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Chemotherapy is more effective in the treatment of peripheral tumors than brain metastases, likely reflecting the reduced ability of chemotherapy to cross the blood-brain barrier (BBB) and blood-tumor barrier at efficacious concentrations. Recent studies demonstrate circadian regulation of the BBB. Thus, we predicted that optimally timed chemotherapy would increase anti-tumor efficacy in a model of brain metastases of breast cancer (BMBC). First, we characterized novel daily alterations in BBB permeability to a commonly used chemotherapeutic, 14C-paclitaxel, within BMBC following injections given at four time points across the day. Peak and trough 14C-paclitaxel concentrations within BMBC occurred during the mid-dark phase and at the beginning of the light phase, respectively. Notably, chemotherapy injections during the dark phase increased cell death within BMBC and delayed onset of neurological symptoms relative to injections during the light phase. These data provide strong evidence for the beneficial effects of chrono-chemotherapy for the treatment of BMBC.

Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.

Purpose: Caregivers share critical insight during their child's stuttering evaluation; yet, there have been no empirical studies evaluating whether caregivers provide similar accounts of their 3- to 6-year-old child's communication attitude compared to their child's self-report. This study examined caregiver- and child-reported communication attitude and assessed potential moderators of more comparable caregiver and child ratings (i.e., caregiver confidence, caregiver-child conflict, observer-rated stuttering severity). Method: One hundred thirteen children who stutter ages 3 through 6 years and a primary caregiver were recruited from clinical settings across the United States. Children completed the Communication Attitude Test for Preschool and Kindergarten Children Who Stutter (KiddyCAT) and three speaking samples, which were recorded to assess observer-rated stuttering severity using the Stuttering Severity Instrument--Fourth Edition. Caregivers predicted their child's communication attitude (C-KiddyCAT) and provided a confidence rating for their prediction. Caregivers also rated caregiver-child conflict using the Child-Parent Relationship Scale-Short Form (CPRS-SF). Multiple regression was used to (a) evaluate whether caregiver C-KiddyCAT scores predicted child KiddyCAT scores and (b) assess potential moderators of the relationship between C-KiddyCAT and KiddyCAT scores. Results: Caregiver ratings of their child's communication attitude (C-KiddyCAT) predicted child communication attitude ratings (KiddyCAT). A significant interaction between caregiver-child conflict (CPRS-SF) and caregiver ratings of their child's communication attitude (C-KiddyCAT) suggested caregiver-child conflict changed the underlying relationship between C-KiddyCAT and KiddyCAT scores, such that low conflict resulted in more similar C-KiddyCAT and KiddyCAT scores. Neither caregiver confidence nor observer-rated stuttering severity influenced the relationship between C-KiddyCAT and KiddyCAT scores. Conclusions: Although many caregivers predicted communication attitude ratings that closely aligned with their child's report, some caregiver-child dyads provided divergent ratings. Clinicians should interpret caregiver predictions of their child's communication attitude within the context of their full evaluation and the caregiver-child relationship. Assessing both self-reported communication attitude and caregiver predictions of their child's communication attitude provides a meaningful starting point to counseling caregivers about cognitive components of stuttering for preschool- and kindergarten-age children who stutter.

Learning to interpret visual representations of data is an important step towards becoming an informed consumer of research. The current study assesses the effectiveness of two versions of a scaffolded online module in improving students' ability to identify main effects and interactions in 2 × 2 factorial designs. Across two experiments (N = 313), we compared exam performance between sections of a lower-division conceptual statistics course that completed the module (in addition to other course activities) to a section that did not complete the module (n = 91). The first iteration of the module (used in Experiment 1, n = 96) was completed once individually and once with peers and did not enhance students' individual performance on conceptually-related exam questions. However, performance on the module was low, indicating that students may have needed more support to benefit from this experience. In Experiment 2 (n = 126), we made three empirically-driven changes to better scaffold student learning: we added a worked example, offered a greater variety of examples, and instructed students to complete the whole activity with peers. Under these conditions, performance increased on related exam questions. We conclude that this freely available module is a promising intervention to strengthen students' ability to understand factorial designs.

Black women remain severely underrepresented in computing despite ongoing efforts to diversify the field. Given that Black women exist at the intersection of both racial and gendered identities, tailored approaches are necessary to address the unique barriers Black women face in computing. However, it is difficult to quantitatively evaluate the efficacy of interventions designed to retain Black women in computing, since samples of computing students typically contain too few Black women for robust statistical analysis. Using about a decade of student survey responses from an National Science Foundation--funded Broadening Participation in Computing alliance, we use regression analyses to quantitatively examine the connection between different types of interventions and Black women's intentions to persist in computing and how this compares to other students (specifically, Black men, white women, and white men). This comparison allows us to quantitatively explore how Black women's needs are both distinct from--and similar to--other students. We find that career awareness and faculty mentorship are the two interventions that have a statistically significant, positive correlation with Black women's computing persistence intentions. No evidence was found that increasing confidence or developing skills/knowledge was correlated with Black women's computing persistence intentions, which we posit is because Black women must be highly committed and confident to pursue computing in college. Last, our results suggest that many efforts to increase the number of women in computing are focused on meeting the needs of white women. While further analyses are needed to fully understand the impact of complex intersectional identities in computing, this large-scale quantitative analysis contributes to our understanding of the nuances of Black women's needs in computing.

Autistic people often experience difficulties navigating face-to-face social interactions. Historically, the empirical literature has characterised these difficulties as cognitive 'deficits' in social information processing. However, the empirical basis for such claims is lacking, with most studies failing to capture the complexity of social interactions, often distilling them into singular communicative modalities (e.g. gaze-based communication) that are rarely used in isolation in daily interactions. The current study examined how gaze was used in concert with communicative hand gestures during joint attention interactions. We employed an immersive virtual reality paradigm, where autistic (n = 22) and non-autistic (n = 22) young people completed a collaborative task with a non-autistic confederate. Integrated eye-, head- and hand-motion-tracking enabled dyads to communicate naturally with each other while offering objective measures of attention and behaviour. Autistic people in our sample were similarly, if not more, effective in responding to hand-cued joint attention bids compared with non-autistic people. Moreover, both autistic and non-autistic people demonstrated an ability to adaptively use gaze information to aid coordination. Our findings suggest that the intersecting fields of autism and social neuroscience research may have overstated the role of eye gaze during coordinated social interactions.

When conducting universal social and emotional learning (SEL) screening, schools need clear decision-making guidelines for selecting informants. The current study examined informant profiles for screening SEL functioning using latent profile analysis with the student and teacher forms of the SSIS SEL Brief Scales for 536 students in grades 3-7. Teacher and student models each had three profiles emerge with roughly similar meanings of the profiles (Developing, Competent, and Advanced profiles), although a larger percentage of students were identified in the developing profile for the student rater. Profile categories aligned for 42% of students, with the most disagreement according between the Competent and Advanced SEL categories. For the teacher and student combined model, five profiles emerged (Competent-Developing, Developing-Competent, Competent-High Competent, Competent-Competent, and Advanced-Competent), with one profile indicating informant agreement. We explore gender and grade setting covariates and discuss implications for multi-informant research and practice.

Background: While vaccines have reduced the incidence of vaccine-preventable diseases, vaccine hesitancy threatens the re-emergence of childhood infectious diseases. Purpose: This randomized controlled study evaluated an online vaccine education program to advance vaccine acceptance among middle-school students. Methodology: Study participants were randomly assigned to an intervention group who viewed the VEP videos or to a comparison group who viewed a science-based video unrelated to vaccines. Results: Knowledge scores improved in both groups and more favorable shifts in vaccine-related beliefs and attitudes occurred in the intervention than in the comparison group. Conclusions: This program can be feasibly delivered via an online platform to middle school students, resulting in shifts in vaccine-related knowledge, beliefs and attitudes. Implications: Delivering evidence-based content to instruct about vaccine effectiveness and safety is an area in which school nurses have demonstrated an important role as a resource for patient education to promote vaccine advocacy.

Musical instrument training has been linked to improved academic and cognitive abilities in children, but it remains unclear why this occurs. Moreover, access to instrument training is not always feasible, thereby leaving less fortunate children without opportunity to benefit from such training. Although music-based video games may be more accessible to a broader population, research is lacking regarding their benefits on academic and cognitive performance. To address this gap, we assessed a custom-designed, digital rhythm training game as a proxy for instrument training to evaluate its ability to engender benefits in math and reading abilities. Furthermore, we tested for changes in core cognitive functions related to math and reading to inform how rhythm training may facilitate improved academic abilities. Classrooms of 8-9 year old children were randomized to receive either 6 weeks of rhythm training (N = 32) or classroom instruction as usual (control; N = 21). Compared to the control group, results showed that rhythm training improved reading, but not math, fluency. Assessments of cognition showed that rhythm training also led to improved rhythmic timing and language-based executive function (Stroop task), but not sustained attention, inhibitory control, or working memory. Interestingly, only the improvements in rhythmic timing correlated with improvements in reading ability. Together, these results provide novel evidence that a digital platform may serve as a proxy for musical instrument training to facilitate reading fluency in children, and that such reading improvements are related to enhanced rhythmic timing ability and not other cognitive functions associated with reading performance.

Currently, the prevalence of autism spectrum disorder (henceforth "autism") is 1 in 36, an increasing trend from previous estimates. In 2015, the United States adopted a new version (International Classification of Diseases, 10th Revision) of the World Health Organization coding system, a standard for classifying medical conditions. Our goal was to examine how the transition to this new coding system impacted autism diagnoses in 10 healthcare systems. We obtained information from electronic medical records and insurance claims data from July 2014 through December 2016 for each healthcare system. We used member enrollment data for 30 consecutive months to observe changes 15 months before and after adoption of the new coding system. Overall, the rates of autism per 1000 enrolled members was increasing for 0- to 5-year-olds before transition to International Classification of Diseases, 10th Revision and did not substantively change after the new coding was in place. There was variation observed in autism diagnoses before and after transition to International Classification of Diseases, 10th Revision for other age groups. The change to the new coding system did not meaningfully affect autism rates at the participating healthcare systems. The increase observed among 0- to 5-year-olds is likely indicative of an ongoing trend related to increases in screening for autism rather than a shift associated with the new coding.

Background: The benefits of friendships among peers with and without intellectual and developmental disabilities are well supported by research. However, little is known about the nature of these inclusive friendships in inclusive college courses. Method: We explored the perspectives of peers on the development of authentic friendships among peers with and without intellectual and developmental disabilities in inclusive college courses in the United States. We used a sequential, explanatory, transformative mixed methods-grounded theory research design. We integrated quantitative (N = 44) and qualitative (N = 8) findings using blended analysis to inform a preliminary grounded theory of inclusive and reciprocal friendships. Results: Quantitative findings suggest two relationships and one predictor of peers' perceived social engagement. Qualitative findings resulted in five themes that promote friendships. Conclusions: We propose that the context for developing inclusive friendships could be fostered using the preparation and actions stages of the grounded theory model.

Background: To build capacity among people with intellectual and developmental disabilities to become co-researchers they need the opportunity to learn about research. Method: An inclusive research team developed an online training to support people with intellectual and developmental disabilities to serve as co-researchers. Seven participants were recruited as pilot trainees. The co-researcher training consisted of two 1-h training sessions. Pre- and post-surveys and a focus group were conducted to examine participant experiences with the co-researcher training. Results: The participants were actively engaged during the co-researcher training sessions and shared they had a positive experience with it. They expressed that people with intellectual and developmental disabilities add value to the research team because of their lived experiences. Conclusion: The co-researcher training can instill a baseline level of knowledge about research in people with intellectual and developmental disabilities, and can be adjusted for different types of research in different settings and organisations.

Starbuck’s is the number one leading coffee company with over thirty-thousand locationsacross the world, while keeping a strong brand image. In 2021, Starbucks had the first store inBuffalo New York petition to unionize while over 300 stores slowly followed. Starbucks workersjoined Starbucks Workers United in hopes to improve working conditions and safety concerns.Now almost two years later, both Starbucks and their workers are in unknown territory that createschallenges amongst managers and their employees due to this stand still. I plan to uncover thechallenges and dynamics of managerial behaviors under the conditions of labor uncertainty alongthe lines of unionized versus non-unionized Starbucks locations. This capstone will uncover thedynamic of factors such as workforce demands, collective bargaining and shifts in the labormarket. I will go into detail around the unionization efforts, the process of negotiations betweenStarbucks and Workers United, and Starbucks adaptation to the evolving labor practices that havebeen put into place. I will also focus on Starbucks leadership approaches and how it relates to thechallenges between emotions with the partners and members of leadership who are not involvedwith the Union. Next, I will go into detail about the challenges managers and employees face withindividual reactions regarding strikes and walkouts, and what this means for Starbucks as a whole.This research will include how Starbucks can navigate this labor uncertainty while upholding theirthird-place standards and ethical employment practices.

Students in STEM and the health sciences have unique learning needs, including preparation for exams required for entering a STEM or health sciences profession. Students in these areas thus often seek, in addition to or instead of traditional course materials and library resources, digital study tools that utilize techniques such as spaced repetition. However, such tools are often sold as individual subscriptions that may be prohibitively expensive. The article outlines four approaches libraries may consider to help make digital study tools in STEM and the health sciences more equitable and affordable: assess, adopt, adapt, and create.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Congenital diarrheas and enteropathies (CODE) are a group of rare, heterogenous, monogenic disorders that lead to chronic diarrhea in infancy. Definitive treatment is rarely available, and supportive treatment is the mainstay. Nutritional management in the form of either specialized formulas, restrictive diet, or parenteral nutrition support in CODE with poor enteral tolerance is the cornerstone of CODE treatment and long-term growth. The evidence to support the use of specific diet regimens and nutritional approaches in most CODE disorders is limited due to the rarity of these diseases and the scant published clinical experience. The goal of this review was to create a comprehensive guide for nutritional management in CODE, based on the currently available literature, disease mechanism, and the PediCODE group experience. Enteral diet management in CODE can be divided into 3 distinct conceptual frameworks: nutrient elimination, nutrient supplementation, and generalized nutrient restriction. Response to nutrient elimination or supplementation can lead to resolution or significant improvement in the chronic diarrhea of CODE and resumption of normal growth. This pattern can be seen in CODE due to carbohydrate malabsorption, defects in fat absorption, and occasionally in electrolyte transport defects. In contrast, general diet restriction is mainly supportive. However, occasionally it allows parenteral nutrition weaning or reduction over time, mainly in enteroendocrine defects and rarely in epithelial trafficking and polarity defects. Further research is required to better elucidate the role of diet in the treatment of CODE and the appropriate diet management for each disease.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 childrens hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

OBJECTIVE: There is widespread overuse of antibiotics in neonatal intensive care units (NICUs). The objective of this study was to safely reduce antibiotic use in participating NICUs by targeting early-onset sepsis (EOS) management. STUDY DESIGN: Twenty-eight NICUs participated in this statewide multicenter antibiotic stewardship quality improvement collaborative. The primary aim was to reduce the total monthly mean antibiotic utilization rate (AUR) by 25% in participant NICUs. RESULT: Aggregate AUR was reduced by 15.3% (p

BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals would benefit significantly from scalable and innovative approaches to testing using functionally comparable reproductive models such as the nematode C. elegans. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in the average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

ObjectiveTo evaluate menstrual cup use and intrauterine device (IUD) expulsion.Study designWe performed a secondary analysis of a 3-year contraceptive efficacy trial comparing two copper 380 mm2 IUDs. Investigators randomized participants approximately 1:4 to the TCu380A or NTCu380-Mini IUD. Approximately 12 months after enrollment began, we advised participants against menstrual cup use due to observed IUD expulsions in cup users. We evaluated IUD expulsion (including spontaneous partial and complete expulsion and accidental self-removal) at 12 and 36 months. We used multivariable logistic regression to evaluate IUD expulsion by age, baseline menstrual volume, body mass index, IUD type, menstrual cup use, parity, and uterine length.ResultsThis analysis included 1046 participants (203 TCu380A and 843 NTCu380-Mini), with 879 (84.0%) nulliparas. Through 12 and 36 months, expulsion occurred in 74 (7.1%, 95% CI 5.5-8.6%) and 133 (12.7%, 95% CI 10.7-14.7%) participants, respectively. Overall, 250 (23.9%) reported menstrual cup use. More menstrual cup users than non-users experienced expulsion through 12 months (32/203 [15.8%] vs. 42/843 [5.0%]) and 36 months (58/250 [23.2%] vs. 75/796 [9.4%]). Through 36 months, NTCu380-Mini menstrual cup users had higher expulsion odds, while TCu380A cup users did not. Menstrual cup users more frequently experienced accidental self-removal than non-users in participants using the TCu380A (3/53 [5.7%] vs. 0/150 [0.0%]) and the NTCu380-Mini (20/197 [10.2%] vs. 7/646 [1.1%]). In multivariable regression, we found increased odds of expulsion through 36 months in participants using menstrual cups with the NTCu380-Mini (aOR 3.13, 95% CI 1.16-8.46) and

INTRODUCTION: While selective dorsal rhizotomy (SDR) was originally described as a multilevel approach, single-level approaches are now popularized. Conus localization is beneficial for operative planning in single-level selective dorsal rhizotomy. Our approach to SDR involves minimal exposure for a single-level laminoplasty, preserving one attached interspinous ligament. Pre-operative conus localization is required for this tailored approach to determine the laminoplasty level and dictate rostral or caudal division of the superior spinus ligament. While rapid MRI sequences have been popularized for pediatric cranial imaging, its utility for spinal imagining is less well-described, and specific application for conus localization has not been reported. OBJECTIVE: Illustrate that rapid MRI without sedation is sufficient to identify conus level for tailored single-level laminoplasty SDR. MATERIAL AND METHODS: Patients undergoing SDR from 2014 to 2022 at one institution were reviewed for type of pre-operative MRI (rapid vs full), conus level, procedural time for MRI, and radiology report. The typical rapid MRI has four sequences utilizing single-shot technique (scout, sagittal T2, axial T2, and axial T1) that typically take less than 1 min each of acquisition time, with non-single-shot sequences added periodically in cooperative patients. To include time for patient positioning, pre-scan shimming, procedural incidentals, and other patient-specific variations, MRI procedure length was recorded as documented in the electronic medical record. RESULTS: N = 100 patients had documentation of an MRI for pre-operative imaging. Seventy-nine of these had a rapid MRI, and 21 required a full MRI with anesthesia for their treatment plan. Mean total procedure time for rapid MRI was 21.5 min (median 17). Mean procedure time for MRI under general anesthesia was 91.2 min (median 94). Of patients with rapid MRI imaging, 2/79 had an ambiguous conus level (1 from motion artifact, 1 from spinal hardware) vs 1/21 with a full MRI under anesthesia (due to spinal hardware). CONCLUSION: Rapid spinal MRI without sedation can be used for conus localization in a pediatric population. This may be routinely used as pre-operative imaging for a single-level approach to selective dorsal rhizotomy, without sedation or intubation procedures.

BACKGROUND: Superior Semicircular Canal Dehiscence (SSCD) is a dehiscence of the otic capsule which normally lies over the superior semicircular canal. This database constitutes the largest series of SSCD patients to date. OBJECTIVE: To determine what preoperative factors, if any, contribute to postoperative outcomes and evaluate symptom resolution in a large SSCD patient cohort. METHODS: A single-institution, retrospective chart review collected patient demographics, intraoperative findings, and pre-and postoperative symptoms. Fishers exact t-test was performed for unpaired categorical variables, with a significance level of p

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

What is Hawaiian cultural identity? What does it mean to be Hawaiian? Out of the process of developing a curriculum for our Keiki Steps program at the Institute of Native Pacific Education and Culture (INPEACE) emerged these profound questions that form the foundation of all of the work that we do. Our Community-Based Inquiry focuses on understanding who we are and how that impacts the ways in which we teach our keiki (children), setting in motion a process that is transforming our understanding of ourselves, our history, and our culture, and changing the way we work with our earliest learners.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

EXECUTIVE SUMMARY: Microbes are all pervasive in their distribution and influence on the functioning and well-being of humans, life in general and the planet. Microbially-based technologies contribute hugely to the supply of important goods and services we depend upon, such as the provision of food, medicines and clean water. They also offer mechanisms and strategies to mitigate and solve a wide range of problems and crises facing humanity at all levels, including those encapsulated in the sustainable development goals (SDGs) formulated by the United Nations. For example, microbial technologies can contribute in multiple ways to decarbonisation and hence confronting global warming, provide sanitation and clean water to the billions of people lacking them, improve soil fertility and hence food production and develop vaccines and other medicines to reduce and in some cases eliminate deadly infections. They are the foundation of biotechnology, an increasingly important and growing business sector and source of employment, and the centre of the bioeconomy, Green Deal, etc. But, because microbes are largely invisible, they are not familiar to most people, so opportunities they offer to effectively prevent and solve problems are often missed by decision-makers, with the negative consequences this entrains. To correct this lack of vital knowledge, the International Microbiology Literacy Initiative-the IMiLI-is recruiting from the global microbiology community and making freely available, teaching resources for a curriculum in societally relevant microbiology that can be used at all levels of learning. Its goal is the development of a society that is literate in relevant microbiology and, as a consequence, able to take full advantage of the potential of microbes and minimise the consequences of their negative activities. In addition to teaching about microbes, almost every lesson discusses the influence they have on sustainability and the SDGs and their ability to solve pressing problems of societal inequalities. The curriculum thus teaches about sustainability, societal needs and global citizenship. The lessons also reveal the impacts microbes and their activities have on our daily lives at the personal, family, community, national and global levels and their relevance for decisions at all levels. And, because effective, evidence-based decisions require not only relevant information but also critical and systems thinking, the resources also teach about these key generic aspects of deliberation. The IMiLI teaching resources are learner-centric, not academic microbiology-centric and deal with the microbiology of everyday issues. These span topics as diverse as owning and caring for a companion animal, the vast range of everyday foods that are produced via microbial processes, impressive geological formations created by microbes, childhood illnesses and how they are managed and how to reduce waste and pollution. They also leverage the exceptional excitement of exploration and discovery that typifies much progress in microbiology to capture the interest, inspire and motivate educators and learners alike. The IMiLI is establishing Regional Centres to translate the teaching resources into regional languages and adapt them to regional cultures, and to promote their use and assist educators employing them. Two of these are now operational. The Regional Centres constitute the interface between resource creators and educators-learners. As such, they will collect and analyse feedback from the end-users and transmit this to the resource creators so that teaching materials can be improved and refined, and new resources added in response to demand: educators and learners will thereby be directly involved in evolution of the teaching resources. The interactions between educators-learners and resource creators mediated by the Regional Centres will establish dynamic and synergistic relationships-a global societally relevant microbiology education ecosystem-in which creators also become learners, teaching resources are optimised and all players/stakeholders are empowered and their motivation increased. The IMiLI concept thus embraces the principle of teaching societally relevant microbiology embedded in the wider context of societal, biosphere and planetary needs, inequalities, the range of crises that confront us and the need for improved decisioning, which should ultimately lead to better citizenship and a humanity that is more sustainable and resilient. ABSTRACT: The biosphere of planet Earth is a microbial world: a vast reactor of countless microbially driven chemical transformations and energy transfers that push and pull many planetary geochemical processes, including the cycling of the elements of life, mitigate or amplify climate change (e.g., Nature Reviews Microbiology, 2019, 17, 569) and impact the well-being and activities of all organisms, including humans. Microbes are both our ancestors and creators of the planetary chemistry that allowed us to evolve (e.g., Lifes engines: How microbes made earth habitable, 2023). To understand how the biosphere functions, how humans can influence its development and live more sustainably with the other organisms sharing it, we need to understand the microbes. In a recent editorial (Environmental Microbiology, 2019, 21, 1513), we advocated for improved microbiology literacy in society. Our concept of microbiology literacy is not based on knowledge of the academic subject of microbiology, with its multitude of component topics, plus the growing number of additional topics from other disciplines that become vitally important elements of current microbiology. Rather it is focused on microbial activities that impact us-individuals/communities/nations/the human world-and the biosphere and that are key to reaching informed decisions on a multitude of issues that regularly confront us, ranging from personal issues to crises of global importance. In other words, it is knowledge and understanding essential for adulthood and the transition to it, knowledge and understanding that must be acquired early in life in school. The 2019 Editorial marked the launch of the International Microbiology Literacy Initiative, the IMiLI. HERE, WE PRESENT: our concept of how microbiology literacy may be achieved and the rationale underpinning it; the type of teaching resources being created to realise the concept and the framing of microbial activities treated in these resources in the context of sustainability, societal needs and responsibilities and decision-making; and the key role of Regional Centres that will translate the teaching resources into local languages, adapt them according to local cultural needs, interface with regional educators and develop and serve as hubs of microbiology literacy education networks. The topics featuring in teaching resources are learner-centric and have been selected for their inherent relevance, interest and ability to excite and engage. Importantly, the resources coherently integrate and emphasise the overarching issues of sustainability, stewardship and critical thinking and the pervasive interdependencies of processes. More broadly, the concept emphasises how the multifarious applications of microbial activities can be leveraged to promote human/animal, plant, environmental and planetary health, improve social equity, alleviate humanitarian deficits and causes of conflicts among peoples and increase understanding between peoples (Microbial Biotechnology, 2023, 16(6), 1091-1111). Importantly, although the primary target of the freely available (CC BY-NC 4.0) IMiLI teaching resources is schoolchildren and their educators, they and the teaching philosophy are intended for all ages, abilities and cultural spectra of learners worldwide: in university education, lifelong learning, curiosity-driven, web-based knowledge acquisition and public outreach. The IMiLI teaching resources aim to promote development of a global microbiology education ecosystem that democratises microbiology knowledge.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

Nicotine and tobacco product (NTP) use remains prevalent in adolescence/young adulthood. The effects of NTPs on markers of brain health during this vulnerable neurodevelopmental period remain largely unknown. This report investigates associations between NTP use and gray matter cerebral blood flow (CBF) in adolescents/young adults. Adolescent/young adult (16-22 years-old) nicotine users (NTP; N = 99; 40 women) and non-users (non-NTP; N = 95; 56 women) underwent neuroimaging sessions including anatomical and optimized pseudo-continuous arterial spin labeling scans. Groups were compared on whole-brain gray matter CBF estimates and their relation to age and sex at birth. Follow-up analyses assessed correlations between identified CBF clusters and NTP recency and dependence measures. Controlling for age and sex, the NTP vs. non-NTP contrast revealed a single cluster that survived thresholding which included portions of bilateral precuneus (voxel-wise alpha