Highly multiplexed design of an allosteric transcription factor to sense novel ligands.

Allosteric transcription factors (aTF), widely used as biosensors, have proven challenging to design for detecting novel molecules because mutation of ligand-binding residues often disrupts allostery. We developed Sensor-seq, a high-throughput platform to design and identify aTF biosensors that bind to non-native ligands. We screened a library of 17,737 variants of the aTF TtgR, a regulator of a multidrug exporter, against six non-native ligands of diverse chemical structures - four derivatives of the cancer therapeutic tamoxifen, the antimalarial drug quinine, and the opiate analog naltrexone - as well as two native flavonoid ligands, naringenin and phloretin. Sensor-seq identified novel biosensors for each of these ligands with high dynamic range and diverse specificity profiles. The structure of a naltrexone-bound design showed shape-complementary methionine-aromatic interactions driving ligand specificity. To demonstrate practical utility, we developed cell-free detection systems for naltrexone and quinine. Sensor-seq enables rapid, scalable design of new biosensors, overcoming constraints of natural biosensors.

A clearing in the objectivity of aesthetics?

As subjective experiences go, beauty matters. Although aesthetics has long been a topic of study, research in this area has not resulted in a level of interest and progress commensurate with its import. Here, we briefly discuss two recent advances, one computational and one neuroscientific, and their pertinence to aesthetic processing. First, we hypothesize that deep neural networks provide the capacity to model representations essential to aesthetic experiences. Second, we highlight the principal gradient as an axis of information processing that is potentially key to examining where and how aesthetic processing takes place in the brain. In concert with established neuroimaging tools, we suggest that these advances may cultivate a new frontier in the understanding of our aesthetic experiences.

THE HENNEPIN DOUBLE-TUBE TECHNIQUE: A MORE EFFICIENT METHOD OF TRACHEAL INTUBATION THROUGH THE LMA FASTRACH.

BACKGROUND: The LMA Fastrach (LMA North America, Inc; hereafter termed the intubating laryngeal mask airway [ILMA]) is an extraglottic device designed to facilitate endotracheal intubation. After the endotracheal tube is placed through the lumen of the ILMA into the trachea, the ILMA is removed, using a proprietary stabilizer rod to hold the tube in place. DISCUSSION: The traditional method of ILMA removal is not optimized for the critically ill patient. It requires the use of unfamiliar equipment, exposes the patient to a significant period without ventilation, and risks tube dislodgement. We designed a simple technique with a double-endotracheal tube setup that addresses these problems using common equipment, allowing for continuous ventilation, and minimizing the risk of tube dislodgement. CONCLUSIONS: The traditional method of ILMA removal around an endotracheal tube is not designed for critically ill patients or the physicians taking care of them. This novel technique is designed to improve the usability of the ILMA for physicians and improve airway outcomes for patients.

Bronchoscopy in the emergency department.

BACKGROUND: Flexible bronchoscopy has been safely used for decades in ambulatory and critical care settings to aid in the diagnosis and treatment of tracheobronchial tree disorders. Although emergency physicians have the requisite skills to operate and interpret flexible bronchoscopy, no reports exist on the use of bronchoscopy by emergency physicians apart from endotracheal tube placement and confirmation. OBJECTIVE: The primary goal of this study was to describe the indications, outcomes and complications of flexible bronchoscopy performed by emergency physicians in an urban academic emergency department. METHODS: This was a single-center retrospective cohort study involving chart and video review of 146 patients over a 10.5-year study period. Patients of any age were included if they had been tracheally intubated or mechanically ventilated and underwent flexible bronchoscopy in the emergency department. After patients were identified, manual chart and video review was used to collect data on patient demographics, indications for intubation, indications for bronchoscopy, details of the bronchoscopy procedure, procedural findings, outcomes of the procedure, complications, provider training levels, and additional bronchoscopies performed after admission. The data was analyzed using descriptive statistics. RESULTS: 146 patients were included in the study and all bronchoscopies were performed or supervised by attending emergency physicians. After bronchoscopy, 24% of patients displayed improvement in oxygenation or lobar collapse while most patients had no change in clinical status. One patient had temporary hypoxemia after bronchoscopy. When another physician performed a subsequent bronchoscopy during admission, the findings were in agreement with the ED bronchoscopy 86% of the time. CONCLUSION: At our institution, emergency physicians can safely and effectively use flexible bronchoscopy to diagnose and treat critically ill patients.

Rapid Sequence Airway with the Intubating Laryngeal Mask in the Emergency Department.

BACKGROUND: The administration of sedation and neuromuscular blockade to facilitate extraglottic device (EGD) placement is known as rapid sequence airway (RSA). In the emergency department (ED), EGDs are used largely as rescue devices. In select patients, there may be significant advantages to using EGDs over laryngoscopy as the primary airway device in the ED. OBJECTIVE: Our study sought to describe the practice of RSA in the ED, including rates of successful oxygenation, ventilation, and complications from EGD use. METHODS: We identified patients in the ED between 2007 and 2017 who underwent RSA with the LMA® Fastrach™ (hereafter termed ILMA; Teleflex Medical Europe Ltd., Athlone, Ireland) placed as the first definitive airway management device. A trained abstractor performed chart and video review of the cases to determine patient characteristics, physician use of the ILMA, indication for ILMA placement, success of oxygenation and ventilation, success of intubation, and complications related to the device. RESULTS: During the study period, 94 patients underwent RSA with the ILMA. Of those, 93 (99%) were successfully oxygenated and ventilated, and when intubation was attempted, 89% were able to be intubated through the ILMA. The incidence of vomiting and aspiration was 1% and 3%, respectively. There were 30 different attending physicians who supervised RSA and the median number was 2 per physician in the 10-year study period. CONCLUSION: The practice of RSA with the ILMA in the ED is associated with a high rate of successful oxygenation, ventilation, and intubation with infrequent complications, even when performed by physicians with few experiences in the approach.

Erector Spinae Plane Block in the Emergency Department for Upper Extremity: A Case Report.

INTRODUCTION: The erector spinae plane block (ESPB) has been described as an effective analgesic modality in the emergency department (ED) for thoracic pain. It has not previously been described to treat ED patients with pain in the upper extremity. CASE REPORT: We present a case of a 52-year-old female who presented to the ED with an acute exacerbation of her chronic radicular left arm pain originating after a fall she sustained one year prior. After a variety of analgesic modalities failed to control her pain, an ESPB was used to successfully treat her pain and facilitate discharge from the ED. CONCLUSION: A significant portion of patients who present to the ED have underlying chronic pain; however, opioids are a potentially dangerous and ineffective modality to treat chronic pain. In addition to avoiding opiates, the ESPB has the advantage of preserving motor function, thus avoiding the complications associated with brachial plexus blockade.

Modified insertion technique for a sustained-release dexamethasone intravitreal implant (Ozurdex®).

PURPOSE: We describe a modified injection technique that adheres a sustained-release dexamethasone intravitreal implant (Ozurdex®) to the vitreous base. OBSERVATIONS: This modified technique was applied after removal of a prior dislocated Ozurdex® that migrated into the anterior chamber in one patient, and also on another patient bothered by perception of a large floater induced by a free-floating Ozurdex® in the vitreous cavity previously inserted with the conventional technique. The main feature of this new technique consisted of altering the conventional "bevel-up" orientation of the insertion needle tip towards the vitreous cavity to the modified "bevel-down" orientation of the needle tip directed towards the pars plana and vitreous base, for the purpose of adhering a portion of or the entire dexamethasone implant to the vitreous base. Neither patient developed postoperative complications with this technique. CONCLUSIONS AND IMPORTANCE: This modified insertion technique allows adherence of Ozurdex® to the vitreous base and avoids adverse effects associated with a free-floating Ozurdex®, such as its migration into the anterior chamber, or visual disturbance associated with movement of the implant.

Pitch Matching Adapts Even for Bilateral Cochlear Implant Users with Relatively Small Initial Pitch Differences Across the Ears.

There is often a mismatch for bilateral cochlear implant (CI) users between the electrodes in the two ears that receive the same frequency allocation and the electrodes that, when stimulated, yield the same pitch. Studies with CI users who have extreme mismatches between the two ears show that adaptation occurs in terms of pitch matching, reducing the difference between which electrodes receive the same frequency allocation and which ones produce the same pitch. The considerable adaptation that occurs for these extreme cases suggests that adaptation should be sufficient to overcome the relatively minor mismatches seen with typical bilateral CI users. However, even those with many years of bilateral CI use continue to demonstrate a mismatch. This may indicate that adaptation only occurs when there are large mismatches. Alternatively, it may indicate that adaptation occurs regardless of the magnitude of the mismatch, but that adaptation is proportional to the magnitude of the mismatch, and thus never fully counters the original mismatch. To investigate this, six bilateral CI users with initial pitch-matching mismatches of less than 3 mm completed a pitch-matching task near the time of activation, 6 months after activation, and 1 year after activation. Despite relatively small initial mismatches, the results indicated that adaptation still occurred.

Corneal Oxidative Damage in Keratoconus Cells due to Decreased Oxidant Elimination from Modified Expression Levels of SOD Enzymes, PRDX6, SCARA3, CPSF3, and FOXM1.

PURPOSE: To compare the levels of gene expression for enzymes involved in production and elimination of reactive oxygen/nitrogen species (ROS/RNS) in normal human corneal cells (NL cells) with those in human corneal cells with keratoconus (KC cells) in vitro. METHODS: Primary NL and KC stromal fibroblast cultures were incubated with apocynin (an inhibitor of NADPH oxidase) or N-nitro-L-arginine (N-LLA; an inhibitor of nitric oxide synthase). ROS/RNS levels were measured using an H2 DCFDA fluorescent assay. The RT2 Profiler™ PCR Array for Oxidative Stress and Antioxidant Defense was used for initial screening of the NL and KC cultures. Transcription levels for genes related to production or elimination of ROS/RNS were analyzed using quantitative PCR. Immunohistochemistry was performed on 10 intact human corneas using antibodies against SCARA3 and CPSF3. RESULTS: Array screening of 84 antioxidant-related genes identified 12 genes that were differentially expressed between NL and KC cultures. Compared with NL cells, quantitative PCR showed that KC cells had decreased expression of antioxidant genes SCARA3 isoform 2 (0.59-fold, P = 0.02) and FOXM1 isoform 1 (0.61-fold, P = 0.03). KC cells also had downregulation of the antioxidant genes SOD1 (0.4-fold, P = 0.0001) and SOD3 (0.37-fold, P = 0.02) but increased expression of SOD2 (3.3-fold, P < 0.0001), PRDX6 (1.47-fold, P = 0.01), and CPSF3 (1.44-fold, P = 0.02). CONCLUSION: The difference in expression of antioxidant enzymes between KC and NL suggests that the oxidative stress imbalances found in KC are caused by defects in ROS/RNS removal rather than increased ROS/RNS production.

Distinct representations of basic taste qualities in human gustatory cortex.

The mammalian tongue contains gustatory receptors tuned to basic taste types, providing an evolutionarily old hedonic compass for what and what not to ingest. Although representation of these distinct taste types is a defining feature of primary gustatory cortex in other animals, their identification has remained elusive in humans, leaving the demarcation of human gustatory cortex unclear. Here we used distributed multivoxel activity patterns to identify regions with patterns of activity differentially sensitive to sweet, salty, bitter, and sour taste qualities. These were found in the insula and overlying operculum, with regions in the anterior and middle insula discriminating all tastes and representing their combinatorial coding. These findings replicated at super-high 7 T field strength using different compounds of sweet and bitter taste types, suggesting taste sensation specificity rather than chemical or receptor specificity. Our results provide evidence of the human gustatory cortex in the insula.

Mitochondrial Impairment in Antibiotic Induced Toxic Optic Neuropathies.

There is growing evidence for the role of mitochondrial dysfunction in the toxic optic neuropathies. Due to the structural similarities between antibiotic targets and mitochondrial machinery, several antibiotics known to cause optic neuropathy have deleterious effects on mitochondrial function. We review the literature on the prevalence, clinical manifestations, and management of antibiotic induced toxic optic neuropathies. The effect of these antibiotics on mitochondrial function in regard to the optic nerve is discussed.

Changing stimulation patterns can change the broadness of contralateral masking functions for bilateral cochlear implant users.

Past studies have found that contralateral masking functions are sharper than ipsilateral masking functions for cochlear implant (CI) users. This could suggest that contralateral masking effects are only sensitive to the peak of the masker stimulation for this population. To determine if that is the case, this study investigated whether using broader stimulation patterns affects the broadness of the contralateral masking function. Contralateral masking functions were measured for six bilateral CI users using both a broad and narrow masker. Findings from this study revealed that the broad masker resulted in a broader contralateral masking function. This would suggest that stimulation outside of the peak of the masker affects contralateral masking functions for CI users.

The Face of Distaste: A Preliminary Study.

Distaste is a primitive rejection impulse triggered by the ingestion of unpleasant tasting substances, many of which are toxic. Theoretical work has suggested that distaste may be the evolutionary precursor for both physical disgust, which serves to defend against disease and other threats to biological fitness, and moral disgust, which defends against threats to the social order. Consistent with this proposal, recent work has found that the facial expression of distaste may be similar to that of disgust. Specifically, raising of the upper lip has been reported in distaste, physical disgust, and moral disgust. However, competing evidence suggests that distaste and disgust expressions may differ, and the facial expressions of adult humans in response to distasteful stimuli remain poorly specified. To address this issue, we conducted a preliminary experiment to investigate the upper lip raise in adult volunteers (N = 15) as they tasted unpleasant, pleasant, and neutral liquids. We found increased raising of the upper lip for bitter and salty tastes relative to water and sweet, suggesting that the upper lip raise is indeed part of the distaste expression. Given evidence that the upper lip raise is also present in physical and moral disgust, these results are consistent with the proposed origins of disgust in distaste.

Reading What the Mind Thinks From How the Eye Sees.

Human eyes convey a remarkable variety of complex social and emotional information. However, it is unknown which physical eye features convey mental states and how that came about. In the current experiments, we tested the hypothesis that the receiver's perception of mental states is grounded in expressive eye appearance that serves an optical function for the sender. Specifically, opposing features of eye widening versus eye narrowing that regulate sensitivity versus discrimination not only conveyed their associated basic emotions (e.g., fear vs. disgust, respectively) but also conveyed opposing clusters of complex mental states that communicate sensitivity versus discrimination (e.g., awe vs. suspicion). This sensitivity-discrimination dimension accounted for the majority of variance in perceived mental states (61.7%). Further, these eye features remained diagnostic of these complex mental states even in the context of competing information from the lower face. These results demonstrate that how humans read complex mental states may be derived from a basic optical principle of how people see.

Attentional and affective consequences of technology supported mindfulness training: a randomised, active control, efficacy trial.

BACKGROUND: Mindfulness training (MT) programs represent an approach to attention training with well-validated mental health benefits. However, research supporting MT efficacy is based predominantly on weekly-meeting, facilitator-led, group-intervention formats. It is unknown whether participants might benefit from neurofeedback-assisted, technology-supported MT (N-tsMT), in which meditation is delivered individually, without the need for a facilitator, travel to a training site, or the presence of a supportive group environment. Mirroring the validation of group MT interventions, the first step in addressing this question requires identifying whether N-tsMT promotes measurable benefits. Here, we report on an initial investigation of a commercial N-tsMT system. METHODS: In a randomized, active control trial, community-dwelling healthy adult participants carried out 6 weeks of daily practice, receiving either N-tsMT (n = 13), or a control condition of daily online math training (n = 13). Training effects were assessed on target measures of attention and well-being. Participants also completed daily post-training surveys assessing effects on mood, body awareness, calm, effort, and stress. RESULTS: Analysis revealed training effects specific to N-tsMT, with attentional improvements in overall reaction time on a Stroop task, and well-being improvements via reduced somatic symptoms on the Brief Symptom Inventory. Attention and well-being improvements were correlated, and effects were greatest for the most neurotic participants. However, secondary, exploratory measures of attention and well-being did not show training-specific effects. N-tsMT was associated with greater body awareness and calm, and initially greater effort that later converged with effort in the control condition. CONCLUSIONS: Preliminary findings indicate that N-tsMT promotes modest benefits for attention and subjective well-being in a healthy community sample relative to an active control condition. However, the findings would benefit from replication in a larger sample, and more intensive practice or more comprehensive MT instruction might be required to promote the broader benefits typically reported in group format, facilitated MT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43629398 . Retrospectively registered on June 16, 2016.

Terminal QRS distortion is present in anterior myocardial infarction but absent in early repolarization.

BACKGROUND: Early repolarization (ER) and acute left anterior descending artery occlusion (LADO) may be difficult to distinguish. Terminal QRS distortion (TQRSD), defined by the absence of both an S wave and J wave in either of leads V2 or V3, is often present in anterior ST-segment elevation myocardial infarction. We hypothesized that this finding would always be absent in ER. METHODS: This was a retrospective analysis of electrocardiograms (ECGs) of consecutive patients who presented to the emergency department with ischemic symptoms and had a cardiologist interpretation of "benign ER" on the initial emergency department ECG. All ECGs were scrutinized for the presence of an S wave and a J wave in leads V2 and V3. Differences in S-wave amplitudes between complexes with and without J waves were analyzed using nonparametric Mann-Whitney testing and confidence intervals around a proportion. RESULTS: One hundred seventy-one patients were identified with benign ER. Zero of 171 had TQRSD (specificity for LADO, 100%; 95% confidence interval, 97.8-100). In lead V2, S waves were absent in only 1 of 171 ECGs; however, in that ECG, a J wave measuring 0.5 mm was present. In lead V3, S waves were absent in 16 ECGs, but all of these ECGs had J waves. When J waves were absent in leads V2 or V3, the corresponding S waves were deeper than S waves in QRS complexes with J waves. CONCLUSION: Terminal QRS distortion was never observed in benign ER. Based on previous studies indicating the presence of TQRSD in LADO, it was, thus, 100% specific to LADO when the differential diagnosis was acute myocardial infarction vs ER.

Perceptually aligning apical frequency regions leads to more binaural fusion of speech in a cochlear implant simulation.

For bilateral cochlear implant users, the left and right arrays are typically not physically aligned, resulting in a degradation of binaural fusion, which can be detrimental to binaural abilities. Perceptually aligning the two arrays can be accomplished by disabling electrodes in one ear that do not have a perceptually corresponding electrode in the other side. However, disabling electrodes at the edges of the array will cause compression of the input frequency range into a smaller cochlear extent, which may result in reduced spectral resolution. An alternative approach to overcome this mismatch would be to only align one edge of the array. By aligning either only the apical or basal end of the arrays, fewer electrodes would be disabled, potentially causing less reduction in spectral resolution. The goal of this study was to determine the relative effect of aligning either the basal or apical end of the electrode with regards to binaural fusion. A vocoder was used to simulate cochlear implant listening conditions in normal hearing listeners. Speech signals were vocoded such that the two ears were either predominantly aligned at only the basal or apical end of the simulated arrays. The experiment was then repeated with a spectrally inverted vocoder to determine whether the detrimental effects on fusion were related to the spectral-temporal characteristics of the stimuli or the location in the cochlea where the misalignment occurred. In Experiment 1, aligning the basal portion of the simulated arrays led to significantly less binaural fusion than aligning the apical portions of the simulated array. However, when the input was spectrally inverted, aligning the apical portion of the simulated array led to significantly less binaural fusion than aligning the basal portions of the simulated arrays. These results suggest that, for speech, with its predominantly low frequency spectral-temporal modulations, it is more important to perceptually align the apical portion of the array to better preserve binaural fusion. By partially aligning these arrays, cochlear implant users could potentially increase their ability to fuse speech sounds presented to the two ears while maximizing spectral resolution.

Spending one's time: the hedonic principle in ad libitum viewing of pictures.

The hedonic principle maintains that humans strive to maximize pleasant feelings and avoid unpleasant feelings. Surprisingly, and contrary to hedonic logic, previous experiments have demonstrated a relationship between picture viewing time and arousal (activation) but not with valence (pleasure vs. displeasure), suggesting that arousal rather than the hedonic principle accounts for how individuals choose to spend their time. In 2 experiments we investigated the arousal and hedonic principles underlying viewing time behavior while controlling for familiarity with stimuli, picture complexity, and demand characteristics. Under ad libitum conditions of picture viewing, we found strong relationships between viewing time, valence, and facial corrugator electomyographic (EMG) activity with familiar but not novel pictures. Viewing time of novel stimuli was largely associated with arousal and visual complexity. We conclude that only after initial information about the stimulus is gathered, where we choose to spend our time is guided by the hedonic principle.

Population coding of affect across stimuli, modalities and individuals.

It remains unclear how the brain represents external objective sensory events alongside our internal subjective impressions of them--affect. Representational mapping of population activity evoked by complex scenes and basic tastes in humans revealed a neural code supporting a continuous axis of pleasant-to-unpleasant valence. This valence code was distinct from low-level physical and high-level object properties. Although ventral temporal and anterior insular cortices supported valence codes specific to vision and taste, both the medial and lateral orbitofrontal cortices (OFC) maintained a valence code independent of sensory origin. Furthermore, only the OFC code could classify experienced affect across participants. The entire valence spectrum was represented as a collective pattern in regional neural activity as sensory-specific and abstract codes, whereby the subjective quality of affect can be objectively quantified across stimuli, modalities and people.