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Sexual violence is common on US college campuses and can result in negative health and academic outcomes. Credit-bearing courses are a possible innovative intervention, but few have been studied, and little is known about enrolled students' experiences. Our institution, located in the Southern United States, developed a semester-long class as a curricular intervention after our institutional climate survey results showed high rates of sexual violence among undergraduate students. Students enrolled in the course wrote a final reflection paper on what they found meaningful about the class (N = 62). Qualitative conventional content analysis was used to examine what students found most salient. Three overarching categories emerged: course content, course delivery and course impact, each with multiple themes. For course content, students wrote about 22 different topics from the class. For course delivery, students discussed the open forum to discuss sexuality, the importance of taking the course in their first year of college and the course structure. For course impact, students discussed gaining new knowledge, questioning prior assumptions, experiencing personal transformation and feeling empowered to act. Results indicated that students had a powerful class experience and that this kind of educational intervention has the potential to positively impact enrolled students.

Objective: This study examined the impact of State and Trait anxiety and dietary intake on college students' gastrointestinal symptoms during the COVID-19 pandemic. Participants: A total of 455 students, aged 18-23, from two residential colleges in the midwestern United States participated in the study during April 2021. Methods: An online questionnaire that included the National Cancer Institute Dietary Screener, State-Trait Inventory for Cognitive and Somatic Anxiety, and an adapted version of the Gastrointestinal Symptoms Questionnaire was used. Stepwise multiple regression analyses and Spearman rho correlation coefficients were used to analyze the data. Results: High rates of State-somatic, State-cognitive, and Trait-somatic anxiety were present in our study population. These anxiety subscales and dietary intake predicted 26% and 3.8% of the GI symptoms variance, respectively. Conclusion: State-anxiety and Trait-somatic anxiety are large factors in predicting GI symptoms compared to dietary intake. College students could seek anxiety-reducing techniques to ease GI symptoms.

Knowing when an event is likely to occur allows attentional resources to be oriented towards that moment in time, enhancing processing of the event. We previously found that children (mean age 11 years) are unable to use endogenous temporal cues (line length) to orient attention in time, despite being able to use endogenous spatial cues (arrows) to orient attention in space. Arrow cues, however, may have proved beneficial by engaging exogenous (automatic), as well as endogenous (voluntary), orienting mechanisms. We therefore conducted two studies in which the exogenous properties of visual temporal cues were increased, to examine whether this helped children orient their attention in time. In the first study, the location of an imperative target was predicted by the direction of a left or right spatial arrow cue while its onset was predicted by the relative duration of a short or long temporal cue. To minimise the influence of rhythmic entrainment in the temporal condition, target onset time (500ms/1100ms) was deliberately chosen so as not to precisely match the duration of the temporal cue (100ms/400ms). Targets appeared either at cued locations/onset times (valid trials) or at unexpected locations/onset times (invalid trials). Adults’ response times were significantly slower for invalid versus valid trials, in both spatial and temporal domains. Despite being slowed by invalid spatial cues, children (mean age 10.7 years) were unperturbed by invalid temporal cues, suggesting that these duration-based temporal cues did not help them orient attention in time. In the second study, we enhanced the exogenous properties of temporal cues further, by presenting multiple temporal cues in an isochronous (rhythmic) sequence. Again, to minimise automatic entrainment, target onset did not match the isochronous interval. Children (mean age 11.4 years), as well as adults, were now significantly slowed by invalid cues in both the temporal and spatial dimension. The sequential, as opposed to single, presentation of temporal cues therefore helped children to orient their attention in time. We suggest that the exogenous properties of sequential presentation provide a temporal scaffold that supports the additional attentional and mnemonic requirements of temporal, as compared to spatial, processing.

Children are able to use spatial cues to orient their attention to discrete locations in space from around 4 years of age. In contrast, no research has yet investigated the ability of children to use informative cues to voluntarily predict when an event will occur in time. The spatial and temporal attention task was used to determine whether children were able to voluntarily orient their attention in time, as well as in space: symbolic spatial and temporal cues predicted where or when an imperative target would appear. Thirty typically developing children (average age 11 yrs) and 32 adults (average age 27 yrs) took part. Confirming previous findings, adults made use of both spatial and temporal cues to optimise behaviour, and were significantly slower to respond to invalidly cued targets in either space or time. Children were also significantly slowed by invalid spatial cues, demonstrating their use of spatial cues to guide expectations. In contrast, children's responses were not slowed by invalid temporal cues, suggesting that they were not using the temporal cue to voluntarily orient attention through time. Children, as well as adults, did however demonstrate signs of more implicit forms of temporal expectation: RTs were faster for long versus short cue-target intervals (the variable foreperiod effect) and slower when the preceding trial's cue-target interval was longer than that on the current trial (sequential effects). Overall, our results suggest that although children implicitly made use of the temporally predictive information carried by the length of the current and previous trial's cue-target interval, they could not deliberately use symbolic temporal cues to speed responses. The developmental trajectory of the ability to voluntarily use symbolic temporal cues is therefore delayed, relative both to the use of symbolic (arrow) spatial cues, and to the use of implicit temporal information.

Abstract Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

Summary: The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Peripheral nerve modulation via electrical stimulation shows promise for treating several diseases, but current approaches lack selectivity, leading to side effects. Exploring selective neuromodulation with commercially available nerve cuffs is impractical due to their high cost and limited spatial resolution. While custom cuffs reported in the literature achieve high spatial resolutions, they require specialized microfabrication equipment and significant effort to produce even a single design. This inability to rapidly and cost-effectively prototype novel cuff designs impedes research into selective neuromodulation therapies in acute studies. To address this, we developed a reproducible method to easily create multi-channel epineural nerve cuffs for selective fascicular neuromodulation. Leveraging commercial flexible printed circuit (FPC) technology, we created cuffs with high spatial resolution (50 μm) and customizable parameters like electrode size, channel count, and cuff diameter. We designed cuffs to accommodate adult mouse or rat sciatic nerves (300–1500 μm diameter). We coated the electrodes with PEDOT:PSS to improve the charge injection capacity. We demonstrated selective neuromodulation in both rats and mice, achieving preferential activation of the tibialis anterior (TA) and lateral gastrocnemius (LG) muscles. Selectivity was confirmed through micro-computed tomography (μCT) and quantified through a selectivity index. These results demonstrate the potential of this fabrication method for enabling selective neuromodulation studies while significantly reducing production time and costs compared to traditional approaches.

Summary: Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor growth and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 8 (DOCK8) on lysosomes. Surprisingly, DOCK8 is aberrantly expressed in a subset of PDAC, where it promotes cell invasion in vitro and in vivo. DOCK8 associates with lysosomes and regulates lysosomal morphology and motility, with loss of DOCK8 leading to increased lysosome size. DOCK8 promotes actin polymerization at the surface of lysosomes while also increasing the proteolytic activity of the lysosomal protease cathepsin B. Critically, depletion of DOCK8 significantly reduces cathepsin-dependent extracellular matrix degradation and impairs the invasive capacity of PDAC cells. These findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation and invasion in pancreatic cancer cells.

Integrative taxonomy is necessary for advancing the field of phycology and understanding regional algal diversity. Collection-based studies for the purposes of providing descriptive voucher flora of living algal communities inform future long-term monitoring and genetic barcoding studies. In this study, littoral composite samples were taken from eight sites (Center Lake, Emerson Bay, Freda Haffner Kettlehole State Preserve, Millers Bay, East Okoboji Lake, West Okoboji Lake, Big Spirit Lake, Upper Gar Lake) in Dickinson County, Iowa, for the purposes of fine level taxonomy. This region has a history of eutrophication, and algal blooms have caused Iowa water resource issues in the past. Micrography for these voucher floras was conducted for taxa representing at least 10% or more of the total estimated algal biomass of evaluated slides. Our voucher floras comprise micrographs of living cells across nine different algal groups and 54 unique taxonomic entities. Unique taxa from these sites include Glaucocystis nostochinearum Itzigsohn, Draparnaldia acuta (C.Agardh) Kützing, and Chaetophoropsis elegans (Roth) B. Wen Liu, Qian Xiong, X.Dong Liu, Z. Yu Hu & G. Xiang Liu. We also document species belonging to toxin-producing Cyanobacteria genera Mycrocystis and Dolichospermum.

Abstract Representative models are needed to screen new therapies for patients with cancer. Cancer organoids are a leap forward as a culture model that faithfully represents the disease. Mouse-derived cancer organoids (MDCOs) are becoming increasingly popular, however there has yet to be a standardized method to assess therapeutic response and identify subpopulation heterogeneity. There are multiple factors unique to organoid culture that could affect how therapeutic response and MDCO heterogeneity are assessed. Here we describe an analysis of nearly 3500 individual MDCOs where individual organoid morphologic tracking was performed. Change in MDCO diameter was assessed in the presence of control media or targeted therapies. Individual organoid tracking was identified to be more sensitive to treatment response than well-level assessment. The impact of different generations of mice of the same genotype, different regions of the colon, and organoid specific characteristics including baseline size, passage number, plating density, and location within the matrix were examined. Only the starting size of the MDCO altered the subsequent growth. These results were corroborated using ~ 1700 patient-derived cancer organoids (PDCOs) isolated from 19 patients. Here we establish organoid culture parameters for individual organoid morphologic tracking to determine therapeutic response and growth/response heterogeneity for translational studies.

The negative impact of adverse experiences in childhood on neurodevelopment is well documented. Less attention however has been given to the impact of variations in “normative” parenting behaviors. The influence of these parenting behaviors is likely to be marked during periods of rapid brain reorganization, such as late childhood. The aim of the current study was to investigate associations between normative parenting behaviors and the development of structural brain networks across late childhood. Data were collected from a longitudinal sample of 114 mother-child dyads (54% female children, M age 8.41 years, SD = 0.32 years), recruited from low socioeconomic areas of Melbourne, Australia. At the first assessment parenting behaviors were coded from two lab-based interaction tasks and structural magnetic resonance imaging (MRI) scans of the children were performed. At the second assessment, approximately 18 months later (M age 9.97 years, SD = 0.37 years) MRI scans were repeated. Cortical thickness (CT) was extracted from T1-weighted images using FreeSurfer. Structural covariance (SC) networks were constructed from partial correlations of CT estimates between brain regions and estimates of network efficiency and modularity were obtained for each time point. The change in these network measures, from Time 1 to Time 2, was also calculated. At Time 2, less positive maternal affective behavior was associated with higher modularity (more segregated networks), while negative maternal affective behavior was not related. No support was found for an association between local or global efficacy and maternal affective behaviors at Time 2. Similarly, no support was demonstrated for associations between maternal affective behaviors and change in network efficiency and modularity, from Time 1 to Time 2. These results indicate that normative variations in parenting may influence the development of structural brain networks in late childhood and extend current knowledge about environmental influences on structural connectivity in a developmental context.

Attention Restoration Theory proposes that exposure to natural environments helps to restore attention. For sustained attention—the ongoing application of focus to a task, the effect appears to be modest, and the underlying mechanisms of attention restoration remain unclear. Exposure to nature may improve attention performance through many means: modulation of alertness and one’s connection to nature were investigated here, in two separate studies. In both studies, participants performed the Sustained Attention to Response Task (SART) before and immediately after viewing a meadow, ocean, or urban image for 40 s, and then completed the Perceived Restorativeness Scale. In Study 1 (n = 68), an eye-tracker recorded the participants’ tonic pupil diameter during the SARTs, providing a measure of alertness. In Study 2 (n = 186), the effects of connectedness to nature on SART performance and perceived restoration were studied. In both studies, the image viewed was not associated with participants’ sustained attention performance; both nature images were perceived as equally restorative, and more restorative than the urban image. The image viewed was not associated with changes in alertness. Connectedness to nature was not associated with sustained attention performance, but it did moderate the relation between viewing the natural images and perceived restorativeness; participants reporting a higher connection to nature also reported feeling more restored after viewing the nature, but not the urban, images. Dissociation was found between the physiological and behavioral measures and the perceived restorativeness of the images. The results suggest that restoration associated with nature exposure is not associated with modulation of alertness but is associated with connectedness with nature.

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

Market-based health services have arisen out of major transformations in US healthcare in the last several decades. This study addresses pricing in the human egg donation market – an under-explored topic despite substantial scholarship on commodification and financial coercion of donors. Through analysis of primary data collected from 276 US fertility clinics and egg donation agencies, I assess what impacts average donor compensation and likelihood of compensation being more than $5000. Drawing on theories of organizational behavior, I test whether organizational characteristics, ecological factors, or regulatory pressure have the greatest impact on donor compensation amounts. I find that compensation is influenced primarily by ecological/market factors. Furthermore, industry self-regulation (measured by professional affiliation) did not deter clinics and agencies from having higher donor compensation levels, despite American Society for Reproduction Medicine recommendations. I conclude by addressing the broader implications of these findings for medical market dynamics and the problem of industry self-regulation.

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) tend to perform cognitive tasks with greater Response Time Variability (RTV). Greater RTV in ADHD may be due to inefficient functional connectivity of the brain during information processing. This study aimed to investigate the relationship between brain connectivity, RTV, and levels of ADHD symptoms. Twenty-eight children aged 9–12 years and 49 adolescents aged 15–18 years performed the Sustained Attention to Response Task (SART) while EEG was recorded. The participants’ levels of ADHD symptoms were measured using self- and parent-rated questionnaires. The ex-Gaussian analysis and The Fast Fourier Transform were used to measure multiple aspects of RTV. Functional connectivity between 64 electrodes was computed during task performance, and global efficiency and modularity were calculated, reflecting integration and segregation of the brain, respectively. There was a positive association between multiple RTV measures and the level of ADHD symptoms, where participants with higher levels of ADHD symptoms showed greater RTV, except for sigma from the ex-Gaussian analysis. More efficient brain network activity, measured by global efficiency, was associated with reduced RTV. Children showed greater RTV and less efficient brain network activity compared with the adolescents. These findings support the view that stable responses are achieved with more integrated (and efficient) brain connectivity.

Introduction: Low-income and racial/ethnic minority preschoolers (aged 2–5 years) are disproportionately affected by obesity and its associated health consequences. Individual-level factors (e.g., diet) and environmental factors (e.g., neighborhood conditions) contribute to these disparities. However, there is limited research examining the role of neighborhood factors on obesity risk specifically among high-risk preschoolers. The objectives of this study are to describe the geographic distribution of preschool patients receiving care at two primary care pediatrics clinics affiliated with an academic medical center, and explore whether exposure to neighborhood crime and poverty is associated with obesity risk among this population.Methods: Cross-sectional multilevel study linking clinical administrative data on patient visits between 2007 and 2012 with data from the American Community Survey and the Baltimore City Police Department. Home addresses of 2–5 year-old patients were geocoded to their neighborhood (i.e., census block group) of residence. We used logistic regression to examine the cross-sectional relationship between obesity and overweight and neighborhood-level factors. All analyses were adjusted for age and gender, and stratified by race/ethnicity (Black, Hispanic, and White).Results: The majority of preschool patients lived in moderate or high crime (84%) or high poverty (54%) neighborhoods. A significantly higher proportion of Black preschoolers lived in high poverty neighborhoods compared to White preschoolers (61% vs. 38%, p < 0.001). Among this clinic-based sample of preschoolers, living in high crime or high poverty neighborhoods was not associated with a clinically significant increased odds of overweight or obesity.Conclusions: This study examines the association between neighborhood factors and obesity and overweight among a clinic-based population of low-income racial/ethnic minority preschoolers. The neighborhoods where preschoolers in this sample lived, on average had higher crime counts and poverty than the citywide average for Baltimore. Our findings also suggest that Black preschoolers are exposed to higher levels of neighborhood poverty compared to Whites. While no meaningful association between these neighborhood factors and odds of obesity or overweight was found in this cross-sectional analysis, our findings suggest avenues for future studies informative to the development of clinic-based obesity management interventions aimed at effectively addressing neighborhood contributors to early childhood obesity disparities.

ABSTRACT Hydrolase are enzymes that regulate diverse biological processes, including posttranslational protein modifications. Recent work identified four active serine hydrolases (ASHs) in Toxoplasma gondii as candidate depalmitoylases. However, only TgPPT1 (ASH1) has been confirmed to remove palmitate from proteins. ASH4 (TgME49_264290) was reported to be refractory to genetic disruption. We demonstrate that recombinant ASH4 is an esterase that processes short acyl esters but not palmitoyl thioesters. Genetic disruption of ASH4 causes defects in cell division and premature scission of parasites from residual bodies. These defects lead to the presence of vacuoles with a disordered intravacuolar architecture, with parasites arranged in pairs around multiple residual bodies. Importantly, we found that the deletion of ASH4 correlates with a defect in radial dispersion from host cells after egress. This defect in dispersion of parasites is a general phenomenon that is observed for disordered vacuoles that occur at low frequency in wild-type parasites, suggesting a possible general link between intravacuolar organization and dispersion after egress. IMPORTANCE This work defines the function of an enzyme in the obligate intracellular parasite Toxoplasma gondii. We show that this previously uncharacterized enzyme is critical for aspects of cellular division by the parasite and that loss of this enzyme leads to parasites with cell division defects and which also are disorganized inside their vacuoles. This leads to defects in the ability of the parasite to disseminate from the site of an infection and may have a significant impact on the parasite's overall infectivity of a host organism.

Both time and number can be represented in spatial terms. While their representation in terms of spatial magnitude (distance or size) might be innate, their representation in terms of spatial position (left/right or up/down) is acquired. In Western culture, the mental timeline represents past/future events or short/long duration on the left/right sides of space, respectively. We conducted two developmental studies to pinpoint the age at which the mental timeline for duration begins to be acquired. Children (aged 5–6, 8, or 10 years old) and adults performed temporal bisection tasks in which relative spatial position (left/right) was manipulated by either arrow direction (Experiment 1) and/or lateralized stimulus location (Experiments 1 and 2). Results first confirmed previous findings that the symbolic representation of spatial position conveyed by arrow stimuli influences the perception of duration in older children. Both 8 and 10 year olds judged the duration of leftward arrows to be shorter than that of rightward arrows. We also showed for the first time that as long as position is manipulated in a non-symbolic way by the visual eccentricity of the stimuli, then even 5–6 year olds’ perception of duration is influenced by spatial position. These children judged the duration of left-lateralized stimuli to be shorter than that of either right-lateralized or centrally located stimuli. These data are consistent with the use of a mental timeline for stimulus duration from the age of 5 years old, with short duration being represented on the left side of space and long duration on the right. Nevertheless, the way in which left and right were manipulated determined the age at which spatial position influenced duration judgment: physical spatial location influenced duration perception from the age of 5 years old whereas arrow direction influenced it from the age of 8. This age-related dissociation may reflect distinct developmental trajectories of automatic versus voluntary spatial attentional mechanisms and, more generally highlights the importance of accounting for attentional ability when interpreting results of duration judgment tasks.

The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. PfFtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites.