Catalytically Active Site Mapping Realized through Energy Transfer Modeling.

The demands of a sustainable chemical industry are a driving force for the development of heterogeneous catalytic platforms exhibiting facile catalyst recovery, recycling, and resilience to diverse reaction conditions. Homogeneous-to-heterogeneous catalyst transitions can be realized through the integration of efficient homogeneous catalysts within porous matrices. Herein, we offer a versatile approach to understanding how guest distribution and evolution impact the catalytic performance of heterogeneous host-guest catalytic platforms by implementing the resonance energy transfer (RET) concept using fluorescent model systems mimicking the steric constraints of targeted catalysts. Using the RET-based methodology, we mapped condition-dependent guest (re)distribution within a porous support on the example of modular matrices such as metal-organic frameworks (MOFs). Furthermore, we correlate RET results performed on the model systems with the catalytic performance of two MOF-encapsulated catalysts used to promote CO2 hydrogenation and ring-closing metathesis. Guests are incorporated using aperture-opening encapsulation, and catalyst redistribution is not observed under practical reaction conditions, showcasing a pathway to advance catalyst recyclability in the case of host-guest platforms. These studies represent the first generalizable approach for mapping the guest distribution in heterogeneous host-guest catalytic systems, providing a foundation for predicting and tailoring the performance of catalysts integrated into various porous supports.

A low-kiloelectronvolt focused ion beam strategy for processing low-thermal-conductance materials with nanoampere currents.

Ion beam-induced heat damage in thermally low conductive specimens such as biological samples is gaining increased interest within the scientific community. This is partly due to the increased use of FIB-SEMs in biology as well as the development of complex materials, such as polymers, which need to be analyzed. The work presented here looks at the physics behind the ion beam-sample interactions and the effect of the incident ion energy (set by the acceleration voltage) on inducing increases in sample temperature and potential heat damage in thermally low conductive materials such as polymers and biological samples. The ion beam-induced heat for different ion beam currents at low acceleration voltages is calculated using Fourier's law of heat transfer, finite element simulations, and numerical modelling results and compared to experiments. The results indicate that with lower accelerator voltages, higher ion beam currents in the nanoampere range can be used to pattern or image soft material and non-resin-embedded biological samples with increased milling speed but reduced heat damage.

Provincial and connector qualities of somatosensory brain network hubs in bipolar disorder.

Brain network hubs are highly connected brain regions serving as important relay stations for information integration. Recent studies have linked mental disorders to impaired hub function. Provincial hubs mainly integrate information within their own brain network, while connector hubs share information between different brain networks. This study used a novel time-varying analysis to investigate whether hubs aberrantly follow the trajectory of other brain networks than their own. The aim was to characterize brain hub functioning in clinically remitted bipolar patients. We analyzed resting-state functional magnetic resonance imaging data from 96 euthymic individuals with bipolar disorder and 61 healthy control individuals. We characterized different hub qualities within the somatomotor network. We found that the somatomotor network comprised mainly provincial hubs in healthy controls. Conversely, in bipolar disorder patients, hubs in the primary somatosensory cortex displayed weaker provincial and stronger connector hub function. Furthermore, hubs in bipolar disorder showed weaker allegiances with their own brain network and followed the trajectories of the limbic, salience, dorsal attention, and frontoparietal network. We suggest that these hub aberrancies contribute to previously shown functional connectivity alterations in bipolar disorder and may thus constitute the neural substrate to persistently impaired sensory integration despite clinical remission.

How signature complexity affects expert and lay ability to distinguish genuine, disguised and simulated signatures.

This study examined how variations in signature complexity affected the ability of forensic document examiners (FDEs) and laypeople to determine whether signatures are authentic or simulated (forged), as well as whether they are disguised. Forty-five FDEs from nine countries evaluated nine different signature comparisons in this online study. Receiver Operating Characteristic (ROC) analyses revealed that FDEs performed in excess of chance levels, but performance varied as a function of signature complexity: Sensitivity (the true-positive rate) did not differ much between complexity levels (i.e., 65% vs. 79% vs. 79% for low vs medium vs high complexity), but specificity (the true-negative rate) was the highest (95%) for the medium complexity signatures and lowest (73%) for low complexity signatures. The specificity of high-complexity signatures (83%) was between these values. The sensitivity for disguised comparisons was only 11% and did not vary across complexity levels. One hundred-one novices also completed the study. A comparison of the area under the ROC curve (AUCs) revealed that FDEs outperformed novices in medium and high-complexity signatures but not low-complexity signatures. Novices also struggled to detect disguised signatures. While these findings elucidate the role of signature complexity in lay and expert evaluations, the error rates observed here may differ from those in forensic practice due to differences in the experimental stimuli and circumstances under which they were evaluated. This investigation of the role of signature complexity in the evaluation process was not intended to estimate error rates in forensic practice.

Patterns and correlates of traumatic stress, depression, anxiety, and moral injury in U.S. health care providers late in the COVID-19 pandemic.

OBJECTIVE: Providing health care during the COVID-19 pandemic has been associated with a high mental health burden for health care providers. This study examined patterns of responses and correlates of class membership across commonly assessed mental health symptoms, psychosocial functioning, and moral injury for providers in the United States in Fall 2022. METHOD: A convenience sample of 1,504 primary care physicians, pediatricians, nurse practitioners, and physician assistants who had been in practice for three or more years (Mage = 46.1 years, SDage = 11.3, 58% male) completed self-report measures in an online, opt-in panel survey from September to November 2022. RESULTS: Using latent class analysis, three classes were identified: No/Low Symptoms (64.8%), High Moral Injury (19.9%), and Elevated Symptoms (15.2%). Several factors were correlated with class membership including age, sex, social support, personal risk of COVID-19, pandemic-related work stressors, proportion of COVID-19 patients seen at the height of the pandemic, and death of a patient due to COVID-19. CONCLUSIONS: This study found high levels of mental health symptoms, and problems with psychosocial functioning and moral injury in health care providers well past the pandemic's peak. The results also demonstrated the importance of considering the unique contribution of moral injury to psychosocial functional difficulties experienced by health care providers during the pandemic given their defined role as essential workers. These findings have implications for preventing and managing mental health problems and burnout among providers postpandemic as well as for future pandemics at both the organizational and individual levels. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Testing trends and co-testing patterns for HIV, hepatitis C and sexually transmitted infections (STIs) in Emergency departments.

Background: Many underserved populations use Emergency Department (EDs) as primary sources of care, representing an important opportunity to provide infectious disease testing and linkage to care. We explored national ED testing trends and co-testing patterns for HIV, hepatitis C, and sexually transmitted infections (STIs). Methods: We used 2010-2019 Healthcare Cost and Utilization Project, Nationwide Emergency Department Sample data to estimate ED visit testing rates for HIV, hepatitis C, chlamydia, gonorrhea, and syphilis infections, identified by Current Procedural Terminology codes. Trends and co-testing (visit with tests for > 1 infection) patterns were analyzed by sociodemographic, hospital, and visit characteristics. Trends were evaluated as the average annual percentage change (AAPC) using the Joinpoint Regression. Results: During 2010-2019, testing events per 1000 visits (AAPCs) increased for HIV from 1.3 to 4.2 (16.3 %), hepatitis C from 0.4 to 2.2 (25.1 %), chlamydia from 9.1 to 16.0 (6.6 %), gonorrhea from 8.4 to 15.7 (7.4 %), and syphilis from 0.7 to 2.0 (12.9 %). Rate increases varied by several characteristics across infections. The largest AAPC increases were among visits by groups with lower base rate testing in 2010, including persons aged ≥ 65 years (HIV: 36.4 %), with Medicaid (HIV: 43.8 %), in the lowest income quintile (hepatitis C: 36.9 %), living in the West (syphilis: 49.4 %) and with non-emergency diagnoses (hepatitis C: 44.1 %). Co-testing increased significantly for all infections except hepatitis C. Conclusions: HIV, hepatitis C, and STI testing increased in EDs during 2010-2019; however, co-testing patterns were inconsistent. Co-testing may improve diagnosis and linkage to care, especially in areas experiencing higher rates of infection.

Potential impact of curative and preventive interventions toward hepatitis C elimination in people who inject drugs-A network modeling study.

BACKGROUND: Injection-equipment-sharing networks play an important role in hepatitis C virus (HCV) transmission among people who inject drugs (PWID). Direct-acting antiviral (DAA) treatments for HCV infection and interventions to prevent HCV transmission are critical components of an overall hepatitis C elimination strategy, but how they contribute to the elimination outcomes in different PWID network settings are unclear. METHODS: We developed an agent-based network model of HCV transmission through the sharing of injection equipment among PWID and parameterized and calibrated the model with rural PWID data in the United States. We modeled curative and preventive interventions at annual coverage levels of 12.5 %, 25 %, or 37.5 % (cumulative percentage of eligible individuals engaged), and two allocation approaches: random vs targeting PWID with more injection partners (hereafter 'degree-based'). We compared the impact of these intervention strategies on prevalence and incidence of HCV infections. We conducted sensitivity analysis on key parameters governing the effects of curative and preventive interventions and PWID network characteristics. RESULTS: Combining curative and preventive interventions at 37.5 % annual coverage with degree-based allocation decreased prevalence and incidence of HCV infection by 67 % and 70 % over two years, respectively. Curative interventions decreased prevalence by six to 12 times more than preventive interventions, while curative and preventive interventions had comparable effectiveness on reducing incidence. Intervention impact increased with coverage almost linearly across all intervention strategies, and degree-based allocation was always more effective than random allocation, especially for preventive interventions. Results were sensitive to parameter values defining intervention effects and network mean degree. CONCLUSION: DAA treatments are effective in reducing both prevalence and incidence of HCV infection in PWID, but preventive interventions play a significant role in reducing incidence when intervention coverage is low. Increasing coverage, including efforts in reaching individuals with the most injection partners, preventing reinfection, and improving compliance and retention in preventive services can substantially improve the outcomes. PWID network characteristics should be considered when designing hepatitis C elimination programs.

Medicaid Expansion and Restriction Policies for Hepatitis C Treatment.

Importance: Hepatitis C can be cured with direct-acting antivirals (DAAs), but Medicaid programs have implemented fibrosis, sobriety, and prescriber restrictions to control costs. Although restrictions are easing, understanding their association with hepatitis C treatment rates is crucial to inform policies that increase access to lifesaving treatment. Objective: To estimate the association of jurisdictional (50 states and Washington, DC) DAA restrictions and Medicaid expansion with the number of Medicaid recipients with filled prescriptions for DAAs. Design, Setting, and Participants: This cross-sectional study used publicly available Medicaid documents and claims data from January 1, 2014, to December 31, 2021, to compare the number of unique Medicaid recipients treated with DAAs in each jurisdiction year with Medicaid expansion status and categories of fibrosis, sobriety, and prescriber restrictions. Medicaid recipients from all 50 states and Washington, DC, during the study period were included. Multilevel Poisson regression was used to estimate the association between Medicaid expansion and DAA restrictive policies on jurisdictional Medicaid DAA prescription fills. Data were analyzed initially from August 15 to November 15, 2023, and subsequently from April 15 to May 9, 2024. Exposures: Jurisdictional Medicaid expansion status and fibrosis, sobriety, and prescriber DAA restrictions. Main Outcomes and Measures: Number of people treated with DAAs per 100 000 Medicaid recipients per year. Results: A total of 381 373 Medicaid recipients filled DAA prescriptions during the study period (57.3% aged 45-64 years; 58.7% men; 15.2% non-Hispanic Black and 52.2% non-Hispanic White). Medicaid nonexpansion jurisdictions had fewer filled DAA prescriptions per 100 000 Medicaid recipients per year than expansion jurisdictions (38.6 vs 86.6; adjusted relative risk [ARR], 0.56 [95% CI, 0.52-0.61]). Jurisdictions with F3 to F4 (34.0 per 100 000 Medicaid recipients per year; ARR, 0.39 [95% CI, 0.37-0.66]) or F1 to F2 fibrosis restrictions (61.9 per 100 000 Medicaid recipients per year; ARR, 0.62 [95% CI, 0.59-0.66]) had lower treatment rates than jurisdictions without fibrosis restrictions (94.8 per 100 000 Medicaid recipients per year). Compared with no sobriety restrictions (113.5 per 100 000 Medicaid recipients per year), 6 to 12 months of sobriety (38.3 per 100 000 Medicaid recipients per year; ARR, 0.65 [95% CI, 0.61-0.71]) and screening and counseling requirements (84.7 per 100 000 Medicaid recipients per year; ARR, 0.87 [95% CI, 0.83-0.92]) were associated with reduced treatment rates, while 1 to 5 months of sobriety was not statistically significantly different. Compared with no prescriber restrictions (97.8 per 100 000 Medicaid recipients per year), specialist consult restrictions was associated with increased treatment (66.2 per 100 000 Medicaid recipients per year; ARR, 1.05 [95% CI, 1.00-1.10]), while specialist required restrictions were not statistically significant. Conclusions and Relevance: In this cross-sectional study, Medicaid nonexpansion status, fibrosis, and sobriety restrictions were associated with a reduction in the number of people with Medicaid who were treated for hepatitis C. Removing DAA restrictions might facilitate treatment of more people diagnosed with hepatitis C.

Acridine photocatalysis enables tricomponent direct decarboxylative amine construction.

Amines are centrally important motifs in medicinal chemistry and biochemistry, and indispensable intermediates and linchpins in organic synthesis. Despite their cross-disciplinary prominence, synthetic access to amine continues to rely on two-electron approaches based on reductions and additions of organometallic reagents, limiting their accessible chemical space and necessitating stepwise preassembly of synthetic precursors. We report herein a homogeneous photocatalytic tricomponent decarboxylative radical-mediated amine construction that enables modular access to α-branched secondary amines directly from the broad and structurally diverse chemical space of carboxylic acids in a tricomponent reaction with aldehydes and aromatic amines. Our studies reveal the key role of acridine photocatalysis acting in concert with copper and Brønsted acid catalytic processes in facilitating the previously inaccessible homogeneous photocatalytic reaction and provide a streamlined segue to a wide range of amines and nonproteinogenic α-amino acids.

Time-varying similarity of neural responses to musical tension is shaped by physical features and musical themes.

The similarity of understanding is important for music experience and communication, but little is understood about the sources of this common knowledge. Although neural responses to the same piece of music are known to be similar across listeners, it remains unclear whether this neural response similarity is linked to musical understanding and the role of dynamic musical attributes in shaping it. Our study addresses this gap by investigating the relationship between neural response similarity, musical tension, and dynamic musical attributes. Using electroencephalography-based inter-subject correlation (EEG-ISC), we examined how the neural response similarity among listeners varies throughout the evaluation of musical tension in the first movement of Beethoven's Piano Sonata No. 8. Participants continuously rated the degree of alignment between musical events and their expectations, while neural activity was recorded using electroencephalography (EEG). The results showed that neural response similarity fluctuated in tandem with musical tension, with increased similarity observed during moments of heightened tension. This time-varying neural response similarity was influenced by two dynamic attributes contributing to musical tension: physical features and musical themes. Specifically, its fluctuation was driven by physical features, and the patterns of its variation were modulated by musical themes, with similar time-varying patterns observed across similar thematic materials. These findings offer valuable insight into the role of dynamic musical attributes in shaping neural response similarity, and reveal an important source and mechanism of shared musical understandings.

Conditional loss of CaMKK2 in Osterix-positive osteoprogenitors enhances osteoblast function in a sex-divergent manner.

Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a multi-functional, serine/threonine protein kinase with predominant roles in inflammation, systemic energy metabolism, and bone remodeling. We previously reported that global ablation of CaMKK2 or its systemic pharmacological inhibition led to bone mass accrual in mice by stimulating osteoblasts and inhibiting osteoclasts. However, a direct, cell-intrinsic role for the kinase in the osteoblast lineage has not been established. Here we report that conditional deletion of CaMKK2 from osteoprogenitors, using the Osterix 1 (Osx1) - GFP::Cre (tetracycline-off) mouse line, resulted in increased trabecular bone mass due to an acute stimulation of osteoblast function in male and female mice. The acute simulation of osteoblasts and bone formation following conditional ablation of osteoprogenitor-derived CaMKK2 was sustained only in female mice. Periosteal bone formation at the cortical bone was enhanced only in male conditional knockout mice without altering cortical bone mass or strength. Prolonged deletion of CaMKK2 in early osteoblasts was accompanied by a stimulation of osteoclasts in both sexes, indicating a coupling effect. Notably, alterations in trabecular and cortical bone mass were absent in the doxycycline-removed "Cre-only" Osx1-GFP::Cre mice. Thus, the increase in osteoblast function at the trabecular and cortical bone surfaces following the conditional deletion of CaMKK2 in osteoprogenitors is indicative of a direct but sex-divergent role for the kinase in osteoblasts.

Interventional probability of causation (IPoC) with epidemiological and partial mechanistic evidence: benzene vs. formaldehyde and acute myeloid leukemia (AML).

INTRODUCTION: Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define interventional probability of causation (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of causal assigned share (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed. Traditional approaches used to evaluate the preventable risk implications of epidemiological associations, including population attributable fraction (PAF) and the Bradford Hill considerations, cannot reveal whether removing a risk factor would reduce disease incidence. We argue that modern formal causal models coupled with causal artificial intelligence (CAI) and realistically partial and imperfect knowledge of underlying disease mechanisms, show great promise for determining and quantifying IPoC and CAS for exposures and diseases of practical interest. METHODS: We briefly review key CAI concepts and terms and then apply them to define IPoC and CAS. We present steps to quantify IPoC using a fully specified causal Bayesian network (BN) model. Useful bounds for quantitative IPoC and CAS calculations are derived for a two-stage clonal expansion (TSCE) model for carcinogenesis and illustrated by applying them to benzene and formaldehyde based on available epidemiological and partial mechanistic evidence. RESULTS: Causal BN models for benzene and risk of acute myeloid leukemia (AML) incorporating mechanistic, toxicological and epidemiological findings show that prolonged high-intensity exposure to benzene can increase risk of AML (IPoC of up to 7e-5, CAS of up to 54%). By contrast, no causal pathway leading from formaldehyde exposure to increased risk of AML was identified, consistent with much previous mechanistic, toxicological and epidemiological evidence; therefore, the IPoC and CAS for formaldehyde-induced AML are likely to be zero. CONCLUSION: We conclude that the IPoC approach can differentiate between likely and unlikely causal factors and can provide useful upper bounds for IPoC and CAS for some exposures and diseases of practical importance. For causal factors, IPoC can help to estimate the quantitative impacts on health risks of reducing exposures, even in situations where mechanistic evidence is realistically incomplete and individual-level exposure-response parameters are uncertain. This illustrates the strength that can be gained for causal inference by using causal models to generate testable hypotheses and then obtaining toxicological data to test the hypotheses implied by the models-and, where necessary, refine the models. This virtuous cycle provides additional insight into causal determinations that may not be available from weight-of-evidence considerations alone.

Acquired amusia after a right middle cerebral artery infarction - a case study.

A 62-year-old musician-MM-developed amusia after a right middle-cerebral-artery infarction. Initially, MM showed melodic deficits while discriminating pitch-related differences in melodies, musical memory problems, and impaired sensitivity to tonal structures, but normal pitch discrimination and spectral resolution thresholds, and normal cognitive and language abilities. His rhythmic processing was intact when pitch variations were removed. After 3 months, MM showed a large improvement in his sensitivity to tonality, but persistent melodic deficits and a decline in perceiving the metric structure of rhythmic sequences. We also found visual cues aided melodic processing, which is novel and beneficial for future rehabilitation practice.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias.

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types. A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.e., US EPA TSCA and NTP OHAT). Several components of the triangulation framework also drew from widely used epidemiological analytic tools such as stratified meta-analysis and sensitivity analysis. Regarding the applied example, fourteen studies were identified and assessed using the following primary study quality domains to explore potential key sources of bias: 1) study design and analysis; 2) study participation; 3) exposure assessment; 4) outcome assessment; and 5) potential confounding. Across studies, methodological limitations possibly contributing to biased results were observed within most domains. Interestingly, results from one study - often providing the largest and least-precise relative risk estimates, likely reflecting study biases, deviated from most primary study findings indicating no such associations. Triangulation of epidemiological evidence appears to be helpful in exploring inconsistent results for the identification of study results possibly reflecting various biases. Nonetheless, triangulation methodologies require additional development and application to real-world examples to enhance objectivity and reproducibility.

Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER.

PURPOSE: Evaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS). METHODS: TAZPOWER was a 28-week randomized, double-blind, and placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40 mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue score. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed. RESULTS: Ten patients entered the OLE; 8 reached the week 168 visit. Elamipretide was well tolerated, with injection-site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE time points (cumulative 96.1 m of improvement [week 168, P = .003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE time points. Three-dimensional (3D) left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes. CONCLUSION: Elamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.

Assessing the usability of an immersive virtual reality grocery store in healthy controls.

BACKGROUND: Immersive virtual reality (IVR) as a research platform to study human behaviors is an emerging field and may be useful for studying self-care management, especially in the gap between formal healthcare recommendations and day-to-day living. Self-care activities, such as grocery shopping, can be challenging for people with chronic illness. We developed an IVR environment that simulates a real-life grocery store and conducted a usability study to demonstrate the safety and acceptability of IVR as an experimental environment. METHODS: This study was a three-arm randomized control trial involving 24 participants, conducted as a usability study to evaluate aspects of the experimental condition including the effectiveness of a training exposure, the occurrence of undesirable effects associated with IVR, and participants' experiences of realism, immersion, and spatial presence. The experiment, using a head mounted device and handheld controllers, included a 10-minute training exposure, followed by one of three unique 30-minute experimental conditions which exposed participants to different combinations of tasks and stimuli, and a post-experience interview. We measured controller errors, undesirable symptoms associated with IVR, and the perception of realism, immersion, and spatial presence. RESULTS: Participants used controllers effectively to interact within the IVR environment. Hand controller use errors were fewer during the experimental conditions compared to the training exposure. Minimal undesirable IVR symptoms were reported. Presence was rated in the middle range with no significant differences based on experimental condition. Overall, user experience feedback was positive. CONCLUSIONS: We demonstrated that participants could engage in our IVR environment without excessive error or experiencing undesirable effects and confirmed that the virtual experience attained a level of presence necessary to effectively engage in the study. These findings give us confidence that this IVR intervention designed to explore instrumental activities of daily living is safe, effective and provides a credible, controlled simulated community-like setting.

Osterix-driven LINC complex disruption in vivo diminishes osteogenesis at 8 weeks but not at 15 weeks.

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formation in vivo, however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Tg(CAG-LacZ/EGFP-KASH2) mice contain a lox-STOP-lox flanked LacZ gene which is deleted upon cre recombination allowing for the overexpression of an EGFP-KASH2 fusion protein. This overexpressed protein disrupts endogenous Nesprin-Sun binding leading to disruption of LINC complexes. Thus, crossing these two lines results in an  Osx- driven  LINC  disruption (ODLD) specific to pre-osteoblasts. In this study, we investigated how this LINC disruption affects exercise-induced bone accrual. ODLD cells had decreased osteogenic and adipogenic potential in vitro compared to non-disrupted controls and sedentary ODLD mice showed decreased bone quality at 8 weeks. Upon access to a voluntary running wheel, ODLD animals showed increased running time and distance; however, our 6-week exercise intervention did not significantly affect bone microarchitecture and bone mechanical properties.