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Abstract Existing research on inclusive STEM-focused high schools (ISHSs) has focused on the design and implementation of ISHSs at the school-level, along with the positive effects of ISHSs on STEM course taking, college majoring, and STEM career orientations. Missing from the literature are studies that foreground the perspectives and voices of students of color and their perceptions of science and scientists from asset-based, critical perspectives. Thus, the purpose of this qualitative case study is to document the perceptions of science and scientists among racially, ethnically, and linguistically minoritized ninth graders at an urban, inclusive STEM-focused high school in a mid-sized, northeastern city in the United States, along with the contexts, sources, and associated experiences informing these perceptions. Iterative cycles of inductive and deductive coding and domain analysis, informed by theoretical perspectives on ecological systems and Discourses, revealed paradoxical perceptions. Students viewed science as a body of knowledge, testing and experimenting, a life-enhancing discovery, building on background information, and connected with other disciplines and everywhere. Students’ perceptions of scientists were both stereotypical and expansive, including that scientists are smart and serious; use science equipment and gear in traditional lab contexts; and are creative, curious, and open-minded. While students primarily identified deceased White males as scientists, three girls of color mentioned counter-stereotypical women and people of color when they thought of science. Students noted that science field trips and after school programs, as well as science in the media and school, informed their perceptions. These findings suggest that despite reform efforts such as Science for All, very little has changed regarding conceptions of science and scientists. What is more, these findings are troubling when minoritized students at an ISHS continue to replicate status quo perceptions of science and scientists. This study has implications for practice, research, and policy related to building on and extending these views in more critically conscious and equity-oriented ways.

Science education reform efforts have called for teaching science to all students, yet the "Science for All" mantra has remained merely rhetoric. Given that multilingual learners continue to face inequities more broadly in the education system and in science, technology, engineering, and mathematics (STEM) subjects in particular, there has been renewed attention to conditions that support more equitable science learning opportunities. In this exploratory, qualitative case study, we intentionally centered the voices of ninth grade multilingual learners by examining their science experiences in a Regents Living Environment class at an urban, inclusive STEM-focused high school (ISHS). Specifically, drawing from ecological and humanizing education theoretical perspectives, we investigated the elements of their experiences that were asset-oriented and humanizing, which promoted a healthy science learning ecosystem, as well as the challenges that coexisted. Qualitative data analysis revealed four main themes. First, multilingual learners appreciated authentic engagement in hands-on, science inquiry opportunities, including developing and implementing their own experiments. Students also noted feelings of joy, comfort, and belonging in their classroom environment that were supported by strong relationships and positive interactions among peers and their teachers. Moreover, students underscored the role of their teachers in intentionally co-creating a science classroom community of belonging and excellence. There were, however, persistent challenges associated with learning science and English simultaneously, in the backdrop of a standardized English-dominant, high-stakes accountability context. These findings have implications for pedagogy, teacher preparation, research, and policy for a more inclusive, asset-oriented, and humanizing science education for multilingual learners that broadens possibilities.

This study examined high school chemistry students' understandings of big ideas--matter and energy, how these understandings are related to macro and submicro representations and fine-grained distinguishing characteristics of students' explanations. The study was conducted in the context of computer-based models and model-based assessments. Qualitative analysis, descriptive statistics and a stepwise Regression model was run to examine students' explanations to assessment questions and their relationship to quantitative measures of students' understandings of big ideas. Students' explanations revealed consistent level 1 and 2 understandings for each big idea. When we examined the relationship between explanations and students' understandings of big ideas, the step-wise regression model was statistically significant for matter and energy. At the fine-grained level, students' explanations revealed distinct clusters--knowledge components that students used to construct descriptive and explanatory explanations for each level of understanding. These findings have implications for effective instructional approaches, targeted enactment of computer-based models and understandings of the range of novice chemistry understanding.

In the wake of the COVID-19 pandemic, which has resulted in the rapid emergence of vaccines, the dual benefits of both science and technology have been lauded, while dominant, deficit-based narratives of vaccine hesitancy and mistrust in science and medicine by the general public, particularly minoritized populations, run rampant. In this paper, we argue for a counternarrative, where instead of erroneously positioning communities of color as the problem, the problem is reframed to consider what the scientific, technological, and science education communities need to do to become more trustworthy and transgress the persistent shortcomings related to racism and injustice. Specifically, in this position paper, we (a) discuss the interactions of science, technology, and society from the perspective of the nature of technology; (b) engage an understanding of how bias, access, and racism operate in and at the intersection of science, technology, and technological systems; (c) discuss implications of these ideas in science education; and finally (d) pose recommendations to counter alienation and racism with an emphasis on a sixth dimension, equitable, social justice criticality, for science-technology education. In conclusion, we make recommendations by centering a more "equitable, social justice criticality" of science and technology.

Abstract TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.

The maternal regulation of diapause is one type of phenotypic plasticity where the experience of the mother leads to changes in the phenotype of her offspring that impact how well-suited they will be to their future environment. Sarcophaga bullata females with a diapause history produce offspring that cannot enter diapause even if they are reared in a diapause inducing environment. Accumulating evidence suggests that microRNAs regulate diapause and, possibly, maternal regulation of diapause. We found significant differences in the abundances of several microRNAs (miR-125–5p, miR-124–3p, miR-31–5p, and miR-277–3p) in brains dissected from adult female S. bullata that had experienced diapause compared to females with no diapause history. We also found moderate differences in the mRNA expression of the circadian-clock related genes, clock, clockwork orange, and period. MiR-124–3p and miR-31–5p are part of a gene network that includes these circadian clock-related genes. Taken together our results suggest the maternal block of diapause in S. bullata is regulated, at least in part, by a network that includes microRNAs and the circadian clock.

ABSTRACTIdentification of favorable biophysical properties for protein therapeutics as part of developability assessment is a crucial part of the preclinical development process. Successful prediction of such properties and bioassay results from calculated in silico features has potential to reduce the time and cost of delivering clinical-grade material to patients, but nevertheless has remained an ongoing challenge to the field. Here, we demonstrate an automated and flexible machine learning workflow designed to compare and identify the most powerful features from computationally derived physiochemical feature sets, generated from popular commercial software packages. We implement this workflow with medium-sized datasets of human and humanized IgG molecules to generate predictive regression models for two key developability endpoints, hydrophobicity and poly-specificity. The most important features discovered through the automated workflow corroborate several previous literature reports, and newly discovered features suggest directions for further research and potential model improvement.

Background The ability of SARS-CoV-2 vaccines to protect against infection and onward transmission determines whether immunisation can control global circulation. We estimated the effectiveness of Pfizer-BioNTech mRNA vaccine (BNT162b2) and Oxford AstraZeneca adenovirus vector vaccine (ChAdOx1) vaccines against acquisition and transmission of the Alpha and Delta variants in a prospective household study in England. Methods Households were recruited based on adult purported index cases testing positive after reverse transcription-quantitative (RT-q)PCR testing of oral-nasal swabs. Purported index cases and their household contacts took oral-nasal swabs on days 1, 3 and 7 after enrolment and a subset of the PCR-positive swabs underwent genomic sequencing conducted on a subset. We used Bayesian logistic regression to infer vaccine effectiveness against acquisition and transmission, adjusted for age, vaccination history and variant. Results Between 2 February 2021 and 10 September 2021, 213 index cases and 312 contacts were followed up. After excluding households lacking genomic proximity (N=2) or with unlikely serial intervals (N=16), 195 households with 278 contacts remained, of whom 113 (41%) became PCR positive. Delta lineages had 1.53 times the risk (95% Credible Interval: 1.04 – 2.20) of transmission than Alpha; contacts older than 18 years old were 1.48 (1.20 – 1.91) and 1.02 (0.93 – 1.16) times more likely to acquire an Alpha or Delta infection than children. Effectiveness of two doses of BNT162b2 against transmission of Delta was 36% (-1%, 66%) and 49% (18%, 73%) for ChAdOx1, similar to their effectiveness for Alpha. Protection against infection with Alpha was higher than for Delta, 69% (9%, 95%) vs. 18% (-11%, 59%), respectively, for BNT162b2 and 24% (-41%, 72%) vs. 9% (-15%, 42%), respectively, for ChAdOx1. Conclusions BNT162b2 and ChAdOx1 reduce transmission of the Delta variant from breakthrough infections in the household setting, although their protection against infection within this setting is low.

This article responds to the question, 'how do doctoral students experience writing within space and time?' Whilst existing studies have understood academic writing to be a social and embodied practice, few have considered the material and temporal assemblages that facilitate everyday experiences of academic writing. Working from a new materialist ontological approach, this article draws on photovoice interviews with 11 doctoral students. Using 'affect' as the unit of analysis, the article explores the capacity of space, materiality and time to affect, and be affected by, experiences of writing. People, things, environment, and emotion all play a role in this 'spacetimemattering' and mean that experiences of writing are not processal, nor homogenous, but rather are ever-shifting assemblages of intra-actions. The article concludes with recommendations that attempt to shift our conceptualisation of doctoral writing, with writing being ultimately critical to doctoral success. In addition, it adds to the emerging literature that applies new materialist theory to studies in higher education.

This article explores the relevance and value of cultural geography within the undergraduate geography curriculum in light of graduate employability. The article is based on the assertion that employability is an objective to which universities are required to engage, and yet, cultural geography, as a sub-discipline, may be more challenging to map against the prevailing neoliberal employability discourse. To bridge this gap, I propose the use of "powerful knowledge" as a conceptual frame in order to demonstrate specific skills and knowledges cultural geography can and does offer the employability agenda. I briefly demonstrate how visual and ethnographic methods are deployed on two current geography courses in the UK in order to engage students with cultural geography. I end by proposing three key forms of powerful knowledge cultural geography has the potential to generate in graduates. These are: (1) situated knowledge and reflexivity; (2) thinking beyond the human, and; (3) a consideration of cultural landscapes.

Disordered immunity, aging, human immunodeficiency virus type one (HIV-1) infection, and responses to antiretroviral therapy are linked. However, how each factor is linked with the other(s) remains incompletely understood. It has been reported that accelerated aging, advanced HIV-1 infection, inflammation, and host genetic factors are associated with host cellular, mitochondrial, and metabolic alterations. However, the underlying mechanism remains elusive. With these questions in mind, we used chronically HIV-1-infected CD34-NSG humanized mice (hu-mice) to model older people living with HIV and uncover associations between HIV-1 infection and aging. Adult humanized mice were infected with HIV-1 at the age of 20 weeks and maintained for another 40 weeks before sacrifice. Animal brains were collected and subjected to transcriptomics, qPCR, and immunofluorescence assays to uncover immune disease-based biomarkers. CD4+ T cell decline was associated with viral level and age. Upregulated C1QA, CD163, and CXCL16 and downregulated LMNA and CLU were identified as age-associated genes tied to HIV-1 infection. Ingenuity pathway analysis affirmed links to innate immune activation, pyroptosis signaling, neuroinflammation, mitochondrial dysfunction, cellular senescence, and neuronal dysfunction. In summary, CD34-NSG humanized mice are identified as a valuable model for studying HIV-1-associated aging. Biomarkers of immune senescence and neuronal signaling are both age- and virus-associated. By exploring the underlying biological mechanisms that are linked to these biomarkers, interventions for next generation HIV-1-infected patients can be realized.

Background: We investigated whether COVID-19 vaccination reduced SARS-CoV-2 infection risk among adult household contacts of COVID-19 index cases during the Alpha, Delta, and Omicron waves in England. Methods: Between February 2021 and February 2022, SARS-CoV-2 RT-PCR nasal swabs were collected from COVID-19-confirmed index cases aged ≥20 years and their household contacts at enrolment and three and seven days thereafter. Generalized Estimating Equations models were fitted with SARS-CoV-2 positivity as the outcome and household contacts’ vaccination status as the main exposure while adjusting for confounders. Results: SARS-CoV-2 infection was confirmed in 238/472 household contacts (50.4%) aged ≥20 years. The adjusted relative risk (95% confidence interval) of infection in vaccinated versus unvaccinated household contacts was 0.50 (0.35–0.72) and 0.69 (0.53–0.90) for receipt of two doses 8–90 and >90 days ago, respectively, and 0.34 (0.23–0.50) for vaccination with three doses 8–151 days ago. Primary vaccination protected household contacts against infection during the Alpha and Delta waves, but only three doses protected during the Omicron wave. Vaccination with three doses in the index case independently reduced contacts’ infection risk: 0.45 (0.23–0.89). Conclusions: Vaccination of household contacts reduces their risk of infection under conditions of household exposure though, for Omicron, only after a booster dose.

We report the discovery of a large impact crater beneath Hiawatha Glacier in northwest Greenland. From airborne radar surveys, we identify a 31-kilometer-wide, circular bedrock depression beneath up to a kilometer of ice. This depression has an elevated rim that cross-cuts tributary subglacial channels and a subdued central uplift that appears to be actively eroding. From ground investigations of the deglaciated foreland, we identify overprinted structures within Precambrian bedrock along the ice margin that strike tangent to the subglacial rim. Glaciofluvial sediment from the largest river draining the crater contains shocked quartz and other impact-related grains. Geochemical analysis of this sediment indicates that the impactor was a fractionated iron asteroid, which must have been more than a kilometer wide to produce the identified crater. Radiostratigraphy of the ice in the crater shows that the Holocene ice is continuous and conformable, but all deeper and older ice appears to be debris rich or heavily disturbed. The age of this impact crater is presently unknown, but from our geological and geophysical evidence, we conclude that it is unlikely to predate the Pleistocene inception of the Greenland Ice Sheet.

This study aimed to identify behaviors that contribute to adaptive performance (AP) among human resource development (HRD) practitioners. We used self-reported incidents of successes and failures on the job. Using a four-stage data analysis strategy, we analyzed qualitative data from 67 respondents and identified four behaviors that contributed to AP: (1) emotional intelligence; (2) consulting; (3) effective communication; and (4) analytic thinking. The findings showed that AP contributing behaviors are significant to how HRD practitioners develop relationships, execute technical tasks, and gather and make sense of data. Besides, for HRD practitioners, AP behaviors are critical for self-awareness and learning from failures and successes. This study showed that incidents of failure offered more insights into AP contributing behaviors than those of success. We extrapolate, mainly since as the incidents of failure were self-reported, that AP contributing behaviors could help HRD practitioners alter their actions as they navigate the overall demands of their work environment. More studies should examine AP, especially at the individual level, through the lens of failure because failure in itself can be transformational. Finally, we recognize that AP is integral to the professionalization of HRD practitioners because their jobs are instrumental to the creation and recreation of human expertise and organizational effectiveness.

Researchers have established the role of tertiary education (TE) in economic development (ED). Globally, TE generates significant and multiple direct, indirect and catalytic economic impacts, which result in well-established benefits pertaining to both individuals and broader economies. Last year, the government of Belize published its first comprehensive trade policy to develop a competitive economy, and it acknowledged that a shortage of skilled labour and competent human capital, among other factors, are core weaknesses towards trade development. Given the timeliness of the government's trade policy, the following research question guided this study: What can tertiary education do to strengthen alignment with economic development in Belize? The findings revealed that three significant and interrelated factors can strengthen the link between TE and ED: they are (1) program development through strategic consultations (2) building on academic strengths and resources to increase the value proposition and (3) the implementation of talent engagement strategies.

Despite recent advances in transgenic animal models and display technologies, humanization of mouse sequences remains one of the main routes for therapeutic antibody development. Traditionally, humanization is manual, laborious, and requires expert knowledge. Although automation efforts are advancing, existing methods are either demonstrated on a small scale or are entirely proprietary. To predict the immunogenicity risk, the human-likeness of sequences can be evaluated using existing humanness scores, but these lack diversity, granularity or interpretability. Meanwhile, immune repertoire sequencing has generated rich antibody libraries such as the Observed Antibody Space (OAS) that offer augmented diversity not yet exploited for antibody engineering. Here we present BioPhi, an open-source platform featuring novel methods for humanization (Sapiens) and humanness evaluation (OASis). Sapiens is a deep learning humanization method trained on the OAS using language modeling. Based on an in silico humanization benchmark of 177 antibodies, Sapiens produced sequences at scale while achieving results comparable to that of human experts. OASis is a granular, interpretable and diverse humanness score based on 9-mer peptide search in the OAS. OASis separated human and non-human sequences with high accuracy, and correlated with clinical immunogenicity. BioPhi thus offers an antibody design interface with automated methods that capture the richness of natural antibody repertoires to produce therapeutics with desired properties and accelerate antibody discovery campaigns. The BioPhi platform is accessible at https://biophi.dichlab.org and https://github.com/Merck/BioPhi.

NK cells have unique attributes to react towards cells undergoing malignant transformation or viral infection. This reactivity is regulated by activating or inhibitory germline encoded receptors. An impaired NK cell function may result from an aberrant expression of such receptors, a condition often seen in patients with hematological cancers. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide and NK cells have emerged as crucial targets for developing immunotherapies. However, there are important gaps concerning the phenotype and behavior of NK cells during emergence of ALL. In this study we analyze the phenotype and function of NK cells from peripheral blood in pediatric patients with ALL at diagnosis. Our results showed that NK cells exhibited an altered phenotype highlighted by a significant reduction in the overall expression and percent representation of activating receptors compared to age-matched controls. No significant differences were found for the expression of inhibitory receptors. Moreover, NK cells with a concurrent reduced expression in various activating receptors, was the dominant phenotype among patients. An alteration in the relative frequencies of NK cells expressing NKG2A and CD57 within the mature NK cell pool was also observed. In addition, NK cells from patients displayed a significant reduction in the ability to sustain antibody-dependent cellular cytotoxicity (ADCC). Finally, an aberrant expression of activating receptors is associated with the phenomenon of leukemia during childhood.

Abstract Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.

In recent years, a set of immune receptors that interact with members of the nectin/nectin-like (necl) family has garnered significant attention as possible points of manipulation in cancer. Central to this axis, CD226, TIGIT, and CD96 represent ligand (CD155)-competitive co-stimulatory/inhibitory receptors, analogous to the CTLA-4/B7/CD28 tripartite. The identification of PVRIG (CD112R) and CD112 has introduced complexity and enabled additional nodes of therapeutic intervention. By virtue of the clinical progression of TIGIT antagonists and emergence of novel CD96- and PVRIG-based approaches, our overall understanding of the ‘CD226 axis’ in cancer immunotherapy is starting to take shape. However, several questions remain regarding the unique characteristics of, and mechanistic interplay between, each receptor-ligand pair. This review provides an overview of the CD226 axis in the context of cancer, with a focus on the status of immunotherapeutic strategies (TIGIT, CD96, and PVRIG) and their underlying biology (i.e., cis/trans interactions). We also integrate our emerging knowledge of the immune populations involved, key considerations for Fc gamma (γ) receptor biology in therapeutic activity, and a snapshot of the rapidly evolving clinical landscape.

Percutaneous catheter ablation is an effective and safe therapy that can eliminate ventricular tachycardia, reducing the risks of both recurrent arrhythmia and shock therapies from a defibrillator. Successful ablation requires accurate identification of arrhythmic substrate and the effective delivery of energy to the targeted tissue. A thorough pre-procedural assessment is needed before considered 3D electroanatomical mapping can be performed. In contemporary practice, this must combine traditional electrophysiological techniques, such as activation and entrainment mapping, with more novel physiological mapping techniques for which there is an ever-increasing evidence base. Novel techniques to maximise energy delivery to the tissue must also be considered and balanced against their associated risks of complication. This review provides a comprehensive appraisal of contemporary practice and the evidence base that supports recent developments in mapping and ablation, while also considering potential future developments in the field.

The purpose of our study was to explore the effect of mentoring, on protégés, in an organization development course. This study is timely, because to enact organization development (OD), practitioners need multiple frameworks to make sense of their contexts. The data sources for this study were diaries. The diaries comprised of three major components. The first was an in-depth introduction of the mentor. Second, protégés reported the new learning as it related to the three concepts. Third, protégés conveyed their reflections of the experience. Two significant findings were revealed. First, the experience helped protégés to deconstruct OD. The deconstruction occurred via four strategies. Second, the protégés asserted confidence in their ability to pursue OD careers.

Increased doctoral student numbers has led to a growth in studies dedicated to doctoral experience. These studies have raised a range of mental health concerns around workload, supervision processes and student well-being. Despite these challenges being well documented, few studies have looked at doctoral student's experiences of accessing non-academic support services. This article presents the findings of a mixed-method study to investigate doctoral experiences of non-academic support, conducted at one British university with a large postgraduate research population. Drawing on focus groups and a student survey, the article concludes that many doctoral students are not accessing institutional support when they could benefit from it, with many turning to external support mechanisms including family, personal doctor and online resources. Five institutional recommendations are proposed to develop improved dedicated doctoral student mental health support: clear signposting, online self-help, workshops, parity of support and supervisor training.

Abstract Decision making in immuno‐oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno‐assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti‐PD‐1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.

This study reports the effect of computer models as formative assessment on high school students' understanding of the nature of models. Nine high school teachers integrated computer models and associated formative assessments into their yearlong high school chemistry course. A pre-test and post-test of students' understanding of the nature of models using a published measurement instrument on the nature of models were conducted. A four-step hierarchical multiple regression and a two-level (level 1--student and level 2--teacher) hierarchical linear modeling were used to test the effect of the intervention on students' understanding of the nature of models. Our analysis revealed a significant effect of frequencies of using computer models for four of the five sub-scales related to the nature of models. The implications of these findings are that, as students have more experience using computer models in their classroom, they develop a better understanding of the nature of models. However, their understanding of models as multiple representations did not show a significant improvement, possibly due to the lack of support from teachers, who in turn need both content and pedagogical supports within their teaching.

This paper describes the development of Connected Chemistry as Formative Assessment (CCFA) pedagogy, which integrates three promising teaching and learning approaches, computer models, formative assessments, and learning progressions, to promote student understanding in chemistry. CCFA supports student learning in making connections among the three domains of chemistry: the macroscopic; the submicroscopic; and the representational. There were 10 sets of computer models and computer-model-based formative assessment tests developed for 10 chemistry topics to enhance student understanding of matter and energy, and models. This article reports the development process of CCFA and evidence supporting the reliability and validity of measures of the formative assessment tests in CCFA based on the Rasch measurement application.

This study assessed the (i) ways in which, and extent to which, several aspects of nature of science (NOS) are represented in high school biology and physics textbooks in the United States (U.S.); (ii) extent to which these representations have changed over the course of several decades; and (iii) relative impact of discipline, and textbook publishers versus authors on the observed patterns. NOS aspects included the empirical, tentative, inferential, creative, theory-laden, and social NOS; myth of "The Scientific Method"; nature of theories and laws; and social and cultural embeddedness of science. The sample included 34 (16 biology and 18 physics) textbooks, which commanded significant shares of the U.S. science textbook market. Textbooks were selected from seven "connected series" (three in biology and four in physics), which spanned 1-5 decades, with five series spanning, at least, 3 decades. Textbooks were scored for the accuracy and manner in which, as well as the extent (in textbook pages) to which, the target NOS aspects were represented. Analyses indicated that, on average, only less than 2.5% of the analyzed textbook pages were dedicated to addressing NOS constructs. Overall, representations of NOS in the textbooks did not differ by content area, were discernibly less than favorable, and did not improve substantially over the past several decades. These trends are incommensurate with the emphasis placed in U.S. reform efforts on helping precollege students develop informed NOS conceptions. Finally, the data strongly suggested that textbook authors have a relatively greater impact on the observed patterns when compared to textbook publishers.

Eukaryotic Ca(2+) regulation involves sequestration into intracellular organelles, and expeditious Ca(2+) release into the cytosol is a hallmark of key signalling transduction pathways. Bulk removal of Ca(2+) after such signalling events is accomplished by members of the Ca(2+):cation (CaCA) superfamily. The CaCA superfamily includes the Na(+)/Ca(2+) (NCX) and Ca(2+)/H(+) (CAX) antiporters, and in mammals the NCX and related proteins constitute families SLC8 and SLC24, and are responsible for the re-establishment of Ca(2+) resting potential in muscle cells, neuronal signalling and Ca(2+) reabsorption in the kidney. The CAX family members maintain cytosolic Ca(2+) homeostasis in plants and fungi during steep rises in intracellular Ca(2+) due to environmental changes, or following signal transduction caused by events such as hyperosmotic shock, hormone response and response to mating pheromones. The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. Here we determine a crystal structure of the Saccharomyces cerevisiae vacuolar Ca(2+)/H(+) exchanger (Vcx1) at 2.3 Å resolution in a cytosol-facing, substrate-bound conformation. Vcx1 is the first structure, to our knowledge, within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism by which the CaCA superfamily performs high-throughput Ca(2+) transport across membranes.

Phosphate is crucial for structural and metabolic needs, including nucleotide and lipid synthesis, signalling and chemical energy storage. Proton-coupled transporters of the major facilitator superfamily (MFS) are essential for phosphate uptake in plants and fungi, and also have a function in sensing external phosphate levels as transceptors. Here we report the 2.9 Å structure of a fungal (Piriformospora indica) high-affinity phosphate transporter, PiPT, in an inward-facing occluded state, with bound phosphate visible in the membrane-buried binding site. The structure indicates both proton and phosphate exit pathways and suggests a modified asymmetrical 'rocker-switch' mechanism of phosphate transport. PiPT is related to several human transporter families, most notably the organic cation and anion transporters of the solute carrier family (SLC22), which are implicated in cancer-drug resistance. We modelled representative cation and anion SLC22 transporters based on the PiPT structure to surmise the structural basis for substrate binding and charge selectivity in this important family. The PiPT structure demonstrates and expands on principles of substrate transport by the MFS transporters and illuminates principles of phosphate uptake in particular.

The Otago Schist in the South Island of New Zealand represents an exhumed Mesozoic accretionary prism. Two coastal areas (Akatore Creek and Bruce Rocks) south of Dunedin preserve structural and geochemical evidence for the development of postmetamorphic hydrothermal systems that involved widespread fluid-rock reaction at shallow crustal depths. The Jurassic to Triassic pumpellyite-actinolite (Akatore Creek) to upper greenschist facies (Bruce Rocks) metamorphic fabrics were crosscut by sets of regionally extensive Cretaceous exhumation joints. Many of the joints were subsequently reactivated to form networks of small-displacement (

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose proliferative effects can contribute to the development of many types of solid tumors when overexpressed. For this reason, EGFR inhibitors such as cetuximab can play an important role in treating cancers such as colorectal cancer and head and neck cancer. Cetuximab is a chimeric monoclonal antibody containing mouse variable regions that bind to EGFR and prevent it from signaling. Although cetuximab has been used clinically since 2004 to successfully control solid tumors, advances in protein engineering have created the opportunity to address some of its shortcomings. In particular, the presence of mouse sequences could contribute to immunogenicity in the form of anti-cetuximab antibodies, and an occupied glycosylation site in FR3 can contribute to hypersensitivity reactions and product heterogeneity. Using simple framework graft or sequence-/structure-guided approaches, cetuximab was humanized onto 11 new frameworks. In addition to increasing humanness and removing the VH glycosylation site, dynamic light scattering revealed increases in stability, and bio-layer interferometry confirmed minimal changes in binding affinity, with patterns emerging across the humanization method. This work demonstrates the potential to improve the biophysical and clinical properties of first-generation protein therapeutics and highlights the advantages of computationally guided engineering.