite advances in screening, diagnosis, and treatment for prostate cancer (PCa), Black men tend to be diagnosed at younger ages, have higher mortality rates, and are at increased risk of recurrence or metastasis compared to their White counterparts. PCa disparities among Black men are caused by a complex interaction of social, behavioral, and biological factors across the public policy, community, organizational, interpersonal, and individual levels. Key contributing factors include mistrust in the health care system, poor communication between patients and providers, low awareness of screening guidelines, and high medical costs. These disparities are further exacerbated by the low representation of Black men in clinical trials, which limits access to high-quality cancer care and generalizability for PCa treatments. In this narrative review of the existing literature, we examined the epidemiology and identified contributing factors, and propose multi-level strategies to address and mitigate disparities among Black men with PCa.

How can the video essay be deployed as a critical tool to analyse ecocinema and its relevance to the current environmental crisis? The Video Essay for Ecocinema course, held in the 2023 spring semester at the Academy of Architecture in Mendrisio, introduced videographic techniques to investigate the topic of ecocinema and critically analyse ecological imaginaries. A heterogeneous bibliography of texts, films and video essays related to ecocinema presented key thematic concepts, including: visualizations of ecological scale(s); the role of affect in producing environmental consciousness; materialising intangible infrastructures and hidden “grey energies”; and the digital footprint of film and media industries. These concepts in turn served as the basis for a distinct series of videographic exercises that prepared students for their final videographic project. The results demonstrate the profound value of the video essay as a pedagogical practice that can provide students with the tools to address such a challenging and multifaceted topic as the global environmental crisis.

Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive pediatric cancer caused by a reciprocal translocation between chromosomes 11 and 22, leading to the formation of the EWSR1::WT1 oncoprotein. DSRCT presents most commonly in the abdominal and pelvic peritoneum and remains refractory to current treatment regimens which include chemotherapy, radiotherapy, and surgery. As a rare cancer, sample and model availability have been a limiting factor to DSRCT research. However, the establishment of rare tumor banks and novel cell lines have recently propelled critical advances in the understanding of DSRCT biology and the identification of potentially promising targeted therapeutics. Here we review model and dataset availability, current understanding of the EWSR1::WT1 oncogenic mechanism, and promising preclinical therapeutics, some of which are now advancing to clinical trials. We discuss efforts to inhibit critical dependencies including NTRK3, EGFR, and CDK4/6 as well as novel immunotherapy strategies targeting surface markers highly expressed in DSRCT such as B7-H3 or neopeptides either derived from or driven by the fusion oncoprotein. Finally, we discuss the prospect of combination therapies and strategies for prioritizing clinical translation.

The AMoRE-II experiment will search for the 0νββ decay of 100Mo nuclei using molybdate crystal scintillators, operating at milli-Kelvin (mK) temperatures, with a total of 80 kg of 100Mo. The background goal for the experiment is 10–4 counts/keV/kg/year in the region of interest around the 0νββ decay Q-value of 3,034 keV. To achieve this level, the rate of background signals arising from emissions produced by decays of radioactive impurities in the detector and shielding materials must be strictly controlled. To do this, concentrations of such impurities are measured and are controlled through materials selection and purification. In this paper, we describe the design and the construction materials used to build the AMoRE-II detector and shielding system, including active and passive shielding, the cryostat, and the detector holders and instrumentation, and we report on measurements of radioactive impurities within candidate and selected materials.

Abstract Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15–25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state, which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks, including 4444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression, including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1-regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties, including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance, making its inhibition a promising target for future combination therapy.

We study paramagnetic quantum criticality in the periodic Anderson model (PAM) using cellular dynamical mean-field theory (CDMFT), with the numerical renormalization group (NRG) as a cluster impurity solver. The PAM describes itinerant c electrons hybridizing with a lattice of localized f electrons. At zero temperature, it exhibits a much-studied quantum phase transition from a Kondo phase to a Ruderman-Kittel-Kasuya-Yosida (RKKY) phase when the hybridization is decreased through a so-called Kondo breakdown quantum critical point (KB QCP). There, Kondo screening of f spins by c electrons breaks down, so that f excitations change their character from somewhat itinerant to mainly localized, while c excitations remain itinerant. Building on Phys. Rev. Lett. 101, 256404 (2008)PRLTAO0031-900710.1103/PhysRevLett.101.256404, which interpreted the KB transition as an orbital-selective Mott transition, we here elucidate its nature in great detail by performing a high-resolution, real-frequency study of various dynamical quantities (susceptibilities, self-energies, and spectral functions). NRG allows us to study the quantum critical regime governed by the QCP and located between two temperature scales, T_{FL}

Abstract Recently, deep generative models using machine intelligence are widely utilized to investigate scientific systems by generating scientific data. In this study, we experiment with a hybrid model of a variational autoencoder (VAE) and a generative adversarial network (GAN) to generate a variety of plausible two-dimensional magnetic topological structure data. Due to the topological properties in the system, numerous and diverse metastable magnetic structures exist, and energy and topological barriers separate them. Thus, generating a variety of plausible spin structures avoiding those barrier states is a challenging problem. The VAE-GAN hybrid model can present an effective approach to this problem because it brings the advantages of both VAE’s diversity and GAN’s fidelity. It allows one to perform various applications including searching a desired sample from a variety of valid samples. Additionally, we perform a discriminator-driven latent sampling (DDLS) using our hybrid model to improve the quality of generated samples. We confirm that DDLS generates various plausible data with large coverage, following the topological rules of the target system.

Abstract We report on the first production of an antihydrogen beam by charge exchange of 6.1 keV antiprotons with a cloud of positronium in the GBAR experiment at CERN. The 100 keV antiproton beam delivered by the AD/ELENA facility was further decelerated with a pulsed drift tube. A 9 MeV electron beam from a linear accelerator produced a low energy positron beam. The positrons were accumulated in a set of two Penning–Malmberg traps. The positronium target cloud resulted from the conversion of the positrons extracted from the traps. The antiproton beam was steered onto this positronium cloud to produce the antiatoms. We observe an excess over background indicating antihydrogen production with a significance of 3–4 standard deviations.

Background: The dense stroma of pancreatic ductal adenocarcinoma (PDAC) is thought to impede tumour drug delivery. LSTA1, a novel cyclic tumour-penetrating peptide internalising arginylglycylaspartic acid, promotes tumour-specific drug delivery. In the phase Ib setting, LSTA1 3.2 mg/kg with gemcitabine and nab-paclitaxel showed a 92% disease control rate at 16 weeks and was well tolerated. Methods/design: This is a multicentre, phase II, double-blinded, placebo-controlled, randomised trial evaluating the activity and safety of LSTA1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Initially, participants were randomised 2 : 1 to receive gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 and LSTA1 3.2 mg/kg or placebo. The trial design was updated in a protocol amendment (v4.0) to include a second placebo-controlled cohort which receives a second dose of LSTA1/placebo 4 h following chemotherapy. Treatment is administered on days 1, 8, and 15 of each 28-day cycle until progression (progressive disease). The sample size is 155 based on a clinically worthwhile increase in 6-month progression-free survival (PFS) of 16%-63% with 80% power and 95% confidence to exclude the null hypothesis. The recruitment period is 22 months and follow-up 18 months. Study endpoints are: (1) PFS; (2) objective response rate (RECIST 1.1), safety (Common Terminology Criteria for Adverse Events v5.0), overall survival, participant-reported outcomes; (3) predictive/prognostic biomarkers via archival tissue, and to assess whether a second dose of LSTA1 warrants further evaluation.