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Epistatic interactions can make the outcomes of evolution unpredictable, but no comprehensive data are available on the extent, direction, rate, and consequences of changes in the effects of mutations as protein sequences evolve. Here we characterize the temporal dynamics of epistatic change by using deep mutational scanning to measure the functional effect of every possible amino-acid mutation in a phylogenetic series of reconstructed ancestral and extant proteins, using the steroid receptor DNA-binding domain as a model. Across a 700-million-year historical trajectory, the effects of most mutations became completely or partially decorrelated from their initial effects. Epistatic interactions caused windows of evolutionary accessibility for most mutations to open and close transiently, shaping the historical fate not only of the mutations that fixed during history but also the far greater number that never did. Most mutations’ effects evolved under Brownian motion: gradual change without directional bias, at a rate that was largely constant across time but varied dramatically among mutations, indicating a neutral process caused by many weak interactions. Protein sequences therefore drift inexorably into contingency and unpredictability, but that process itself is statistically predictable, given sufficient phylogenetic and experimental data.

Summary Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Funding Humanigen.

Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis. Here, we used intracranial neural recordings in three patients with severe depression to investigate the neural substrates of this disorder. Across prefrontal regions, we found that reduced depression severity is associated with decreased low-frequency neural activity and increased high-frequency activity. When constraining our model to decode using a single region, spectral changes in the anterior cingulate cortex best predicted depression severity in all three subjects. Relaxing this constraint revealed unique, individual-specific sets of spatio-spectral features predictive of symptom severity, reflecting the heterogeneous nature of depression. The ability to decode depression severity from neural activity increases our fundamental understanding of how depression manifests in the human brain and provides a target neural signature for personalized neuromodulation therapies.

Binocular rivalry occurs when incompatible images are presented simultaneously but separately to each eye. Perceptual dominance reverses over time such that one image temporarily dominates perception, while the other image is suppressed. Prior research has shown that briefly-presented probes modulate perception such that probes presented to the suppressed eye tend to produce shorter percept durations relative to when probes are presented to the dominant eye. This pattern suggests that probes strengthen the competitive strength of the image over which they appear. However, it remains unclear whether probe-modulated effects on binocular rivalry are equivalent across the visual field, in particular as a function of whether probes appear within the region of interocular conflict (i.e on-object) or outside the region of interocular conflict (i.e. off-object). We tested this by manipulating whether probes appeared on-object or off-object. We replicate prior work showing that suppressed-eye probes produce shorter percept durations relative to dominant-eye probes. Critically, however, we show that percept duration also varies as a function of whether probes appear on vs. off the rivalry objects; that is, differences in percept duration between suppressed-eye and dominant-eye probes were much larger for on-object than off-object probes. Importantly, however, the difference between suppressed-eye and dominant-eye probes was still significant for off-object probes. Together these results suggest dynamic mechanisms at work in probe-mediated rivalry, such that on-object probe effects are larger relative to smaller, yet reliable off-object effects.

The brightest Fast Blue Optical Transients (FBOTs) are mysterious extragalactic explosions that may represent a new class of astrophysical phenomena. Their fast time to maximum brightness of less than a week and decline over several months and atypical optical spectra and evolution are difficult to explain within the context of core-collapse of massive stars which are powered by radioactive decay of Nickel-56 and evolve more slowly. AT2018cow (at redshift of 0.014) is an extreme FBOT in terms of rapid evolution and high luminosities. Here we present evidence for a high-amplitude quasi-periodic oscillation (QPO) of AT2018cow's soft X-rays with a frequency of 224 Hz (at 3.7$\sigma$ significance level or false alarm probability of 0.02%) and fractional root-mean-squared amplitude of >30%. This signal is found in the average power density spectrum taken over the entire 60-day outburst and suggests a highly persistent signal that lasts for a billion cycles. The high frequency (rapid timescale) of 224 Hz (4.4 ms) argues for a compact object in AT2018cow, which can be a neutron star or black hole with a mass less than 850 solar masses. If the QPO is the spin period of a neutron star, we can set limits on the star's magnetic field strength. Our work highlights a new way of using high time-resolution X-ray observations to study FBOTs., Comment: Published in Nature astronomy on 13th December 2021

The success of deep brain stimulation (DBS) for treating Parkinson's disease has led to its application to several other disorders, including treatment-resistant depression. Results with DBS for treatment-resistant depression have been heterogeneous, with inconsistencies largely driven by incomplete understanding of the brain networks regulating mood, especially on an individual basis. We report results from the first subject treated with DBS for treatment-resistant depression using an approach that incorporates intracranial recordings to personalize understanding of network behavior and its response to stimulation. These recordings enabled calculation of individually optimized DBS stimulation parameters using a novel inverse solution approach. In the ensuing double-blind, randomized phase incorporating these bespoke parameter sets, DBS led to remission of symptoms and dramatic improvement in quality of life. Results from this initial case demonstrate the feasibility of this personalized platform, which may be used to improve surgical neuromodulation for a vast array of neurologic and psychiatric disorders.

Skin-interfaced medical devices are critically important for diagnosing disease, monitoring physiological health and establishing control interfaces with prosthetics, computer systems and wearable robotic devices. Skin-like epidermal electronic technologies can support these use cases in soft and ultrathin materials that conformally interface with the skin in a manner that is mechanically and thermally imperceptible. Nevertheless, schemes so far have limited the overall sizes of these devices to less than a few square centimetres. Here, we present materials, device structures, handling and mounting methods, and manufacturing approaches that enable epidermal electronic interfaces that are orders of magnitude larger than previously realized. As a proof-of-concept, we demonstrate devices for electrophysiological recordings that enable coverage of the full scalp and the full circumference of the forearm. Filamentary conductive architectures in open-network designs minimize radio frequency-induced eddy currents, forming the basis for structural and functional compatibility with magnetic resonance imaging. We demonstrate the use of the large-area interfaces for the multifunctional control of a transhumeral prosthesis by patients who have undergone targeted muscle-reinnervation surgery, in long-term electroencephalography, and in simultaneous electroencephalography and structural and functional magnetic resonance imaging.

The mechanisms of visuospatial attention are mediated by two distinct fronto-parietal networks: a bilateral dorsal network (DAN), involved in the voluntary orientation of visuospatial attention, and a ventral network (VAN), lateralized to the right hemisphere, involved in the reorienting of attention to unexpected, but relevant, stimuli. The present study consisted of two aims: 1) to characterize the spatio-temporal dynamics of attention and 2) to examine the predictive interactions between and within the two attention systems along with visual areas, by using fast optical imaging combined with Granger causality. Data were collected from young healthy participants performing a discrimination task in a Posner-like paradigm. Functional analyses revealed bilateral dorsal parietal (i.e. dorsal regions included in the DAN) and visual recruitment during orienting, highlighting a recursive predictive interplay between specific dorsal parietal regions and visual cortex. Moreover, we found that both attention networks are active during reorienting, together with visual cortex, highlighting a mutual interaction among dorsal and visual areas, which, in turn, predicts subsequent ventral activity. For attentional reorienting our findings indicate that dorsal and visual areas encode disengagement of attention from the attended location and trigger reorientation to the unexpected location. Ventral network activity could instead reflect post-perceptual maintenance of the internal model to generate and keep updated task-related expectations.

Experimentalists studying multisensory integration compare neural responses to multisensory stimuli with responses to the component modalities presented in isolation. This procedure is problematic for multisensory speech perception since audiovisual speech and auditory-only speech are easily intelligible but visual-only speech is not. To overcome this confound, we developed intracranial encephalography (iEEG) deconvolution. Individual stimuli always contained both auditory and visual speech but jittering the onset asynchrony between modalities allowed for the time course of the unisensory responses and the interaction between them to be independently estimated. We applied this procedure to electrodes implanted in human epilepsy patients (both male and female) over the posterior superior temporal gyrus (pSTG), a brain area known to be important for speech perception. iEEG deconvolution revealed sustained, positive responses to visual-only speech and larger, phasic responses to auditory-only speech. Confirming results from scalp EEG, responses to audiovisual speech were weaker than responses to auditory- only speech, demonstrating a subadditive multisensory neural computation. Leveraging the spatial resolution of iEEG, we extended these results to show that subadditivity is most pronounced in more posterior aspects of the pSTG. Across electrodes, subadditivity correlated with visual responsiveness, supporting a model in visual speech enhances the efficiency of auditory speech processing in pSTG. The ability to separate neural processes may make iEEG deconvolution useful for studying a variety of complex cognitive and perceptual tasks.Significance statementUnderstanding speech is one of the most important human abilities. Speech perception uses information from both the auditory and visual modalities. It has been difficult to study neural responses to visual speech because visual-only speech is difficult or impossible to comprehend, unlike auditory-only and audiovisual speech. We used intracranial encephalography (iEEG) deconvolution to overcome this obstacle. We found that visual speech evokes a positive response in the human posterior superior temporal gyrus, enhancing the efficiency of auditory speech processing.

Research on the neural correlates of consciousness (NCC) has implicated an assortment of brain regions, ERP components, and network properties associated with visual awareness. Recently, the P3b ERP component has emerged as a leading NCC candidate. However, typical P3b paradigms depend on the detection of some stimulus change, making it difficult to separate brain processes elicited by the stimulus itself from those associated with updates or changes in visual awareness. Here we used binocular rivalry to ask whether the P3b is associated with changes in awareness even in the absence of changes in the object of awareness. We recorded ERPs during a probe-mediated binocular rivalry paradigm in which brief probes were presented over the image in either the suppressed or dominant eye to determine whether the elicited P3b activity is probe or reversal related. We found that the timing of P3b (but not its amplitude) was closely related to the timing of the report of a perceptual change rather than to the onset of the probe. This is consistent with the proposal that P3b indexes updates in conscious awareness, rather than being related to stimulus processing per se. Conversely, the probe-related P1 amplitude (but not its latency) was associated with reversal latency, suggesting that the degree to which the probe is processed increases the likelihood of a fast perceptual reversal. Finally, the response-locked P3b amplitude (but not its latency) was associated with the duration of an intermediate stage between reversals in which parts of both percepts coexist (piecemeal period). Together, the data suggest that the P3b reflects an update in consciousness and that the intensity of that process (as indexed by P3b amplitude) predicts how immediate that update is.

Visual information about speech content from the talker’s mouth is often available before auditory information from the talker's voice. Here we examined perceptual and neural responses to words with and without this visual head start. For both types of words, perception was enhanced by viewing the talker's face, but the enhancement was significantly greater for words with a head start. Neural responses were measured from electrodes implanted over auditory association cortex in the posterior superior temporal gyrus (pSTG) of epileptic patients. The presence of visual speech suppressed responses to auditory speech, more so for words with a visual head start. We suggest that the head start inhibits representations of incompatible auditory phonemes, increasing perceptual accuracy and decreasing total neural responses. Together with previous work showing visual cortex modulation (Ozker et al., 2018b) these results from pSTG demonstrate that multisensory interactions are a powerful modulator of activity throughout the speech perception network.

Vision provides a perceptual head start for speech perception because most speech is “mouth-leading”: visual information from the talker’s mouth is available before auditory information from the voice. However, some speech is “voice-leading” (auditory before visual). Consistent with a model in which vision modulates subsequent auditory processing, there was a larger perceptual benefit of visual speech for mouth-leading vs. voice-leading words (28% vs. 4%). The neural substrates of this difference were examined by recording broadband high-frequency activity from electrodes implanted over auditory association cortex in the posterior superior temporal gyrus (pSTG) of epileptic patients. Responses were smaller for audiovisual vs. auditory-only mouth-leading words (34% difference) while there was little difference (5%) for voice-leading words. Evidence for cross-modal suppression of auditory cortex complements our previous work showing enhancement of visual cortex (Ozker et al., 2018b) and confirms that multisensory interactions are a powerful modulator of activity throughout the speech perception network.Impact StatementHuman perception and brain responses differ between words in which mouth movements are visible before the voice is heard and words for which the reverse is true.

In Fig. 4c of this Article, the scale bar units were incorrectly stated as ‘μV’; the correct units are ‘mV’. The figure has now been amended accordingly.

With the growing capacity in biodiesel production and the resulting glut of the glycerol by-product, there is increasing interest in finding alternative uses for crude glycerol. One option may be to burn it locally for combined process heat and power, replacing fossil fuels and improving the economics of biodiesel production. However, due to its low energy density, high viscosity, and high auto-ignition temperature, glycerol is difficult to burn. Additionally, the composition of the glycerol by-product can change dramatically depending upon the biodiesel feedstock (e.g., vegetable oils or rendered animal fats), the catalyst used, and the degree of post-reaction cleanup (e.g., acidulation and demethylization). This paper reports the results of experiments to (1) develop a prototype high-swirl refractory burner designed for retrofit applications in commercial-scale fire-tube package boilers, and (2) provide an initial characterization of emissions generated during combustion of crude glycerol in a laboratory-scale moderate-swirl refractory-lined furnace. We report a range of emissions measurements, including nitrogen oxides, total hydrocarbons, and particle mass for two grades of crude glycerol (methylated and demethylated) and compare these to No. 2 fuel oil and propane. We also present preliminary data on the emissions of select carbonyls (by cartridge DNPH). Results indicate that a properly designed refractory burner can provide the thermal environment to effectively combust glycerol, but that high particulate emissions due to residual catalysts are likely to be an issue for crude glycerol combustion.

Cryptococcus neoformans meningitis occurs in 30%–50% of human immunodeficiency virus (HIV)–infected individuals in sub-Saharan Africa and the developing world [1–3] and accounts for 13%–44% of all HIV-associated deaths in the developing world [4]. A recent analysis estimated that, each year, there are >900,000 cases of and ~600,000 deaths due to C. neoformans meningitis globally, with most cases occurring in sub-Saharan Africa [5]. Although the incidence of C. neoformans meningitis has decreased dramatically in the United States and parts of the world where antiretroviral therapy is available [1], this disease has emerged as an important complication of solid organ transplantation [6, 7] and immune reconstitution syndrome [8]. HIV-associated cryptococcosis almost always occurs when an individual’s CD4+ T cell level is significantly

Since the publication of NUREG/CR-6850/EPRI 1011989 in 2005, the US nuclear industry has sought to re-evaluate the default peak heat release rates (HRRs) for electrical enclosure fires typically used as fire modeling inputs to support fire probabilistic risk assessments (PRAs), considering them too conservative. HRRs are an integral part of the fire phenomenological modeling phase of a fire PRA, which consists of identifying fire scenarios which can damage equipment or hinder human actions necessary to prevent core damage. Fire ignition frequency, fire growth and propagation, fire detection and suppression, and mitigating equipment and actions to prevent core damage in the event fire damage still occurred are all parts of a fire PRA. The fire growth and propagation phase incorporates fire phenomenological modeling where HRRs have a key effect. A major effort by the Electric Power Research Institute and Science Applications International Corporation in 2012 was not endorsed by the US Nuclear Regulatory Commission (NRC) for use in risk-informed, regulatory applications. Subsequently the NRC, in conjunction with the National Institute of Standards and Technology, conducted a series of tests for representative nuclear power plant electrical enclosure fires designed to definitively establish more realistic peak HRRs for these often important contributors to fire risk. The results from these tests are statistically analyzed to develop two probabilistic distributions for peak HRR per unit mass of fuel that refine the values from NUREG/CR-6850, thereby providing a fairly simple means by which to estimate peak HRRs from electrical enclosure fires for fire modeling in support of fire PRA. Unlike NUREG/CR-6850, where five different distributions are provided, or NUREG-2178, which now provides 31, the peak HRRs for electrical enclosure fires can be characterized by only two distributions. These distributions depend only on the type of cable, namely qualified versus unqualified, for which the mean peak HRR per unit mass is 11.3 and 23.2 kW/kg, respectively, essentially a factor of two difference. Two-sided, 90th percentile confidence bounds are 0.0915 to 41.2 kW/kg for qualified cables, and 0.0272 to 95.9 kW/kg for unqualified cables. From the mean (~70th percentile) upward, the peak HRR/kg for unqualified cables is roughly twice that for qualified, increasing slightly with higher percentile, an expected phenomenological trend. Simulations using variable fuel loadings are performed to demonstrate how the results from this analysis may be used for nuclear power plant applications.

The TiCl4 based CVD-Ti process has been identified as the candidate of choice for the advanced contact metallization. A BKM wet clean recovery (WCR) procedure, involving extended chamber seasoning, has been developed for the CVD-Ti process. The new WCR methodology takes only 5 wafer processing to stabilize the CVD-Ti chamber condition and film properties. It has been found that a chamber seasoning for 200 sec, performed after every idle time (greater than 15 min.) and thermal periodic clean (at wafer count # 200), helps to maintain the CVD-Ti process performance. The reliability of the new chamber operating procedures was validated through a successful 3000 wafer marathon demonstration.

This paper discusses TiCl 4 based PECVD Ti and CVD TiN processes that enable a critical contact technology for cost effective gigabit DRAMs. The PECVD Ti contact silicidation process and the CVD TiN barrier process together allow for reliable contact metallization with excellent contact resistance and leakage current performance for aspect ratios >12:1. Such capability has allowed a substantial increase in capacitor height alleviating the need for either a change in the capacitor dielectric as well as allowing the continuation of the bitline over capacitor metallization architecture. In addition, the in-situ silicidation capability of the PECVD Ti process allows for the elimination of the contact silicidation anneal step. When used as the top electrode in Ta 2 O 5 based capacitor structures, TiCl 4 based CVD TiN provides for reliable metallization with excellent leakage current performance. Preliminary results show that CVD TiN provides the capability for a complete plug fill with no peeling or cracking.