Millisecond-scale motor encoding in a cortical vocal area.

Studies of motor control have almost universally examined firing rates to investigate how the brain shapes behavior. In principle, however, neurons could encode information through the precise temporal patterning of their spike trains as well as (or instead of) through their firing rates. Although the importance of spike timing has been demonstrated in sensory systems, it is largely unknown whether timing differences in motor areas could affect behavior. We tested the hypothesis that significant information about trial-by-trial variations in behavior is represented by spike timing in the songbird vocal motor system. We found that neurons in motor cortex convey information via spike timing far more often than via spike rate and that the amount of information conveyed at the millisecond timescale greatly exceeds the information available from spike counts. These results demonstrate that information can be represented by spike timing in motor circuits and suggest that timing variations evoke differences in behavior.

Controlling Self-Assembling Peptide Hydrogel Properties through Network Topology.

Self-assembling peptide-based hydrogels have encountered increasing interest in the recent years as scaffolds for 3D cell culture or for controlled drug delivery. One of the main challenges is the fine control of the mechanical properties of these materials. The bulk properties of hydrogels not only depend on the intrinsic properties of the fibers but also on the network topology formed. In this work we show how fiber-fiber interactions can be manipulated by design to control the final hydrogel network topology and therefore control the final properties of the material. This was achieved by exploiting the design features of ß-sheet forming peptides based on hydrophobic and hydrophilic residue alternation and exploiting the ability of the arginine's guanidine side group to interact with itself and with other amino acid side groups. By designing octa-peptides based on phenylalanine, glutamic acid, lysine, and arginine, we have investigated how fiber association and bundling affect the dynamic shear modulus of hydrogels and how it can be controlled by design. This work opens the possibility to fine-tune by design the bulk properties of peptide hydrogels.

Dynamic encoding of speech sequence probability in human temporal cortex.

Sensory processing involves identification of stimulus features, but also integration with the surrounding sensory and cognitive context. Previous work in animals and humans has shown fine-scale sensitivity to context in the form of learned knowledge about the statistics of the sensory environment, including relative probabilities of discrete units in a stream of sequential auditory input. These statistics are a defining characteristic of one of the most important sequential signals humans encounter: speech. For speech, extensive exposure to a language tunes listeners to the statistics of sound sequences. To address how speech sequence statistics are neurally encoded, we used high-resolution direct cortical recordings from human lateral superior temporal cortex as subjects listened to words and nonwords with varying transition probabilities between sound segments. In addition to their sensitivity to acoustic features (including contextual features, such as coarticulation), we found that neural responses dynamically encoded the language-level probability of both preceding and upcoming speech sounds. Transition probability first negatively modulated neural responses, followed by positive modulation of neural responses, consistent with coordinated predictive and retrospective recognition processes, respectively. Furthermore, transition probability encoding was different for real English words compared with nonwords, providing evidence for online interactions with high-order linguistic knowledge. These results demonstrate that sensory processing of deeply learned stimuli involves integrating physical stimulus features with their contextual sequential structure. Despite not being consciously aware of phoneme sequence statistics, listeners use this information to process spoken input and to link low-level acoustic representations with linguistic information about word identity and meaning.

Methods and measures in food service food safety research: A review of the published literature.

Purpose: Food handlers working in food service establishments need to perform appropriate and consistent food safety practices to ensure that the prepared food is safe for consumers to eat, as a failure to do so may lead to foodborne illness. It is important to have an in-depth understanding of food handler food safety behaviour in the food service sector to design targeted educational interventions and approaches to safeguard consumers. The purpose of this review is to provide insight to the existing body of research regarding food handler food safety in the food service sector, and to identify future research needs in terms of methods and measures. Methods: This study is a review of published food safety research studies (n = 118) focusing on food handlers in the food service sector conducted between 2001 and 2021. Data were collated regarding the methods used and the measures assessed in published studies to identify the gaps in current knowledge related to food safety in food service. Findings: The majority of studies were conducted in the United States (29%), Brazil (17%) and United Kingdom (7%). A large proportion were carried out in restaurants (70%). Less than a third of studies (28%) relied on a mixed method approach for data collection; and only 12% of studies assessed a combination of cognitive and behavioural measures. Observation was used in only 29% of studies. A lack of observational data detailing food safety practices such as handwashing, temperature control, separation and cleaning was determined. Significance: Such findings indicate a greater need for mixed method approach in future food safety research. It is recommended that the understanding of food handler food safety performance is best obtained through a combined assessment of cognitive and behavioural measures with subsequent triangulation of findings to reduce bias and to obtain reliable results.

Self-assembly and gelation properties of glycine/leucine Fmoc-dipeptides.

Self-assembly of aromatic peptide amphiphiles is known to be driven by a combination of π-π stacking of the aromatic moieties and hydrogen bonding between the peptide backbones, with possible stabilisation from the amino acid side chains. Phenylalanine-based Fmoc-dipeptides have previously been reported for their characteristic apparent pKa transitions, which were shown to coincide with significant structural and morphological changes that were peptide sequence dependent. Here, phenylalanine was replaced by leucine and the effect on the self-assembling behaviour of Fmoc-dipeptides was measured using potentiometry, fluorescence and infrared spectroscopy, transmission electron microscopy, X-ray scattering and shear rheometry. This study provides additional cues towards the elucidation of the sequence-structure relationship in self-assembling aromatic peptide amphiphiles.

Predictors of risk of relapse in classic Hodgkin lymphoma.

Using multiparametric flow cytometric analysis, in a cohort of 62 patients with classic Hodgkin lymphoma having a median follow-up period of 69.5 months, we found-patients who experienced primary resistance or disease relapse (DR) had lower percentage of rosetted Hodgkin Reed-Sternberg cells (HRS-cells) as compared with patients who achieved sustained complete remission (SCR) (p=0.022); patients >35 years of age had higher percentage of HRS-cells (p=0.017) and lower percentage of B cells (p=0.017) and the nodular sclerosis subtype had higher percentage of B-cells (p=0.046) and activated B-cells (p=0.03). The proportion of SCR and DR subsets did not differ by histological subtypes, disease stage or age groups.

Rapid artificial intelligence solutions in a pandemic-The COVID-19-20 Lung CT Lesion Segmentation Challenge.

Artificial intelligence (AI) methods for the automatic detection and quantification of COVID-19 lesions in chest computed tomography (CT) might play an important role in the monitoring and management of the disease. We organized an international challenge and competition for the development and comparison of AI algorithms for this task, which we supported with public data and state-of-the-art benchmark methods. Board Certified Radiologists annotated 295 public images from two sources (A and B) for algorithms training (n=199, source A), validation (n=50, source A) and testing (n=23, source A; n=23, source B). There were 1,096 registered teams of which 225 and 98 completed the validation and testing phases, respectively. The challenge showed that AI models could be rapidly designed by diverse teams with the potential to measure disease or facilitate timely and patient-specific interventions. This paper provides an overview and the major outcomes of the COVID-19 Lung CT Lesion Segmentation Challenge - 2020.

Cooperative and reciprocal chiral structure formation of an alanine-based peptide confined at the surface of cationic surfactant membranes.

The confinement of anionic oligoalanine peptides at the surface of cationic membranes can cooperatively reinforce peptide/peptide interactions and induce secondary-structure formation, and, reciprocally, induce chirality expression of the membrane at the mesoscopic level, thus leading to the formation of three-dimensional chiral fibrillar networks. Such a strong binding effect of peptides with cationic membranes and the resulting cooperative assembly behaviors are observed with two different types of cationic surfactant, namely, two-head two-tail gemini and one-head two-tail surfactants. The ensemble of assembly properties, such as critical micellar concentration (cmc), Krafft temperature (T(k) ), molecular area at the air/water interface, molecular organization (as studied by FTIR attenuated total reflectance (ATR) measurements and small-angle X-ray scattering), and morphology of the aggregates (as observed by optical and electron microscopy studies), are reported. The results clearly demonstrate that the molecular organization and mesoscopic supramolecular structures are controlled by a subtle balance between the peptide/peptide interactions, ionic interactions between the membranes and peptides, and the interactions the between surfactant molecules, which are governed by hydrophobicity and steric interactions. Investigation into such cooperative organization can shed light on the mechanism of supramolecular chirality expression in membrane systems and allow understanding of the structure of peptides in interactions with lipid bilayers.

Effect of glycine substitution on Fmoc-diphenylalanine self-assembly and gelation properties.

We have investigated the self-assembly behavior of fluorenyl-9-methoxycarbonyl (Fmoc)-FG, Fmoc-GG, and Fmoc-GF and compared it to that of Fmoc-FF using potentiometry, fluorescence and infrared spectroscopy, transmission electron microscopy, wide-angle X-ray scattering, and oscillatory rheometry. Titration experiments revealed a substantially shifted apparent pK(a) transition for Fmoc-FG, Fmoc-GG, and Fmoc-GF. The apparent pK(a) values observed correlated with the hydrophobicity (log P) of the Fmoc-dipeptide molecules. Fmoc-GG and Fmoc-GF were found to self-assemble only in their protonated form (below their apparent pK(a)), while Fmoc-FG formed self-assembled structures above and below its apparent pK(a). Fmoc-GG and Fmoc-FG were found to form hydrogels below their apparent pK(a) transitions in agreement with the entangled fibers morphologies revealed by TEM. Unlike Fmoc-FF and Fmoc-GG, Fmoc-FG showed unusual gelation behavior as gels were found to form upon heating. Fmoc-GF formed precipitates instead of a hydrogel below its apparent pK(a) in agreement with the formation of micrometer scale sheetlike structures observed by TEM. The fact that all four Fmoc-dipeptides were found to self-assemble suggests that the main driving force behind the self-assembly process is a combination of the hydrophobic and π-π interactions of the fluorenyl moieties with a secondary role for hydrogen bonding of the peptidic components. The nature of the peptidic tail was found to have a pronounced effect on the type of self-assembled structure formed. This work indicates that the substitution of phenylalanine by glycine significantly impacts on the mode of assembly and illustrates the versatility of aromatic peptide amphiphiles in the formation of structurally diverse nanostructures.

Human cortical encoding of pitch in tonal and non-tonal languages.

Languages can use a common repertoire of vocal sounds to signify distinct meanings. In tonal languages, such as Mandarin Chinese, pitch contours of syllables distinguish one word from another, whereas in non-tonal languages, such as English, pitch is used to convey intonation. The neural computations underlying language specialization in speech perception are unknown. Here, we use a cross-linguistic approach to address this. Native Mandarin- and English- speaking participants each listened to both Mandarin and English speech, while neural activity was directly recorded from the non-primary auditory cortex. Both groups show language-general coding of speaker-invariant pitch at the single electrode level. At the electrode population level, we find language-specific distribution of cortical tuning parameters in Mandarin speakers only, with enhanced sensitivity to Mandarin tone categories. Our results show that speech perception relies upon a shared cortical auditory feature processing mechanism, which may be tuned to the statistics of a given language.

Rapid Artificial Intelligence Solutions in a Pandemic - The COVID-19-20 Lung CT Lesion Segmentation Challenge.

Artificial intelligence (AI) methods for the automatic detection and quantification of COVID-19 lesions in chest computed tomography (CT) might play an important role in the monitoring and management of the disease. We organized an international challenge and competition for the development and comparison of AI algorithms for this task, which we supported with public data and state-of-the-art benchmark methods. Board Certified Radiologists annotated 295 public images from two sources (A and B) for algorithms training (n=199, source A), validation (n=50, source A) and testing (n=23, source A; n=23, source B). There were 1,096 registered teams of which 225 and 98 completed the validation and testing phases, respectively. The challenge showed that AI models could be rapidly designed by diverse teams with the potential to measure disease or facilitate timely and patient-specific interventions. This paper provides an overview and the major outcomes of the COVID-19 Lung CT Lesion Segmentation Challenge - 2020.

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly.

The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution. Here, we show that the mitochondrial proteome, particularly the respiratory chain, is enriched for small proteins. Using a prediction and validation pipeline for SEPs, we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN, a 71 a.a. peptide encoded by C12orf73, is essential for respiratory chain complex III (CIII) assembly. In human cells, BRAWNIN is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In zebrafish, Brawnin deletion causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BRAWNIN is essential for vertebrate oxidative phosphorylation. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.

Matrix Mechanics Influence Fibroblast-Myofibroblast Transition by Directing the Localization of Histone Deacetylase 4.

INTRODUCTION: The propagation of mechanochemical signals from the extracellular matrix to the cell nucleus has emerged as a central feature in regulating cellular differentiation and de-differentiation. This process of outside-in signaling and the associated mechanotransduction pathways have been well described in numerous developmental and pathological contexts. However, it remains less clear how mechanotransduction influences the activity of chromatin modifying enzymes that direct gene expression programs. OBJECTIVES: The primary objective of this study was to explore how matrix mechanics and geometric confinement influence histone deacetylase (HDAC) activity in fibroblast culture. METHODS: Polyacrylamide hydrogels were formed and functionalized with fibronectin patterns using soft lithography. Primary mouse embryonic fibroblasts (MEFs) were cultured on the islands until confluent, fixed, and immunolabeled for microscopy. RESULTS: After 24 h MEFs cultured on soft hydrogels (0.5 kPa) show increased expression of class I HDACs relative to MEFs cultured on stiff hydrogels (100 kPa). A member of the class II family, HDAC4 shows a similar trend; however, there is a pronounced cytoplasmic localization on soft hydrogels suggesting a role in outside-in cytoplasmic signaling. Pharmacological inhibitor studies suggest that the opposing activities of extracellular related kinase 1/2 (ERK) and protein phosphatase 2a (PP2a) influence the localization of HDAC4. MEFs cultured on the soft hydrogels show enhanced expression of markers associated with a fibroblast-myofibroblast transition (Paxillin, αSMA). CONCLUSIONS: We show that the phosphorylation state and cellular localization of HDAC4 is influenced by matrix mechanics, with evidence for a role in mechanotransduction and the regulation of gene expression associated with fibroblast-myofibroblast transitions. This work establishes a link between outside-in signaling and epigenetic regulation, which will assist efforts aimed at controlling gene regulation in engineered extracellular matrices.

Peptide hydrogels as mucoadhesives for local drug delivery.

We have investigated the possibility of using self-assembling peptide-based viscous solutions and hydrogels as mucoadhesives for the improved delivery of drugs to local mucosal surfaces. The stability of the samples under flow after deposition on a mucosal surface mimic was studied using a simplified in vitro model. Subsequently lidocaine and flurbiprofen, two commercial drugs, were incorporated into the viscous solutions and hydrogels and their release properties investigated using the same model. Peptide-based hydrogels showed a good resistance to erosion under flow conditions. Addition of the soluble drug (lidocaine at low pH) resulted in a stiffening of the samples but did not affect the overall peptide release. Although for this drug the conditions were not favourable, improved retention of the drug was observed for the stiffest samples tested. In the case of the insoluble drug (flurbiprofen) the samples mechanical properties were not altered when the drug was incorporated, however the sample stability and peptide release were. For mechanically weaker samples the presence of the drug as insoluble small particles resulted in an increase in their susceptibility to physically erode when a flow of medium was applied over its surface. On the other hand mechanically stronger samples showed an improved resistance to erosion, which resulted in enhanced drug retention.

Fmoc-diphenylalanine self-assembly mechanism induces apparent pKa shifts.

We report the effect of pH on the self-assembly process of Fmoc-diphenylalanine (Fmoc-FF) into fibrils consisting of antiparallel beta-sheets, and show that it results in two apparent pKa shifts of approximately 6.4 and approximately 2.2 pH units above the theoretical pKa (3.5). Using Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), wide angle X-ray scattering (WAXS), and oscillatory rheology, these two transitions were shown to coincide with significant structural changes. An entangled network of flexible fibrils forming a weak hydrogel dominates at high pH, while nongelling flat rigid ribbons form at intermediate pH values. Overall, this study provides further understanding of the self-assembly mechanism of aromatic short peptide derivatives.