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Oral medications for chronic conditions often involve a variety of instructions, including time of day/dosing, drug interactions, and food intake restrictions. However, the extent to which patients follow these instructions is unclear. We surveyed patients from the US and Europe (UK, France, Germany, Italy, Spain) who were prescribed sulfonylureas (SU: glimepiride, glipizide, or gliclazide) for diabetes or levothyroxine for hypothyroidism. Patients kept a daily diary for 3–5 days documenting their adherence to three criteria: dosing regimen including time of day, warning labels including drug interactions, and food restrictions. A total of 421 US and 493 European patients took the study medications; 546 patients took SU and 368 took levothyroxine. Overall, 48% of patients were males; 46% were age 65 years or older. Despite most patients having received instructions on medication requirements (US 71%, EU 75%), most patients reported being only somewhat knowledgeable (US 69%; EU 71%). Adherence, measured by the proportion of the days a participant was adherent to each category out of the observational period (ranging from 3–5 days), varied by type of instruction, with the poorest adherence observed for food restriction requirements (US 34% of the observation days, EU 26%) compared to warning labels (US 77%, EU 67%) and dosing regimen (US 85%, EU 87%). Patients adhered to dosing and cautionary instructions across the majority of the study period but were largely non-adherent to food intake restrictions. Improved communication and increased emphasis on food intake restrictions is needed when advising patients on their medications.

The Saharo-Arabian desert is part of the largest near-continuous chain of drylands stretching from north-western Africa to the northern China. This harsh and often hyper-arid belt acts as a transition zone separating major biogeographic realms, including the Palearctic, Afrotropics and Indomalayan. This aridity is thought responsible for the creation of unique geographic endemism between Africa and Eurasia. However, there are no direct hydroclimate records from the Arabian hyper-arid interior before the mid-Pleistocene, leaving the terrestrial hydroclimate and the role of Arabia as a biogeographic crossroads or barrier largely unknown.We use desert speleothems preserved from the northern Arabian interior to identify past humid phases over the last 8 million years. These are particularly useful terrestrial climate archives as they act as underground rain gauges, requiring a minimum of ~300 mm a-1 precipitation, pedogenesis and vegetation cover to form. Moreover, they can be accurately and precisely dated and are subsequently a valuable tool in identifying past large-scale hydrological and vegetation changes in ancient drylands. Our data reveal evidence of multiple ‘windows of opportunity’ of climate amelioration, allowing biogeographic exchange and dispersals to occur across the Arabian hyper-arid zone. Further, the novel analyses of the isotopic composition (d18O and d2H) of speleothem fluid inclusion waters, representing ‘fossil rainwater’, reveal the diminishing influence of tropical rain-belt precipitation in Arabia across Earth’s transition from a largely ‘ice-free’ northern hemisphere to an ‘ice-age’ world. The extent of Arabian aridity may thus be important in controlling biogeographic dispersals through the Arabian corridor, becoming increasingly less favourable through time. This is supported by fossil evidence which suggest that exchange between biogeographic regions across the Old World Savannah Biome were favoured in the Late Miocene, but became increasingly latitudinally fragmented from the Pliocene onwards. These results have significant implications for understanding the drivers of dryland aridity in non-polar deserts globally.

The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the central point upon which cardiac muscle contraction occurs. This review focuses on the many signaling components and mechanisms of regulation that impact cardiac sarcomere function. We highlight the roles of the thick and thin filament, both as necessary structural and regulatory building blocks of the sarcomere as well as targets of functionally impactful modifications. Currently, a new focus emerging in the field is inter-myofilament signaling, and we discuss here the important mediators of this mechanism, including myosin-binding protein C and titin. As the understanding of sarcomere signaling advances, so do the methods with which it is studied. This is reviewed here through discussion of recent live muscle systems in which the sarcomere can be studied under intact, physiologically relevant conditions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively.We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV.We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay.SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpOCoronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

The global development and modern distribution of arid zones in subtropical regions (drylands) are likely associated with the global cooling marking the dawn of the Quaternary (~2.6 Ma). This coincides with global shifts in ocean circulation patterns, the intensification of the Walker-Hadley circulation, declining atmospheric CO2, the initiation of glacial–interglacial cycles and the intensification of Northern Hemisphere glaciation, the combination of which has led to the current global distribution of non-polar deserts at ~30° latitude. Although modern drylands represent Earth’s largest terrestrial biome, covering ~46% of global land surfaces and supporting a global population of ~3 billion people, it is currently unclear how drylands will change under future climate change scenarios. Speleothems, preserved in arid-zone caves, are particularly useful terrestrial climate archives as they act as underground rain gauges, which require a minimum of ~300 mm a-1 precipitation, pedogenesis and vegetation cover to form. Moreover, they can be accurately and precisely dated and are subsequently a valuable tool in identifying past large-scale hydrological and vegetation changes in ancient drylands. Here, we present new data from speleothems during past ‘warm periods’ from the Arabian hyper-arid zone. We apply a novel technique of extracting speleothem fluid inclusions waters to reconstruct the isotopic composition (d18O and d2H) of ‘fossil rainwater’ preserved in the speleothem fabric pristinely over millions of years. Speleothem evidence suggests that during the last 7 million years, the Sahara-Arabian desert experienced numerous intermittent humid phases, typically occurring with periods of low global ice-volume and warmer global temperatures. We further explore tropical push-pull mechanisms driving heating of the deep tropics and subsequent expansion of the tropical zone and synchronicity of humid phases regionally. These results have significant implications for understanding the drivers of dryland aridity in non-polar deserts globally.

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results: Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm.

OBJECTIVE The aim of this study is to elucidate the unique challenges faced by pediatric emergency medicine (PEM) physicians from racial/ethnic groups underrepresented in medicine (URiM). METHODS This study is a subanalysis of data from 18 URiM faculty from a sample of 51 semistructured key informant interviews with PEM faculty in the top NIH-funded pediatric departments and highest-volume pediatric EDs in the country. Faculty are from eight hospitals representing a spectrum of geographic locations including the northeastern, midwestern, western, and southern regions of the country. RESULTS Of 18 study participants, the majority were Black (72.2%) and female (83.3%). Three main thematic categories were identified: challenges related to race, support systems, and suggested strategies to improve diversity and inclusion in PEM. A common race-related experience was microaggressions from colleagues and patients. Additionally, when attempting to lead and assert themselves, URiM women in particular were perceived as "angry" and "intimidating" in a way that non-URiM peers were not. As a result of these negative experiences, participants described the need to go above and beyond to prove themselves. Such pressure produced stress and feelings of isolation. Participants combatted these stressors through resilience strategies such as formal mentorship and peer and family support. Participants indicated the need to increase diversity and create more inclusive work environments, which would benefit both URiM physician wellness and the diverse patients they serve. CONCLUSION Those URiM in PEM face subtle racial discrimination at an institutional, peer, and patient level. The stress caused by this discrimination may further contribute to physician burnout in PEM. While URiMs adopt individual resilience strategies, their unique challenges suggest the need for departmental and institutional efforts to promote greater diversity and inclusion for physician wellness, retention, and quality patient care.

The sarcomere is the functional unit of cardiac muscle, essential for normal heart function. To date, it has not been possible to study, in real time, thin filament-based activation dynamics in live cardiac muscle. We report here results from a cardiac troponin C (TnC) FRET-based biosensor integrated into the cardiac sarcomere via stoichiometric replacement of endogenous TnC. The TnC biosensor provides, for the first time, evidence of multiple thin filament activating ligands, including troponin I interfacing with TnC and cycling myosin, during a cardiac twitch. Results show that the TnC FRET biosensor transient significantly precedes that of peak twitch force. Using small molecules and genetic modifiers known to alter sarcomere activation, independently of the intracellular Ca(2+) transient, the data show that the TnC biosensor detects significant effects of the troponin I switch domain as a sarcomere-activating ligand. Interestingly, the TnC biosensor also detected the effects of load-dependent altered myosin cycling, as shown by a significant delay in TnC biosensor transient inactivation during the isometric twitch. In addition, the TnC biosensor detected the effects of myosin as an activating ligand during the twitch by using a small molecule that directly alters cross-bridge cycling, independently of the intracellular Ca(2+) transient. Collectively, these results aid in illuminating the basis of cardiac muscle contractile activation with implications for gene, protein, and small molecule-based strategies designed to target the sarcomere in regulating beat-to-beat heart performance in health and disease.

Background Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis. Methods This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family’s experiences preceding the patient’s diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data. Results Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers’ management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset. Conclusions While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed.

Women continue to be underrepresented in leadership positions. This underrepresentation is at least partly driven by gender stereotypes that associate men, but not women, with achievement-oriented, agentic traits (e.g., assertive and decisive). These stereotypes are expressed and perpetuated in language, with women being described in less agentic terms than men. The present research suggests that appointing women to the top tiers of management can mitigate these deep-rooted stereotypes that are expressed in language. We use natural language processing techniques to analyze over 43,000 documents containing 1.23 billion words, finding that hiring female chief executive officers and board members is associated with changes in organizations' use of language, such that the semantic meaning of being a woman becomes more similar to the semantic meaning of agency. In other words, hiring women into leadership positions helps to associate women with characteristics that are critical for leadership success. Importantly, our findings suggest that changing organizational language through increasing female representation might provide a path for women to break out of the double bind: when female leaders are appointed into positions of power, women are more strongly associated with the positive aspects of agency (e.g., independent and confident) in language but not at the cost of a reduced association with communality (e.g., kind and caring). Taken together, our findings suggest that female representation is not merely an end, but also a means to systemically change insidious gender stereotypes and overcome the trade-off between women being perceived as either competent or likeable.

What does it mean to be (seen as) human? Ten studies explore this age-old question and show that gender is a critical feature of perceiving humanness, being more central to conceptions of humanness than other social categories (race, age, sexual orientation, religion, disability). Our first six studies induce humanization (i.e., anthropomorphism) and measure social-category ascription. Across different manipulations (e.g., having participants recall experiences, observe moving shapes, imagine nonhuman entities as people, and create a human form), we find that gender is the most strongly ascribed social category and the one that uniquely predicts humanization. To provide further evidence that gender is central to conceptions of personhood, and to examine the consequences of withholding it, we then demonstrate that removing gender from virtual humans (Study 5), human groups (Study 6), alien species (Study 7), and individuals (Study 8) leads them to be seen as less human. The diminished humanness ascribed to nongendered and genderless targets is due, at least in part, to the lack of a gender schema to guide facile and efficient sensemaking. The relative difficulty perceivers had in making sense of nongendered targets predicted diminished humanness ratings. Finally, we demonstrate downstream consequences of stripping a target of gender: Perceivers consider them less relatable and more socially distant (Study 8). These results have theoretical implications for research on gender, (de)humanization, anthropomorphism, and social cognition, more broadly. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background Neutrophils play a role in innate immunity and are critical for clearance of Staphylococcus aureus. Current understanding of neutrophil bactericidal effects is that NADPH oxidase produces reactive oxygen species (ROS), mediating bacterial killing. Neutrophils also contain numerous mitochondria; since these organelles lack oxidative metabolism, their function is unclear. We hypothesize that mitochondria in human neutrophils contribute to the bactericidal capacity of S. aureus. Methods and Findings: Using human neutrophils isolated from healthy volunteers (n = 13; 7 females, 6 males), we show that mitochondria are critical in the immune response to S. aureus. Using live-cell and fixed confocal, and transmission electron microscopy, we show mitochondrial tagging of bacteria prior to ingestion and surrounding of phagocytosed bacteria immediately upon engulfment. Further, we demonstrate that mitochondria are ejected from intact neutrophils and engage bacteria during vital NETosis. Inhibition of the mitochondrial electron transport chain at Complex III, but not Complex I, attenuates S. aureus killing by 50 ± 7%, comparable to the NADPH oxidase inhibitor apocynin. Similarly, mitochondrial ROS scavenging using MitoTEMPO attenuates bacterial killing 112 ± 60% versus vehicle control. Antimycin A treatment also reduces mitochondrial ROS production by 50 ± 12% and NETosis by 53 ± 5%. Conclusions We identify a previously unrecognized role for mitochondria in human neutrophils in the killing of S. aureus. Inhibition of electron transport chain Complex III significantly impairs antimicrobial activity. This is the first demonstration that vital NETosis, an early event in the antimicrobial response, occurring within 5 min of bacterial exposure, depends on the function of mitochondrial Complex III. Mitochondria join NADPH oxidase as bactericidal ROS generators that mediate the bactericidal activities of human neutrophils., Graphical abstract Image 1, Highlights • This study evaluates the role of neutrophil mitochondria in the immune response to Staphylococcus aureus. • Mitochondrial electron transport chain inhibition at Complex III significantly attenuates neutrophil bactericidal activity.

Cardiomyopathies affect as many as 1 in 500 adults, with hypertrophic cardiomyopathy (HCM) being the most commonly inherited heart disease. Although there are various genetic mutations which cause HCM, 40-50% of mutations identified in patients with this disease are found in the cardiac myosin-binding protein C (MyBP-C) gene. Thus, understanding this protein's role in sarcomere activation is critical for the development of effective therapeutic strategies. Previous work has identified MyBP-C as a key modulator of the sarcomere through inter-myofilament signaling. Although these studies have provided valuable information on the function of MyBP-C protein, the bulk of this work has been done with either in vitro protein recombination or permeabilized muscle. Unfortunately, these systems lack significant physiological features of muscle, such as load and intact excitation-contraction coupling mechanisms. Therefore, a large gap exists in the ability to monitor muscle sarcomere activation in an intact system in real time. In order to further advance the study of sarcomere activation in HCM disease models, specifically those targeting MyBP-C, a cardiac specific myofilament-targeted FRET based biosensor has been designed and validated. This new sarcomere activation biosensor reports real-time myofilament dynamics during physiological twitch contractions in live cardiac muscle. This allows for the in vivo biophysical tracking of FRET-detected conformation changes in TnC, which reflect the ensemble of regulatory events which lead to sarcomere activation. Currently, the biosensor is being utilized to investigate changes in sarcomere activation in MyBP-C knockout mice. We find that intact cardiac muscle under load shows slowed isometric twitch relaxation kinetics in MyBP-C knockout mice versus controls. In concert with thin and thick filament modifying small molecules, this biosensor system will be used to investigate sarcomere-based mechanisms of intact cardiac muscle performance in health and disease.

Women continue to be underrepresented in STEM (science, technology, engineering, math) fields. As such, there has been an increased interest in interventions to reduce bias against, and increase inclusion of, women in STEM. In this paper, we compare and contrast two commonly used strategies: awareness and blindness. We demonstrate that gender-blindness—a diversity ideology that advocates for downplaying gender differences, rather than embracing them—has the potential to diminish stereotyping of women in STEM fields. In six total studies, we show that men who believe, or are primed with, gender-blindness (compared to gender-awareness) are less likely to endorse gender stereotypes around women's STEM competencies. By measuring (Study 1) and manipulating ( Studies 2 –5) gender-blindness, we show that gender-blindness (compared to awareness) minimizes the gender gap on explicit stereotyping measures, as well as diminishes STEM stereotyping in target evaluations. Across six studies, we show the influence of diversity ideologies on stereotyping of women in STEM.

OBJECTIVE To evaluate adherence to an institutional continuous infusion propofol policy for sedation in mechanically ventilated patients, investigate the rate of propofol-related infusion syndrome (PRIS), and explore areas of improvement to enhance policy compliance and safety. METHODS This was a single center, retrospective chart review of patients admitted to a pediatric or cardiac intensive care unit within a large free-standing quaternary care pediatric hospital who received continuous propofol for non-procedural continuous sedation for at least 6 hours between 2014 and 2019. Propofol exposure (dose and duration), laboratory data, and hemodynamic outcomes of patients were evaluated. RESULTS A total of 104 patients (108 admissions and 133 treatment courses) met inclusion criteria. Policy adherence to propofol dosing and duration limitations were 70% (93/133 courses) and 68% (91/133 courses), respectively. Adherence to all elements of laboratory and hemodynamic monitoring was 23%. Hypotension and bradycardia were common among patients during propofol treatment courses. Except for hypertriglyceridemia, no significant difference in specific laboratory values were detected between patients exposed to greater than 66 mcg/kg/min (4 mg/kg/hr), compared with those exposed to less than 66 mcg/kg/min of propofol. Patients receiving therapy for longer than 48 hours had the highest rates of laboratory values associated with PRIS. No patient in the study cohort met full criteria for PRIS. CONCLUSIONS Adherence to elements of an institutional propofol policy was variable. Improvements in policy adherence may be enhanced by updating policy features, leveraging the electronic medical record order-set, and gaining consensus among key stakeholders.

Past research has assumed that social egalitarians reject group-based hierarchies and advocate for equal treatment of all groups. However, contrary to popular belief, we argue that egalitarian advocacy predicts greater likelihood to support "Succession"-based ageism, which prescribes that older adults step aside to free up coveted opportunities (e.g., by retiring). Although facing their own forms of discrimination, older individuals are perceived as blocking younger people, and other unrepresented groups, from opportunities-that in turn, motivates egalitarian advocates to actively discriminate against older adults. In 9 separate studies (N = 3,277), we demonstrate that egalitarian advocates endorse less prejudice toward, and show more support for, women and racial minorities, but harbor more prejudice toward (Studies 1 and 2), and show less advocacy for (Studies 3-6), older individuals. We demonstrate downstream consequences of this effect, such as support for, and resource allocation to, diversity initiatives (Studies 3-6). Further, we isolate perceived opportunity blocking as a critical mediator, demonstrating that egalitarian advocates believe that older individuals actively obstruct more deserving groups from receiving necessary resources and support to get ahead (Studies 4-6). Finally, we explore the intersectional nature of this effect (Study 7). Together this research suggests that when it comes to egalitarianism, equality for all may only mean equality for some. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dissolved silicon (DSi) is a key nutrient in the oceans, but there are few data available regarding Si isotopes in coastal aquifers. Here we investigate the Si isotopic composition of 12 fresh and 17 saline groundwater samples from Rottnest Island, Western Australia, which forms part of the world’s most extensive aeolianite deposit (the Tamala Limestone Formation). Two bedrock samples were also collected from Rottnest Island for Si isotope analysis. The δ30Si values of groundwaters ranged from −0.39 to +3.60 ‰ with an (average: +1.59 ‰) and the rock samples were −0.76 and −0.13 ‰. Due to the relatively low concentrations of DSi (64 to 196 μM) and clay-forming cations in fresh groundwaters, the correlation between δ30Si values and DSi concentrations (ρ = 0.59, p = 0.02) may be explained by Si adsorption onto Fe-Al (oxy)hydroxides present in the aquifer. An increase in groundwater δ30Si in association with the occurrence of water-rock interactions may explain the spatial pattern in δ30Si across the aquifer, and is consistent with the correlation between δ30Si and tritium activities when considering all groundwaters (ρ = −0.68, p = 0.0002). In the deeper aquifer, the inverse correlation between DSi and Cl concentrations (ρ = −0.79, p = 0.04) for the more saline groundwaters is attributed to groundwater mixing with local seawater that is depleted in DSi (

BACKGROUND: Prostate cancer is the most frequently diagnosed and treated cancer in the US Department of Veterans Affairs (VA). As the leading philanthropic source for prostate cancer research, the Prostate Cancer Foundation (PCF) entered into a unique public-private biomedical research partnership with the VA with the goal of addressing the urgent health challenges faced by veterans with prostate cancer. OBSERVATIONS: With a commitment of $50 million from PCF and the VA’s vast medical center infrastructure, the PCF-VA partnership has established 12 precision oncology Centers of Excellence to date, forming a collaborative network called the Precision Oncology Program for Cancer of the Prostate (POPCaP) Network. A 4-year review reveals the importance of executive leadership, mission-driven advocacy, setting shared ambitious goals, maximizing existing infrastructure and human capital, recruiting talent and resources, and creating space for adaptation and iteration in the context of a learning health care system. CONCLUSIONS: The PCF-VA partnership seeks to continue translating clinical research into national standards of care for veterans and serves as an innovative model of public-private collaborations for future health initiatives.

It is notable that across distinct, siloed, and disconnected areas of psychology (e.g., developmental, personality, social), there exist two dimensions (the “Big Two”) that capture the ways in which people process, perceive, and navigate their social worlds. Despite their subtle distinctions and nomenclature, each shares the same underlying content; one revolves around independence, goal pursuit, and achievement, and the other revolves around other-focus, social orientation, and desire for connection. Why have these two dimensions emerged across disciplines, domains, and decades? Our answer: gender. We argue that the characteristics of the Big Two (e.g., agency/competence, communion/warmth) are reflections of psychological notions of masculinity and femininity that render gender the basis of the fundamental lens through which one sees the social world. Thus, although past work has identified the Big Two as a model to understand social categories, we argue that gender itself is the social category that explains the nature of the Big Two. We outline support for this theory and suggest implications of a gendered cognition in which gender not only provides functional utility for cognitive processing but simultaneously enforces gender roles and limits men and women’s opportunities. Recognizing that the Big Two reflect masculinity and femininity does not confine people to act in accordance with their gender but rather allows for novel interventions to reduce gender-based inequities.

Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations inTo test for a role ofWe observed an increased burden of rare, predicted deleterious germline variants inPAH is the first human disease related to potential

Effectively delegating work to others is considered critical to managerial success, as it frees up managers’ time and develops subordinates’ skills. We propose that female leaders are less likely t...

Nicotinic acetylcholine receptors (nAChR) are present in many excitable tissues and are found both pre and post-synaptically. Through their non-specific cationic permeability, these nAChRs have excitatory roles in neurotransmission, neuromodulation, synaptic plasticity, and neuroprotection. Thus, nAChR mislocalization or functional deficits are associated with many neurological disease states. Therefore identifying the mechanisms that regulate nAChR expression and function will inform our understanding of normal as well as pathological physiological conditions and offer avenues for potential therapeutic advances. Taking advantage of the genetic tractability of the soil nematode Caenorhabditis elegans, a forward genetic screen was performed to isolate regulators of the vertebrate α7 nAChR homologue ACR-16. From this screen a novel regulator of the ACR-16 receptor was identified, the sarco(endo)plasmic reticulum calcium ATPase sca-1. The sca-1 mutant affects ACR-16 receptor level at the NMJ, receptor functionality, and synaptic transmission. Responses to pressure-ejected nicotine in sca-1 mutants are indistinguishable from wild type, which implies the ACR-16 receptors are mislocalized at the NMJ. Changes in cytosolic baseline calcium levels in sca-1 and other mutants indicates a calcium-driven regulation mechanism of the α7-like NAChR ACR-16.

The propensity to “gender”—or conceptually divide entities by masculinity versus femininity—is pervasive. Such gendering is argued to hinder gender equality, as it reifies the bifurcation of men and women into two unequal categories, leading many to advocate for a “de-gendering movement.” However, gendering is so prevalent that individuals can also gender entities far removed from human sex categories of male and female (i.e., weather, numbers, sounds) due to the conceptual similarities they share with our notions of masculinity and femininity (e.g., tough, tender). While intuition might predict that extending gender to these (human-abstracted) entities only further reinforces stereotypes, the current work presents a novel model and evidence demonstrating the opposing effect. Five studies demonstrate that gendering human-abstracted entities highlights how divorced psychological notions of gender are from biological sex, thereby decreasing gender stereotyping and penalties toward stereotype violators, through reducing essentialist views of gender. Rather than “de-gendering” humans, we demonstrate the potential benefits of “dehumanizing gender.”

Despite a substantial amount of animal data linking deficits in memory inhibition to the development of overeating and obesity, few studies have investigated the relevance of memory inhibition to uncontrolled eating in humans. Further, although memory for recent eating has been implicated as an important contributor to satiety and energy intake, the possibility that variations in episodic memory relate to individual differences in food intake control has been largely neglected. To examine these relationships, we recruited ninety-three adult subjects to attend a single lab session where we assessed body composition, dietary intake, memory performance, and eating behaviors (Three Factor Eating Questionnaire). Episodic recall and memory inhibition were assessed using a well-established measure of memory interference (Retrieval Practice Paradigm). Hierarchical regression analyses indicated that memory inhibition was largely unrelated to participants' eating behaviors; however, episodic recall was reliably predicted by restrained vs. uncontrolled eating: recall was positively associated with strategic dieting (β = 2.45, p = 0.02), avoidance of fatty foods (β = 3.41, p = 0.004), and cognitive restraint (β = 1.55, p = 0.04). In contrast, recall was negatively associated with uncontrolled eating (β = −1.15, p = 0.03) and emotional eating (β = −2.46, p = 0.04). These findings suggest that episodic memory processing is related to uncontrolled eating in humans. The possibility that deficits in episodic memory may contribute to uncontrolled eating by disrupting memory for recent eating is discussed.

BACKGROUND Numerous studies have shown that there are links between obesity, liver fat and the gut microbiome. However, there are mixed results on whether probiotics could impact the gut microbiome and/or help to decrease liver fat and obesity outcomes. OBJECTIVE This study aimed to determine whether a probiotic supplement (VSL#3® ) intervention altered gut microbiota and/or gut hormones associated with appetite regulation. The secondary aim of this study was to determine whether VSL#3® altered body composition and liver fat and fibrosis. METHODS We conducted a double-blind, randomized placebo-controlled trial in 19 obese Latino adolescents. The intervention consisted of three packets per day of VSL#3® or a matched placebo for 16 weeks. Pre-intervention and post-intervention measures included gut microbial abundance, gut appetite regulating hormones, anthropometrics, body composition, liver fat and liver fibrosis. We conducted linear models to determine whether there were any significant differences in the changes in these outcomes following VSL#3® intervention. RESULTS Compared with placebo, adolescents that received VSL#3 had significant increases in total adiposity (%) (+1.7 ± 0.6 vs. -1.3 ± 0.5, p

Ascribing and denying humanity has profound consequences, often leading to devastating outcomes (e.g., violence, genocide). As such, understanding what, exactly, makes “someone human” becomes imperative. In this paper, we leverage the ubiquitous Big Two dimensions of social perception (agency and communality) to examine the process of humanization. In five studies (N = 1900), we find that the “Big Two” dimensions—agency (assertiveness, competence) and communality (warmth, kindness)—predict humanization, and critically, we show the primacy of communality in this process. We find that communality takes primacy in humanization when anthropomorphizing, describing an alien species, or ascribing humanness to real-world social targets (Studies 1–3); it is only for contexts where, or targets for whom, agency is particularly relevant that agency predicts humanization (Studies 4–5). We conclude with implications for research on (de)humanization, mind-perception, and social-perception.

The ways in which we discuss gender (embracing vs. downplaying difference) has implications for women’s workplace confidence and behavior, especially in male-dominated environments and positions of power. In five total studies (N = 1453), across a variety of samples, we found that gender-blindness—the belief that gender differences should be downplayed—is a more adaptive strategy for increasing female workplace confidence than gender-awareness—the belief that gender differences should be celebrated. In addition to increasing confidence, gender-blindness was related to actions necessary for reducing gender disparities (e.g., risk-taking, negotiation). We found that perceived gender differences in agency (i.e., assertiveness, independence) accounts for gender differences in workplace confidence, especially in male-dominated environments (e.g., business school) and positions of power (managerial positions). Finally, we found that gender-blindness either lessened or had no effect on men’s confidence, demonstrating the unique positive effect of gender-blindness on women’s confidence. Together, this research highlights the potential for downplaying differences, instead of emphasizing them, to combat the confidence gap.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.

The model organism C. elegans provides an excellent system to perform in vivo calcium imaging. Its transparent body and genetic manipulability allow for the targeted expression of genetically encoded calcium sensors. This protocol outlines the use of these sensors for the in vivo imaging of calcium dynamics in targeted cells, specifically the body wall muscles of the worms. By utilizing the co-expression of presynaptic channelrhodopsin, stimulation of acetylcholine release from excitatory motor neurons can be induced using blue light pulses, resulting in muscle depolarization and reproducible changes in cytoplasmic calcium levels. Two worm immobilization techniques are discussed with varying levels of difficulty. Comparison of these techniques demonstrates that both approaches preserve the physiology of the neuromuscular junction and allow for the reproducible quantification of calcium transients. By pairing optogenetics and functional calcium imaging, changes in postsynaptic calcium handling and homeostasis can be evaluated in a variety of mutant backgrounds. Data presented validates both immobilization techniques and specifically examines the roles of the C. elegans sarco(endo)plasmic reticular calcium ATPase and the calcium-activated BK potassium channel in the body wall muscle calcium regulation.

The model organism C. elegans provides an excellent system to perform in vivo calcium imaging. Its transparent body and genetic manipulability allow for the targeted expression of genetically encoded calcium sensors. This protocol outlines the use of these sensors for the in vivo imaging of calcium dynamics in targeted cells, specifically the body wall muscles of the worms. By utilizing the co-expression of presynaptic channelrhodopsin, stimulation of acetylcholine release from excitatory motor neurons can be induced using blue light pulses, resulting in muscle depolarization and reproducible changes in cytoplasmic calcium levels. Two worm immobilization techniques are discussed with varying levels of difficulty. Comparison of these techniques demonstrates that both approaches preserve the physiology of the neuromuscular junction and allow for the reproducible quantification of calcium transients. By pairing optogenetics and functional calcium imaging, changes in postsynaptic calcium handling and homeostasis can be evaluated in a variety of mutant backgrounds. Data presented validates both immobilization techniques and specifically examines the roles of the C. elegans sarco(endo)plasmic reticular calcium ATPase and the calcium-activated BK potassium channel in the body wall muscle calcium regulation.

Human and animal studies have shown that heavy cannabis (CB) use interacts with glutamatergic signaling. Additionally, recent studies have suggested that glutamate (Glu) may drive resting state functional connectivity (RSfc). The aims of the current preliminary study were to: 1) determine whether dorsal anterior cingulate cortex (dACC) Glu is related to RSfc between the dACC and two nodes of the reward network, the nucleus accumbens (NAc) and hippocampus (Hp); and 2) determine whether CB use interacts with the relationship between dACC Glu and RSfc. A group of 23 chronic CB users and 23 healthy controls participated in this multimodal MRI study. Glu levels were assessed in the dACC using magnetic resonance spectroscopy (MRS). Linear regression models were used to determine whether dACC Glu and CB use predicts RSfc between the dACC and the NAc and Hp. While the effect size is small, the results showed that the connectivity between the dACC and right NAc was predicted by the interaction between dACC Glu levels and monthly CB use. Additionally, while there is some suggestion that dACC Glu is correlated with dACC-hippocampal connectivity, unlike for dACC/NAc connectivity the relationship between them does not appear to be affected by CB use. These preliminary findings are significant in that they demonstrate the need for future studies with larger sample sizes to better characterize the relationship between resting state connectivity and neurochemistry as well as to characterize how CB use interacts with that relationship.