Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and Polygenic Risk Scores to inform Colorectal Cancer screening.

INTRODUCTION: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize Colorectal Cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening to standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of "no CRC", CRC stages (A-D) and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared to SOC. The incremental cost-effectiveness ratio (ICER) was $124,415 per quality-adjusted life-year (QALY); screening had a 69% probability of being cost-effective using a willingness to pay threshold of $150,000/QALY. Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared to 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

Evaluation of modified clear Twin Block aligner in treating adolescents with skeletal class II malocclusion: A two-centre cephalometric study.

INTRODUCTION: The purpose of this study was to evaluate the therapeutic effect of modified clear Twin Block (CTB) aligner and traditional twin block (TB) appliance from skeletal, dentoalveolar and soft tissue changes in adolescents with skeletal class II malocclusion. METHODS: A total of 80 adolescents, included in this study from two medical centres, were distributed into CTB group, TB group and control group based on the treatment they received. Lateral cephalograms at pre-treatment (T1) and post-treatment (T2) were measured by modified Pancherz's cephalometric analysis, and dentoskeletal and soft tissue changes were analysed by independent-sample t-test, paired-sample t-test, ANOVA test and Scheffe's Post Hoc test. RESULTS: Seventy-five adolescents completed the study, including 32 in the CTB group, 32 in the TB group and 11 in the control group. Both CTB and TB treatment showed significant differences in most dentoskeletal and soft tissue measurements. Compared with the control group, improvements were observed in class II molar relationship through significant different in S Vert/Ms-S Vert/Mi in the CTB group (P < .01) and the TB group (P < .001), as well as deep overjet through significant different in S Vert/Is-S Vert/Ii in the CTB group (P < .001) and the TB group (P < .001). Besides, the CTB group also showed less protrusion of lower incisors and resulted in a more significant improvement in profile with fewer adverse effects on speaking, eating and social activities. CONCLUSIONS: For adolescents with skeletal class II malocclusion, CTB appliance was as effective as TB on improving dentoskeletal and soft tissue measurements, featuring more reliable teeth control and patient acceptance.

Prioritizing Quality Measures in Acute Stroke Care : A Cost-Effectiveness Analysis.

BACKGROUND: The American Heart Association and American Stroke Association (AHA/ASA) endorsed 15 process measures for acute ischemic stroke (AIS) to improve the quality of care. Identifying the highest-value measures could reduce the administrative burden of quality measure adoption while retaining much of the value of quality improvement. OBJECTIVE: To prioritize AHA/ASA-endorsed quality measures for AIS on the basis of health impact and cost-effectiveness. DESIGN: Individual-based stroke simulation model. DATA SOURCES: Published literature. TARGET POPULATION: U.S. patients with incident AIS. TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: Current versus complete (100%) implementation at the population level of quality measures endorsed by the AHA/ASA with sufficient clinical evidence (10 of 15). OUTCOME MEASURES: Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and incremental net health benefits. RESULTS OF BASE-CASE ANALYSIS: Discounted life-years gained from complete implementation would range from 472 (tobacco use counseling) to 34 688 (early carotid imaging) for an annual AIS patient cohort. All AIS quality measures were cost-saving or highly cost-effective by AHA standards (<$50 000 per QALY for high-value care). Early carotid imaging and intravenous tissue plasminogen activator contributed the largest fraction of the total potential value of quality improvement (measured as incremental net health benefit), accounting for 72% of the total value. The top 5 quality measures accounted for 92% of the total potential value. RESULTS OF SENSITIVITY ANALYSIS: A web-based user interface allows for context-specific sensitivity and scenario analyses. LIMITATION: Correlations between quality measures were not incorporated. CONCLUSION: Substantial variation exists in the potential net benefit of quality improvement across AIS quality measures. Benefits were highly concentrated among 5 of 10 measures assessed. Our results can help providers and payers set priorities for quality improvement efforts and value-based payments in AIS care. PRIMARY FUNDING SOURCE: National Institute of Neurological Disorders and Stroke.

Relationships between functional temporomandibular joint space and disc morphology, position, and condylar osseous condition in patients with temporomandibular disorder.

OBJECTIVE: To investigate the correlations between joint space and temporomandibular joint (TMJ) components and the compressive states of the disc and condyle subsequent to joint space changes. MATERIALS AND METHODS: A total of 240 TMJs were categorized according to disc morphology, disc position, and condylar osseous condition. The two-dimensional (2D) and three-dimensional (3D) measurements were compared. The functional joint space (FJS) and disc areas on closed- and open-mouth images (DA-C and DA-O) were also calculated, and the joint space was measured in five directions. Different groups of TMJ components were compared. A spring model was used to simulate the effect of condylar displacement on the disc and condyle. RESULTS: Disc morphology was strongly correlated with its position. The measurements were equivalent between 2D and 3D methods. DA-C and FJS differed significantly between groups. The DA-C to FJS ratio differed between the Class 2 and Class 3 groups and between disc displacement groups with and without reduction. Altered disc morphology and position were correlated with significant changes in joint space in the 60°, 90°, and 120° directions. Despite minor discrepancies among condylar osseous conditions, reduced joint space was correlated with bone destruction at the corresponding site. The spring model stimulation revealed that condylar displacement caused elevated stresses on the disc and condyle. CONCLUSIONS: Condylar displacement causes joint space alterations while exerting compressive pressure on both the disc and condyle. CLINICAL RELEVANCE: Proper condylar positioning within the fossa is recommended to ensure sufficient articular disc accommodation.

Exploring the molecular mechanism of comorbidity of autism spectrum disorder and inflammatory bowel disease by combining multiple data sets.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is difficult to diagnose. Inflammatory bowel disease (IBD) is a common chronic digestive disease. Previous studies have shown a potential correlation between ASD and IBD, but the pathophysiological mechanism remains unclear. The purpose of this research was to examine the biological mechanisms underlying the differentially expressed genes (DEGs) of ASD and IBD using bioinformatics tools. METHODS: Limma software was used to evaluate the DEGs between ASD and IBD. The GSE3365, GSE18123, and GSE150115 microarray data sets were acquired from the Gene Expression Omnibus (GEO) database. We then performed 6 analyses, namely, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation; weighted gene coexpression network analysis; correlation analysis of hub genes with autophagy, ferroptosis and immunity; transcriptional regulation analysis of hub genes; single-cell sequencing analysis; and potential therapeutic drug prediction. RESULTS: A total of 505 DEGs associated with ASD and 616 DEGs associated with IBD were identified, and 7 genes overlapped between these sets. GO and KEGG analyses revealed several pathways enriched in both diseases. A total of 98 common genes related to ASD and IBD were identified by weighted gene coexpression network analysis (WGCNA), and 4 hub genes were obtained by intersection with the 7 intersecting DEGs, which were PDGFC, CA2, GUCY1B3 and SDPR. We also found that 4 hub genes in the two diseases were related to autophagy, ferroptosis or immune factors. In addition, motif-TF annotation analysis showed that cisbp__M0080 was the most relevant motif. We also used the Connectivity Map (CMap) database to identify 4 potential therapeutic agents. CONCLUSION: This research reveals the shared pathogenesis of ASD and IBD. In the future, these common hub genes may provide new targets for further mechanistic research as well as new therapies for patients with ASD and IBD.

An atypical Phytophthora sojae RxLR effector manipulates host vesicle trafficking to promote infection.

In plants, the apoplast is a critical battlefield for plant-microbe interactions. Plants secrete defense-related proteins into the apoplast to ward off the invasion of pathogens. How microbial pathogens overcome plant apoplastic immunity remains largely unknown. In this study, we reported that an atypical RxLR effector PsAvh181 secreted by Phytophthora sojae, inhibits the secretion of plant defense-related apoplastic proteins. PsAvh181 localizes to plant plasma membrane and essential for P. sojae infection. By co-immunoprecipitation assay followed by liquid chromatography-tandem mass spectrometry analyses, we identified the soybean GmSNAP-1 as a candidate host target of PsAvh181. GmSNAP-1 encodes a soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein, which associates with GmNSF of the SNARE complex functioning in vesicle trafficking. PsAvh181 binds to GmSNAP-1 in vivo and in vitro. PsAvh181 interferes with the interaction between GmSNAP-1 and GmNSF, and blocks the secretion of apoplastic defense-related proteins, such as pathogenesis-related protein PR-1 and apoplastic proteases. Taken together, these data show that an atypical P. sojae RxLR effector suppresses host apoplastic immunity by manipulating the host SNARE complex to interfere with host vesicle trafficking pathway.

Framework for determining the optimal course of action when efficiency and affordability measures differ by perspective in cost-effectiveness analysis-with an illustrative case of HIV treatment in Mozambique.

BACKGROUND: Cost-effectiveness analysis (CEA) is a standard tool for evaluating health programs and informing decisions about resource allocation and prioritization. Most CEAs evaluating health interventions in low- and middle-income countries adopt a health sector perspective, accounting for resources funded by international donors and country governments, while often excluding out-of-pocket expenditures and time costs borne by program beneficiaries. Even when patients' costs are included, a companion analysis focused on the patient perspective is rarely performed. We view this as a missed opportunity. METHODS: We developed methods for assessing intervention affordability and evaluating whether optimal interventions from the health sector perspective also represent efficient and affordable options for patients. We mapped the five different patterns that a comparison of the perspective results can yield into a practical framework, and we provided guidance for researchers and decision-makers on how to use results from multiple perspectives. To illustrate the methodology, we conducted a CEA of six HIV treatment delivery models in Mozambique. We conducted a Monte Carlo microsimulation with probabilistic sensitivity analysis from both patient and health sector perspectives, generating incremental cost-effectiveness ratios for the treatment approaches. We also calculated annualized patient costs for the treatment approaches, comparing the costs with an affordability threshold. We then compared the cost-effectiveness and affordability results from the two perspectives using the framework we developed. RESULTS: In this case, the two perspectives did not produce a shared optimal approach for HIV treatment at the willingness-to-pay threshold of 0.3 × Mozambique's annual GDP per capita per DALY averted. However, the clinical 6-month antiretroviral drug distribution strategy, which is optimal from the health sector perspective, is efficient and affordable from the patient perspective. All treatment approaches, except clinical 1-month distributions of antiretroviral drugs which were standard before Covid-19, had an annual cost to patients less than the country's annual average for out-of-pocket health expenditures. CONCLUSION: Including a patient perspective in CEAs and explicitly considering affordability offers decision-makers additional insights either by confirming that the optimal strategy from the health sector perspective is also efficient and affordable from the patient perspective or by identifying incongruencies in value or affordability that could affect patient participation.

Contribution of classical complement activation and IgM to the control of Rickettsia infection.

Pathogenic Rickettsia are obligate intracellular bacteria and the etiologic agents of many life-threatening infectious diseases. Due to the serious nature of these infections, it is imperative to both identify the responsive immune sensory pathways and understand the associated immune mechanisms that restrict Rickettsia proliferation. Previous studies have demonstrated that the mammalian complement system is both activated during Rickettsia infection and contributes to the immune response to infection. To further define this component of the mammalian anti-Rickettsia immune response, we sought to identify the mechanism(s) of complement activation during Rickettsia infection. We have employed a series of in vitro and in vivo models of infection to investigate the role of the classical complement activation pathway during Rickettsia infection. Depletion or elimination of complement activity demonstrates that both C1q and pre-existing IgM contribute to complement activation; thus implicating the classical complement system in Rickettsia-mediated complement activation. Elimination of the classical complement pathway from mice increases susceptibility to R. australis infection with both increased bacterial loads in multiple tissues and decreased immune activation markers. This study highlights the role of the classical complement pathway in immunity against Rickettsia and implicates resident Rickettsia-responsive IgM in the response to infection.

Microbe-derived non-necrotic glycoside hydrolase family 12 proteins act as immunogenic signatures triggering plant defenses.

Plant pattern recognition receptors (PRRs) are sentinels at the cell surface sensing microbial invasion and activating innate immune responses. During infection, certain microbial apoplastic effectors can be recognized by plant PRRs, culminating in immune responses accompanied by cell death. However, the intricated relationships between the activation of immune responses and cell death are unclear. Here, we studied the glycoside hydrolase family 12 (GH12) protein, Ps109281, secreted by Phytophthora sojae into the plant apoplast during infection. Ps109281 exhibits xyloglucanase activity, and promotes P. sojae infection in a manner dependent on the enzyme activity. Ps109281 is recognized by the membrane-localized receptor-like protein RXEG1 and triggers immune responses in various plant species. Unlike other characterized GH12 members, Ps109281 fails to trigger cell death in plants. The loss of cell death induction activity is closely linked to a sequence polymorphism at the N-terminus. This sequence polymorphism does not affect the in planta interaction of Ps109281 with the recognition receptor RXEG1, indicating that cell death and immune response activation are determined using different regions of the GH12 proteins. Such GH12 protein also exists in other Phytophthora and fungal pathogens. Taken together, these results unravel the evolution of effector sequences underpinning different immune outputs.

Cost-effectiveness analysis of sequential fecal microbiota transplantation for fulminant Clostridioides difficile infection.

BACKGROUND AND AIM: Fulminant Clostridioides difficile infections (FCDI) account for 8% of cases and substantial healthcare burden. Fecal microbiota transplantation is recommended for recurrent CDI, but emerging data support use for FCDI. We aimed to assess the cost-effectiveness of a sequential fecal microbiota transplantation (sFMT) protocol for FCDI compared with current standard therapy. METHODS: A Markov model simulated patients with FCDI in a 1-year time horizon. The treatment algorithm for up to three sFMTs, clinical probabilities, and direct costs were used from published sources. Outcomes were quality-adjusted life years (QALYs) and costs. The healthcare sector perspective was used with a willingness-to-pay threshold of $100 000 per QALY. RESULTS: Sequential fecal microbiota transplantation (FMT) for FCDI was associated with lower overall cost ($28 309 vs $33 980) and higher QALY (0.765 vs 0.686) compared with standard therapy. sFMT is cost-effective in 100% of iterations. sFMT remained cost-effective at cure rates > 44.8% for the first FMT and at stool preparation cost < $6944 per instillation. We find a wide range of efficacies for the first versus second FMT at which sFMT is still preferred. Value of information analysis estimates the expected value of perfect information to be low at $1.89 per person, quantified with net monetary benefit. CONCLUSIONS: An sFMT strategy strongly dominates standard therapy, with lower cost and higher QALY. Sensitivity analysis demonstrates benefit even if FMT cure rates are lower than expected and when multiple FMTs are required. FMT material in 2020 was priced at $1695 per treatment but remains cost-effective at a much higher cost.

An integrated framework for modelling quantitative effects of entry restrictions and travel quarantine on importation risk of COVID-19.

OBJECTIVE: As the potential spread of COVID-19 sparked by imported cases from overseas will pose continuous challenges, it is essential to estimate the effects of control measures on reducing the importation risk of COVID-19. Our objective is to provide a framework of methodology for quantifying the combined effects of entry restrictions and travel quarantine on managing the importation risk of COVID-19 and other pandemics by leveraging different sets of parameters. METHODS: Three major categories of control measures on controlling importation risk were parameterized and modelled by the framework: 1) entry restrictions, 2) travel quarantine, and 3) domestic containment measures. Integrating the parameterized intensity of control measures, a modified SEIR model was developed to simulate the case importation and local epidemic under different scenarios of global epidemic dynamics. A web-based tool was also provided to enable interactive visualization of epidemic simulation. RESULTS: The simulated number of case importation and local spread modelled by the proposed framework of methods fitted well to the historical epidemic curve of China and Singapore. Based on the simulation results, the total numbers of infected cases when reducing 30% of visitor arrivals would be 88·4 (IQR 87·5-89·6) and 58·8 (IQR 58·3-59·5) times more than those when reducing 99% of visitor arrivals in mainland China and Singapore respectively, assuming actual time-varying Rt and travel quarantine policy. If the number of global daily new infections reached 100,000, 85%-91% of inbound travels should be reduced to keep the daily new infected number below 100 for a country with a similar travel volume as Singapore (daily 52,000 tourist arrivals in 2019). Whereas if the number was lower than 10,000, the daily new infected case would be less than 100 even with no entry restrictions. DISCUSSIONS: We proposed a framework that first estimated the intensity of travel restrictions and local containment measures for countries since the first overseas imported case. Our approach then quantified the combined effects of entry restrictions and travel quarantine using a modified SEIR model to simulate the potential epidemic spread under hypothetical intensities of these control measures. We also developed a web-based system that enables interactive simulation, which could serve as a valuable tool for health system administrators to assess policy effects on managing the importation risk. By leveraging different sets of parameters, it could adapt to any specific country and specific type of epidemic. CONCLUSIONS: This framework has provided a valuable tool to parameterize the intensity of control measures, simulate both the case importation and local epidemic, and quantify the combined effects of entry restrictions and travel quarantine on managing the importation risk.

Phosphotransferase System Uptake and Metabolism of the ß-Glucoside Salicin Impact Group A Streptococcal Bloodstream Survival and Soft Tissue Infection.

Streptococcus pyogenes (group A Streptococcus [GAS]), a major human-specific pathogen, relies on efficient nutrient acquisition for successful infection within its host. The phosphotransferase system (PTS) couples the import of carbohydrates with their phosphorylation prior to metabolism and has been linked to GAS pathogenesis. In a screen of an insertional mutant library of all 14 annotated PTS permease (EIIC) genes in MGAS5005, the annotated ß-glucoside PTS transporter (bglP) was found to be crucial for GAS growth and survival in human blood and was validated in another M1T1 GAS strain, 5448. In 5448, bglP was shown to be in an operon with a putative phospho-ß-glucosidase (bglB) downstream and a predicted antiterminator (licT) upstream. Using defined nonpolar mutants of the ß-glucoside permease (bglP) and ß-glucosidase enzyme (bglB) in 5448, we showed that bglB, not bglP, was important for growth in blood. Furthermore, transcription of the licT-blgPB operon was found to be repressed by glucose and induced by the ß-glucoside salicin as the sole carbon source. Investigation of the individual bglP and bglB mutants determined that they influence in vitro growth in the ß-glucoside salicin; however, only bglP was necessary for growth in other non-ß-glucoside PTS sugars, such as fructose and mannose. Additionally, loss of BglP and BglB suggests that they are important for the regulation of virulence-related genes that control biofilm formation, streptolysin S (SLS)-mediated hemolysis, and localized ulcerative lesion progression during subcutaneous infections in mice. Thus, our results indicate that the ß-glucoside PTS transports salicin and its metabolism can differentially influence GAS pathophysiology during soft tissue infection.

Cost-effectiveness microsimulation of catheter-directed thrombolysis in submassive pulmonary embolism using a right ventricular function model.

Approximately 30-50% of hemodynamically stable patients presenting with acute pulmonary embolism (PE) have evidence of right ventricular (RV) dysfunction. These patients are classified as submassive PE and the role of reperfusion therapy remains unclear. We sought to identify the circumstances under which catheter-directed thrombolysis (CDT) would represent high-value care for submassive PE. We used a computer-based, individual-level, state-transition model with one million simulated patients to perform a cost-effectiveness analysis comparing the treatment of submassive PE with CDT followed by anticoagulation to treatment with anticoagulation alone. Because RV function impacts prognosis and is commonly used in PE outcomes research, our model used RV dysfunction to differentiate health states. One-way, two-way, and probabilistic sensitivity analyses were used to quantify model uncertainty. Our base case analysis generated an incremental cost-effectiveness ratio (ICER) of $119,326 per quality adjusted life year. Sensitivity analyses resulted in ICERs consistent with high-value care when CDT conferred a reduction in the absolute probability of RV dysfunction of 3.5% or more. CDT yielded low-value ICERs if the absolute reduction was less than 1.56%. Our model suggests that catheter-directed thrombolytics represents high-value care compared to anticoagulation alone when CDT offers an absolute improvement in RV dysfunction of 3.5% or more, but there is substantial uncertainly around these results. We estimated the monetary value of clarifying the costs and consequences surrounding RV dysfunction after submassive PE to be approximately $268 million annually, suggesting further research in this area could be highly valuable.

Functional and structural characterization of the chikungunya virus translational recoding signals.

Climate change and human globalization have spurred the rapid spread of mosquito-borne diseases to naïve populations. One such emerging virus of public health concern is chikungunya virus (CHIKV), a member of the Togaviridae family, genus Alphavirus CHIKV pathogenesis is predominately characterized by acute febrile symptoms and severe arthralgia, which can persist in the host long after viral clearance. CHIKV has also been implicated in cases of acute encephalomyelitis, and its vertical transmission has been reported. Currently, no FDA-approved treatments exist for this virus. Recoding elements help expand the coding capacity in many viruses and therefore represent potential therapeutic targets in antiviral treatments. Here, we report the molecular and structural characterization of two CHIKV translational recoding signals: a termination codon read-through (TCR) element located between the nonstructural protein 3 and 4 genes and a programmed -1 ribosomal frameshift (-1 PRF) signal located toward the 3' end of the CHIKV 6K gene. Using Dual-Luciferase and immunoblot assays in HEK293T and U87MG mammalian cell lines, we validated and genetically characterized efficient TCR and -1 PRF. Analyses of RNA chemical modification data with selective 2'-hydroxyl acylation and primer extension (SHAPE) assays revealed that CHIKV -1 PRF is stimulated by a tightly structured, triple-stem hairpin element, consistent with previous observations in alphaviruses, and that the TCR signal is composed of a single large multibulged hairpin element. These findings illuminate the roles of RNA structure in translational recoding and provide critical information relevant for design of live-attenuated vaccines against CHIKV and related viruses.

Modelling the cost-effectiveness of pay-for-performance in primary care in the UK.

BACKGROUND: Introduced in 2004, the United Kingdom's (UK) Quality and Outcomes Framework (QOF) is the world's largest primary-care pay-for-performance programme. Given some evidence of the benefits and the substantial costs associated with the QOF, it remains unclear whether the programme is cost-effective. Therefore, we assessed the cost-effectiveness of continuing versus stopping the QOF. METHODS: We developed a lifetime simulation model to estimate quality-adjusted life years (QALYs) and costs for a UK population cohort aged 40-74 years (n = 27,070,862) exposed to the QOF and for a counterfactual scenario without exposure. Based on a previous retrospective cross-country analysis using data from 1994 to 2010, we assumed the benefits of the QOF to be a change in age-adjusted mortality of -3.68 per 100,000 population (95% confidence interval -8.16 to 0.80). We used cost-effectiveness thresholds of £30,000/QALY, £20,000/QALY and £13,000/QALY to determine the optimal strategy in base-case and sensitivity analyses. RESULTS: In the base-case analysis, continuing the QOF increased population-level QALYs and health-care costs yielding an incremental cost-effectiveness ratio (ICER) of £49,362/QALY. The ICER remained >£30,000/QALY in scenarios with and without non-fatal outcomes or increased drug costs, and under differing assumptions about the duration of QOF benefit following its hypothetical discontinuation. The ICER for continuing the programme fell below £30,000/QALY when QOF incentive payments were 36% lower (while preserving QOF mortality benefits), and in scenarios where the QOF resulted in substantial reductions in health-care spending or non-fatal cardiovascular disease events. Continuing the QOF was cost-effective in 18%, 3% and 0% of probabilistic sensitivity analysis iterations using thresholds of £30,000/QALY, £20,000/QALY and £13,000/QALY, respectively. CONCLUSIONS: Compared to stopping the QOF and returning all associated incentive payments to the National Health Service, continuing the QOF is not cost-effective. To improve population health efficiently, the UK should redesign the QOF or pursue alternative interventions.

Stability of the human Hsp90-p50Cdc37 chaperone complex against nucleotides and Hsp90 inhibitors, and the influence of phosphorylation by casein kinase 2.

The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein-protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90ß-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2) did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM), while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands.

Improved stomatognathic model for highly realistic finite element analysis of temporomandibular joint biomechanics.

BACKGROUND: Mechanical response analysis of the temporomandibular joint (TMJ) is crucial for understanding the occurrence and development of diseases. However, the realistic modeling of the TMJ remains challenging because of its complex composition and multivariate associations. OBJECTIVE: This study aims to develop a highly realistic stomatognathic model that accurately represents the geometric accuracy, structural integrity, and material properties. And further optimizes the interference and establishes the application range of the simplifications and the assumptions. METHODS: Geometric reconstruction of the bone was based on high-resolution image data, with the accuracy of the occlusal surface ensured by plaster cast model registration. Soft tissues such as cartilage, the disc, the periodontal ligament (PDL), and disc attachments often need to be approximated or assumed. Therefore, the finite element methods (FEM) was used to optimize these assumptions, including 1) the biomechanical effects of the thickness and modulus of the PDL, 2) the approximation of the geometry and material behavior of the disc, and 3) the simplification of the loading and boundary conditions. RESULTS: 1) The deformation of the PDL causes tooth movement, which spreads to the distal condyle and further effects the TMJ load situation, 2) Disc reconstructed by MRI and hyperelastic material behavior are necessary for accurate TMJ loading analyses, 3) The loss of relative sliding movement between teeth interferes with realistic TMJ loading. CONCLUSION: The improved stomatognathic model delivers highly realistic and validated simulation, offering theoretical guidance for virtual treatments and TMJ multivariate overload studies.

Effect of occlusal contact on TMJ loading during occlusion: An in silico study.

Alterations in occlusal features may have significant consequences, ranging from dental aesthetics to health issues. Temporomandibular joint disorders (TMDs) are often associated with joint overload, and the correlation between occlusal features and TMDs has been thoroughly discussed. In current work, we introduced a novel stomatognathic model that aligns well with in vivo experimental measurements, specifically designed to decouple the impact of occlusal contact and periodontal ligament (PDL) negative feedback on temporomandibular joint (TMJ) loading. Utilizing an in-silico approach, the simulation analysis included six symmetric occlusal contact scenarios. Furthermore, a biomechanical lever model was employed to clarify the mechanical mechanism and investigate the multi-factorial effects of TMJ overload. These findings indicate that anterior shifts in the occlusal centre lead to increased TMJ loading, particularly in occlusal contact cases with anteroposterior changes. Considering the symmetrical distribution of occlusal contact, mediolateral alterations had a more modest effect on TMJ loading. Additionally, potential negative feedback activated by principal strain of periodontal could not only alleviate joint load but also diminish occlusal force. These investigations enhance our understanding of the intricate interactions between masticatory muscles, occlusal forces, and joint contact forces, thereby providing motivation for future comprehensive studies on TMJ biomechanical overload.

Meddling with the microbiota: Fungal tricks to infect plant hosts.

Plants associate with a wealth of microbes, collectively referred to as the plant microbiota, whose composition is determined by host plant genetics, immune responses, environmental factors and intermicrobial relations. Unsurprisingly, microbiota compositions change during disease development. Recent evidence revealed that some of these changes can be attributed to effector proteins with antimicrobial activities that are secreted by plant pathogens to manipulate host microbiota to their advantage. Intriguingly, many of these effectors have ancient origins, predating land plant emergence, and evolved over long evolutionary trajectories to acquire selective antimicrobial activities to target microbial antagonists in host plant microbiota. Thus, we argue that host-pathogen co-evolution likely involved arms races within the host-associated microbiota.

A proposed novel digital condylar position adjustment technique to help restore a normal disc-condyle relationship.

Objectives: To demonstrate a novel digital technique that enables real-time visualisation of occlusal transfer and adjustment of condyle position, to (1) improve the repeatability of occlusal transfer and the accuracy of condyle position adjustment and (2) be clinically effective in helping to restore the disc-condyle relationship. Materials and methods: Three participants were included in the study and underwent facebow transfers using two different methods. The digital method used patient-related three-dimensional imaging data matched with digital dental casts for occlusal transfer. The conventional method used anatomical facebows. The condylar position was adjusted based on occlusal transfer results. The results were evaluated and compared in three dimensions. In addition, clinical application data from 36 patients were analysed before and after condylar position adjustment. Statistical significance was set at p < 0.05. Results: Differences in the spatial positions of the three anatomical structures reproduced by both methods were statistically significant (p = 0.000). After adjusting the rotation of the condylar position, the positional deviation of the condylar point along the X- and Z-axes was significantly lower in the digital group (p < 0.05). After adjustment for translation (X and Z), the positional deviation showed no difference along the X- and Z-axes (p > 0.05) but a significant difference along the Y-axis (p < 0.001). Conclusion: A novel digital technique for occlusal transfer and condylar position adjustment was presented. This technique simplifies clinical practice, improves the accuracy of results, and can help restore a normal disc-condyle relationship.