One of the principle tenets of modern behavioral ethics is thathuman morality is dynamic and malleable. Recent work intechnology ethics has highlighted the role technologies canplay in this process. As such, it is the responsibility oftechnology designers to actively identify and address possi-ble negative consequences of such technological mediation. Inthis work, we examine dialogue systems employed by currentrobotic agents, arguing that they can have deleterious effectson both the human moral ecosystem and human perception ofthe robots, regardless of the robots’ actual ethical competence.We present a preliminary Bayesian analysis of empirical datasuggesting that the architectural status quo of clarification re-quest generation systems may (1) cause robots to unintention-ally miscommunicate their ethical intentions (our two tests forthis yielded Bayes factors of 1319 and 1099) and (2) weakenhumans’ contextual application of moral norms (Bayes fac-tor of 1069).

Referring expression understanding and generation are critical for robots to communicate about the world around them. Recently there have been significant advances on the problem of referring expression understanding, also known as reference resolution, with researchers presenting approaches to both incremental reference resolution (i.e., processing referring expressions word by word in real-time as they are spoken) and open-world reference resolution (i.e., resolving references both to known and previously unknown entities). In this work, we combine insights from these approaches to present IPOWER: the first algorithm for performing reference resolution incrementally in open-world environments.

Type IV CRISPR systems encode CRISPR associated (Cas)-like proteins that combine with small RNAs to form multi-subunit ribonucleoprotein complexes. However, the lack of Cas nucleases, integrases, and other genetic features commonly observed in most CRISPR systems has made it difficult to predict type IV mechanisms of action and biological function. Here we summarize recent bioinformatic and experimental advancements that collectively provide the first glimpses into the function of specific type IV subtypes. We also provide a bioinformatic and structural analysis of type IV-specific proteins within the context of multi-subunit (class 1) CRISPR systems, informing future studies aimed at elucidating the function of these cryptic systems.

Optical coherence tomography (OCT) is an evolving noninvasive imaging modality and has been used to image the larynx during surgical endoscopy. The design of an OCT sampling device capable of capturing images of the human larynx during a typical office based laryngoscopy examination is discussed. Both patient's and physician's movements were addressed. In vivo OCT imaging of the human larynx is demonstrated. Though the long focal length limits the lateral resolution of the image, the basement membrane can still be readily distinguished. Office-based OCT has the potential to guide surgical biopsies, direct therapy, and monitor disease. This is a promising imaging modality to study the larynx.

Objectives

Optical coherence tomography (OCT) is a new imaging modality that uses near-infrared light to produce cross-sectional images of tissue with a resolution approaching that of light microscopy. We have previously reported use of OCT imaging of the vocal folds (VFs) during direct laryngoscopy with a probe held in contact or near-contact with the VFs. This aim of this study was to develop and evaluate a novel OCT system integrated with a surgical microscope to allow hands-free OCT imaging of the VFs, which could be performed simultaneously with microscopic visualization.

Methods

We performed a prospective evaluation of a new method of acquiring OCT images of the VFs.

Results

An OCT system was successfully integrated with a surgical microscope to permit noncontact OCT imaging of the VFs of 10 patients. With this novel device we were able to identify VF epithelium and lamina propria; however, the resolution was reduced compared to that achieved with the standard contact or near-contact OCT.

Conclusions

Optical coherence tomography is able to produce high-resolution images of vocal fold mucosa to a maximum depth of 1.6 mm. It may be used in the diagnosis of VF lesions, particularly early squamous cell carcinoma, in which OCT can show disruption of the basement membrane. Mounting the OCT device directly onto the operating microscope allows hands-free noncontact OCT imaging and simultaneous conventional microscopic visualization of the VFs. However, the lateral resolution of the OCT microscope system is 50 microm, in contrast to the conventional handheld probe system (10 microm). Although such images at this resolution are still useful clinically, improved resolution would enhance the system's performance, potentially enabling real-time OCT-guided microsurgery of the larynx.

Genetic conflict between viruses and their hosts drives evolution and genetic innovation. Prokaryotes evolved CRISPR-mediated adaptive immune systems for protection from viral infection, and viruses have evolved diverse anti-CRISPR (Acr) proteins that subvert these immune systems. The adaptive immune system in Pseudomonas aeruginosa (type I-F) relies on a 350 kDa CRISPR RNA (crRNA)-guided surveillance complex (Csy complex) to bind foreign DNA and recruit a trans-acting nuclease for target degradation. Here, we report the cryo-electron microscopy (cryo-EM) structure of the Csy complex bound to two different Acr proteins, AcrF1 and AcrF2, at an average resolution of 3.4 Å. The structure explains the molecular mechanism for immune system suppression, and structure-guided mutations show that the Acr proteins bind to residues essential for crRNA-mediated detection of DNA. Collectively, these data provide a snapshot of an ongoing molecular arms race between viral suppressors and the immune system they target.

Recently renamed, metabolic dysfunction-associated steatotic liver disease remains a leading cause of chronic liver disease worldwide. Regular physical activity is recommended as a treatment for all with this condition because it is highly efficacious, especially when exercise training is undertaken with a specific goal in mind. Despite decades of research demonstrating exercises efficacy, key questions remain about the mechanism of benefit and most efficacious dose, as well as the independent impact on liver histology. To answer these questions, we present the design of a 16-week randomized controlled clinical trial of 45 adults aged 18-69 years with metabolic dysfunction-associated steatohepatitis. The primary aim of this study is to better understand the dose required and mechanisms to explain how exercise impacts multiple clinical end points in metabolic dysfunction-associated steatohepatitis. The primary outcome is MRI-measured liver fat. Secondary outcomes include other biomarkers of liver fibroinflammation, liver histology, and mechanistic pathways, as well as cardiometabolic risk and quality of life. This is the first study to compare different doses of exercise training to determine if there is a differential impact on imaging and serum biomarkers as well as liver histology.

Purpose

Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.

Patients and methods

Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684).

Results

Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients.

Conclusions

Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.

The Curiosity rover discovered fine-grained sedimentary rocks, which are inferred to represent an ancient lake and preserve evidence of an environment that would have been suited to support a martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. Carbon, hydrogen, oxygen, sulfur, nitrogen, and phosphorus were measured directly as key biogenic elements; by inference, phosphorus is assumed to have been available. The environment probably had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars.