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.

Stress fracture of the first rib in a hockey goalie.

First rib stress fractures are uncommon in athletes and diagnosis requires a high degree of clinical suspicion. Diagnostic delay may increase risk of poor healing and long-term complications. Case reports and series describe these injuries primarily in overhead athletes; proposed contributing factors include anatomic susceptibility to stress and repetitive opposing muscular forces. We describe an ice hockey goalie with acute-on-chronic thoracic back pain who was found to have a first rib stress fracture, which to our knowledge is the first reported in this sport. We hypothesize that biomechanical stress from new stick positioning contributed to the injury. Our patient recovered symptomatically with conservative treatment; however, imaging suggested nonunion of the fracture site and possible pseudoarthrosis.

Outcomes of a Novel Spine Virtual Fracture Clinic in an Australian Tertiary Hospital.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: To determine the proportion of referrals diverted by the SVFC from traditional outpatient clinic management. SUMMARY OF BACKGROUND DATA: The consistent rise in demand for orthopaedic outpatient clinic services is creating marked challenges to the provision of quality care. Virtual fracture clinics for upper and lower limb fractures have reduced the burden on outpatient clinics through telephone-based management of these conditions. To date, no study describes the expansion of virtual care to the spine trauma population. METHODS: A study of spine fractures referred to the RMH Department of Orthopaedic Surgery was conducted comparing outcomes prior to (January to December 2021) and following (July 2022 to November 2023) implementation of a spine virtual fracture clinic (SVFC). The primary aim of this study was to investigate the effects of a telephone-based SVFC on outpatient clinic activity, represented by the proportion of referrals discharged without requiring in-person clinic review. Secondary aims included appointment utilisation, lost to follow-up rates, duration of care, missed or mis-diagnoses, unplanned operations and complications. RESULTS: A total of 91.9% (n=666) referrals managed by the SVFC were discharged without in-person clinic attendance. Compared to outpatient clinic management (n=150 referrals), SVFC implementation was associated with reductions in the average number of consultations per referral (1.8 versus 2.4, P<0.001), appointments not attended (5% versus 13%, P<0.001), referrals lost to follow-up (0 versus 10.7%, P<0.001) and a shorter duration of care (median 48 d versus 58 d, P<0.001). A total of 65 patients (8.1%) were redirected to in-person clinics of which three underwent surgical intervention. No diagnostic errors, complications or adverse events were identified. CONCLUSION: This study demonstrates that a SVFC is an effective and safe alternative pathway to traditional hospital-based outpatient clinics with low-risk for any adverse outcomes.

Driving value-based healthcare through a new vision for Queensland's health system.

The purpose of this case study is to explain the development of Queensland's strategic approach to health system reform, which promotes partnership across the health system to better deliver integrated and value-based health care across the continuum of care. The new health system vision was informed by undertaking literature searches on national and international health system approaches to reform and supported by extensive consultation across Queensland with more than 1100 stakeholders. Thematic analysis was undertaken to identify key themes that were translated into a high-level vision document that communicated Queensland's renewed focus on wellness and delivering more care in the community. This was circulated to stakeholders for iterative and collaborative refinement before final approvals. Collaboratively and iteratively developing the new health system vision for Queensland with key stakeholders has contributed to a shared understanding and ownership of a vision that is committed to system reform, focused on delivering high-value care that reflects what is important to consumers and health system stakeholders.

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.

Evaluations of dyadic synchrony: observers' traits influence estimation and enjoyment of synchrony in mirror-game movements.

While evidence abounds that motor synchrony is a powerful form of 'social glue' for those involved, we have yet to understand how observers perceive motor synchrony: can observers estimate the degree of synchrony accurately? Is synchrony aesthetically pleasing? In two preregistered experiments (n = 161 each), we assess how accurately observers can estimate the degree of synchrony in dyads playing the mirror game, and how much observers enjoy watching these movements. We further assess whether accuracy and enjoyment are influenced by individual differences in self-reported embodied expertise (ability to reproduce movements, body awareness, body competence), psychosocial resources (extraversion, self-esteem), or social competencies (empathy, autistic traits), while objectively controlling for the degree of measured synchrony and complexity. The data revealed that observers' estimated synchrony with poor accuracy, showing a tendency to underestimate the level of synchrony. Accuracy for low synchrony improved with increasing body competence, while accuracy for high synchrony improved with increasing autistic traits. Observers' enjoyment of dyadic movements correlated positively with the degree of measured synchrony, the predictability of the movements, and the observer's empathy. Furthermore, very low enjoyment was associated with increased body perception. Our findings indicate that accuracy in perceiving synchrony is closely linked to embodiment, while aesthetic evaluations of action hinge on individual differences.

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.

A functional and structural comparative analysis of large tumor antigens reveals evolution of different importin α-dependent nuclear localization signals.

Nucleocytoplasmic transport regulates the passage of proteins between the nucleus and cytoplasm. In the best characterized pathway, importin (IMP) α bridges cargoes bearing basic, classical nuclear localization signals (cNLSs) to IMPß1, which mediates transport through the nuclear pore complex. IMPα recognizes three types of cNLSs via two binding sites: the major binding site accommodates monopartite cNLSs, the minor binding site recognizes atypical cNLSs, while bipartite cNLSs simultaneously interact with both major and minor sites. Despite the growing knowledge regarding IMPα-cNLS interactions, our understanding of the evolution of cNLSs is limited. We combined bioinformatic, biochemical, functional, and structural approaches to study this phenomenon, using polyomaviruses (PyVs) large tumor antigens (LTAs) as a model. We characterized functional cNLSs from all human (H)PyV LTAs, located between the LXCXE motif and origin binding domain. Surprisingly, the prototypical SV40 monopartite NLS is not well conserved; HPyV LTA NLSs are extremely heterogenous in terms of structural organization, IMPα isoform binding, and nuclear targeting abilities, thus influencing the nuclear accumulation properties of full-length proteins. While several LTAs possess bipartite cNLSs, merkel cell PyV contains a hybrid bipartite cNLS whose upstream stretch of basic amino acids can function as an atypical cNLS, specifically binding to the IMPα minor site upon deletion of the downstream amino acids after viral integration in the host genome. Therefore, duplication of a monopartite cNLS and subsequent accumulation of point mutations, optimizing interaction with distinct IMPα binding sites, led to the evolution of bipartite and atypical NLSs binding at the minor site.

Structural determinants of phosphorylation-dependent nuclear transport of HCMV DNA polymerase processivity factor UL44.

Human cytomegalovirus DNA polymerase processivity factor UL44 is transported into the nucleus by importin (IMP) α/ß through a classical nuclear localization signal (NLS), and this region is susceptible to cdc2-mediated phosphorylation at position T427. Whilst phosphorylation within and close to the UL44 NLS regulates nuclear transport, the details remain elusive, due to the paucity of structural information regarding the role of negatively charged cargo phosphate groups. We addressed this issue by studying the effect of UL44 T427 phosphorylation on interaction with several IMPα isoforms by biochemical and structural approaches. Phosphorylation decreased UL44/IMPα affinity 10-fold, and a comparative structural analysis of UL44 NLS phosphorylated and non-phosphorylated peptides complexed with mouse IMPα2 revealed the structural rearrangements responsible for phosphorylation-dependent inhibition of UL44 nuclear import.

Effect of Ethanol-exposure on Innate Immune Response in Sepsis.

Alcohol use disorder, reported by one in eight critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyper-inflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol-exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol-exposure with sepsis, but targeted treatments have remained elusive. In this manuscript, we outline the effects of ethanol-exposure on various innate immune cell types in general and during sepsis.

Perceptions of intelligence & sentience shape children's interactions with robot reading companions.

The potential for robots to support education is being increasingly studied and rapidly realised. However, most research evaluating education robots has neglected to examine the fundamental features that make them more or less effective, given the needs and expectations of learners. This study explored how children's perceptions, expectations and experiences are shaped by aesthetic and functional features during interactions with different robot 'reading buddies'. We collected a range of quantitative and qualitative measures of subjective experience before and after children read a book with one of three different robots. An inductive thematic analysis revealed that robots have the potential offer children an engaging and non-judgemental social context to promote reading engagement. This was supported by children's perceptions of robots as being intelligent enough to read, listen and comprehend the story, particularly when they had the capacity to talk. A key challenge in the use of robots for this purpose was the unpredictable nature of robot behaviour, which remains difficult to perfectly control and time using either human operators or autonomous algorithms. Consequently, some children found the robots' responses distracting. We provide recommendations for future research seeking to position seemingly sentient and intelligent robots as an assistive tool within and beyond education settings.

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.

Enzyme-Triggered l-α/d-Peptide Hydrogels as a Long-Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs.

Eradicating HIV/AIDS by 2030 is a central goal of the World Health Organization. Patient adherence to complicated dosage regimens remains a key barrier. There is a need for convenient long-acting formulations that deliver drugs over sustained periods. This paper presents an alternative platform, an injectable in situ forming hydrogel implant to deliver a model antiretroviral drug (zidovudine [AZT]) over 28 days. The formulation is a self-assembling ultrashort d or l-α peptide hydrogelator, namely phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY[p]-OH), covalently conjugated to zidovudine via an ester linkage. Rheological analysis demonstrates phosphatase enzyme instructed self-assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggest hydrogels form narrow radius (≈2 nm), large length fibers closely fitting the flexible cylinder elliptical model. d-Peptides are particularly promising for long-acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progress under physiological conditions (37 °C, pH 7.4, H2 O). Subcutaneous administration of Napffk(AZT)Y[p]G-OH in Sprague Dawley rats demonstrate zidovudine blood plasma concentrations within the half maximal inhibitory concentration (IC50 ) range (30-130 ng mL-1 ) for 35 days. This work is a proof-of-concept for the development of a long-acting combined injectable in situ forming peptide hydrogel implant. These products are imperative given their potential impact on society.

Importin α/ß-dependent nuclear transport of human parvovirus B19 nonstructural protein 1 is essential for viral replication.

Human parvovirus B19 (B19V) is a major human pathogen causing a variety of diseases, characterized by a selective tropism to human progenitor cells in bone marrow. In similar fashion to all Parvoviridae members, the B19V ssDNA genome is replicated within the nucleus of infected cells through a process which involves both cellular and viral proteins. Among the latter, a crucial role is played by non-structural protein (NS)1, a multifunctional protein involved in genome replication and transcription, as well as modulation of host gene expression and function. Despite the localization of NS1 within the host cell nucleus during infection, little is known regarding the mechanism of its nuclear transport pathway. In this study we undertake structural, biophysical, and cellular approaches to characterize this process. Quantitative confocal laser scanning microscopy (CLSM), gel mobility shift, fluorescence polarization and crystallographic analysis identified a short sequence of amino acids (GACHAKKPRIT-182) as the classical nuclear localization signal (cNLS) responsible for nuclear import, mediated in an energy and importin (IMP) α/ß-dependent fashion. Structure-guided mutagenesis of key residue K177 strongly impaired IMPα binding, nuclear import, and viral gene expression in a minigenome system. Further, treatment with ivermectin, an antiparasitic drug interfering with the IMPα/ß dependent nuclear import pathway, inhibited NS1 nuclear accumulation and viral replication in infected UT7/Epo-S1 cells. Thus, NS1 nuclear transport is a potential target of therapeutic intervention against B19V induced disease.

Structural Characterization of Porcine Adeno-Associated Virus Capsid Protein with Nuclear Trafficking Protein Importin Alpha Reveals a Bipartite Nuclear Localization Signal.

Adeno-associated viruses (AAV) are important vectors for gene therapy, and accordingly, many aspects of their cell transduction pathway have been well characterized. However, the specific mechanisms that AAV virions use to enter the host nucleus remain largely unresolved. We therefore aimed to reveal the interactions between the AAV Cap protein and the nuclear transport protein importin alpha (IMPα) at an atomic resolution. Herein we expanded upon our earlier research into the Cap nuclear localization signal (NLS) of a porcine AAV isolate, by examining the influence of upstream basic regions (BRs) towards IMPα binding. Using a high-resolution crystal structure, we identified that the IMPα binding determinants of the porcine AAV Cap comprise a bipartite NLS with an N-terminal BR binding at the minor site of IMPα, and the previously identified NLS motif binding at the major site. Quantitative assays showed a vast difference in binding affinity between the previously determined monopartite NLS, and bipartite NLS described in this study. Our results provide a detailed molecular view of the interaction between AAV capsids and the nuclear import receptor, and support the findings that AAV capsids enter the nucleus by binding the nuclear import adapter IMPα using the classical nuclear localization pathway.

Feeling loved as a strong link in relationship interactions: Partners who feel loved may buffer destructive behavior by actors who feel unloved.

Feeling loved (loved, cared for, accepted, valued, understood) is inherently dyadic, yet most prior theoretical perspectives and investigations have focused on how actors feeling (un)loved shapes actors' outcomes. Adopting a dyadic perspective, the present research tested whether the established links between actors feeling unloved and destructive (critical, hostile) behavior depended on partners' feelings of being loved. Does feeling loved need to be mutual to reduce destructive behavior, or can partners feeling loved compensate for actors feeling unloved? In five dyadic observational studies, couples were recorded discussing conflicts, diverging preferences or relationship strengths, or interacting with their child (total N = 842 couples; 1,965 interactions). Participants reported how much they felt loved during each interaction and independent coders rated how much each person exhibited destructive behavior. Significant Actors' × Partners' Felt-Loved interactions revealed a strong-link/mutual felt-unloved pattern: partners' high felt-loved buffered the damaging effect of actors' low felt-loved on destructive behavior, resulting in actors' destructive behavior mostly occurring when both actors' and partners' felt-loved was low. This dyadic pattern also emerged in three supplemental daily sampling studies. Providing directional support for the strong-link/mutual felt-unloved pattern, in Studies 4 and 5 involving two or more sequential interactions, Actors' × Partners' Felt-Loved in one interaction predicted actors' destructive behavior within couples' subsequent conflict interactions. The results illustrate the dyadic nature of feeling loved: Partners feeling loved can protect against actors feeling unloved in challenging interactions. Assessing Actor × Partner effects should be equally valuable for advancing understanding of other fundamentally dyadic relationship processes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Value attributed to text-based archives generated by artificial intelligence.

Openly available natural language generation (NLG) algorithms can generate human-like texts across domains. Given their potential, ethical challenges arise such as being used as a tool for misinformation. It is necessary to understand both how these texts are generated from an algorithmic point of view, and how they are evaluated by a general audience. In this study, our aim was to investigate how people react to texts generated algorithmically, whether they are indistinguishable from original/human-generated texts, and the value people assign these texts. Using original text-based archives, and text-based archives generated by artificial intelligence (AI), findings from our preregistered study (N = 228) revealed that people were more likely to preserve original archives compared with AI-generated archives. Although participants were unable to accurately distinguish between AI-generated and original archives, participants assigned lower value to archives they categorized as AI-generated compared with those they categorized as original. People's judgements of value were also influenced by their attitudes toward AI. These findings provide a richer understanding of how the emergent practice of automated text creation alters the practices of readers and writers, and have implications for how readers' attitudes toward AI affect the use and value of AI-based applications and creations.

The computer, A choreographer? Aesthetic responses to randomly-generated dance choreography by a computer.

Is artificial intelligence (AI) changing our culture or creating its own? With advancements in AI and machine learning, artistic creativity is moving to a brave new world of possibility and complexity, while at the same time posing challenging questions, such as what defines something as art, what is the role of human creativity in an automated world, and do we evaluate artificial art in the same way as art made by humans? Across two pre-registered and statistically powered experiments we shed light on the nature of aesthetic responses toward computer-generated art by investigating observer prejudices against computer-generated dance choreography, and the impact of expertise and pre-conceived beliefs about the origin of artistic creation. Our results provide substantive evidence that an explicit bias exists among dance experts against computer-generated choreography. The mere belief about a dance work's origin biases aesthetic responses toward artworks among both dance experts and dance naïve participants. The implications of the current study serve to inform several disciplines across the arts and sciences including but not limited to empirical aesthetics, artificial intelligence, engineering, robotics, and social cognition and neuroscience. Along with physical form and content of artificial agents and art productions, the viewers' knowledge and attitudes toward artistic AI and artificial agents will need to be taken into consideration for effective human-computer/human-AI interactions.

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.