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Humans commonly engage in tasks that require or are made more efficient by coordinating with other humans. In this paper we introduce a task dynamics approach for modeling multi-agent interaction and decision making in a pick and place task where an agent must move an object from one location to another and decide whether to act alone or with a partner. Our aims were to identify and model (1) the affordance related dynamics that define an actor's choice to move an object alone or to pass it to their co-actor and (2) the trajectory dynamics of an actor's hand movements when moving to grasp, relocate, or pass the object. Using a virtual reality pick and place task, we demonstrate that both the decision to pass or not pass an object and the movement trajectories of the participants can be characterized in terms of a behavioral dynamics model. Simulations suggest that the proposed behavioral dynamics model exhibits features observed in human participants including hysteresis in decision making, non-straight line trajectories, and non-constant velocity profiles. The proposed model highlights how the same low-dimensional behavioral dynamics can operate to constrain multiple (and often nested) levels of human activity and suggests that knowledge of what, when, where and how to move or act during pick and place behavior may be defined by these low dimensional task dynamics and, thus, can emerge spontaneously and in real-time with little a priori planning.

BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance. Importantly, our results also demonstrate that the BRCA1-PALB2 interaction dictates the choice between HR and SSA. These studies establish functional and mutational landscapes of BRCA1 for HDR and therapy resistance, while revealing novel insights into BRCA1 regulatory mechanisms and HDR pathway choice.

Introduction This module teaches medical students about shock through a flipped classroom approach. By the conclusion of the module, students are able to differentiate the main types of shock, recognize clinical signs of shock, and formulate initial treatment plans. The flipped classroom approach means that students complete the lower levels of cognitive work (gaining knowledge and comprehension) outside of class, so that they can focus on the higher forms of cognitive work (application, analysis, synthesis, and evaluation) in class with the support of their peers and instructors. Methods Prior to class, students complete advance preparation by reading selected articles. In class, students work through case-based discussion questions in teams. Results This module has been successfully implemented, with survey data from students showing higher self-rated confidence in their ability to achieve specified objectives after completion of the module. According to survey data, students felt they learned more from the class than from a traditional lecture format, and the class promoted teamwork skills. Discussion This module provides a tool for pediatric faculty instructors to redesign a traditional lecture-based class on shock into an interactive, case-based session that uses the flipped classroom approach.

We aimed to define characteristics of TB patients in Puducherry and two districts of Tamil Nadu, India and calculate the population attributable fractions (PAF) of TB from malnutrition and alcohol.New smear-positive TB cases were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT India) cohort. Census and National Family Health Survey data were used for comparisons.Data were analyzed for 409 participants enrolled between May 2014-June 2016; 307 (75.1%) were male, 60.2% were malnourished (body mass index [BMI]

Background: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy and is treated with a combination of cytoreductive surgery and platinum-based chemotherapy. Extended length of stay (LOS) after surgery can affect patient morbidity, overall costs, and hospital resource utilization. The primary objective of this study was to identify factors contributing to prolonged LOS for women undergoing surgery for ovarian cancer. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify women from 2012−2016 who underwent hysterectomy for ovarian, fallopian tube and peritoneal cancer. The primary outcome was LOS >50th percentile. Preoperative and intraoperative variables were examined to determine which were associated with prolonged LOS. Results: From 2012−2016, 1771 women underwent elective abdominal surgery for OC and were entered in the ACS-NSQIP database. The mean and median LOS was 4.6 and 4.0 days (IQR 0−38), respectively. On multivariate analysis, factors associated with prolonged LOS included: American Society of Anesthesiologists (ASA) Classification III (aOR 1.71, 95% CI 1.38−2.13) or IV (aOR 1.88, 95% CI 1.44−2.46), presence of ascites (aOR 1.88, 95% CI 1.44−2.46), older age (aOR 1.23, 95% CI 1.13−1.35), platelet count >400,000/mm3 (aOR 1.74, 95% CI 1.29−2.35), preoperative blood transfusion (aOR 11.00, 95% CI 1.28−94.77), disseminated cancer (aOR 1.28, 95% CI 1.03−1.60), increased length of operation (121−180 min, aOR 1.47, 95% CI 1.13-1.91; >180 min, aOR 2.78, 95% CI 2.13−3.64), and postoperative blood transfusion within 72 h of incision (aOR 2.04, 95% CI 1.59−2.62) (p < 0.05 for all). Conclusions: Longer length of hospital stay following surgery for OC is associated with many patient, disease, and treatment-related factors. The extent of surgery, as evidenced by perioperative blood transfusion and length of surgical procedure, is a factor that can potentially be modified to shorten LOS, improve patient outcomes, and reduce hospital costs.

Cold-water corals, similar to tropical corals, contain diverse and complex microbial assemblages. These bacteria provide essential biological functions within coral holobionts, facilitating increased nutrient utilization and production of antimicrobial compounds. To date, few cold-water octocoral species have been analyzed to explore the diversity and abundance of their microbial associates. For this study, 23 samples of the family Anthothelidae were collected from Norfolk (n = 12) and Baltimore Canyons (n = 11) from the western Atlantic in August 2012 and May 2013. Genetic testing found that these samples comprised two Anthothela species (Anthothela grandiflora and Anthothela sp.) and Alcyonium grandiflorum. DNA was extracted and sequenced with primers targeting the V4-V5 variable region of the 16S rRNA gene using 454 pyrosequencing with GS FLX Titanium chemistry. Results demonstrated that the coral host was the primary driver of bacterial community composition. Al. grandiflorum, dominated by Alteromonadales and Pirellulales had much higher species richness, and a distinct bacterial community compared to Anthothela samples. Anthothela species (A. grandiflora and Anthothela sp.) had very similar bacterial communities, dominated by Oceanospirillales and Spirochaetes. Additional analysis of core-conserved bacteria at 90% sample coverage revealed genus level conservation across Anthothela samples. This core included unclassified Oceanospirillales, Kiloniellales, Campylobacterales, and genus Spirochaeta. Members of this core were previously recognized for their functional capabilities in nitrogen cycling and suggest the possibility of a nearly complete nitrogen cycle within Anthothela species. Overall, many of the bacterial associates identified in this study have the potential to contribute to the acquisition and cycling of nutrients within the coral holobiont.

Changes in both swallowing and taste commonly occur in advanced age, though the relationship between the two is unknown. This study examined the association between a water swallow screen test and taste identification and intensity rating. Participants included 47 community-dwelling women aged 85⁻94 years. Participants completed three trials of a water swallow screen and were observed for signs of aspiration, which, if present, indicated failure. Four pure taste stimuli at low and high concentrations and water were presented, and participants selected one of five taste labels and rated their intensity on the generalized Labeled Magnitude Scale. Ratios of intensity ratings were computed for each taste stimulus to compare the perception of low and high concentrations. The association between water swallow screen failure, correct taste identification, and taste intensity ratio was evaluated with logistic regression modeling, with mediating factors of frailty and number of comorbidities. Failure of three water swallow screen trials was associated with a higher taste intensity ratio for caffeine (bitter) and a lower taste intensity ratio for sucrose (sweet). Correct identification of taste, frailty, and number of comorbidities were not associated with failure of any number of water swallow screen trials. Intensity ratings of certain tastes may be associated with swallowing in old-old women. Heightened vigilance in this population may be necessary to prevent complications related to dietary intake.

As society embraces technology to support collaboration anywhere and at anytime, there is a growing opportunity for artificial agents to support such collaboration. However, little seems known about how such agents impact the behavioural performance of human teams. To answer this, we devised a Wizard of Oz study where teams of 3 participants located and corralled targets into a containment area in a virtual desert environment. The Wizard played the role of an artificial intelligent operator who had a map view showing the location of participants, targets and the containment area, and could verbally communicate this information. The Wizard operated under two conditions: they could solely use the map view to decide what responses to utter (non-responsive interaction) or could also listen to participant queries (responsive interaction). The results revealed that participant performance was unaffected by responsive interaction condition, despite having a significantly more favourable perception of a responsive agent.

Humans are social animals. Human cognition evolved in a social context. Human cognition develops in a social context. Thus, both the internal mechanisms of cognition and the information we use are social. In this workshop, we aim to extend the boundaries of cognitive sciences beyond individual minds. Following the lead of Dingemanse et al. (2023), we put interaction in focus as a complementary starting point for the study of human cognition.

Solving problems with others not only reduces the time required to complete a challenge but may also enable the discovery of novel strategies that qualitatively change how a problem is approached. At the dyadic level, the laboratory-based ‘shepherding task’ demonstrated that, when tasked to contain evasive agents to a centralized location, some participants discover a non-obvious but optimal strategy to solve the task. This paper quantified the interactions between participants engaged in the task using Multidimensional Cross-Recurrence Quantification Analysis (MdCRQA), applied to each participant’s gaze and hand movements. The results demonstrated that strategy discoverers exhibited greater amounts of incidental coupling than non-discoverers prior to discovery. Once discovered, the strategy reduced the strength of coupling between participants, indicating that the strategy also reduced coordination demands. Future work will investigate whether differences in problem-solving can be attributable to differences in the perceptual features participants use which scaffold the discovery of task-optimal solutions.

Collaboration and teaming are critical for solving complex problems. However, little is known about how group dynamics affect teaming behaviours and, ultimately, problem-solving effectiveness. The present study aimed to validate a novel measure of the dynamics of team communication – here termed turn-taking entropy – and to investigate what aspects of those dynamics affect collaborative-problem-solving performance. Thirty-two teams of 4 were asked to complete a simulated crisis-response task in which they had to rank 15 items in order of their importance to their team’s survival (first individually and then as a team). Group responses were better than the aggregated individual responses of team members (suggesting teaming benefits), and were better when team members had task-relevant skills and knowledge. However, response quality was not significantly related to task completion time. Additionally, the proposed entropy measure appeared to capture group communication dynamics, and appeared to differentiate stable an unstable patterns of communication. Implications and directions for future research are discussed.

Deep reinforcement learning (DRL) is capable of training agents that exceed human-levels of performance in multi-agent tasks. However, the behaviors exhibited by these agents are not guaranteed to be human-like or human-compatible. This poses a problem if the goal is to design agents capable of collaborating with humans or augmenting human actions in cooperative or team-based tasks. Indeed, recommender systems designed to augment human decision-making need to not only recommend actions that align with the task goal, but which also maintain coordinative behaviors between agents. The current study simultaneously explored skill learning performance of human learners when working alongside different artificial agents (AAs) during a collaborative problem-solving task, as well as evaluated the effectiveness of the same AAs as action decision recommender systems to aid learning. The action decisions of the AAs were either modelled by a heuristic model based on human performance or by a deep neural network trained by reinforcement learning using self-play. In addition to evaluating skill learning performance, the current study also tested the congruence between the decisions of the AAs with actual decisions made by humans. Results demonstrate that the performance of humans was significantly worse when working alongside the DRL AA compared to the heuristic AA. Additionally, the action decisions participants made also showed less allignment with the recommendations made by the DRL AA.

Agents trained using deep reinforcement learning (DRL) are capable of meeting or exceeding human-levels of performance in multi-agent tasks. However, the behaviors exhibited by these agents are not guaranteed to be human-like or human-compatible. This poses a problem if the goal is to design agents capable of collaborating with humans in cooperative or team-based tasks. Previous approaches to encourage the development of human-compatible agents have relied on pre-recorded human data during training. However, such data is not available for the majority of everyday tasks. Importantly, research on human perceptual-motor behavior has found that task-directed behavior is often low-dimensional and can be decomposed into a defined set of dynamical perceptual-motor primitives (DPMPs). Accordingly, we propose a hierarchical approach to simplify DRL training by defining the action dynamics of agents using DPMPs at the lower level, while using DRL to train the decision-making dynamics of agents at the higher level. We evaluate our approach using a multi-agent shepherding task used to study human and multi-agent coordination. Our hierarchical, DRL-DPMP approach resulted in agents which trained faster than vanilla, black-box DRL agents. Further, the hierarchical agents reached higher levels of performance not only when interacting with each other during self-play, but also when completing the task alongside agents embodying models of novice and expert human behavior. Finally, the hierarchical DRL-DPMP agents developed decision-making policies that outperformed heuristic-based agents used in previous research in human-agent coordination.

Interpersonal coordination is a key determinant of successful social interaction but is disrupted for people who experience social anxiety. Effective coordination rests on individuals directing their attention toward others, an effect well-documented in previous literature. Yet, little research has considered the concurrent behaviour of interaction partners. Using a novel virtual reality task, we investigated how partner gaze (i.e., direct vs. averted) influenced the emergence of interpersonal coordination. The results revealed two novel effects: (i) spontaneous coordination was diminished in the averted (cf. direct) gaze condition; (ii) spontaneous coordination was positively related to symptoms of social anxiety, but only when partner gaze was averted. This latter finding contrasts the extant literature and points to interaction intensity as a factor governing the social anxiety-coordination association. More broadly, this work provides further evidence that emergent patterns of interpersonal coordination fluctuate as a function of changes in social context and the behaviour of others.

Social cognition is shaped by cultural and social-psychological contexts. Depending on the social cues displayed, the cognitive processes that emerge during embodied social interactions can vary. This study explored the influence of gender diverse social cues on interpersonal coordination and decision-making during dyadic interaction in virtual reality. Participants embodied either a transgender or cisgender avatar and interacted with a transgender confederate (human-controlled virtual agent). Results suggest that transgender embodied women and men displayed more interpersonal affiliation, via their coordination dynamics with the confederate, after an explicit gender identity disclosure. Additionally, cognitive flexibility for ambiguous decisions was influenced by attributions of responsibility made toward the confederate. However, cisgender embodied men did not substantially change their decision-making behaviours or increase their coordination with the confederate. Viscerally taking on the perspective and appearance of a transgender person, achieved through virtual embodiment and interaction, may support positive interactions between cisgender and transgender communities.

To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported.

In this work we present a dual-phase diffusion tensor imaging (DTI) technique that incorporates a correction scheme for the cardiac material strain, based on 3D myocardial tagging.In vivo dual-phase cardiac DTI with a stimulated echo approach and 3D tagging was performed in 10 healthy volunteers. The time course of material strain was estimated from the tagging data and used to correct for strain effects in the diffusion weighted acquisition. Mean diffusivity, fractional anisotropy, helix, transverse and sheet angles were calculated and compared between systole and diastole, with and without strain correction. Data acquired at the systolic sweet spot, where the effects of strain are eliminated, served as a reference.The impact of strain correction on helix angle was small. However, large differences were observed in the transverse and sheet angle values, with and without strain correction. The standard deviation of systolic transverse angles was significantly reduced from 35.9±3.9° to 27.8°±3.5° (p

We used 14 years of state licensure and classroom data from Virginia to follow 19,878 special education teachers (SETs) who completed either the alternative route (AR) internship or traditional programs. Findings reveal that a greater percentage of SETs of color participated in AR programs compared to traditional licensure programs, while a greater percentage of White SETs completed traditional programs. SETs of color attained approximately three fewer years of service time if they completed the AR program compared to traditional programs. For White SETs, a difference of less than 1 year was found. For SETs from AR programs who did not complete 27 credit hours of university coursework, attrition occurred at higher rates within the first 3 years of service. Implications for future research on AR internship programs and teachers of color are provided, informing both policy and practice.

Special education teachers of color are underrepresented in research about attrition and retention, despite evidence of their role in the academic, social, and emotional success of students of color. We used critical quantitative methods and structural equation modeling to investigate the attrition and retention variability between special education teachers (SETs) of color and White SETs. We sampled 778 SETs and found SETs of color reported higher rates of intent to remain in the profession than White SETs. SETs of color in urban schools also rated supports higher than White SETs, based on school geographical location, suggesting higher retention of SETs of color in urban schools. We offer implications for ensuring SETs of color are reflected in research, and policy and practice recommendations to move the discussion of race and teacher shortage forward in the field.

Rapid non-genomic effects of 17β-estradiol are elicited by the activation of different estrogen receptor-α isoforms. Presence of surface binding sites for estrogen have been identified in cells transfected with full-length estrogen receptor-α66 (ER66) and the truncated isoforms, estrogen receptor-α46 (ER46) and estrogen receptor-α36 (ER36). However, the binding affinities of the membrane estrogen receptors (mERs) remain unknown due to the difficulty of developing of stable mER-transfected cell lines with sufficient mER density, which has largely hampered biochemical binding studies. The present study utilized cell-free expression systems to determine the binding affinities of 17β-estradiol to mERs, and the relationship among palmitoylation, membrane insertion and binding affinities. Saturation binding assays of human mERs revealed that [³H]-17β-estradiol bound ER66 and ER46 with Kd values of 68.81 and 60.72 pM, respectively, whereas ER36 displayed no specific binding within the tested concentration range. Inhibition of palmitoylation or removal of the nanolipoprotein particles, used as membrane substitute, reduced the binding affinities of ER66 and ER46 to 17β-estradiol. Moreover, ER66 and ER46 bound differentially with some estrogen receptor agonists and antagonists, and phytoestrogens. In particular, the classical estrogen receptor antagonist, ICI 182,780, had a higher affinity for ER66 than ER46. In summary, the present study defines the binding affinities for human estrogen receptor-α isoforms, and demonstrates that ER66 and ER46 show characteristics of mERs. The present data also indicates that palmitoylation and membrane insertion of mERs are important for proper receptor conformation allowing 17β-estradiol binding. The differential binding of ER66 and ER46 with certain compounds substantiates the prospect of developing mER-selective drugs.

BackgroundHeterogeneous nuclear ribonucleoprotein C1/C2 (hnRNP C) is a core component of 40S ribonucleoprotein particles that bind pre-mRNAs and influence their processing, stability and export. Breast cancer tumor suppressors BRCA1, BRCA2 and PALB2 form a complex and play key roles in homologous recombination (HR), DNA double strand break (DSB) repair and cell cycle regulation following DNA damage.MethodsPALB2 nucleoprotein complexes were isolated using tandem affinity purification from nuclease-solubilized nuclear fraction. Immunofluorescence was used for localization studies of proteins. siRNA-mediated gene silencing and flow cytometry were used for studying DNA repair efficiency and cell cycle distribution/checkpoints. The effect of hnRNP C on mRNA abundance was assayed using quantitative reverse transcriptase PCR.Results and significanceWe identified hnRNP C as a component of a nucleoprotein complex containing breast cancer suppressor proteins PALB2, BRCA2 and BRCA1. Notably, other components of the 40S ribonucleoprotein particle were not present in the complex. hnRNP C was found to undergo significant changes of sub-nuclear localization after ionizing radiation (IR) and to partially localize to DNA damage sites. Depletion of hnRNP C substantially altered the normal balance of repair mechanisms following DSB induction, reducing HR usage in particular, and impaired S phase progression after IR. Moreover, loss of hnRNP C strongly reduced the abundance of key HR proteins BRCA1, BRCA2, RAD51 and BRIP1, which can be attributed, at least in part, to the downregulation of their mRNAs due to aberrant splicing. Our results establish hnRNP C as a key regulator of BRCA gene expression and HR-based DNA repair. They also suggest the existence of an RNA regulatory program at sites of DNA damage, which involves a unique function of hnRNP C that is independent of the 40S ribonucleoprotein particles and most other hnRNP proteins.

Mismatch repair (MMR) plays a pivotal role in keeping the genome stable. MMR dysfunction can lead to carcinogenesis by gene mutation accumulation. HMSH2 and hMLH1 are two key components of MMR. High or low expression of them often mark the status of MMR function. Mutations (EGFR, KRAS, etc) are common in non-small cell lung cancer (NSCLC). However, it is not clear what role MMR plays in NSCLC gene mutations. The expression of MMR proteins hMSH2 and hMLH1, and the proliferation markers PCNA and Ki67 were measured by immunohistochemistry in 181 NSCLCs. EGFR and KRAS mutations were identified by high resolution melting analysis. Stronger hMLH1 expression correlated to a higher frequency of EGFR mutations in exon 19 and 21 (p

The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo.The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment.In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin.This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.

Objectives: This systematic review compares the impact of ball and locator attachments on marginal bone loss in implant-retained overdentures in completely edentulous patients. Method and materials: Following PRISMA guidelines, health science librarians completed literature searches from inception to 17 March 2023 in seven databases. There were 15,686 items exported to EndNote from Embase.com, CINAHL (EBSCO), Cochrane Library, Ovid MEDLINE-ALL, PubMed, Scopus, and Web of Science. Hand-searching added four more articles. After deduplication, 6,756 items were screened for eligibility. Twenty-nine studies were assessed by full text, of which ten studies, involving 424 subjects, were included in the review. Risk of bias assessment was conducted using the Cochrane risk-of-bias tool and the Newcastle-Ottawa scale. A meta-analysis was performed to synthesize and analyze the collective data from the selected studies. Results: The included studies used diverse methodologies, implant systems, and loading protocols. Most studies reported no significant difference in marginal bone loss between ball and locator attachments. The meta-analysis revealed high heterogeneity. Conclusion: The results of this systematic review suggest that ball and locator attachments exhibit similar performance in terms of marginal bone loss in implant-retained overdentures. However, the limited number, risk of bias, and heterogeneity of studies highlight the need for standardized research designs and larger sample sizes in future investigations to draw more definitive conclusions. [ABSTRACT FROM AUTHOR]

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.

Cataract, a clouding of the eye lens from protein precipitation, affects millions of people every year. The lens proteins, the crystallins, show extensive post-translational modifications (PTMs) in cataractous lenses. The most common PTMs, deamidation and oxidation, promote crystallin aggregation; however, it is not clear precisely how these PTMs contribute to crystallin insolubilization. Here, we report six crystal structures of the lens protein γS-crystallin (γS): one of the wild-type and five of deamidated γS variants, from three to nine deamidation sites, after sample aging. The deamidation mutations do not change the overall fold of γS; however, increasing deamidation leads to accelerated disulfide-bond formation. Addition of deamidated sites progressively destabilized protein structure, and the deamidated variants display an increased propensity for aggregation. These results suggest that the deamidated variants are useful as models for accelerated aging; the structural changes observed provide support for redox activity of γS-crystallin in the lens.

Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs), which are critical for orchestrating the antiinflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2- deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, single-cell RNA-Seq (scRNA-Seq) analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxia- response genes. These findings support the importance of a glycolysis/HIF1a axis in promoting G-MDSC antiinflammatory activity and biofilm persistence during PJI., Introduction Staphylococcus aureus is a leading cause of healthcare-and community-associated infections (1). This is due, in part, to numerous virulence factors that allow the bacterium to adapt and thrive in [...]

With artificial intelligence technologies becoming commonplace today, enhancing the efficiency of human-artificial agent (AA) interactions has become increasingly important. A growing body of research has revealed how dynamic motor primitives (DMPs) of human perceptual-motor behavior can be used to create ‘human-like’ AAs, primarily focusing on cooperative tasks. Using air hockey as a representative task, the current experiment is the first part of a large study aimed at determining the utility of DMP-based models for developing ‘human-like’ competitive AAs. Participants played against a preliminary DMP model and the differences in their behaviors were analyzed. Based on these observed differences, a revised model is proposed, with preliminary results revealing that the new model exhibits behaviors more consistent with those of humans. A major implication of this work is that it presents a framework for creating ‘human-like’ AAs that capture the essential human decision and movement dynamics without requiring large human gameplay datasets.

Joint pick and place tasks occur in many interpersonal scenarios, such as when two people pick up and pass dishes. Previous studies have demonstrated that low-dimensional models can accurately capture the dynamics of pick and place motor behaviors in a controlled 2D environment. The current study models the dynamics of pick-up and pass decisions within a less restrictive virtual reality mediated 3D joint pick and place task. Findings indicate that reach-normalized distance measures, between participants and objects/targets, could accurately predict pick-up and pass decisions. Findings also reveal that participants took longer to pick-up objects where division of labor boundaries were less obvious and tended to pass in locations maximizing the dyad’s efficiency. This study supports the notion that individuals are more likely to engage in interpersonal behavior when a task goal is perceived as difficult or unattainable (i.e., not afforded). Implications of findings for human-artificial agent interactions are discussed.