Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Diversity of electroencephalographic patterns during propofol-induced burst suppression.

Burst suppression is a brain state consisting of high-amplitude electrical activity alternating with periods of quieter suppression that can be brought about by disease or by certain anesthetics. Although burst suppression has been studied for decades, few studies have investigated the diverse manifestations of this state within and between human subjects. As part of a clinical trial examining the antidepressant effects of propofol, we gathered burst suppression electroencephalographic (EEG) data from 114 propofol infusions across 21 human subjects with treatment-resistant depression. This data was examined with the objective of describing and quantifying electrical signal diversity. We observed three types of EEG burst activity: canonical broadband bursts (as frequently described in the literature), spindles (narrow-band oscillations reminiscent of sleep spindles), and a new feature that we call low-frequency bursts (LFBs), which are brief deflections of mainly sub-3-Hz power. These three features were distinct in both the time and frequency domains and their occurrence differed significantly across subjects, with some subjects showing many LFBs or spindles and others showing very few. Spectral-power makeup of each feature was also significantly different across subjects. In a subset of nine participants with high-density EEG recordings, we noted that each feature had a unique spatial pattern of amplitude and polarity when measured across the scalp. Finally, we observed that the Bispectral Index Monitor, a commonly used clinical EEG monitor, does not account for the diversity of EEG features when processing the burst suppression state. Overall, this study describes and quantifies variation in the burst suppression EEG state across subjects and repeated infusions of propofol. These findings have implications for the understanding of brain activity under anesthesia and for individualized dosing of anesthetic drugs.

MultiSero: An Open-Source Multiplex-ELISA Platform for Measuring Antibody Responses to Infection.

A multiplexed enzyme-linked immunosorbent assay (ELISA) that simultaneously measures antibody binding to multiple antigens can extend the impact of serosurveillance studies, particularly if the assay approaches the simplicity, robustness, and accuracy of a conventional single-antigen ELISA. Here, we report on the development of multiSero, an open-source multiplex ELISA platform for measuring antibody responses to viral infection. Our assay consists of three parts: (1) an ELISA against an array of proteins in a 96-well format; (2) automated imaging of each well of the ELISA array using an open-source plate reader; and (3) automated measurement of optical densities for each protein within the array using an open-source analysis pipeline. We validated the platform by comparing antibody binding to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antigens in 217 human sera samples, showing high sensitivity (0.978), specificity (0.977), positive predictive value (0.978), and negative predictive value (0.977) for classifying seropositivity, a high correlation of multiSero determined antibody titers with commercially available SARS-CoV-2 antibody tests, and antigen-specific changes in antibody titer dynamics upon vaccination. The open-source format and accessibility of our multiSero platform can contribute to the adoption of multiplexed ELISA arrays for serosurveillance studies, for SARS-CoV-2 and other pathogens of significance.

Factors influencing medical students' approaches to learning in Qatar.

BACKGROUND: This study investigated the relevance of the revised 2-factor study process questionnaire (R-SPQ-2F) for exploring medical students' approaches to learning in Qatar and identify how factors like gender, age, educational attainment, and prior experience with health care influence students' adoption of deep approaches to learning. METHODS: The sample consisted of 108 medical students (44% male, 56% female) from all four years of medical school at Weill Cornell Medicine-Qatar (WCM-Q). Participants completed the 20-item R-SPQ-2F questionnaire to measure their learning approaches through a structural model contrasting deep and surface learning. Participants also completed a survey collecting demographic information. RESULTS: Statistical analysis revealed significant differences in deep learning approaches across year levels for both men and women. Additionally, educational attainment played a significant role in students' approaches to learning. CONCLUSIONS: Based on structural equation modeling, this cross-verification study supports the R-SPQ-2F instrument and offers additional evidence for its robustness and application to medical education. These findings may help educational and program leaders in Qatar better understand medical students' learning approaches to enhance their pedagogical practices.

multiSero: open multiplex-ELISA platform for analyzing antibody responses to SARS-CoV-2 infection.

Serology has provided valuable diagnostic and epidemiological data on antibody responses to SARS-CoV-2 in diverse patient cohorts. Deployment of high content, multiplex serology platforms across the world, including in low and medium income countries, can accelerate longitudinal epidemiological surveys. Here we report multiSero, an open platform to enable multiplex serology with up to 48 antigens in a 96-well format. The platform consists of three components: ELISA-array of printed proteins, a commercial or home-built plate reader, and modular python software for automated analysis (pysero). We validate the platform by comparing antibody titers against the SARS-CoV-2 Spike, receptor binding domain (RBD), and nucleocapsid (N) in 114 sera from COVID-19 positive individuals and 87 pre-pandemic COVID-19 negative sera. We report data with both a commercial plate reader and an inexpensive, open plate reader (nautilus). Receiver operating characteristic (ROC) analysis of classification with single antigens shows that Spike and RBD classify positive and negative sera with the highest sensitivity at a given specificity. The platform distinguished positive sera from negative sera when the reactivity of the sera was equivalent to the binding of 1 ng mL âˆ'1 RBD-specific monoclonal antibody. We developed normalization and classification methods to pool antibody responses from multiple antigens and multiple experiments. Our results demonstrate a performant and accessible pipeline for multiplexed ELISA ready for multiple applications, including serosurveillance, identification of viral proteins that elicit antibody responses, differential diagnosis of circulating pathogens, and immune responses to vaccines.

Investigating Visual Crowding of Objects in Complex Real-World Scenes.

Visual crowding, the impairment of object recognition in peripheral vision due to flanking objects, has generally been studied using simple stimuli on blank backgrounds. While crowding is widely assumed to occur in natural scenes, it has not been shown rigorously yet. Given that scene contexts can facilitate object recognition, crowding effects may be dampened in real-world scenes. Therefore, this study investigated crowding using objects in computer-generated real-world scenes. In two experiments, target objects were presented with four flanker objects placed uniformly around the target. Previous research indicates that crowding occurs when the distance between the target and flanker is approximately less than half the retinal eccentricity of the target. In each image, the spacing between the target and flanker objects was varied considerably above or below the standard (0.5) threshold to either suppress or facilitate the crowding effect. Experiment 1 cued the target location and then briefly flashed the scene image before participants could move their eyes. Participants then selected the target object's category from a 15-alternative forced choice response set (including all objects shown in the scene). Experiment 2 used eye tracking to ensure participants were centrally fixating at the beginning of each trial and showed the image for the duration of the participant's fixation. Both experiments found object recognition accuracy decreased with smaller spacing between targets and flanker objects. Thus, this study rigorously shows crowding of objects in semantically consistent real-world scenes.

Scale-free vertical tracking microscopy.

The behavior and microscale processes associated with freely suspended organisms, along with sinking particles underlie key ecological processes in the ocean. Mechanistically studying such multiscale processes in the laboratory presents a considerable challenge for microscopy: how to measure single cells at microscale resolution, while allowing them to freely move hundreds of meters in the vertical direction? Here we present a solution in the form of a scale-free, vertical tracking microscope, based on a 'hydrodynamic treadmill' with no bounds for motion along the axis of gravity. Using this method to bridge spatial scales, we assembled a multiscale behavioral dataset of nonadherent planktonic cells and organisms. Furthermore, we demonstrate a 'virtual-reality system for single cells', wherein cell behavior directly controls its ambient environmental parameters, enabling quantitative behavioral assays. Our method and results exemplify a new paradigm of multiscale measurement, wherein one can observe and probe macroscale and ecologically relevant phenomena at microscale resolution. Beyond the marine context, we foresee that our method will allow biological measurements of cells and organisms in a suspended state by freeing them from the confines of the coverslip.

The Scene Perception & Event Comprehension Theory (SPECT) Applied to Visual Narratives.

Understanding how people comprehend visual narratives (including picture stories, comics, and film) requires the combination of traditionally separate theories that span the initial sensory and perceptual processing of complex visual scenes, the perception of events over time, and comprehension of narratives. Existing piecemeal approaches fail to capture the interplay between these levels of processing. Here, we propose the Scene Perception & Event Comprehension Theory (SPECT), as applied to visual narratives, which distinguishes between front-end and back-end cognitive processes. Front-end processes occur during single eye fixations and are comprised of attentional selection and information extraction. Back-end processes occur across multiple fixations and support the construction of event models, which reflect understanding of what is happening now in a narrative (stored in working memory) and over the course of the entire narrative (stored in long-term episodic memory). We describe relationships between front- and back-end processes, and medium-specific differences that likely produce variation in front-end and back-end processes across media (e.g., picture stories vs. film). We describe several novel research questions derived from SPECT that we have explored. By addressing these questions, we provide greater insight into how attention, information extraction, and event model processes are dynamically coordinated to perceive and understand complex naturalistic visual events in narratives and the real world.

Visualization and Quantitation of Phase-Separated Droplet Formation by Human HP1α.

The ability of the heterochromatin protein-1 (HP1) to phase separate into droplets suggests new mechanisms of gene organization in the cell nucleus. An accumulating body of work suggests that other nuclear proteins also display phase separation behaviors in vitro. To understand the mechanistic and biological significance of such droplet formation a rigorous biophysical characterization of this behavior is necessary. Herein we describe procedures for imaging HP1 droplets by brightfield microscopy, and two methods to quantify phase separation.

Propofol for Treatment-Resistant Depression: A Pilot Study.

Background: We hypothesized that propofol, a unique general anesthetic that engages N-methyl-D-aspartate and gamma-aminobutyric acid receptors, has antidepressant properties. This open-label trial was designed to collect preliminary data regarding the feasibility, tolerability, and efficacy of deep propofol anesthesia for treatment-resistant depression. Methods: Ten participants with moderate-to-severe medication-resistant depression (age 18-45 years and otherwise healthy) each received a series of 10 propofol infusions. Propofol was dosed to strongly suppress electroencephalographic activity for 15 minutes. The primary depression outcome was the 24-item Hamilton Depression Rating Scale. Self-rated depression scores were compared with a group of 20 patients who received electroconvulsive therapy. Results: Propofol treatments were well tolerated by all subjects. No serious adverse events occurred. Montreal Cognitive Assessment scores remained stable. Hamilton scores decreased by a mean of 20 points (range 0-45 points), corresponding to a mean 58% improvement from baseline (range 0-100%). Six of the 10 subjects met the criteria for response (>50% improvement). Self-rated depression improved similarly in the propofol group and electroconvulsive therapy group. Five of the 6 propofol responders remained well for at least 3 months. In posthoc analyses, electroencephalographic measures predicted clinical response to propofol. Conclusions: These findings demonstrate that high-dose propofol treatment is feasible and well tolerated by individuals with treatment-resistant depression who are otherwise healthy. Propofol may trigger rapid, durable antidepressant effects similar to electroconvulsive therapy but with fewer side effects. Controlled studies are warranted to further evaluate propofol's antidepressant efficacy and mechanisms of action. ClinicalTrials.gov: NCT02935647.

The Role of Phase Separation in Heterochromatin Formation, Function, and Regulation.

In eukaryotic cells, structures called heterochromatin play critical roles in nuclear processes ranging from gene repression to chromosome segregation. Biochemical and in vivo studies over the past several decades have implied that the diverse functions of heterochromatin rely on the ability of these structures to spread across large regions of the genome, to compact the underlying DNA, and to recruit different types of activities. Recent observations have suggested that heterochromatin may possess liquid droplet-like properties. Here, we discuss how these observations provide a new perspective on the mechanisms for the assembly, regulation, and functions of heterochromatin.

Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin.

Gene silencing by heterochromatin is proposed to occur in part as a result of the ability of heterochromatin protein 1 (HP1) proteins to spread across large regions of the genome, compact the underlying chromatin and recruit diverse ligands. Here we identify a new property of the human HP1α protein: the ability to form phase-separated droplets. While unmodified HP1α is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation-driven phase separation can be promoted or reversed by specific HP1α ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1α droplets, but molecules such as the transcription factor TFIIB show no preference. Using a single-molecule DNA curtain assay, we find that both unmodified and phosphorylated HP1α induce rapid compaction of DNA strands into puncta, although with different characteristics. We show by direct protein delivery into mammalian cells that an HP1α mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1α. These findings suggest that heterochromatin-mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands on the basis of nuclear context.

The relative roles of visuospatial and linguistic working memory systems in generating inferences during visual narrative comprehension.

This study investigated the relative roles of visuospatial versus linguistic working memory (WM) systems in the online generation of bridging inferences while viewers comprehend visual narratives. We contrasted these relative roles in the visuospatial primacy hypothesis versus the shared (visuospatial & linguistic) systems hypothesis, and tested them in 3 experiments. Participants viewed picture stories containing multiple target episodes consisting of a beginning state, a bridging event, and an end state, respectively, and the presence of the bridging event was manipulated. When absent, viewers had to infer the bridging-event action to comprehend the end-state image. A pilot study showed that after viewing the end-state image, participants' think-aloud protocols contained more inferred actions when the bridging event was absent than when it was present. Likewise, Experiment 1 found longer viewing times for the end-state image when the bridging-event image was absent, consistent with viewing times revealing online inference generation processes. Experiment 2 showed that both linguistic and visuospatial WM loads attenuated the inference viewing time effect, consistent with the shared systems hypothesis. Importantly, however, Experiment 3 found that articulatory suppression did not attenuate the inference viewing time effect, indicating that (sub)vocalization did not support online inference generation during visual narrative comprehension. Thus, the results support a shared-systems hypothesis in which both visuospatial and linguistic WM systems support inference generation in visual narratives, with the linguistic WM system operating at a deeper level than (sub)vocalization.

What Would Jaws Do? The Tyranny of Film and the Relationship between Gaze and Higher-Level Narrative Film Comprehension.

What is the relationship between film viewers' eye movements and their film comprehension? Typical Hollywood movies induce strong attentional synchrony-most viewers look at the same things at the same time. Thus, we asked whether film viewers' eye movements would differ based on their understanding-the mental model hypothesis-or whether any such differences would be overwhelmed by viewers' attentional synchrony-the tyranny of film hypothesis. To investigate this question, we manipulated the presence/absence of prior film context and measured resulting differences in film comprehension and eye movements. Viewers watched a 12-second James Bond movie clip, ending just as a critical predictive inference should be drawn that Bond's nemesis, "Jaws," would fall from the sky onto a circus tent. The No-context condition saw only the 12-second clip, but the Context condition also saw the preceding 2.5 minutes of the movie before seeing the critical 12-second portion. Importantly, the Context condition viewers were more likely to draw the critical inference and were more likely to perceive coherence across the entire 6 shot sequence (as shown by event segmentation), indicating greater comprehension. Viewers' eye movements showed strong attentional synchrony in both conditions as compared to a chance level baseline, but smaller differences between conditions. Specifically, the Context condition viewers showed slightly, but significantly, greater attentional synchrony and lower cognitive load (as shown by fixation probability) during the critical first circus tent shot. Thus, overall, the results were more consistent with the tyranny of film hypothesis than the mental model hypothesis. These results suggest the need for a theory that encompasses processes from the perception to the comprehension of film.

Linking attentional processes and conceptual problem solving: visual cues facilitate the automaticity of extracting relevant information from diagrams.

This study investigated links between visual attention processes and conceptual problem solving. This was done by overlaying visual cues on conceptual physics problem diagrams to direct participants' attention to relevant areas to facilitate problem solving. Participants (N = 80) individually worked through four problem sets, each containing a diagram, while their eye movements were recorded. Each diagram contained regions that were relevant to solving the problem correctly and separate regions related to common incorrect responses. Problem sets contained an initial problem, six isomorphic training problems, and a transfer problem. The cued condition saw visual cues overlaid on the training problems. Participants' verbal responses were used to determine their accuracy. This study produced two major findings. First, short duration visual cues which draw attention to solution-relevant information and aid in the organizing and integrating of it, facilitate both immediate problem solving and generalization of that ability to new problems. Thus, visual cues can facilitate re-representing a problem and overcoming impasse, enabling a correct solution. Importantly, these cueing effects on problem solving did not involve the solvers' attention necessarily embodying the solution to the problem, but were instead caused by solvers attending to and integrating relevant information in the problems into a solution path. Second, this study demonstrates that when such cues are used across multiple problems, solvers can automatize the extraction of problem-relevant information extraction. These results suggest that low-level attentional selection processes provide a necessary gateway for relevant information to be used in problem solving, but are generally not sufficient for correct problem solving. Instead, factors that lead a solver to an impasse and to organize and integrate problem information also greatly facilitate arriving at correct solutions.

Blur Detection is Unaffected by Cognitive Load.

Blur detection is affected by retinal eccentricity, but is it also affected by attentional resources? Research showing effects of selective attention on acuity and contrast sensitivity suggests that allocating attention should increase blur detection. However, research showing that blur affects selection of saccade targets suggests that blur detection may be pre-attentive. To investigate this question, we carried out experiments in which viewers detected blur in real-world scenes under varying levels of cognitive load manipulated by the N-back task. We used adaptive threshold estimation to measure blur detection thresholds at 0°, 3°, 6°, and 9° eccentricity. Participants carried out blur detection as a single task, a single task with to-be-ignored letters, or an N-back task with four levels of cognitive load (0, 1, 2, or 3-back). In Experiment 1, blur was presented gaze-contingently for occasional single eye fixations while participants viewed scenes in preparation for an easy picture recognition memory task, and the N-back stimuli were presented auditorily. The results for three participants showed a large effect of retinal eccentricity on blur thresholds, significant effects of N-back level on N-back performance, scene recognition memory, and gaze dispersion, but no effect of N-back level on blur thresholds. In Experiment 2, we replicated Experiment 1 but presented the images tachistoscopically for 200 ms (half with, half without blur), to determine whether gaze-contingent blur presentation in Experiment 1 had produced attentional capture by blur onset during a fixation, thus eliminating any effect of cognitive load on blur detection. The results with three new participants replicated those of Experiment 1, indicating that the use of gaze-contingent blur presentation could not explain the lack of effect of cognitive load on blur detection. Thus, apparently blur detection in real-world scene images is unaffected by attentional resources, as manipulated by the cognitive load produced by the N-back task.

Mechanisms of functional promiscuity by HP1 proteins.

Heterochromatin protein 1 (HP1) proteins were originally identified as critical components in heterochromatin-mediated gene silencing and are now recognized to play essential roles in several other processes including gene activation. Several eukaryotes possess more than one HP1 paralog. Despite high sequence conservation, the HP1 paralogs achieve diverse functions. Further, in many cases, the same HP1 paralog is implicated in multiple functions. Recent biochemical studies have revealed interesting paralog-specific biophysical differences and unanticipated conformational versatility in HP1 proteins that may account for this functional promiscuity. Here we review these findings and describe a molecular framework that aims to link the conformational flexibility of HP1 proteins observed in vitro with their functional promiscuity observed in vivo.

The spatiotemporal dynamics of scene gist recognition.

Viewers can rapidly extract a holistic semantic representation of a real-world scene within a single eye fixation, an ability called recognizing the gist of a scene, and operationally defined here as recognizing an image's basic-level scene category. However, it is unknown how scene gist recognition unfolds over both time and space-within a fixation and across the visual field. Thus, in 3 experiments, the current study investigated the spatiotemporal dynamics of basic-level scene categorization from central vision to peripheral vision over the time course of the critical first fixation on a novel scene. The method used a window/scotoma paradigm in which images were briefly presented and processing times were varied using visual masking. The results of Experiments 1 and 2 showed that during the first 100 ms of processing, there was an advantage for processing the scene category from central vision, with the relative contributions of peripheral vision increasing thereafter. Experiment 3 tested whether this pattern could be explained by spatiotemporal changes in selective attention. The results showed that manipulating the probability of information being presented centrally or peripherally selectively maintained or eliminated the early central vision advantage. Across the 3 experiments, the results are consistent with a zoom-out hypothesis, in which, during the first fixation on a scene, gist extraction extends from central vision to peripheral vision as covert attention expands outward.

A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly.

A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.

A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress.

The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ~78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Electron microscopy and biochemical analyses revealed that the RQC forms a stable complex with 60S ribosomal subunits containing stalled polypeptides and triggers their degradation. A negative feedback loop regulates the RQC, and Hsf1 senses an RQC-mediated translation-stress signal distinctly from other stresses. Our work reveals the range of stresses Hsf1 monitors and elucidates a conserved cotranslational protein quality control mechanism.