Fish couple forecasting with feedback control to chase and capture moving prey.

Predator-prey interactions are fundamental to ecological and evolutionary dynamics. Yet, predicting the outcome of such interactions-whether predators intercept prey or fail to do so-remains a challenge. An emerging hypothesis holds that interception trajectories of diverse predator species can be described by simple feedback control laws that map sensory inputs to motor outputs. This form of feedback control is widely used in engineered systems but suffers from degraded performance in the presence of processing delays such as those found in biological brains. We tested whether delay-uncompensated feedback control could explain predator pursuit manoeuvres using a novel experimental system to present hunting fish with virtual targets that manoeuvred in ways that push the limits of this type of control. We found that predator behaviour cannot be explained by delay-uncompensated feedback control, but is instead consistent with a pursuit algorithm that combines short-term forecasting of self-motion and prey motion with feedback control. This model predicts both predator interception trajectories and whether predators capture or fail to capture prey on a trial-by-trial basis. Our results demonstrate how animals can combine short-term forecasting with feedback control to generate robust flexible behaviours in the face of significant processing delays.

Widespread Associations between Behavioral Metrics and Brain Microstructure in ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviors. A diagnosis of ASD is provided by a clinician following cognitive and behavioral evaluations, but there is currently no biomarker associating these metrics with neurological changes. Our lab has previously found that g-ratio, the proportion of axon width to myelin diameter, and axonal conduction velocity, which is associated with the capacity of an axon to carry information, are both decreased in ASD individuals. By associating these differences with performance on cognitive and behavioral tests, we can evaluate which tests most reveal changes in the brain. Analyzing 273 participants (148 with ASD) ages 8-to-17 (49% female) through an NIH-sponsored Autism Centers of Excellence (ACE) network (Grant#: MH100028), we observe widespread associations between behavioral and cognitive evaluations of autism and between behavioral and microstructural metrics. Analyzing data from all participants, conduction velocity but not g-ratio was significantly associated with many behavioral metrics. However, this pattern was reversed when looking solely at ASD participants. This reversal may suggest that the mechanism underlying differences between autistic and non-autistic individuals may be distinct from the mechanism underlying ASD behavioral severity. Two additional machine learning cluster analyses applied to neuroimaging data reinforce the association between neuroimaging and behavioral metrics and suggest that age-related maturation of brain metrics may drive changes in ASD behavior. By associating neuroimaging metrics with ASD, it may be possible to measure and identify individuals at high risk of ASD before behavioral tests can detect them.

The association between bullying victimization and back pain in young people: a systematic literature review and meta-analysis.

ABSTRACT: Back pain is a common and recurrent health complaint in adolescence. Psychosocial factors may be associated with the onset and persistence of back pain symptoms. This systematic review aims to determine the association between bullying victimization and back pain in young people. Observational studies that quantified the association between bullying victimization and back pain in participants were included in this systematic review. Estimates of associations and confidence intervals were extracted. A random effects meta-analysis of estimates of association was performed. The quality of evidence was assessed using the Joanna Briggs Institute critical appraisal checklist for analytical cross-sectional studies. Database searches yielded 18,311 citations. Nineteen studies (n = 212,058, 51.4% female) were included in our review. Meta-analysis showed a positive association between bullying victimization and back pain (odds ratio 1.93, confidence interval 1.75-2.13). Subgroup analysis showed no statistically significant effect of sex, age, bullying type, pain type, recall periods, bullying frequency, back pain frequency, risk estimate adjustment, and study critical appraisal rating. All studies were rated at moderate-high risk of bias. Our synthesis of evidence found a weak-moderate association between bullying victimization and back pain in young people. Methodological shortcomings and heterogeneity in the field limit causal inference. Future longitudinal studies are required.

Can ChatGPT Answer Patient Questions Regarding Reverse Shoulder Arthroplasty?

INTRODUCTION: In recent years, Artificial Intelligence (AI) has seen substantial progress in its utilization, with Chat Generated Pre-Trained Transformer (ChatGPT) emerging as a popular language model. The purpose of this study was to test the accuracy and reliability of ChatGPT's responses to frequently asked questions (FAQ) pertaining to reverse shoulder arthroplasty (RSA). METHODS: The ten most common FAQs were queried from institution patient education websites. These ten questions were then input into the chatbot during a single session without additional contextual information. The responses were then critically analyzed by two orthopedic surgeons for clarity, accuracy, and the quality of evidence-based information using The Journal of the American Medical Association (JAMA) Benchmark criteria and the DISCERN score. The readability of the responses was analyzed using the Flesch-Kincaid Grade Level. RESULTS: In response to the ten questions, the average DISCERN score was 44 (range 38-51). Seven responses were classified as fair and three were poor. The JAMA Benchmark criteria score was 0 for all responses. Furthermore, the average Flesch-Kincaid Grade Level was 14.35, which correlates to a college graduate reading level. CONCLUSION: Overall, ChatGPT was able to provide fair responses to common patient questions. However, the responses were all written at a college graduate reading level and lacked reliable citations. The readability greatly limits its utility. Thus, adequate patient education should be done by orthopedic surgeons. This study underscores the need for patient education resources that are reliable, accessible, and comprehensible. LEVEL OF EVIDENCE: IV.

Mcam stabilizes a luminal progenitor-like breast cancer cell state via Ck2 control and Src/Akt/Stat3 attenuation.

Cell state control is crucial for normal tissue development and cancer cell mimicry of stem/progenitor states, contributing to tumor heterogeneity, therapy resistance, and progression. Here, we demonstrate that the cell surface glycoprotein Mcam maintains the tumorigenic luminal progenitor (LP)-like epithelial cell state, leading to Basal-like mammary cancers. In the Py230 mouse mammary carcinoma model, Mcam knockdown (KD) destabilized the LP state by deregulating the Ck2/Stat3 axis, causing a switch to alveolar and basal states, loss of an estrogen-sensing subpopulation, and resistance to tamoxifen-an effect reversed by Ck2 and Stat3 inhibitors. In vivo, Mcam KD blocked generation of Basal-like tumors and Sox10+Krt14+ cells. In human tumors, MCAM loss was largely exclusive of the Basal-like subtype, linked instead to proliferative Luminal subtypes, including often endocrine-resistant Luminal B cancers. This study has implications for developing therapies targeting MCAM, CK2, and STAT3 and their likely effective contexts.

Transperineal vs Transrectal Prostate Biopsy-The PREVENT Randomized Clinical Trial.

This randomized clinical trial compares the effect of transperineal vs transrectal prostate biopsy on infection rates after biopsy.

Complete resolution across the neodymium/samarium isotopic envelope with a liquid sampling-atmospheric pressure glow discharge - Orbitrap mass spectrometer.

RATIONALE: Nd and Sm isotope ratios play an important role in geological dating and as nuclear forensic signatures; however, the overlap of the respective 144, 148, 150 Nd/Sm isobars requires prior separations to be performed before analysis on typical MS platforms. The work presented here overcomes these isobaric interferences using ultrahigh-mass resolution to alleviate interference without prior chemical separations. METHODS: A liquid sampling-atmospheric pressure glow discharge ion source was coupled to a standard, QExactive Focus Orbitrap mass spectrometer, providing a mass resolution of ~80 k. A Spectroswiss FTMS booster X2 data acquisition package was used to collect extended transients, providing much higher mass resolution; ~230 k and ~600 k are employed here for Nd and Sm isotopes. RESULTS: While the standard Orbitrap resolution is far greater than typical "atomic" MS platforms, it was insufficient to alleviate all isobars. The use of a resolution of ~230 k resulted in baseline separation across the entire isotopic envelope for both Nd and Sm. Isotope ratios obtained from Nd:Sm mixtures using high-resolution were equivalent to those found for individual-element solutions, while isotope ratios obtained at a resolution of ~80 k (standard for the OEM data system) showed large deviations. CONCLUSIONS: Use of ultrahigh-resolution is an attractive alternative to extensive chemical separations to alleviate severe isobaric interferences. Sufficient mass resolution greatly reduces/eliminates the need for sample manipulations (separations) before analysis while reducing costs and total analysis times.

Transitions of Care in Patients With Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are a group of inherited conditions caused by damaged monogenic variants that result in impairment and/or dysregulation within the immune system. IEI are typically diagnosed in infancy or early childhood, with clinical presentations that include increased susceptibility to infections, immune dysregulation, autoinflammation, bone marrow failure, and/or malignancy. Historically, transitions of care experienced by patients with IEI have not been well described in the literature. However, with treatment advances extending the long-term survival of patients, this has become a primary area of research. It is crucial to establish guidelines and recommendations specific to the transition of patients with IEI. Transitions may include patients who naturally progress from pediatric to adult care, from inpatient to outpatient settings, or from their established health care team to a new team (ie, moving from one geographic area to another). This narrative review summarizes the current data on transitions of care and describes the health care challenges and patient-related barriers impacting transitions of care. Frameworks with practical guidance on how health care practitioners can better manage care transitions faced by patients with IEI are presented.

Therapeutic Drug Monitoring of Long-Acting Rilpivirine and Cabotegravir for Treatment of HIV-1 Infection-A Case Series of Five Patients With One Virologic Failure After Development of Two-Class Resistance.

Virologic failure of long-acting rilpivirine/cabotegravir is rare but may result in severely limited treatment options. Known risk factors cannot predict all cases. Therapeutic drug monitoring (TDM) may help identify patients at risk, but reliable thresholds are missing. We report retrospective TDM in a cohort of 5 patients, including 1 virological failure.

Development of an automated 3D high content cell screening platform for organoid phenotyping.

The use of organoid models in biomedical research has grown substantially since their inception. As they gain popularity among scientists seeking more complex and biologically relevant systems, there is a direct need to expand and clarify potential uses of such systems in diverse experimental contexts. Herein we outline a high-content screening (HCS) platform that allows researchers to screen drugs or other compounds against three-dimensional (3D) cell culture systems in a multi-well format (384-well). Furthermore, we compare the quality of robotic liquid handling with manual pipetting and characterize and contrast the phenotypic effects detected by confocal imaging and biochemical assays in response to drug treatment. We show that robotic liquid handling is more consistent and amendable to high throughput experimental designs when compared to manual pipetting due to improved precision and automated randomization capabilities. We also show that image-based techniques are more sensitive to detecting phenotypic changes within organoid cultures than traditional biochemical assays that evaluate cell viability, supporting their integration into organoid screening workflows. Finally, we highlight the enhanced capabilities of confocal imaging in this organoid screening platform as they relate to discerning organoid drug responses in single-well co-cultures of organoids derived from primary human biopsies and patient-derived xenograft (PDX) models. Altogether, this platform enables automated, imaging-based HCS of 3D cellular models in a non-destructive manner, opening the path to complementary analysis through integrated downstream methods.

Proteomic profiling identifies a direct interaction between heat shock transcription factor 2 and the focal adhesion adapter talin-1.

Heat shock factor 2 (HSF2) is a versatile transcription factor that regulates gene expression under stress conditions, during development, and in disease. Despite recent advances in characterizing HSF2-dependent target genes, little is known about the protein networks associated with this transcription factor. In this study, we performed co-immunoprecipitation coupled with mass spectrometry analysis to identify the HSF2 interactome in mouse testes, where HSF2 is required for normal sperm development. Endogenous HSF2 was discovered to form a complex with several adhesion-associated proteins, a finding substantiated by mass spectrometry analysis conducted in human prostate carcinoma PC-3 cells. Notably, this group of proteins included the focal adhesion adapter protein talin-1 (TLN1). Through co-immunoprecipitation and proximity ligation assays, we demonstrate the conservation of the HSF2-TLN1 interaction from mouse to human. Additionally, employing sequence alignment analyses, we uncovered a TLN1-binding motif in the HSF2 C terminus that binds directly to multiple regions of TLN1 in vitro. We provide evidence that the 25 C-terminal amino acids of HSF2, fused to EGFP, are sufficient to establish a protein complex with TLN1 and modify cell-cell adhesion in human cells. Importantly, this TLN1-binding motif is absent in the C-terminus of a closely related HSF family member, HSF1, which does not form a complex with TLN1. These results highlight the unique molecular characteristics of HSF2 in comparison to HSF1. Taken together, our data unveil the protein partners associated with HSF2 in a physiologically relevant context and identifies TLN1 as the first adhesion-related HSF2-interacting partner.

IKKɛ induces STING non-IFN immune responses via a mechanism analogous to TBK1.

The cGAS-STING pathway responds to cytosolic DNA to elicit host immunity to infection. The activation of stimulator of interferon genes (STING) can trigger a number of critical cellular responses including inflammation, noncanonical autophagy, lipid metabolism, senescence, and cell death. STING-mediated immunity through the production of type I interferons (IFNs) and nuclear factor kappa B (NF-κB)-driven proinflammatory cytokines is primarily driven via the effector protein TBK1. We have previously found that IκBα kinase epsilon (IKKε), a homolog of TBK1, can also facilitate STING-NF-κB responses. Therefore, a thorough understanding of how IKKε participates in STING signaling is essential. Here, we used a combination of genetic and biochemical approaches to provide mechanistic details into how IKKε confers non-IFN (e.g., NF-κB and MAPK) STING responses in macrophages, including in the absence of TBK1. We demonstrate a conserved mechanism of STING binding between TBK1 and IKKε. These findings strengthen our understanding of cGAS-STING signaling and the preservation of host immunity in cases of TBK1-deficiency.

The impact of diabetes and presurgical glycemic control on wound morbidity following open complex abdominal wall reconstruction: a single-center experience.

INTRODUCTION: Numerous studies have identified diabetes mellites (DM) as a significant risk factor for postoperative wound morbidity, with suboptimal preoperative glycemic control (GC) posing an even greater risk. However, this data largely excludes ventral hernia patients. Our study examined the association between diabetes and preoperative GC and postoperative outcomes following open complex abdominal wall reconstruction (AWR). METHODS: We identified diabetic patients who had undergone open, elective, clean VHR with transversus abdominis release (TAR) and permanent synthetic mesh at the Cleveland Clinic Foundation between January 2014 and December 2023. Their 30-day outcomes were compared to non-diabetic patients undergoing the same procedure. Subsequently, diabetic patients were categorized based on GC. status: "Optimal GC" (HbA1c < 7%), "Sub-optimal GC" (HbA1c 7-8.4%), and "Poor GC" (HbA1c ≥ 8.5%) and their outcomes were compared. RESULTS: 514 patients with DM who underwent clean elective TAR were identified, of which 431 met the inclusion criteria. GC was deemed optimal in 255 patients, sub-optimal in 128, and poor in 48 patients. Demographics were similar, except for anticoagulation treatment (p = 0.014). The entire study population exhibited significantly higher rates of wound morbidities and overall complications compared to non-diabetic patients. However, rates of surgical site infection (SSI), surgical site occurrence (SSO), SSO requiring procedural intervention (SSOPI), and reoperation did not differ significantly among the three cohorts of presurgical glycemic control (p = 0.82, p = 0.46, p = 0.51, p = 0.78), respectively. No occurrence of mesh removal was documented. CONCLUSION: In general, diabetes is a marker for increased wound morbidity and complications following complex abdominal wall reconstruction. However, we could not establish a hard cutoff to justify withholding surgery in symptomatic patients based on an arbitrary HbA1C level. We believe this data is important for shared decision-making when considering AWR for symptomatic ventral hernias in diabetic patients.

Closing the Loop on Concentric Tube Robot Design: A Case Study on Micro-Laryngeal Surgery.

Concentric tube robots (CTRs) are well-suited to address the unique challenges of minimally invasive surgical procedures due to their small size and ability to navigate highly constrained environments. However, uncertainties in the manufacturing process can lead to challenges in the transition from simulated designs to physical robots. In this work, we propose an end-to-end design workflow for CTRs that considers the oftenoverlooked impact of manufacturing uncertainty, focusing on two primary sources - tube curvature and diameter. This comprehensive approach incorporates a two-step design optimization and an uncertainty-based selection of manufacturing tolerances. Simulation results highlight the substantial influence of manufacturing uncertainties, particularly tube curvature, on the physical robot's performance. By integrating these uncertainties into the design process, we can effectively bridge the gap between simulation and real-world performance. Two hardware experiments validate the proposed CTR design workflow. The first experiment confirms that the performance of the physical robot lies within the simulated probability distribution from the optimization, while the second experiment demonstrates the feasibility of the overall system for use in micro-laryngeal surgical tasks. This work not only contributes to a more comprehensive understanding of CTR design by addressing manufacturing uncertainties, but also creates a new framework for robust design, as illustrated in the context of microlaryngeal surgery.

Cdc14 phosphatases use an intramolecular pseudosubstrate motif to stimulate and regulate catalysis.

Cdc14 phosphatases are related structurally and mechanistically to protein tyrosine phosphatases (PTPs) but evolved a unique specificity for phosphoSer-Pro-X-Lys/Arg sites primarily deposited by cyclin-dependent kinases. This specialization is widely conserved in eukaryotes. The evolutionary reconfiguration of the Cdc14 active site to selectively accommodate phosphoSer-Pro likely required modification to the canonical PTP catalytic cycle. While studying Saccharomyces cerevisiae Cdc14, we discovered a short sequence in the disordered C terminus, distal to the catalytic domain, which mimics an optimal substrate. Kinetic analyses demonstrated this pseudosubstrate binds the active site and strongly stimulates rate-limiting phosphoenzyme hydrolysis, and we named it "substrate-like catalytic enhancer" (SLiCE). The SLiCE motif is found in all Dikarya fungal Cdc14 orthologs and contains an invariant glutamine, which we propose is positioned via substrate-like contacts to assist orientation of the hydrolytic water, similar to a conserved active site glutamine in other PTPs that Cdc14 lacks. AlphaFold2 predictions revealed vertebrate Cdc14 orthologs contain a conserved C-terminal alpha helix bound to the active site. Although apparently unrelated to the fungal sequence, this motif also makes substrate-like contacts and has an invariant glutamine in the catalytic pocket. Altering these residues in human Cdc14A and Cdc14B demonstrated that it functions by the same mechanism as the fungal motif. However, the fungal and vertebrate SLiCE motifs were not functionally interchangeable, illuminating potential active site differences during catalysis. Finally, we show that the fungal SLiCE motif is a target for phosphoregulation of Cdc14 activity. Our study uncovered evolution of an unusual stimulatory pseudosubstrate motif in Cdc14 phosphatases.

"Does an Additional Advanced Degree Influence Career Trajectory as a Shoulder and Elbow Surgeon?"

BACKGROUND: As orthopedic surgery becomes increasingly competitive, orthopedic surgeons are now pursuing advanced degrees more frequently to enhance their resumes or gain additional expertise. The specific impact of this additional training and education on a surgeon's career trajectory is not well defined. The purpose of this study was to understand the impact of an advanced degree on the academic career of orthopedic shoulder and elbow surgeons. METHODS: Orthopedic shoulder and elbow fellowship-trained surgeons were identified using the directory listed on the American Shoulder and Elbow Surgeons website. Demographics, education, and current professional roles were obtained. Research productivity was obtained using SCOPUS and Google Scholar. Advanced degrees were defined as those additional to the primary medical degree (Doctor of Medicine [MD] or Doctor of Osteopathic Medicine [DO]). Outcome measures collected included timing of advanced degree obtainment, current academic and leadership roles, leadership on journal editorial boards, and research productivity. Statistical analysis was performed using the chi-square test and Mann-Whitney U test to determine the association of advanced degrees on outcome measures. RESULTS: In total, 893 orthopedic shoulder and elbow surgeons were identified, of whom 129 had advanced degrees. Most common advanced degrees included Master of Science (MS/MSc; 43%), Master of Business Administration (MBA; 23%), and Doctor of Philosophy (PhD; 13%). The most common period of degree obtainment was before medical school (35%) with the least common times being after medical school/before residency (0.9%) and between residency and fellowship training (0.9%). Surgeons who held advanced degrees demonstrated greater research productivity, with a higher h-index (p < 0.001), a greater number of citations (p < 0.001), and more publications (p < 0.001). Of the 523 shoulder and elbow surgeons who worked at an academic institution, those holding advanced degrees were more likely to serve as orthopedic department chair (p < 0.001) and serve an editorial board position (< 0.001). CONCLUSION: This study found that having an advanced degree as an orthopedic shoulder and elbow surgeon was linked to higher research impact and productivity and an increased likelihood of becoming a department chair and holding an editorial position. These significant findings can help future trainees and department leadership in understanding the importance and impact of additional training on career trajectories for academic faculty.

Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis.

Tissue mechanical properties are determined mainly by the extracellular matrix (ECM) and actively maintained by resident cells. Despite its broad importance to biology and medicine, tissue mechanical homeostasis remains poorly understood. To explore cell-mediated control of tissue stiffness, we developed mutations in the mechanosensitive protein talin 1 to alter cellular sensing of ECM. Mutation of a mechanosensitive site between talin 1 rod-domain helix bundles R1 and R2 increased cell spreading and tension exertion on compliant substrates. These mutations promote binding of the ARP2/3 complex subunit ARPC5L, which mediates the change in substrate stiffness sensing. Ascending aortas from mice bearing these mutations showed less fibrillar collagen, reduced axial stiffness, and lower rupture pressure. Together, these results demonstrate that cellular stiffness sensing contributes to ECM mechanics, directly supporting the mechanical homeostasis hypothesis and identifying a mechanosensitive interaction within talin that contributes to this mechanism.

Neural mechanisms responsible for vagus nerve stimulation-dependent enhancement of somatosensory recovery.

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized, moderate intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.

Opportunities and challenges for the U.S. laboratory response to highly pathogenic avian influenza A(H5N1).

On March 25, 2024 an outbreak of highly pathogenic avian influenza (HPAI) A H5N1 was identified in dairy cows across multiple farms in the United States. Zoonotic cases originating in individuals with close contact to infected herds and poultry flocks have been subsequently identified. Spillover events such as this raise the specter of recent pandemics including COVID-19 and Mpox and may lead clinical laboratories to assess their capacity for diagnosis of HPAI H5N1. In this review, we detail the origins of the H5N1 clade 2.3.4.4b outbreak as well as the existing capacity to identify HPAI H5N1 as influenza A virus by commercially available assays. Furthermore, we highlight the absence of commercially available influenza A H5 subtyping assays and limitations associated with the current 510(k)-cleared assay. This outbreak also serves as an early opportunity to assess the new and unknown regulatory challenges faced by laboratory-developed tests in light of the FDA's final rule on in vitro diagnostic devices. National agencies along with public health and clinical laboratories all serve an essential role in the response to HPAI H5N1. To most effectively utilize each group's strength requires open communication and willingness to embrace novel approaches.