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As we age, we accumulate a wealth of information about the surrounding world. Evidence from visual search suggests that older adults retain intact knowledge for where objects tend to occur in everyday environments (semantic information) that allows them to successfully locate objects in scenes, but may overrely on semantic guidance. We investigated age differences in the allocation of attention to semantically informative and visually salient information in a task in which the eye movements of younger (N = 30, aged 18-24) and older (N = 30, aged 66-82) adults were tracked as they described real-world scenes. We measured the semantic information in scenes based on "meaning map" ratings from a norming sample of young and older adults, and image salience as graph-based visual saliency. Logistic mixed-effects modeling was used to determine whether, controlling for center bias, fixated scene locations differed in semantic informativeness and visual salience from locations that were not fixated, and whether these effects differed for young and older adults. Semantic informativeness predicted fixated locations well overall, as did image salience, although unique variance in the model was better explained by semantic informativeness than image salience. Older adults were less likely to fixate informative locations in scenes than young adults were, though the locations older adults' fixated were independently predicted well by informativeness. These results suggest young and older adults both use semantic information to guide attention in scenes and that older adults do not overrely on semantic information across the board. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Tissue-resident memory CD8+ T (TRM) cells are a subset of memory T cells that play a critical role in limiting early pathogen spread and controlling infection. TRM cells exhibit differences across tissues, but their potential heterogeneity among distinct anatomic compartments within the small intestine and colon has not been well recognized. Here, by analyzing TRM cells from the lamina propria and epithelial compartments of the small intestine and colon, we showed that intestinal TRM cells exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional, epigenetic, and functional heterogeneity. The T-box transcription factor Eomes, which represses TRM cell formation in some tissues, exhibited unexpected context-specific regulatory roles in supporting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of intestinal TRM cells.

High-resolution scans of immunohistochemical (IHC) stains of Alzheimer's disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC-autoradiography images. Postmortem anterior cingulate (AC) and corpus callosum (CC) from AD and control (CN) subjects were IHC stained with anti-Aβ for Aβ plaques and autoradiography with [18F]flotaza and [125I]IBETA for Aβ plaques. For Tau, [124I]IPPI, a new radiotracer, was synthesized and evaluated in the AD brain. For Tau imaging, brain slices were IHC stained with anti-Tau and autoradiography using [125I]IPPI and [124I]IPPI. Annotations for Aβ plaques and Tau using QuPath for training and pixel classifiers were generated to measure the percent of the area of Aβ plaques and Tau in each slice. The binding of [124I]IPPI was observed in all AD brains with an AC/CC ratio > 10. Selectivity to Tau was shown by blocking [124I]IPPI with MK-6240. Percent positivity for Aβ plaques was 4-15%, and for Tau, it was 1.3 to 35%. All IHC Aβ plaque-positive subjects showed [18F]flotaza and [125I]IBETA binding with a positive linear correlation (r2 > 0.45). Tau-positive subjects showed [124/125I]IPPI binding with a stronger positive linear correlation (r2 > 0.80). This quantitative IHC-autoradiography approach provides an accurate measurement of Aβ plaques and Tau within and across subjects.

Increased monoamine oxidase-A (MAO-A) activity in Alzheimer's disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 for MAO-A, [18F]flotaza and [125I]IBETA for Aβ plaques, [124/125I]IPPI for tau, and [18F]FEPPA for TSPO imaging. Brain sections of the anterior cingulate (AC; gray matter GM) and corpus callosum (CC; white matter WM) from cognitively normal control (CN, n = 6) and AD (n = 6) subjects were imaged using autoradiography and immunostaining. Using competition with clorgyline and (R)-deprenyl, the binding of [18F]FAZIN3 was confirmed to be selective to MAO-A levels in the AD brain sections. Increases in MAO-A, Aβ plaque, tau, and TSPO activity were found in the AD brains compared to the control brains. The [18F]FAZIN3 ratio in AD GM versus CN GM was 2.80, suggesting a 180% increase in MAO-A activity. Using GM-to-WM ratios of AD versus CN, a >50% increase in MAO-A activity was observed (AD/CN = 1.58). Linear positive correlations of [18F]FAZIN3 with [18F]flotaza, [125I]IBETA, and [125I]IPPI were measured and suggested an increase in MAO-A activity with increases in Aβ plaques and tau activity. Our results support the finding that MAO-A activity is elevated in the anterior cingulate cortex in AD and thus may provide a new biomarker for AD in this brain region.

Abstract Expendable Bathythermographs (XBTs) are oceanographic instruments that fall through the ocean's water column and measure ocean temperature with depth. In many instances, however, XBTs continue to record temperature after they impact the seabed. Here we show evidence that XBTs produce unique temperature responses when they impact the seabed that depend directly on seabed physical properties. Specifically, standard‐use XBTs (e.g., T‐4s and T‐5s), when deployed above a mud‐rich seabed, require significant time (tens of minutes) to equilibrate to steady‐state seafloor temperatures after seabed impact. In contrast, XBTs deployed above sand‐rich sediments equilibrate to seabed temperatures rapidly (644k XBT measurements exist publicly (via the National Oceanographic and Atmospheric Administration website), and >74,000 XBTs record temperatures post seabed impact, we suggest that XBT data represents a large, low‐cost, and currently untapped data set for characterizing seabed physical properties globally.

Biomaterials that can be reversibly stiffened and shaped could be useful in broad biomedical applications where form-fitting scaffolds are needed. Here we investigate the combination of strong non-linear elasticity in biopolymer networks with the reconfigurability of packed hydrogel particles within a composite biomaterial. By packing microgels into collagen-1 networks and characterizing their linear and non-linear material properties, we empirically determine a scaling relationship that describes the synergistic dependence of the material's linear elastic shear modulus on the concentration of both components. We perform high-strain rheological tests and find that the materials strain stiffen and also exhibit a form of programmability, where no applied stress is required to maintain stiffened states of deformation after large strains are applied. We demonstrate that this non-linear rheological behavior can be used to shape samples that do not spontaneously relax large-scale bends, holding their deformed shapes for days. Detailed analysis of the frequency-dependent rheology reveals an unexpected connection to the rheology of living cells, where models of soft glasses capture their low-frequency behaviors and polymer elasticity models capture their high-frequency behaviors.

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.

Dual-phase xenon time projection chamber (TPC) detectors have demonstratedsuperior search sensitivities to dark matter over a wide range of particlemasses. To extend their sensitivity to include low-mass dark matterinteractions, it is critical to characterize both the light and chargeresponses of liquid xenon to sub-keV nuclear recoils. In this work, we report anew nuclear recoil calibration in the LUX detector $\textit{in situ}$ usingneutron events from a pulsed Adelphi Deuterium-Deuterium neutron generator. Wedemonstrate direct measurements of light and charge yields down to 0.45 keV(1.4 scintillation photons) and 0.27 keV (1.3 ionization electrons),respectively, approaching the physical limit of liquid xenon detectors. Wediscuss the implication of these new measurements on the physics reach ofdual-phase xenon TPCs for nuclear-recoil-based low-mass dark matter detection.

We present the results from combining machine learning with the profile likelihood fit procedure, using data from the Large Underground Xenon (LUX) dark matter experiment. This approach demonstrates reduction in computation time by a factor of 30 when compared with the previous approach, without loss of performance on real data. We establish its flexibility to capture nonlinear correlations between variables (such as smearing in light and charge signals due to position variation) by achieving equal performance using pulse areas with and without position-corrections applied. Its efficiency and scalability furthermore enables searching for dark matter using additional variables without significant computational burden. We demonstrate this by including a light signal pulse shape variable alongside more traditional inputs, such as light and charge signal strengths. This technique can be exploited by future dark matter experiments to make use of additional information, reduce computational resources needed for signal searches and simulations, and make inclusion of physical nuisance parameters in fits tractable.

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P

Uncapped free 20S proteasomes are abundant and active in cells, and yet their degraded intracellular protein substrates have remained underexplored. In their recent study, Sharon and colleagues (Pepelnjak et al, 2024) developed an advanced proteomics method (PiP-MS) to comprehensively explore 20S proteasome substrates in the human proteome.

Abstract Background Previous research has demonstrated that early weight gain in family-based treatment (FBT) is predictive of remission for adolescents with anorexia nervosa (AN). However, no published data has addressed if early weight gain is also predictive of reaching weight restoration (i.e., 95% EBW) in patients with avoidant/restrictive food intake disorder (ARFID). Furthermore, no studies have evaluated the performance of the statistical models used to predict weight restoration at the end of treatment. This study sought to examine whether early weight gain in ARFID is predictive of weight restoration at 20 weeks using ROC analysis. Additionally, this study assessed how accurately the model classified patients and what types of misclassifications occurred. Methods Participants (n = 130, 57.7% cisgender female 70.0% white) received virtual outpatient FBT. Receiver operating characteristics (ROC) were used to predict successful weight restoration at end of treatment, using early weight gain as the predictor. Twenty weeks was considered as the end of treatment, to align with the definition of end of treatment in FBT clinical trials. ROC analyses demonstrated that gaining at least 6.2 pounds by week 5 of treatment was the strongest predictor of achieving 95% EBW at 20 weeks (AUC = 0.72 [0.63, 0.81]). ROC analyses misclassified 35% of patients; the most common misclassification was predicting that a patient would not achieve 95% EBW when they actually did (61.6%). A logistical regression model, which included the patients’ %EBW at admission in addition to early weight gain as a predictor, outperformed the ROC analyses (AUC = 0.90 [0.85, 0.95]) and provided additional context by showing the probability that a patient would succeed. Conclusion Taken together, research demonstrates that early weight gain is a useful predictor of 95% EBW at 20 weeks of treatment for patients with ARFID who require weight restoration. Furthermore, results suggest that statistical models need to take into account additional information, such as %EBW at admission, along with early weight gain in order to more accurately predict which patients will reach weight restoration at week 20.

Abstract Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although global APA dysregulation is frequently associated with poor prognosis, the importance of most individual APA events is controversial simply because few have been functionally studied. Here, we address this gap by developing a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumor growth in vivo. Our screen reveals individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer. For example, forced Atg7 3′ UTR lengthening in mouse melanoma suppresses ATG7 protein levels, slows tumor growth, and improves host survival; similarly, in clinical human melanoma, a long ATG7 3′ UTR is associated with significantly prolonged patient survival. Overall, our study provides an easily adaptable means to functionally dissect APA in physiological systems and directly quantifies the contributions of recurrent APA events to tumorigenic phenotypes.

Abstract Background With effective antiretroviral therapy, people with HIV (PWH) are living longer and aging; the majority of PWH in the United States are now over the age of 50 and in women have gone through the menopause transition. Menopause potentiates skeletal bone loss at the spine, hip, and radius in PWH. The alveolar bone which surronds the teeth is different than long bones because it is derived from the neural crest. However, few studies have assessed the oral health and alveolar bone in middle aged and older women with HIV. Therefore, the objective of this study was to evaluate periodontal disease and alveolar bone microarchitecture in postmenopausal women with HIV. Methods 135 self-reported postmenopausal women were recruited (59 HIV-, 76 HIV + on combination antiretroviral therapy with virological suppression) from a single academic center. The following parameters were measured: cytokine levels (IFN-γ, TNF-α, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17 A, OPG, and RANKL) in gingival crevicular fluid, bleeding on probing, probing depth, clinical attachment loss, number of teeth present, alveolar crestal height, and alveolar bone microarchitecture. Results The mean age of participants was 57.04+/-6.25 years and a greater proportion of women with HIV were black/African American (HIV + 68.42%, HIV- 23.73%; p

Gene editing using CRISPR/Cas (clustered regularly interspaced palindromic repeats/CRISPR-associated) is under development as a therapeutic tool for the modification of genes in eukaryotic cells. While much effort has focused on CRISPR/Cas9 systems from Streptococcus pyogenes and Staphylococcus aureus, alternative CRISPR systems have been identified from non-pathogenic microbes, including previously unknown class 2 systems, adding to a diverse toolbox of CRISPR/Cas enzymes. The Cas12e enzymes from non-pathogenic Deltaproteobacteria (CasX1, DpeCas12e) and Planctomycetes (CasX2, PlmCas12e) are smaller than Cas9, have a selective protospacer adjacent motif (PAM), and deliver a staggered cleavage cut with a 5–7 nucleotide overhang. We investigated the impact of guide RNA spacer length and alternative PAM sequences on cleavage activity to determine optimal conditions for PlmCas12e cleavage of the cellular gene CCR5 (CC-Chemokine receptor-5). CCR5 encodes the CCR5 coreceptor used by human immunodeficiency virus-type 1 (HIV-1) to infect target cells. A 32 base-pair deletion in CCR5 (CCR5-$\Delta $32) is responsible for HIV-1 resistance and reported cures following bone marrow transplantation. Consequently, CCR5 has been an important target for gene editing utilizing CRISPR/Cas. We determined that CCR5 cleavage activity varied with the target site, spacer length, and the fourth nucleotide in the previously described PAM sequence, TTCN. Our analyses demonstrated a PAM preference for purines (adenine, guanine) over pyrimidines (thymidine, cytosine) in the fourth position of the CasX2 PAM. This improved understanding of CasX2 cleavage requirements facilitates the development of therapeutic strategies to recreate the CCR5-$\Delta $32 mutation in haematopoietic stem cells.

ObjectiveInvestigate associations between endplate and motion segment magnetic resonance imaging (MRI) characteristics and treatment outcomes following basivertebral nerve radiofrequency ablation (BVN RFA) in patients with clinically suspected vertebral endplate pain (VEP).DesignAggregated cohort study of 296 participants treated with BVN RFA from three prospective clinical trials.MethodsBaseline MRI characteristics were analyzed using stepwise logistic regression to identify factors associated with treatment success. Predictive models used three definitions of treatment success: (1) ≥50% low back pain (LBP) visual analog scale (VAS), (2) ≥15-point Oswestry Disability Index (ODI), and (3) ≥50% VAS or ≥15-point ODI improvements at 3-months post-BVN RFA.ResultsThe presence of lumbar facet joint fluid (odds ratio [OR] 0.586) reduced the odds of BVN RFA treatment success in individuals with clinically suspected VEP. In patients with a less advanced degenerative disc disease (DDD) profile, a > 50% area of the endplate with bone marrow intensity changes (BMIC) was predictive of treatment success (OR 4.689). Both regressions areas under the curve (AUCs) were under 70%, indicating low predictive value. All other vertebral endplate, intervertebral disc, nerve roots facet joint, spinal segmental alignment, neuroforamina, lateral recesses, and central canal MRI characteristics were not associated with BVN RFA success.ConclusionsIn patients with vertebrogenic low back pain with Modic changes, the presence of degenerative findings of the anterior and posterior column was not associated with a clinically important impact on BVN RFA treatment success. None of the models demonstrated strong predictive value, indicating that the use of objective imaging biomarkers (Type 1 and/or 2 Modic changes) and a correlating presentation of pain remain the most useful patient selection factors for BVN RFA.

ObjectiveDevelop pain location "maps" and investigate the relationship between low back pain (LBP)-exacerbating activities and treatment response to basivertebral nerve radiofrequency ablation (BVN RFA) in patients with clinically suspected vertebral endplate pain (VEP).DesignAggregated cohort study of 296 patients treated with BVN RFA at 33 centers in three prospective trials.MethodsParticipant demographics, pain diagrams, and LBP-exacerbating activities were analyzed for predictors using stepwise logistic regression. Treatment success definitions were: (1) ≥50% LBP visual analog scale (VAS), (2) ≥15-point Oswestry Disability Index (ODI), and (3) ≥50% VAS or ≥15-point ODI improvements at 3 months post-BVN RFA.ResultsMidline LBP correlated with BVN RFA treatment success in individuals with clinically-suspected VEP. Duration of pain ≥5 years (OR 2.366), lack of epidural steroid injection within 6 months before BVN RFA (OR 1.800), lack of baseline opioid use (OR 1.965), LBP exacerbation with activity (OR 2.099), and a lack of LBP with spinal extension (OR 1.845) were factors associated with increased odds of treatment success. Regressions areas under the curve (AUCs) were under 70%, indicative of low predictive value.ConclusionsThis study demonstrates that midline LBP correlates with BVN RFA treatment success in individuals with VEP. While none of the regression models demonstrated strong predictive value, the pain location and exacerbating factors identified in this analysis may aid clinicians in identifying patients where VEP should be more strongly suspected. The use of objective imaging biomarkers (Type 1 and/or 2 Modic changes) and a correlating presentation of anterior spinal element pain remain the most useful patient selection factors for BVN RFA.

As we act on the world around us, our eyes seek out objects we plan to interact with. A growing body of evidence suggests that overt visual attention selects objects in the environment that could be interacted with, even when the task precludes physical interaction. In previous work, objects that afford grasping interactions influenced attention when static scenes depicted reachable spaces, and attention was otherwise better explained by general informativeness. Because grasping is but one of many object interactions, previous work may have downplayed the influence of object affordances on attention. The current study investigated the relationship between overt visual attention and object affordances versus broadly construed semantic information in scenes as speakers describe or memorize scenes. In addition to meaning and grasp maps-which capture informativeness and grasping object affordances in scenes, respectively-we introduce interact maps, which capture affordances more broadly. In a mixed-effects analysis of 5 eyetracking experiments, we found that meaning predicted fixated locations in a general description task and during scene memorization. Grasp maps marginally predicted fixated locations during action description for scenes that depicted reachable spaces only. Interact maps predicted fixated regions in description experiments alone. Our findings suggest observers allocate attention to scene regions that could be readily interacted with when talking about the scene, while general informativeness preferentially guides attention when the task does not encourage careful consideration of objects in the scene. The current study suggests that the influence of object affordances on visual attention in scenes is mediated by task demands.

Objective  This study aimed to evaluate the impact of endoscopic anterior cranial base (ACB) surgery on sinonasal symptoms in the pediatric population utilizing the Sino-Nasal Outcome Test (SNOT)-22 questionnaire. Design  This is a retrospective review. Setting  The study was conducted at a tertiary academic medical center. Participants  Thirty-four consecutive patients, age 6 to 17 years, M:F 14:20, who underwent endoscopic ACB surgery from July 2008 to August 2019. Ten patients had baseline and a minimum of two subsequent postoperative SNOT-22 questionnaires available for analysis. Main Outcome Measures  Baseline and postoperative SNOT-22 scores were compared. The mean change from baseline sinonasal symptom scores in the pediatric and historical adult cohorts was compared. Results  The mean baseline SNOT-22 score for our 10 patient cohort was 0.46 out of 5 for each of the first 10 sinonasal-specific questions. This worsened to 1.69 at 1 month and returned to near baseline, 0.7, at 3 months postoperatively. The mean quality-of-life score improved to 0.91 at 1 month and 0.6 at 3 months postoperatively. The mean change from baseline for the following items: need to blow nose, runny nose, postnasal discharge, thick nasal discharge, wake up at night, reduced concentration, and frustrated/restless/irritable were similar to those in our historical adult cohort at 3 months postoperatively. Conclusion  Endoscopic ACB surgery in the pediatric population results in increased sinonasal symptom morbidity in the early postoperative period; however, symptoms return to near baseline by ∼3 months, and quality-of-life scores progressively improve in the postoperative period. These trends were similar to those seen in our historic adult cohort.