Advanced Detection of Failed LEDs in a Short Circuit for Automotive Lighting Applications.

This paper addresses the issue of LED short-circuit fault detection in signaling and lighting systems in the automotive industry. The conventional diagnostic method commonly implemented in newer vehicles relies on measuring the voltage drop across different LED branches and comparing it with threshold values indicating faults caused by open circuits or LED short circuits. With this algorithm, detecting cases of a few LEDs short-circuited within a branch, particularly a single malfunctioning LED, is particularly challenging. In this work, two easily implementable algorithms are proposed to address this issue within the vehicle's control unit. One is based on a mathematical prediction model, while the other utilizes a neural network. The results obtained offer a 100% LED short-circuit fault detection rate in the majority of analyzed cases, representing a significant improvement over the conventional method, even in scenarios involving a single malfunctioning LED within a branch. Additionally, the neural network-based model can accurately predict the number of failed LEDs.

A Dynamic Endonasal Columellar Strut Placement.

The dynamic retrograde intercrural columellar strut graft placement is a novel technique for a columellar strut insertion via a hemi-transfixion incision in patients undergoing endonasal functional or cosmetic surgery. It has a maximally concealed incision and does not disrupt major or minor tip support mechanisms. In our article, we give a detailed description of this unique surgical technique. Laryngoscope, 134:1246-1248, 2024.

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

OBJECTIVE: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. METHODS: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. RESULTS: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. SIGNIFICANCE: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed.

Hamstring injuries in the national football league: An epidemiological study.

Background: While numerous studies have evaluated National Football League injuries, there is limited literature evaluating hamstring injuries sustained in games. Our primary aim is to analyze the effect of player position on the relative incidence of hamstring injuries in the National Football League. Our secondary aims are to analyze the effects of field surface, week of the season, and short rest weeks. Methods: Official National Football League game books containing injury data from the 2013-2016 regular seasons were used. Data were analyzed to determine the incidence of hamstring injuries by field surface, rest, and week of the season. Field surface was considered either turf or grass. Short rest was considered four days. Relative incidence of hamstring injuries by position was performed with standardized incidence ratios. P values < 0.05 were considered statistically significant. Results: Seventy-eight qualifying hamstring injuries were identified and included in our analysis. Linebackers had the highest relative incidence per play with a standardized incidence ratio of 2.02 (CI: 1.14-2.91), followed by Defensive Backs (1.62; 95% CI: 1.14-1.62). Offensive linemen and defensive linemen had standardized incidence ratios significantly less than 1. Fifty-seven percent of hamstring injuries occurred on turf fields (p = 0.082). There was no significant difference between the proportion of hamstring injuries that occurred on short rest and the proportion of games played on short rest (p = 0.959). Hamstring injuries were not more likely to occur than the pooled group of all other types of injuries on short rest (p = 0.861). With a 17-week season, the mean week of hamstring injury was 8.05 (95% CI: 7.06-9.04), while the median week was 7.5. Conclusions: Linebackers and Defensive Backs have the highest relative incidence of hamstring injuries compared to other position groups, while offensive and defensive linemen have the lowest. Field surface and a short rest period did not show significance.

Characteristics and Trends of the Most Cited Clinical Orthopaedics and Related Research Articles.

Background: Clinical Orthopaedics and Related Research is one of the most influential and reputable scientific journals in the field of orthopaedics. Some of the most reputable publications related to orthopaedic research can be attributed to this journal and it continues to have a significant impact on modern research. Objective: The purpose of this study is to identify the most influential articles, in terms of number of citations, published by Clinical Orthopaedics and Related Research. The goal of analyzing the most cited articles in is to create a baseline for future researchers to build upon and to uncover any trends in orthopaedic research. Methods: Preferred Reporting Items for Systematic Reviews guidelines were used to structure the data collection and analysis of this study. The Scopus database was used to compile the publication data. Data was then exported to an excel sheet to be further analyzed via a multi-author review process. Results: The most cited article was "A Clinical Method of Functional Assessment of the Shoulder" by Constant et al.. The 50 articles analyzed in this study were cited a total of 32,404 times, averaging 719 citations per year, per publication. The oldest article was published in 1971, and the newest in 2008. The United States was the country with the most attributable publications and The University of Florida was the most contributory institution. Conclusions: Our study recognizes Clinical Orthopaedics and Related research as having a strong predilection for older articles and a continued strength for modern publications.

Effect of Passing Plays on Injury Rates in the National Football League.

ABSTRACT: Burke, J, Geller, JS, Perez, JR, Naik, K, Vidal, AF, Baraga, MG, and Kaplan, LD. The effect of passing plays on injury rates in the national football league. J Strength Cond Res 35(12S): S1-S4, 2021-The National Football League (NFL) has one of the highest all-cause injury rates in sports, yet our understanding of extrinsic injury risk factors is limited. The objective of this study was to assess the effect of play type on injury incidence in the NFL. We obtained data for every regular season game played during the 2013-2016 seasons from the official NFL game books. There were 2,721 in-game injuries during the 4 seasons examined, with an overall rate of 1.33 injuries per team per game. For statistical analysis, p < 0.05 was considered significant. Passing plays conferred significantly higher odds of injury than running plays (odds ratio [OR] 1.4, 95% confidence interval [CI]: 1.3-1.5, p < 0.0001). This primarily stems from increased risks in quarterbacks (OR 6.9, 95% CI: 3.6-13.3, p < 0.0001), receivers (OR 5.0, 95% CI: 3.7-6.6, p < 0.0001), and defensive backs (OR 2.3, 95% CI: 1.9-2.7, p < 0.0001). Our study suggests that passing plays confer a greater risk of overall injuries in the NFL when compared with running plays, specifically regarding concussions and core or trunk injuries.

The Effect of Thursday Night Games on In-Game Injury Rates in the National Football League.

BACKGROUND: Although claims of increased injury rates with Thursday night National Football League (NFL) games exist, a paucity of data exist substantiating these claims. PURPOSE: To evaluate the effect of rest between games on in-game injury rates as it pertains to overall injury incidence, location, and player position. STUDY DESIGN: Descriptive epidemiologic study. METHODS: Data were obtained from official NFL game books for regular season games from all 32 teams for the 2013-2016 seasons. All in-game injuries recorded in official game books were included. Rest periods between games were classified as short (4 days), regular (6-8 days), or long (≥10 days). Overall observed injury rates per team-game were analyzed in relation to different rest periods using negative binomial regression. For results with significant overall findings, pairwise comparisons were tested using the Wald chi-square test. Exploratory secondary analyses were performed in a similar fashion to assess differences in injury rates for the different rest periods when stratified by anatomic location and player position. RESULTS: A total of 2846 injuries were identified throughout the 4 seasons. There was an overall significant difference in injuries per team-game between short, regular, and long rest (P = .01). With short rest, an observed mean of 1.26 injuries per game (95% CI, 1.06-1.49) was significantly different from the 1.53 observed injuries per game with regular rest (95% CI, 1.46-1.60; P = .03), but not compared with the 1.34 observed injuries per game with long rest (P = .56). For player position, only the tight end, linebacker, and fullback group demonstrated significant differences between the injury rates for different rest categories. Quarterback was the only position with more injuries during games played on Thursday compared with both regular and long rest. This specific analysis was underpowered and the difference was not significant (P = .08). No differences were found regarding injury rates in correlation with differences in rest periods with different injury locations. CONCLUSION: A short rest period between games is not associated with increased rates of observed injuries reported in NFL game books; rather, our data suggest there are significantly fewer injuries for Thursday night games compared with games played on regular rest. Future research correlating rest and quarterback injury rates is warranted.

Limb salvage reconstruction: Radiologic features of common reconstructive techniques and their complications.

Limb salvage surgery refers to orthopaedic procedures designed to resect tumors and reconstruct limbs. Improvements in managing malignant bone lesions have led to a dramatic shift in limb salvage procedures. Orthopaedic surgeons now employ four main reconstructive procedures: endoprosthesis, autograft, bulk allograft, and allograft prosthetic composite. While each approach has its advantages, each technique is associated with complications. Furthermore, knowledge of procedure specific imaging findings can lead to earlier complication diagnosis and improved clinical outcomes. The aim of this article is to review leading reconstructive options available for limb salvage surgery and present a case series illustrating the associated complications.

MRI of Superior Capsular Reconstruction.

Massive irreparable rotator cuff tears can be a challenging problem for arthroscopists in the perioperative setting because the typical treatment, reverse total shoulder arthroplasty, may not be the best option for all patients. Superior capsular reconstruction (SCR) is an advancing treatment option for patients with rotator cuff tears that are neither amenable to primary repair nor ideal for arthroplasty. Patient selection, which is strongly dependent on preoperative imaging findings, is an important step in obtaining favorable surgical outcomes. The tissue quality and tear type are particularly important when considering SCR for a patient. When unsuccessful SCR is suspected, postoperative MRI of the shoulder offers the surgeon and radiologist a means of evaluating the integrity and fixation of the graft. Fluid-sensitive MRI sequences are best for examining the final SCR construct, with high-signal-intensity fluid interruptions within the graft and the presence or worsening of shoulder arthropathy indicating graft failure. The indications for SCR are discussed, and the normal postoperative MRI findings after SCR are described in this review. In addition, the common types of SCR graft failure and associated imaging findings are described and illustrated. ©RSNA, 2020.

Novel approach to improve patient satisfaction in the outpatient clinic setting.

BACKGROUND: With evolving reimbursement patterns and an emphasis on value-based care, patient satisfaction is increasingly becoming a more important metric. However, there remains a dearth of literature examining potential strategies to improve patient satisfaction in the outpatient setting. This study investigates if overall perception of care is influenced by providing biosketch cards to new patients in an outpatient Sports Medicine clinic. METHODS: 144 new patients were assigned to an intervention group based on the date of visit from 3/2017 to 8/2017. Eligible patients received a treating physician biosketch card (Group A), clinical practice biosketch card (Group B) or no additional literature (Control group) during the clinic check-out process. Via email, patients were asked to rate: 1- quality of care, 2- treated with courtesy and respect, 3- listened to carefully, 4- was explained things in a way you could understand, 5- overall rating, 6- recommend to family and friend? We also collected age, gender, level of education, and response time. The three groups were compared. RESULTS: 96 (66.7%) patients responded with 32 patients in each group (physician biosketch, clinic biosketch, no intervention). There were no significant demographic differences between the groups. The average age was 51.8 years with 52% being male. Mean time from visit to response was 1.6 days. The only significant difference occurred for rating "how would you rate your orthopedic doctor with treating you with courtesy and respect?", however, post hoc analysis failed to reveal a significant difference in response between each study group. There was no statistical difference between the remaining questions on patient satisfaction. CONCLUSION: Increasing a new patient's awareness, via physician or clinic information sheets, has no added benefit for patient satisfaction in the outpatient sports medicine setting.

Patient-Reported Knee Outcome Scores With Soft Tissue Quadriceps Tendon Autograft Are Similar to Bone-Patellar Tendon-Bone Autograft at Minimum 2-Year Follow-up: A Retrospective Single-Center Cohort Study in Primary Anterior Cruciate Ligament Reconstruction Surgery.

BACKGROUND: Quadriceps tendon (QT)-bone autografts used during anterior cruciate ligament (ACL) reconstruction have provided comparable outcomes and decreased donor-site morbidity when compared with bone-patellar tendon-bone (BPTB) autografts. No study has directly compared the outcomes of the all-soft tissue QT autograft with that of the BPTB autograft. HYPOTHESIS: Patient-reported knee outcome scores and rates of postoperative complication after primary ACL reconstruction with QT autografts are no different from BPTB autografts at a minimum 2-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 75 patients who underwent primary autograft ACL reconstruction with QT or BPTB autografts between January 1, 2015, and March 31, 2016, at a single hospital center were contacted by telephone and asked to complete the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation, Tegner activity level scale, and Lysholm knee scoring scale. Information about the subsequent surgeries performed on the operative knee was also collected. Statistical analysis was performed using the Kruskal-Wallis test and the Fisher exact test for categorical data. RESULTS: Fifty patients (28 QT, 22 BPTB) completed the surveys at a mean follow-up of 33.04 months (range, 24-44 months). For the QT versus the BPTB group respectively, the median IKDC scores were 94.83 (interquartile range [IQR], 7.61) versus 94.83 (IQR, 10.92) (P = .47), the median Tegner scores were 6 (IQR, 2.5) versus 6 (IQR, 2.75) (P = .48), and the median Lysholm scores were 95 (IQR, 9) versus 95 (IQR, 13) (P = .27). Additionally, 2 QT patients and 3 BPTB patients required follow-up arthroscopy for arthrolysis (P = .64). There was 1 graft failure in the QT group requiring revision surgery. CONCLUSION: There was no statistical difference in patient-reported knee outcomes or graft complication rates between the QT and BPTB autograft groups at a minimum 2-year follow-up after primary ACL reconstruction. This study highlights that the all-soft tissue QT autograft may be a suitable graft choice for primary ACL reconstruction.

Novel tricyclic glycal-based TRIB1 inducers that reprogram LDL metabolism in hepatic cells.

Increased expression of the Tribbles pseudokinase 1 gene (TRIB1) is associated with lower plasma levels of LDL cholesterol and triglycerides, higher levels of HDL cholesterol and decreased risk of coronary artery disease and myocardial infarction. We identified a class of tricyclic glycal core-based compounds that upregulate TRIB1 expression in human HepG2 cells and phenocopy the effects of genetic TRIB1 overexpression as they inhibit expression of triglyceride synthesis genes and ApoB secretion in cells. In addition to predicted effects related to downregulation of VLDL assembly and secretion these compounds also have unexpected effects as they upregulate expression of LDLR and stimulate LDL uptake. This activity profile is unique and favorably differs from profiles produced by statins or other lipoprotein targeting therapies. BRD8518, the initial lead compound from the tricyclic glycal class, exhibited stereochemically dependent activity and the potency far exceeding previously described benzofuran BRD0418. Gene expression profiling of cells treated with BRD8518 demonstrated the anticipated changes in lipid metabolic genes and revealed a broad stimulation of early response genes. Consistently, we found that BRD8518 activity is MEK1/2 dependent and the treatment of HepG2 cells with BRD8518 stimulates ERK1/2 phosphorylation. In agreement with down-regulation of genes controlling triglyceride synthesis and assembly of lipoprotein particles, the mass spectrometry analysis of cell extracts showed reduced rate of incorporation of stable isotope labeled glycerol into triglycerides in BRD8518 treated cells. Furthermore, we describe medicinal chemistry efforts that led to identification of BRD8518 analogs with enhanced potency and pharmacokinetic properties suitable for in vivo studies.

Tissue Engineering and Cell-Based Therapies for Fractures and Bone Defects.

Bone fractures and segmental bone defects are a significant source of patient morbidity and place a staggering economic burden on the healthcare system. The annual cost of treating bone defects in the US has been estimated to be $5 billion, while enormous costs are spent on bone grafts for bone injuries, tumors, and other pathologies associated with defective fracture healing. Autologous bone grafts represent the gold standard for the treatment of bone defects. However, they are associated with variable clinical outcomes, postsurgical morbidity, especially at the donor site, and increased surgical costs. In an effort to circumvent these limitations, tissue engineering and cell-based therapies have been proposed as alternatives to induce and promote bone repair. This review focuses on the recent advances in bone tissue engineering (BTE), specifically looking at its role in treating delayed fracture healing (non-unions) and the resulting segmental bone defects. Herein we discuss: (1) the processes of endochondral and intramembranous bone formation; (2) the role of stem cells, looking specifically at mesenchymal (MSC), embryonic (ESC), and induced pluripotent (iPSC) stem cells as viable building blocks to engineer bone implants; (3) the biomaterials used to direct tissue growth, with a focus on ceramic, biodegradable polymers, and composite materials; (4) the growth factors and molecular signals used to induce differentiation of stem cells into the osteoblastic lineage, which ultimately leads to active bone formation; and (5) the mechanical stimulation protocols used to maintain the integrity of the bone repair and their role in successful cell engraftment. Finally, a couple clinical scenarios are presented (non-unions and avascular necrosis-AVN), to illustrate how novel cell-based therapy approaches can be used. A thorough understanding of tissue engineering and cell-based therapies may allow for better incorporation of these potential therapeutic approaches in bone defects allowing for proper bone repair and regeneration.

Accuracy of auxiliary density functional theory hybrid calculations for activation and reaction enthalpies of pericyclic reactions.

Auxiliary density functional theory (ADFT) hybrid calculations are based on the variational fitting of the Coulomb and Fock potential and, therefore, are free of four-center electron repulsion integrals. So far, ADFT hybrid calculations have been validated successfully for standard enthalpies of formation. In this work the accuracy of ADFT hybrid calculations for the description of pericyclic reactions was quantitatively validated at the B3LYP/6-31G*/GEN-A2* level of theory. Our comparison with conventional Kohn-Sham density functional theory (DFT) results shows that the DFT and ADFT activation and reaction enthalpies are practically indistinguishable. A systematic study of various functionals (PBE, B3LYP, PBE0, CAMB3LYP, CAMPBE0 and HSE06) and basis sets (6-31G*, DZVP-GGA and aug-cc-pVXZ; X = D, T and Q) revealed that the ADFT HSE06/aug-cc-pVTZ/GEN-A2* level of theory yields best balanced accuracy for the activation and reaction enthalpies of the studied pericyclic reactions. With the successfully validate ADFT composite approach consisting of PBE/DZVP-GGA/GEN-A2* structure and transition state optimizations and single-point HSE06/aug-cc-pVTZ/GEN-A2* energy calculations, an accurate, reliable and efficient computational approach for the study of pericyclic reactions in systems at the nanometer scale is proposed.

High Throughput Screen Identifies Interferon γ-Dependent Inhibitors of Toxoplasma gondii Growth.

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of antimicrobial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low µM concentrations and that demonstrated enhanced potency in the presence of a low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of light chain 3 (LC3) to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ dependence was shared among the majority of analogs from 6 priority scaffolds, and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding.

Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. We sought to establish a method for developing new chemical compounds that specifically induce autophagy. To do this, we developed two assays to identify compounds that target a key regulatory node of autophagy induction-specifically, the binding of Bcl-2 (a negative regulator of autophagy) to Beclin 1 (an allosteric modulator of the Beclin 1/VPS34 lipid kinase complex that functions in autophagy initiation). These assays use either a split-luciferase assay to measure Beclin 1/Bcl-2 binding in cells or an AlphaLISA assay to directly measure direct Beclin 1/Bcl-2 binding in vitro. We screened two different chemical compound libraries, comprising ∼300 K compounds, to identify small molecules that disrupt Beclin 1/Bcl-2 binding and induce autophagy. Three novel compounds were identified that directly inhibit Beclin 1/Bcl-2 interaction with an IC50 in the micromolar range and increase autophagic flux. These compounds do not demonstrate significant cytotoxicity, and they exert selectivity for disruption of Bcl-2 binding to the BH3 domain of Beclin 1 compared with the BH3 domain of the pro-apoptotic Bcl-2 family members, Bax and Bim. Thus, we have identified candidate molecules that serve as lead templates for developing potent and selective Beclin 1/Bcl-2 inhibitors that may be clinically useful as autophagy-inducing agents.

The Autophagy-Related Beclin-1 Protein Requires the Coiled-Coil and BARA Domains To Form a Homodimer with Submicromolar Affinity.

Beclin-1 (BECN1) is an essential component of macroautophagy. This process is a highly conserved survival mechanism that recycles damaged cellular components or pathogens by encasing them in a bilayer vesicle that fuses with a lysosome to allow degradation of the vesicular contents. Mutations or altered expression profiles of BECN1 have been linked to various cancers and neurodegenerative diseases. Viruses, including HIV and herpes simplex virus 1 (HSV-1), are also known to specifically target BECN1 as a means of evading host defense mechanisms. Autophagy is regulated by the interaction between BECN1 and Bcl-2, a pro-survival protein in the apoptotic pathway that stabilizes the BECN1 homodimer. Disruption of the homodimer by phosphorylation or competitive binding promotes autophagy through an unknown mechanism. We report here the first recombinant synthesis (3-5 mg/L in an Escherichia coli culture) and characterization of full-length, human BECN1. Our analysis reveals that full-length BECN1 exists as a soluble homodimer (KD ∼ 0.45 µM) that interacts with Bcl-2 (KD = 4.3 ± 1.2 µM) and binds to lipid membranes. Dimerization is proposed to be mediated by a coiled-coil region of BECN1. A construct lacking the C-terminal BARA domain but including the coiled-coil region exhibits a homodimer KD 3.5-fold weaker than that of full-length BECN1, indicating that both the BARA domain and the coiled-coil region of BECN1 contribute to dimer formation. Using site-directed mutagenesis, we show that residues at the C-terminus of the coiled-coil region previously shown to interact with the BARA domain play a key role in dimerization and mutations weaken the interface by ∼5-fold.

Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease.

Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics.

Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells.

Enhancing production of the anti-inflammatory cytokine interleukin-10 (IL-10) is a promising strategy to suppress pathogenic inflammation. To identify new mechanisms regulating IL-10 production, we conducted a phenotypic screen for small molecules that enhance IL-10 secretion from activated dendritic cells. Mechanism-of-action studies using a prioritized hit from the screen, BRD6989, identified the Mediator-associated kinase CDK8, and its paralog CDK19, as negative regulators of IL-10 production during innate immune activation. The ability of BRD6989 to upregulate IL-10 is recapitulated by multiple, structurally differentiated CDK8 and CDK19 inhibitors and requires an intact cyclin C-CDK8 complex. Using a highly parallel pathway reporter assay, we identified a role for enhanced AP-1 activity in IL-10 potentiation following CDK8 and CDK19 inhibition, an effect associated with reduced phosphorylation of a negative regulatory site on c-Jun. These findings identify a function for CDK8 and CDK19 in regulating innate immune activation and suggest that these kinases may warrant consideration as therapeutic targets for inflammatory disorders.