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Disabled people are uniquely positioned in relation to the digital turn. Academic ableism, the inaccessibility of digital space, and gaps in digital literacy present barriers, while, at the same time, disabled, Deaf, and neurodivergent people’s access knowledge is at the forefront of innovations in culture and crip technoscience. This article explores disability, technology, and access through the concept of crip digital intimacy, a term that describes the relational and affective advances that disabled people make within digital space and through digital technology toward accessing the arts. We consider how moments of crip digital intimacy emerged through Accessing the Arts: Centring Disability Perspectives in Access Initiatives—a research project that explored how to make the arts more accessible through engaging disabled artist-participants in virtual storytelling, knowledge sharing, and art-making activities. Our analysis tracks how crip digital intimacies emerged through the ways participants collectively organized and facilitated access for themselves and each other. Guided by affordance theory and in line with the political thrust of crip technoscience, crip legibility, and access intimacy, we argue that crip digital intimacy emphasizes the interdependent and relational nature of access, recognizes the creativity and vitality of nonnormative bodyminds, and understands disability as a political—and frequently transgressive—way of being in the world.

The high cost of elder care combined with the shortage of caregivers lead us to consider how service robots can be affordably leveraged to support the independence of elders and the work of their caregivers and clinicians. Our objective is to gain design insight into tasks older adults desire to accomplish daily in a low-resource, assisted living setting and how an affordable service robot could suit. A need-finding design approach consisting of focus groups and surveys was completed with three stakeholders groups: Elders, Clinicians, and Caregivers. Stakeholders were asked to identify and then prioritize service tasks by importance and frustration. Thirty-six unique high priority tasks were identified. Instrumental activities of daily living, a desire to have their preferences known, leisure activities, and increased opportunities for socialization were the most important tasks that the elders wanted a low-cost mobile service robot to address. Clinicians and caregivers prioritized highly safety-related reminders and assistance in complying with care plans in assessment of elder task needs. Service robots exist that do some, but not all of these desired tasks. An effective and affordable service robot requires design trade-offs in terms of cost, preference and complexity. A low-cost robot targeting reminders, companion walking, hydration and fetching assistance was suggested as an initial prototype. Prototypes may address high priority desires of all stakeholders, but robots that can intervene and affect long-lasting changes in elder care are still needed.

The impact of first-generation covalent KRAS G12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS G12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS G12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS G12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS G12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS G12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically. The success of KRAS G12C mutation specific inhibitors in patients with KRAS-driven tumours is limited by the emergence of acquired resistance. Here, the authors characterise olomorasib, a next-generation covalent KRAS G12C-mutant inhibitor, demonstrating efficacy in the presence of clinically relevant resistance mutations in preclinical KRAS-driven cancer models.

Higher education institution leaders have experienced tumultuous changes in the external environment, resulting in changes within their institutions. Leaders can maximize their human resources and reduce the potential negative outcomes of these changes through increased employee engagement, which has been associated with increased positive organizational outcomes. The problem addressed in this quantitative research study was the lack of employee engagement by employees within higher education institutions with respect to the job demands-resources (JD-R) theory of engagement (Bakker, 2017; Bakker & Demerouti, 2017). Using Schaufeli’s (2015) emerging engaging leadership theory, the purpose of the current research study was to investigate the relationship between engaging leadership, basic psychological need satisfaction, and employee engagement in a private higher education institution in the United States. Engaging leaders, who inspire, strengthen, and connect with employees satisfy their employees’ basic psychological needs of autonomy, competence, and relatedness, respectively. When employees’ basic psychological needs are satisfied, employees exhibit increased employee engagement as identified in the job demands-resources theory. Using a quantitative research methodology, participants completed an online questionnaire. Descriptive analyses, Pearson’s correlations, linear regression analyses, and Sobel’s mediation model were utilized to analyze the data. Positive correlations were found between the study variables, and basic psychological need satisfaction fully mediated the relationship between engaging leadership and employee engagement. Based on the findings, higher education institution leaders could develop training opportunities to increase engaging leadership among leaders. By increasing employee engagement through increased engaging leadership, higher education institution leaders may experience increased positive organizational outcomes in the face of rapid external change.

The impact of first-generation covalent KRAS inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.

Testing the testers: While classroom teachers generally would be the ones giving the exam, an outside company such as Educational Testing Service--the company that administers the SAT, among other tests--should make unannounced spot checks to ensure test integrity. And because some \"bad-apple\" teachers cheat to boost their own class' scores for financial reward, no teacher should directly administer the test to his or her own class.

Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the full longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity.

As the COVID-19 pandemic upended the 2019–2020 school year, education systems scrambled to meet the needs of students and families with little available data on how school closures may impact learning. In this study, we produced a series of projections of COVID-19-related learning loss based on (a) estimates from absenteeism literature and (b) analyses of summer learning patterns of 5 million students. Under our projections, returning students are expected to start fall 2020 with approximately 63 to 68% of the learning gains in reading and 37 to 50% of the learning gains in mathematics relative to a typical school year. However, we project that losing ground during the school closures was not universal, with the top third of students potentially making gains in reading.

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridium difficile infection (R-CDI), but its mechanisms remain poorly understood. Emerging evidence suggests that gut bile acids have significant influence on the physiology of C. difficile, and therefore on patient susceptibility to recurrent infection. We analyzed spore germination of 10 clinical C. difficile isolates exposed to combinations of bile acids present in patient feces before and after FMT. Bile acids at concentrations found in patients' feces prior to FMT induced germination of C. difficile, although with variable potency across different strains. However, bile acids at concentrations found in patients after FMT did not induce germination and inhibited vegetative growth of all C. difficile strains. Sequencing of the newly identified germinant receptor in C. difficile, CspC, revealed a possible correspondence of variation in germination responses across isolates with mutations in this receptor. This may be related to interstrain variability in spore germination and vegetative growth in response to bile acids seen in this and other studies. These results support the idea that intra-colonic bile acids play a key mechanistic role in the success of FMT, and suggests that novel therapeutic alternatives for treatment of R-CDI may be developed by targeted manipulation of bile acid composition in the colon.

Emerging infectious diseases in humans are frequently caused by pathogens originating from animal hosts, and zoonotic disease outbreaks present a major challenge to global health. To investigate drivers of virus spillover, we evaluated the number of viruses mammalian species have shared with humans. We discovered that the number of zoonotic viruses detected in mammalian species scales positively with global species abundance, suggesting that virus transmission risk has been highest from animal species that have increased in abundance and even expanded their range by adapting to human-dominated landscapes. Domesticated species, primates and bats were identified as having more zoonotic viruses than other species. Among threatened wildlife species, those with population reductions owing to exploitation and loss of habitat shared more viruses with humans. Exploitation of wildlife through hunting and trade facilitates close contact between wildlife and humans, and our findings provide further evidence that exploitation, as well as anthropogenic activities that have caused losses in wildlife habitat quality, have increased opportunities for animal–human interactions and facilitated zoonotic disease transmission. Our study provides new evidence for assessing spillover risk from mammalian species and highlights convergent processes whereby the causes of wildlife population declines have facilitated the transmission of animal viruses to humans.