TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury.

Sepsis is a systemic inflammatory response that requires effective macrophage metabolic functions to resolve ongoing inflammation. Previous work showed that the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), mediates macrophage phagocytosis and cytokine production in response to lung infection. Here, we show that TRPV4 regulates glycolysis in a stiffness-dependent manner by augmenting macrophage glucose uptake by GLUT1. In addition, TRPV4 is required for LPS-induced phagolysosome maturation in a GLUT1-dependent manner. In a cecal slurry mouse model of sepsis, TRPV4 regulates sepsis-induced glycolysis as measured by BAL fluid (BALF) lactate and sepsis-induced lung injury as measured by BALF total protein and lung compliance. TRPV4 is necessary for bacterial clearance in the peritoneum to limit sepsis-induced lung injury. It is interesting that BALF lactate is increased in patients with sepsis compared with healthy control participants, supporting the relevance of lung cell glycolysis to human sepsis. These data show that macrophage TRPV4 is required for glucose uptake through GLUT1 for effective phagolysosome maturation to limit sepsis-induced lung injury. Our work presents TRPV4 as a potential target to protect the lung from injury in sepsis.

In Situ Forming, Enzyme-Responsive Peptoid-Peptide Hydrogels: An Advanced Long-Acting Injectable Drug Delivery System.

Long-acting drug delivery systems are promising platforms to improve patient adherence to medication by delivering drugs over sustained periods and removing the need for patients to comply with oral regimens. This research paper provides a proof-of-concept for the development of a new optimized in situ forming injectable depot based on a tetrabenzylamine-tetraglycine-d-lysine-O-phospho-d-tyrosine peptoid-D-peptide formulation ((NPhe)4GGGGk(AZT)y(p)-OH). The chemical versatility of the peptoid-peptide motif allows low-molecular-weight drugs to be precisely and covalently conjugated. After subcutaneous injection, a hydrogel depot forms from the solubilized peptoid-peptide-drug formulation in response to phosphatase enzymes present within the skin space. This system is able to deliver clinically relevant concentrations of a model drug, the antiretroviral zidovudine (AZT), for 35 days in Sprague-Dawley rats. Oscillatory rheology demonstrated that hydrogel formation began within ∼30 s, an important characteristic of in situ systems for reducing initial drug bursts. Gel formation continued for up to ∼90 min. Small-angle neutron scattering data reveal narrow-radius fibers (∼0.78-1.8 nm) that closely fit formation via a flexible cylinder elliptical model. The inclusion of non-native peptoid monomers and D-variant amino acids confers protease resistance, enabling enhanced biostability to be demonstrated in vitro. Drug release proceeds via hydrolysis of an ester linkage under physiological conditions, releasing the drug in an unmodified form and further reducing the initial drug burst. Subcutaneous administration of (NPhe)4GGGGk(AZT)y(p)-OH to Sprague-Dawley rats resulted in zidovudine blood plasma concentrations within the 90% maximal inhibitory concentration (IC90) range (30-130 ng mL-1) for 35 days.

Awareness of embodiment enhances enjoyment and engages sensorimotor cortices.

Whether in performing arts, sporting, or everyday contexts, when we watch others move, we tend to enjoy bodies moving in synchrony. Our enjoyment of body movements is further enhanced by our own prior experience with performing those movements, or our 'embodied experience'. The relationships between movement synchrony and enjoyment, as well as embodied experience and movement enjoyment, are well known. The interaction between enjoyment of movements, synchrony, and embodiment is less well understood, and may be central for developing new approaches for enriching social interaction. To examine the interplay between movement enjoyment, synchrony, and embodiment, we asked participants to copy another person's movements as accurately as possible, thereby gaining embodied experience of movement sequences. Participants then viewed other dyads performing the same or different sequences synchronously, and we assessed participants' recognition of having performed these sequences, as well as their enjoyment of each movement sequence. We used functional near-infrared spectroscopy to measure cortical activation over frontotemporal sensorimotor regions while participants performed and viewed movements. We found that enjoyment was greatest when participants had mirrored the sequence and recognised it, suggesting that awareness of embodiment may be central to enjoyment of synchronous movements. Exploratory analyses of relationships between cortical activation and enjoyment and recognition implicated the sensorimotor cortices, which subserve action observation and aesthetic processing. These findings hold implications for clinical research and therapies seeking to foster successful social interaction.

An open-label clinical trial to evaluate the efficacy of an elemental diet for the diagnosis of adverse food reactions in dogs.

BACKGROUND: The diagnosis of cutaneous adverse food reactions (CAFR) in dogs is dependent on a diet trial and provocative challenge. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of an elemental diet for the diagnosis of CAFR in dogs. ANIMALS: Sixty-two client-owned nonseasonally pruritic dogs. MATERIALS AND METHODS: A prospective, uncontrolled, observational elimination diet trial study. Dogs were fed a commercially available elemental canine diet (Pro Plan Veterinary Diets EL Elemental Canine Formula, Nestlé Purina PetCare Company) for up to eight weeks. Pruritus was assessed using a validated Visual Analog Scale (PVAS), lesions with the Canine Atopic Dermatitis and Severity Index, 4th iteration (CADESI-04) and gastrointestinal (GI) signs with a client questionnaire. All dogs were challenged with their previous diet for up to 14 days. Treats were added from Day (D)7 to D14. RESULTS: Forty-five dogs completed the study. Eighteen (40%) of these were diagnosed with CAFR and 27 (60%) were diet-nonresponsive (NR). Dogs with CAFR flared on provocative challenges within 14 days. The smallest volume of previous diet that induced a CAFR flare was one teaspoon in two dogs (11.1%). The mean number of days leading to a provocation of clinical signs was 4.88 days. Gastrointestinal signs improved in both groups. Eight of the dogs with CAFR (44.4%) were subsequently maintained on the elemental diet alone. CONCLUSION AND CLINICAL RELEVANCE: Pro Plan Veterinary Diets EL Elemental Canine Formula is efficacious for the diagnosis of canine CAFR. One teaspoon of the offending diet may induce clinical signs in some dogs with CAFR.

The McNorm library: creating and validating a new library of emotionally expressive whole body dance movements.

The ability to exchange affective cues with others plays a key role in our ability to create and maintain meaningful social relationships. We express our emotions through a variety of socially salient cues, including facial expressions, the voice, and body movement. While significant advances have been made in our understanding of verbal and facial communication, to date, understanding of the role played by human body movement in our social interactions remains incomplete. To this end, here we describe the creation and validation of a new set of emotionally expressive whole-body dance movement stimuli, named the Motion Capture Norming (McNorm) Library, which was designed to reconcile a number of limitations associated with previous movement stimuli. This library comprises a series of point-light representations of a dancer's movements, which were performed to communicate to observers neutrality, happiness, sadness, anger, and fear. Based on results from two validation experiments, participants could reliably discriminate the intended emotion expressed in the clips in this stimulus set, with accuracy rates up to 60% (chance = 20%). We further explored the impact of dance experience and trait empathy on emotion recognition and found that neither significantly impacted emotion discrimination. As all materials for presenting and analysing this movement library are openly available, we hope this resource will aid other researchers in further exploration of affective communication expressed by human bodily movement.

Dancing robots: Social interactions are performed, not depicted.

Clark and Fischer's depiction hypothesis is based on examples of western mimetic art. Yet social robots do not depict social interactions, but instead perform them. Similarly, dance and performance art do not rely on depiction. Kinematics and expressivity are better predictors of dance aesthetics and of effective social interactions. In this way, social robots are more like dancers than actors.

Autonomous social robots are real in the mind's eye of many.

Clark and Fischer's dismissal of extant human-robot interaction research approaches limits opportunities to understand major variables shaping people's engagement with social robots. Instead, this endeavour categorically requires multidisciplinary approaches. We refute the assumption that people cannot (correctly or incorrectly) represent robots as autonomous social agents. This contradicts available empirical evidence, and will become increasingly tenuous as robot automation improves.

Feeling Appreciated Buffers Against the Negative Effects of Unequal Division of Household Labor on Relationship Satisfaction.

Decades of research from across the globe highlight unequal and unfair division of household labor as a key factor that leads to relationship distress and demise. But does it have to? Testing a priori predictions across three samples of individuals cohabiting with a romantic partner during the COVID-19 pandemic (N = 2,193, including 476 couples), we found an important exception to this rule. People who reported doing more of the household labor and who perceived the division as more unfair were less satisfied across the early weeks and ensuing months of the pandemic, but these negative effects disappeared when people felt appreciated by their partners. Feeling appreciated also appeared to buffer against the negative effects of doing less, suggesting that feeling appreciated may offset the relational costs of unequal division of labor, regardless of who contributes more. These findings generalized across gender, employment status, age, socioeconomic status, and relationship length.

People's dispositional cooperative tendencies towards robots are unaffected by robots' negative emotional displays in prisoner's dilemma games.

The study explores the impact of robots' emotional displays on people's tendency to cooperate with a robot opponent in prisoner's dilemma games. Participants played iterated prisoner's dilemma games with a non-expressive robot (as a measure of cooperative baseline), followed by an angry, and a sad robot, in turn. Based on the Emotion as Social Information model, we expected participants with higher cooperative predispositions to cooperate less when a robot displayed anger, and cooperate more when the robot displayed sadness. Contrarily, according to this model, participants with lower cooperative predispositions should cooperate more with an angry robot and less with a sad robot. The results of 60 participants failed to support the predictions. Only the participants' cooperative predispositions significantly predicted their cooperative tendencies during gameplay. Participants who cooperated more in the baseline measure also cooperated more with the robots displaying sadness and anger. In exploratory analyses, we found that participants who accurately recognised the robots' sad and angry displays tended to cooperate less with them overall. The study highlights the impact of personal factors in human-robot cooperation, and how these factors might surpass the influence of bottom-up emotional displays by the robots in the present experimental scenario.

Exploring the relationship between anthropomorphism and theory-of-mind in brain and behaviour.

The process of understanding the minds of other people, such as their emotions and intentions, is mimicked when individuals try to understand an artificial mind. The assumption is that anthropomorphism, attributing human-like characteristics to non-human agents and objects, is an analogue to theory-of-mind, the ability to infer mental states of other people. Here, we test to what extent these two constructs formally overlap. Specifically, using a multi-method approach, we test if and how anthropomorphism is related to theory-of-mind using brain (Experiment 1) and behavioural (Experiment 2) measures. In a first exploratory experiment, we examine the relationship between dispositional anthropomorphism and activity within the theory-of-mind brain network (n = 108). Results from a Bayesian regression analysis showed no consistent relationship between dispositional anthropomorphism and activity in regions of the theory-of-mind network. In a follow-up, pre-registered experiment, we explored the relationship between theory-of-mind and situational and dispositional anthropomorphism in more depth. Participants (n = 311) watched a short movie while simultaneously completing situational anthropomorphism and theory-of-mind ratings, as well as measures of dispositional anthropomorphism and general theory-of-mind. Only situational anthropomorphism predicted the ability to understand and predict the behaviour of the film's characters. No relationship between situational or dispositional anthropomorphism and general theory-of-mind was observed. Together, these results suggest that while the constructs of anthropomorphism and theory-of-mind might overlap in certain situations, they remain separate and possibly unrelated at the personality level. These findings point to a possible dissociation between brain and behavioural measures when considering the relationship between theory-of-mind and anthropomorphism.

Unravelling the antimicrobial activity of peptide hydrogel systems: current and future perspectives.

The use of hydrogels has garnered significant interest as biomaterial and drug delivery platforms for anti-infective applications. For decades antimicrobial peptides have been heralded as a much needed new class of antimicrobial drugs. Self-assembling peptide hydrogels with inherent antimicrobial ability have recently come to the fore. However, their fundamental antimicrobial properties, selectivity and mechanism of action are relatively undefined. This review attempts to establish a link between antimicrobial efficacy; the self-assembly process; peptide-membrane interactions and mechanical properties by studying several reported peptide systems: ß-hairpin/ß-loop peptides; multidomain peptides; amphiphilic surfactant-like peptides and ultrashort/low molecular weight peptides. We also explore their role in the formation of amyloid plaques and the potential for an infection etiology in diseases such as Alzheimer's. We look briefly at innovative methods of gel characterization. These may provide useful tools for future studies within this increasingly important field.

Examining the value of body gestures in social reward contexts.

Brain regions associated with the processing of tangible rewards (such as money, food, or sex) are also involved in anticipating social rewards and avoiding social punishment. To date, studies investigating the neural underpinnings of social reward have presented feedback via static or dynamic displays of faces to participants. However, research demonstrates that participants find another type of social stimulus, namely, biological motion, rewarding as well, and exert effort to engage with this type of stimulus. Here we examine whether feedback presented via body gestures in the absence of facial cues also acts as a rewarding stimulus and recruits reward-related brain regions. To achieve this, we investigated the neural underpinnings of anticipating social reward and avoiding social disapproval presented via gestures alone, using a social incentive delay task. As predicted, the anticipation of social reward and avoidance of social disapproval engaged reward-related brain regions, including the nucleus accumbens, in a manner similar to previous studies' reports of feedback presented via faces and money. This study provides the first evidence that human body motion alone engages brain regions associated with reward processing in a similar manner to other social (i.e. faces) and non-social (i.e. money) rewards. The findings advance our understanding of social motivation in human perception and behavior.

Observing Action Sequences Elicits Sequence-Specific Neural Representations in Frontoparietal Brain Regions.

Learning new skills by watching others is important for social and motor development throughout the lifespan. Prior research has suggested that observational learning shares common substrates with physical practice at both cognitive and brain levels. In addition, neuroimaging studies have used multivariate analysis techniques to understand neural representations in a variety of domains, including vision, audition, memory, and action, but few studies have investigated neural plasticity in representational space. Therefore, although movement sequences can be learned by observing other people's actions, a largely unanswered question in neuroscience is how experience shapes the representational space of neural systems. Here, across a sample of male and female participants, we combined pretraining and posttraining fMRI sessions with 6 d of observational practice to determine whether the observation of action sequences elicits sequence-specific representations in human frontoparietal brain regions and the extent to which these representations become more distinct with observational practice. Our results showed that observed action sequences are modeled by distinct patterns of activity in frontoparietal cortex and that such representations largely generalize to very similar, but untrained, sequences. These findings advance our understanding of what is modeled during observational learning (sequence-specific information), as well as how it is modeled (reorganization of frontoparietal cortex is similar to that previously shown following physical practice). Therefore, on a more fine-grained neural level than demonstrated previously, our findings reveal how the representational structure of frontoparietal cortex maps visual information onto motor circuits in order to enhance motor performance.SIGNIFICANCE STATEMENT Learning by watching others is a cornerstone in the development of expertise and skilled behavior. However, it remains unclear how visual signals are mapped onto motor circuits for such learning to occur. Here, we show that observed action sequences are modeled by distinct patterns of activity in frontoparietal cortex and that such representations largely generalize to very similar, but untrained, sequences. These findings advance our understanding of what is modeled during observational learning (sequence-specific information), as well as how it is modeled (reorganization of frontoparietal cortex is similar to that previously shown following physical practice). More generally, these findings demonstrate how motor circuit involvement in the perception of action sequences shows high fidelity to prior work, which focused on physical performance of action sequences.

Structural characterization of a short-chain dehydrogenase/reductase from multi-drug resistant Acinetobacter baumannii.

Acinetobacter baumannii (A. baumannii) is a clinically relevant, highly drug-resistant pathogen of global concern. An attractive approach to drug design is to specifically target the type II fatty acid synthesis (FASII) pathway which is critical in Gram negative bacteria and is significantly different to the type I fatty acid synthesis (FASI) pathway found in mammals. Enzymes involved in FASII include members of the short-chain dehydrogenase/reductase (SDR) superfamily. SDRs are capable of performing a diverse range of biochemical reactions against a broad spectrum of substrates whilst maintaining conserved structural features and sequence motifs. Here, we use X-ray crystallography to describe the structure of an SDR from the multi-drug resistant bacteria A. baumannii, previously annotated as a putative FASII FabG enzyme. The protein was recombinantly expressed, purified, and crystallized. The protein crystals diffracted to 2.0 Šand the structure revealed a FabG-like fold. Functional assays revealed, however, that the protein was not active against the FabG substrate, acetoacetyl-CoA. This study highlights that database annotations may show the necessary structural hallmarks of such proteins, however, they may not be able to cleave substrates that are typical of FabG enzymes. These results are important for the selection of target enzymes in future drug development.

Probing the self-assembled structures and pKa of hydrogels using electrochemical methods.

The surface chemistry of the aggregated structures that form the scaffold in self-assembled hydrogels - their charge, hydrophobicity and ion-binding dynamics - plays an important role in determining the gel properties and the gel's suitability for specific applications. However, there are limited methods available for the study of this surface chemistry. Here, we show that electrochemical techniques can be used to measure the surface chemical properties of the self-assembled aggregate structures and also to determine the pKa of the gelators. We also provide a method to quickly determine whether a functionalised-dipeptide will form a gel or not. This method has scope for use in high-throughput screening and further complex pH-triggered self-assembled gelation systems.

Stress Mitigation Strategies for Trauma Nurses: A Case Study.

Trauma nurses encounter multiple intense stressors on a regular basis. These nurses not only treat the injured patient following a traumatic event but then interact with family members who are also impacted by the event. Repeated experiences with significant trauma can have cumulative effects and negatively impact these nurses and the entire trauma team. Professional nursing associations make recommendations promoting wellness, and health care organizations implement wellness programs that foster and support mind, body, and spirit health. Individuals cope with and respond to stress in different ways, dependent on their unique backgrounds, beliefs, and support systems. Because of these differences, it is important for organizations to offer various ways for nurses and team members to process their reactions and use effective strategies to effectively manage stress. The organization highlighted in this case study offers several stress mitigation programs and techniques designed to support the overall health of trauma nurses and restore their emotional well-being, so that they are best able to care for their injured patients.

Controlled Tuning of the Properties in Optoelectronic Self-Sorted Gels.

Multicomponent supramolecular gels have great potential for optoelectronics. Ideally, we could control the self-assembly of multiple components across many length scales, from the primary assembled structures to how these are arranged in space. This would allow energy transfer between p-type and n-type fibers to be controlled. Usually, a single network is formed and analyzed. It is not clear how most networks could be modified, and certainly not how these might be differentiated. Here, we address both of these issues. We show how the different components in a multicomponent gel can be differentiated by small-angle neutron scattering using contrast-matching experiments. The rate of self-assembly can be used to vary the networks that are formed, leading directly to changes in the efficiency of electron transfer. The assembly kinetics can therefore be used to prepare different networks from the same primary building blocks and primary self-assembled structures. We expect that these advances will allow multicomponent systems to become effective electronic materials.

Anodal tDCS over Primary Motor Cortex Provides No Advantage to Learning Motor Sequences via Observation.

When learning a new motor skill, we benefit from watching others. It has been suggested that observation of others' actions can build a motor representation in the observer, and as such, physical and observational learning might share a similar neural basis. If physical and observational learning share a similar neural basis, then motor cortex stimulation during observational practice should similarly enhance learning by observation as it does through physical practice. Here, we used transcranial direct-current stimulation (tDCS) to address whether anodal stimulation to M1 during observational training facilitates skill acquisition. Participants learned keypress sequences across four consecutive days of observational practice while receiving active or sham stimulation over M1. The results demonstrated that active stimulation provided no advantage to skill learning over sham stimulation. Further, Bayesian analyses revealed evidence in favour of the null hypothesis across our dependent measures. Our findings therefore provide no support for the hypothesis that excitatory M1 stimulation can enhance observational learning in a similar manner to physical learning. More generally, the results add to a growing literature that suggests that the effects of tDCS tend to be small, inconsistent, and hard to replicate. Future tDCS research should consider these factors when designing experimental procedures.

Dance Training Shapes Action Perception and Its Neural Implementation within the Young and Older Adult Brain.

How we perceive others in action is shaped by our prior experience. Many factors influence brain responses when observing others in action, including training in a particular physical skill, such as sport or dance, and also general development and aging processes. Here, we investigate how learning a complex motor skill shapes neural and behavioural responses among a dance-naïve sample of 20 young and 19 older adults. Across four days, participants physically rehearsed one set of dance sequences, observed a second set, and a third set remained untrained. Functional MRI was obtained prior to and immediately following training. Participants' behavioural performance on motor and visual tasks improved across the training period, with younger adults showing steeper performance gains than older adults. At the brain level, both age groups demonstrated decreased sensorimotor cortical engagement after physical training, with younger adults showing more pronounced decreases in inferior parietal activity compared to older adults. Neural decoding results demonstrate that among both age groups, visual and motor regions contain experience-specific representations of new motor learning. By combining behavioural measures of performance with univariate and multivariate measures of brain activity, we can start to build a more complete picture of age-related changes in experience-dependent plasticity.

Using guitar learning to probe the Action Observation Network's response to visuomotor familiarity.

Watching other people move elicits engagement of a collection of sensorimotor brain regions collectively termed the Action Observation Network (AON). An extensive literature documents more robust AON responses when observing or executing familiar compared to unfamiliar actions, as well as a positive correlation between amplitude of AON response and an observer's familiarity with an observed or executed movement. On the other hand, emerging evidence shows patterns of AON activity counter to these findings, whereby in some circumstances, unfamiliar actions lead to greater AON engagement than familiar actions. In an attempt to reconcile these conflicting findings, some have proposed that the relationship between AON response amplitude and action familiarity is nonlinear in nature. In the present study, we used an elaborate guitar training intervention to probe the relationship between movement familiarity and AON engagement during action execution and action observation tasks. Participants underwent fMRI scanning while executing one set of guitar sequences with a scanner-compatible bass guitar and observing a second set of sequences. Participants then acquired further physical practice or observational experience with half of these stimuli outside the scanner across 3 days. Participants then returned for an identical scanning session, wherein they executed and observed equal numbers of familiar (trained) and unfamiliar (untrained) guitar sequences. Via region of interest analyses, we extracted activity within AON regions engaged during both scanning sessions, and then fit linear, quadratic and cubic regression models to these data. The data best support the cubic regression models, suggesting that the response profile within key sensorimotor brain regions associated with the AON respond to action familiarity in a nonlinear manner. Moreover, by probing the subjective nature of the prediction error signal, we show results consistent with a predictive coding account of AON engagement during action observation and execution that also takes into account effects of changes in neural efficiency.