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The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras. Here, we ask whether similar pockets are present in GTPases beyond K-Ras. We systematically surveyed members of the Ras, Rho, and Rab family of GTPases and found that many GTPases exhibit targetable switch II pockets. Notable differences in the composition and conservation of key residues offer potential for the development of optimized inhibitors for many members of this previously undruggable family.

K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.

Protein properties and interactions have been widely investigated by using external labels. However, the micromolar sensitivity of the current dyes limits their applicability due to the high material consumption and assay cost. In response to this challenge, we synthesized a series of cyanine5 (Cy5) dye-based quencher molecules to develop an external dye technique to probe proteins at the nanomolar protein level in a high-throughput one-step assay format. Several families of Cy5 dye-based quenchers with ring and/or side-chain modifications were designed and synthesized by introducing organic small molecules or peptides. Our results showed that steric hindrance and electrostatic interactions are more important than hydrophobicity in the interaction between the luminescent negatively charged europium-chelate-labeled peptide (Eu-probe) and the quencher molecules. The presence of substituents on the quencher indolenine rings reduces their quenching property, whereas the increased positive charge on the indolenine side chain improved the interaction between the quenchers and the luminescent compound. The designed quencher structures entirely altered the dynamics of the Eu-probe (protein-probe) for studying protein stability and interactions, as we were able to reduce the quencher concentration 100-fold. Moreover, the new quencher molecules allowed us to conduct the experiments using neutral buffer conditions, known as the peptide-probe assay. These improvements enabled us to apply the method in a one-step format for nanomolar protein-ligand interaction and protein profiling studies instead of the previously developed two-step protocol. These improvements provide a faster and simpler method with lower material consumption.

New Zealand’s older Indigenous people (Māori) are underserved and underrepresented as consumers of aged residential care services (ARC). This study seeks to ascertain, from the perspectives of older Māori and whānau (family), the influence of structural factors that impact the process of seeking aged residential care. This study used a qualitative Kaupapa Māori research approach. In-depth interviews were undertaken with older Māori (n = 30) and whānau members (n = 18). Interviews were audio recorded and transcribed with themes identified using thematic analysis. Structural barriers related to ‘Navigation’ and ‘Service design and locality’ were identified by older Māori and whānau which provide insight into the oppressive nature of structural racism and highlighting various factors that affect older Māori and whānau access to ARC. Equity approaches that focus on optimising Māori access to ARC are needed in order to move ARC services towards equity. ARC services provide an important service for older New Zealanders. Our findings challenge and disrupt the universalistic nature that underpin New Zealand health structures. Health decision-makers should consider these findings to address the powerful and damaging effects structural racism has that compromise older Māori and whānau uptake and access to ARC services.

Feasibility of volumetric modulated arc therapy (VMAT) for partial breast irradiation (PBI) with simultaneous integrated boost (SIB) to tumour bed was investigated. Four plans were created for 10 patients: 30 Gy/5 fractions, 26 Gy/5 fractions with 30 Gy SIB, 40.05 Gy/15 fractions, and 40.05 Gy/15 fractions with 48 Gy SIB. SIB in the 5 fraction arm had reduced ipsilateral breast dose relative to uniform dose. SIB in the 15 fraction arm had noninferior conformity compared to uniform dose. Addition of SIB did not increase other organ-at-risk doses or plan complexity. VMAT PBI with SIB was feasible for both fractionation regimens.

Despite the recent attention of historians to the influence of Cold War politics in and on Ireland, literary scholarship has been more reticent when it comes to reading mid-century Irish writing as part of a broader international field of Cold War fiction. While some work has been conducted to situate individual writers, such as Samuel Beckett and John Banville, within an international political milieu, this essay proposes that the Cold War had a much broader impact on Irish writing than has previously been considered. This essay wades into the possibilities of this proposed area of interest through a reading of the Cold War political undercurrents moving within William Trevor’s 1972 short story ‘The Ballroom of Romance’. The story of Bridie’s disappointing evening in the eponymous dancehall has largely been read as an examination of rural disillusionment within an Ireland facing economic and cultural stagnation. Yet American influence suffuses the story. On the one hand, that influence can be felt in the presence of American cultural importation, or ‘soft power’; on the other hand, that influence can be found in the allusions to the shift in Irish economic policy in the mid-twentieth century away from protectionism and towards foreign investment. The most prominent dream amongst the locals who gather at the Ballroom of Romance – the rumours of American investment in a concrete factory in Kilmalough – places Trevor’s story firmly within the politics of global capitalism at the height of the Cold War in the early 1970s. Recognising that ‘Americanisation’ is bound up with Cold War policy affords the opportunity to read the dreams of rural Ireland within the context of global politics – and the failure of these dreams suggests that the reach of Trevor’s criticism need not necessarily be limited to boundaries of county and nation.

The transcription factor and tumor suppressor protein p53 is the most frequently mutated and inactivated gene in cancer. Mutations in p53 result in deregulated cell proliferation and genomic instability, both hallmarks of cancer. There are currently no therapies available that directly target mutant p53 to rescue wild-type function. In this study, we identify covalent compsounds that selectively react with the p53 somatic mutant cysteine Y220C and restore wild-type thermal stability.SignificanceThe tumor suppressor p53 is the most mutated gene in cancer, and yet no therapeutics to date directly target the mutated protein to rescue wild-type function. In this study, we identify the first allele-specific compound that selectively reacts with the cysteine p53 Y220C to rescue wild-type thermal stability and gene activation. See related commentary by Lane and Verma, p. 14. This article is highlighted in the In This Issue feature, p. 1.

Introduction: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) represent a high-risk for venous thromboembolism (VTE) due to malignancy, prolonged surgery and immobility. We investigated the incidence of and risk factors for VTE following CRS/IPC. Materials and methods: Data was analysed on 130 CRS/IPC performed over a 6-year period at a single centre, the Western Australian Peritonectomy Service (WAPS), on lower gastrointestinal neoplasia: pseudomyxoma peritoneii (PMP), colorectal cancer (CRC) and appendix cancer (AC). Data was analysed by univariate and multivariate logistic regression to identify risk factors for VTE. Results: 31 patients (24 %) experienced a VTE. The percentages of VTE among patients with PMP (n = 50), CRC (n = 53) and AC (n = 27) were 36 %, 17 % and 15 % respectively. 60 % of these cases were asymptomatic. The odds of VTE were higher for PMP patients than in patients with a other histopathology (OR=2.9, p = 0.01). Other significant risk factors for VTE on univariate analysis were PCI (OR=1.07, p = 0.001), pelvic dissection (OR=5.52, p = 0.001) and operation time (OR=1.36, p = 0.001). Conclusion: This study demonstrates high rates of VTE in patients undergoing CRS/IPC. Patients with PMP have a three-fold higher risk of VTE compared to other malignancies (CRC+AC). As most VTE cases were asymptomatic, aggressive early investigation and intervention is indicated for patients undergoing CRS/IPC.

Purpose: There are a wide variety of intraoperative techniques available in breast surgery to achieve low rates for positive margins of excision. The objective of this systematic review was to determine the pooled diagnostic accuracy of intraoperative breast margin assessment techniques that have been evaluated in clinical practice. Methods: This study was performed in accordance with PRISMA guidelines. A systematic search of the literature was conducted to identify studies assessing the diagnostic accuracy of intraoperative margin assessment techniques. Only clinical studies with raw diagnostic accuracy data as compared with final permanent section histopathology were included in the meta-analysis. A bivariate model for diagnostic meta-analysis was used to determine overall pooled sensitivity and specificity. Results: Sixty-one studies were eligible for inclusion in this systematic review and meta-analysis. Cytology demonstrated the best diagnostic accuracy, with pooled sensitivity of 0.92 (95 % CI 0.77–0.98) and a pooled specificity of 0.95 (95 % CI 0.90–0.97). The findings also indicate good diagnostic accuracy for optical spectroscopy, with a pooled sensitivity of 0.86 (95 % CI 0.76–0.93) and a pooled specificity of 0.92 (95 % CI 0.82–0.97). Conclusion: Pooled data indicate that optical spectroscopy, cytology and frozen section have the greatest diagnostic accuracy of currently available intraoperative margin assessment techniques. However, long turnaround time for results and their resource intensive nature has prevented widespread adoption of these methods. The aim of emerging technologies is to compete with the diagnostic accuracy of these established techniques, while improving speed and usability.

Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.

KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer.

B-Myb is a highly conserved member of the vertebrate Myb family of transcription factors that plays a critical role in cell-cycle progression and proliferation. Myb proteins activate Myb-dependent promoters by interacting specifically with Myb-binding site (MBS) sequences using their DNA-binding domain (DBD). Transactivation of MBS promoters by B-Myb is repressed by its negative regulatory domain (NRD), and phosphorylation of the NRD by Cdk2-CyclinA relieves the repression to activate B-Myb-dependent promoters. However, the structural mechanisms underlying autoinhibition and activation of B-Myb-mediated transcription have been poorly characterized. Here, we determined that a region in the B-Myb NRD (residues 510-600) directly associates with the DBD and inhibits binding of the DBD to the MBS DNA sequence. We demonstrate using biophysical assays that phosphorylation of the NRD at T515, T518, and T520 is sufficient to disrupt the interaction between the NRD and the DBD, which results in increased affinity for MBS DNA and increased B-Myb-dependent promoter activation in cell assays. Our biochemical characterization of B-Myb autoregulation and the activating effects of phosphorylation provide insight into how B-Myb functions as a site-specific transcription factor.

Background: Aggressive metastasis directed treatment of extracranial oligometastatic breast cancer with the aim of increasing disease-free survival has emerged as a new potential treatment paradigm, however there is currently a lack of data to assist in identifying the subset of patients who will potentially benefit most. This single-institute retrospective cohort study aimed to evaluate survival outcomes for patients with a solitary extracranial metastasis from breast cancer and to assess for significant prognostic factors. Methods and materials: Medical records of 70 female breast cancer patients with a solitary extracranial metastasis actively managed at the Peter MacCallum Cancer Centre (PMCC) Melbourne Campus between 2000 and 2019 were reviewed. Kaplan-Meier curves were used to estimate overall survival (OS), local progression free survival (LPFS) and distant progression free survival (DPFS). Results: Median follow-up period was 9.4 years. The study included 40 hormone receptor positive/HER2 negative (HR+HER2-), 14 hormone receptor positive/HER2 positive (HR+HER2+), 3 hormone receptor negative/HER2 positive (HR-HER2+), 9 triple negative (TNBC) and 4 unclassified breast cancer patients. 5-year OS rate for all patients was 46%, LPFS rate was 56% and DPFS was 20%. Tumour receptor group had a statistically significant association with OS and DPFS rates. TNBC patients had significantly poorer OS and DPFS rates in comparison to HR+HER2-patients. Conclusion: Among patients with a solitary extracranial metastasis from breast cancer, TNBC was associated with the poorest OS and DPFS rates. Identification of other significant prognostic factors for oligometastatic breast cancer patients may inform guidelines for metastasis directed treatments.

The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene expression.

BackgroundCatheter ablation (CA) for symptomatic atrial fibrillation (AF) offers the best outcomes for patients. Despite the benefits of CA, a significant proportion of patients suffer a recurrence; hence, there is scope to potentially improve outcomes through technical innovations such as ablation index (AI) guidance during AF ablation. We present real-world 5-year follow-up data of AI-guided pulmonary vein isolation.MethodsWe retrospectively followed 123 consecutive patients who underwent AI-guided CA shortly after its introduction to routine practice. Data were collected from the MPH AF Ablation Registry with the approval of the institutional research board.ResultsOur patient cohort was older, with higher BMI, greater CHA2DS2-VASc scores, and larger left atrial sizes compared to similar previously published cohorts, while gender balance and other characteristics were similar. The probability of freedom from atrial arrhythmia with repeat procedures is as follows: year 1: 0.95, year 2: 0.92, year 3: 0.85, year 4: 0.79, and year 5: 0.72. Age >75 years (p = 0.02, HR: 2.7, CI: 1.14–6.7), BMI >35 kg/m2 (p = 0.0009, HR: 4.6, CI: 1.8–11.4), and left atrial width as measured on CT in the upper quartile (p = 0.04, HR: 2.5, CI: 1–5.7) were statistically significant independent predictors of recurrent AF.ConclusionAI-guided CA is an effective treatment for AF, with 95.8% of patients remaining free from atrial arrhythmia at 1 year and 72.3% at 5 years, allowing for repeat procedures. It is safe with a low major complication rate of 1.25%. Age >75 years, BMI >35 kg/m2, and markedly enlarged atria were associated with higher recurrence rates.

We present the first high performance compiler for very large scale quantum error correction: it translates an arbitrary quantum circuit to surface code operations based on lattice surgery. Our compiler offers an end to end error correction workflow implemented by a pluggable architecture centered around an intermediate representation of lattice surgery instructions. Moreover, the compiler supports customizable circuit layouts, can be used for quantum benchmarking and includes a quantum resource estimator. The compiler can process millions of gates using a streaming pipeline at a speed geared towards real-time operation of a physical device. We compiled within seconds 80 million logical surface code instructions, corresponding to a high precision Clifford+T implementation of the 128-qubit Quantum Fourier Transform (QFT).

This research report provides an overview of the R&D efforts at Educational Testing Service related to its capability for automated scoring of nonnative spontaneous speech with the "SpeechRater"? automated scoring service since its initial version was deployed in 2006. While most aspects of this R&D work have been published in various venues in recent years, no comprehensive account of the current state of SpeechRater has been provided since the initial publications following its first operational use in 2006. After a brief review of recent related work by other institutions, we summarize the main features and feature classes that have been developed and introduced into SpeechRater in the past 10 years, including features measuring aspects of pronunciation, prosody, vocabulary, grammar, content, and discourse. Furthermore, new types of filtering models for flagging nonscorable spoken responses are described, as is our new hybrid way of building linear regression scoring models with improved feature selection. Finally, empirical results for SpeechRater 5.0 (operationally deployed in 2016) are provided.

# Background Acetabular dysplasia (AD) is defined as a structurally deficient acetabulum and is a well-recognized cause of hip pain in young adults. While treatment of severe AD with a periacetabular osteotomy has demonstrated good long-term outcomes, a trial of non-operative management is often recommended in this population. This may be especially true in patients with milder deformities. Currently, there is a paucity of research pertaining to non-operative management of individuals with AD. # Purpose To present expert-driven non-operative rehabilitation guidelines for use in individuals with AD. # Study Design Delphi study # Methods A panel of 15 physiotherapists from North America who were identified as experts in non-operative rehabilitation of individuals with AD by a high-volume hip preservation surgeon participated in this Delphi study. Panelists were presented with 16 questions regarding evaluation and treatment principles of individuals with AD. A three-step Delphi method was utilized to establish consensus on non-operative rehabilitation principles for individuals presenting with AD. # Results Total (100%) participation was achieved for all three survey rounds. Consensus, defined a piori as > 75%, was reached for 16/16 questions regarding evaluation principles, activity modifications, appropriate therapeutic exercise progression, return to activity/sport criteria, and indications for physician referral. # Conclusion This North American based Delphi study presents expert-based consensus on non-operative rehabilitation principles for use in individuals with AD. Establishing guidelines for non-operative management in this population will help reduce practice variation and is the first step in stratifying individuals who would benefit from non-operative management. Future research should focus on patient-reported outcomes and rate of subsequent surgical intervention to determine the success of the guidelines reported in this study. # Level of Evidence Level V

# Background Non-arthritic intra-articular hip pain, caused by various pathologies, leads to impairments in range of motion, strength, balance, and neuromuscular control. Although functional performance tests offer valuable insights in evaluating these patients, no clear consensus exists regarding the optimal tests for this patient population. # Purpose This study aimed to establish expert consensus on the application and selection of functional performance tests in individuals presenting with non-arthritic intra-articular hip pain. # Study Design A modified Delphi technique was used with fourteen physical therapy experts, all members of the International Society for Hip Arthroscopy (ISHA). The panelists participated in three rounds of questions and related discussions to reach full consensus on the application and selection of functional performance tests. # Results The panel agreed that functional performance tests should be utilized at initial evaluation, re-evaluations, and discharge, as well as criterion for assessing readiness for returning to sports. Tests should be as part of a multimodal assessment of neuromuscular control, strength, range of motion, and balance, applied in a graded fashion depending on the patient's characteristics. Clinicians should select functional performance tests with objective scoring criteria and prioritize the use of tests with supporting psychometric evidence. A list of recommended functional performance tests with varying intensity levels is provided. Low-intensity functional performance tests encompass controlled speed in a single plane with no impact. Medium-intensity functional performance tests involve controlled speed in multiple planes with low impact. High-intensity functional performance tests include higher speeds in multiple planes with higher impact and agility requirements. Sport-specific movement tests should mimic the patient's particular activity or sport. # Conclusion This international consensus statement provides recommendations for clinicians regarding selection and utilization of functional performance tests for those with non-arthritic intra-articular hip pain. These recommendations will encourage greater consistency and standardization among clinicians during a physical therapy assessment.

This report focused on a timely marine conservation issue in Pūpūkea, O‘ahu, Hawai’i regarding the lack of enforceable administrative rules in Kapoʻo, also known as the Pūpūkea or Sharks Cove tidepool, that is a part of the Pūpūkea Marine Life Conservation District (MLCD). To support the rule change process to revise the administrative rules, I worked with Mālama Pūpūkea-Waimea (MPW), a local nonprofit, to create and apply an ArcGIS Story Map. To build the Story Map, I explored available published literature, examined human use data from Kapo‘o, and observations from beach closures in response to the COVID-19 pandemic. From theliterature, I gleaned information on the role and function of tide pools in Hawai‘i, impacts from recreational use in coastal environments, marine managed areas in Hawai‘i. From the human use data, I found that the majority of visitors at Kapo‘o engaged in swimming, snorkeling, and shoreline use; and the monthly average number of people participating in these three activities combined increased by 58 people, or 7%, from 2017 to 2019. Observations during a two-month beach closure due to the pandemic included an anecdotal increase of juvenile fish, native algae, and sightings of rarely observed marine life, with no to minimal human disturbance. The Story Map will be used by MPW to educate the Pūpūkea community and visitors and will support the group through the future rulemaking process to make MLCD rules enforceable in Kapoʻo. Future studies will be conducted to understand Kapo‘o’s ecological role in the MLCD, to explore its role as a nursery and refuge for marine life, and to determine the magnitude of fishing andrecreational impacts on the ecosystem.

The five-protein MuvB core complex is highly conserved in animals. This nuclear complex interacts with RB-family tumor suppressor proteins and E2F-DP transcription factors to form DREAM complexes that repress genes that regulate cell cycle progression and cell fate. The MuvB core complex also interacts with Myb family oncoproteins to form the Myb-MuvB complexes that activate many of the same genes. We show that animal-type Myb genes are present in Bilateria, Cnidaria and Placozoa, the latter including the simplest known animal species. However, bilaterian nematode worms lost their animal-type Myb genes hundreds of millions of years ago. Nevertheless, amino acids in the LIN9 and LIN52 proteins that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in Caenorhabditiselegans Here, we show that, despite greater than 500 million years since their last common ancestor, the Drosophila melanogaster Myb protein can bind to the nematode LIN9-LIN52 proteins in vitro and can cause a synthetic multivulval (synMuv) phenotype in vivo This phenotype is similar to that caused by loss-of-function mutations in C. elegans synMuvB-class genes including those that encode homologs of the MuvB core, RB, E2F and DP. Furthermore, amino acid substitutions in the MuvB-binding domain of Drosophila Myb that disrupt its functions in vitro and in vivo also disrupt these activities in C. elegans We speculate that nematodes and other animals may contain another protein that can bind to LIN9 and LIN52 in order to activate transcription of genes repressed by DREAM complexes.

Abstract Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation.

Predicting and analyzing multimodal dialog user experience (UX) metrics, such as overall call experience, caller engagement, and latency, among other metrics, in an ongoing manner is important for evaluating such systems. We investigate automated prediction of multiple such metrics collected from crowdsourced interactions with an open-source, cloud-based multimodal dialog system in the educational domain. We extract features from both the audio and video signals and examine the efficacy of multiple machine learning algorithms in predicting these performance metrics. The best performing audio features consist of multiple low-level audio descriptors--intensity, loudness, cepstra, pitch, and so on--and their functionals, extracted using the OpenSMILE toolkit, while the video features are bags of visual words that use 3D Scale-Invariant Feature Transform descriptors. We find that our proposed methods outperform the majority vote classification baseline in predicting various UX metrics rated by both the user and experts. Our results suggest that such automated prediction of performance metrics can not only inform the qualitative and quantitative analysis of dialogs but also be potentially incorporated into dialog management routines for positively impacting UX and other metrics during the course of the interaction.

We present work in progress on a multimodal dialog system for English language assessment using a modular cloud-based architecture adhering to open industry standards. Among the modules being developed for the system, multiple modules heavily exploit machine learning techniques, including speech recognition, spoken language proficiency rating, speaker recognition, and the scoring of behaviors in multimodal data streams.

This report is the fifth in a series concerning English language proficiency (ELP) assessments for English learners (ELs) in kindergarten through 12th grade in the United States. The series, produced by Educational Testing Service (ETS), is intended to provide theory and evidence-based principles and recommendations for improving next-generation ELP assessment systems, policies, and practices and to stimulate discussion on better serving K-12 EL students. The first report articulated a high-level conceptualization of next generation ELP assessment systems (Hauck, Wolf, & Mislevy, 2016). The second report addressed accessibility issues in the context of ELP assessments for ELs and ELs with disabilities (Guzman-Orth, Laitusis, Thurlow, & Christensen, 2016). The third report focused on critical policy and research issues of summative ELP assessments that state use for accountability purposes (Wolf, Guzman-Orth, & Hauck, 2016). The fourth report dealt with one of the major uses of ELP assessments--the initial identification and classification of ELs (Lopez, Pooler, & Linquanti, 2016). The present report discusses approaches to using automated scoring technology for the evaluation of student-spoken responses on K-12 ELP assessments. As many states have begun to use computer-based ELP assessments, there is a growing interest in automated scoring of spoken responses to increase the efficiency of scoring. This report delineates major areas to consider in using automated speech scoring for K-12 ELP assessments (i.e., assessment construct and task design, scoring and score reporting, and artificial intelligence (AI) model development and test delivery) and makes recommendations for states on how to evaluate these considerations and determine a path forward.

Mycotic pseudoaneurysms (PA) are an infrequent complication of infective endocarditis (IE). However, due to advanced imaging modality and early therapy, this complication has been seen less frequently in the past few years. The reported incidence is 5%–15% of the patients, with the most common site being intracranial vessels (up to 65%), followed by abdominal and then peripheral vessels. We describe a young patient with a bicuspid aortic valve complicated by IE, who developed a giant mycotic PA. This was treated with a cover stent of the aneurysmal segment, which was complicated by distal stent migration and eventually managed with bypass surgery.

The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. Surprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib. Palbociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells. Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors.

Altered HPA-axis functioning is a hypothesized mechanism for worsened cognition in depression. The current study examines the indirect effects of depression on processing speed, executive functioning, and memory as a function of the HPA-axis. 38 individuals with a depression diagnosis and 50 healthy controls (HCs) aged 18-86 underwent neuropsychological testing and at-home diurnal salivary cortisol collection. Depression was assessed via structured clinical interviews and rating scales. Cognitive composite scores were derived from factor analysis. Daytime cortisol exposure was estimated using area under the curve (AUC). Depression was associated with higher cortisol levels and slower processing speed . A significant suppression effect of AUC was present on the relationship between depression and processing speed. Limitations include the cross-sectional design and limited sample heterogeneity. Though poorly modulated HPA-axis is one proposed mechanism of cognitive alterations in depression, our results did not support this conclusion for processing speed. Alternative mechanisms should be considered to inform interventions to target cognitive alterations in depression.

Overexpression of the oncogene MYBL2 (B-Myb) is associated with increased cell proliferation and serves as a marker of poor prognosis in cancer. However, the mechanism by which B-Myb alters the cell cycle is not fully understood. In proliferating cells, B-Myb interacts with the MuvB core complex including LIN9, LIN37, LIN52, RBBP4, and LIN54, forming the MMB (Myb-MuvB) complex, and promotes transcription of genes required for mitosis. Alternatively, the MuvB core interacts with Rb-like protein p130 and E2F4-DP1 to form the DREAM complex that mediates global repression of cell cycle genes in G0/G1, including a subset of MMB target genes. Here, we show that overexpression of B-Myb disrupts the DREAM complex in human cells, and this activity depends on the intact MuvB-binding domain in B-Myb. Furthermore, we found that B-Myb regulates the protein expression levels of the MuvB core subunit LIN52, a key adapter for assembly of both the DREAM and MMB complexes, by a mechanism that requires S28 phosphorylation site in LIN52. Given that high expression of B-Myb correlates with global loss of repression of DREAM target genes in breast and ovarian cancer, our findings offer mechanistic insights for aggressiveness of cancers with MYBL2 amplification, and establish the rationale for targeting B-Myb to restore cell cycle control.

The management of atrial septal defects (ASDs) has been revolutionized by the advent of percutaneous transvenous occlusion devices. This case series describes techniques required to perform a transeptal puncture safely and effectively in patients postimplantation of an atrial septal defect occluder to facilitate catheter ablation of atrial arrhythmias. (Level of Difficulty: Intermediate.)