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.

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.

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.

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.

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.

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.

Antioxidant defense of Nrf2 vs pro-inflammatory system of NF-κB during the amoebic liver infection in hamster.

Entamoeba histolytica is the causative agent of amoebic liver abscess (ALA), which course with an uncontrolled inflammation and nitro-oxidative stresses, although it is well known that amoeba has an effective defence mechanisms against this toxic environment, the underlying molecular factors responsible for progression of tissue damage remain largely unknown. The purpose of the present study was to determine during the acute stage of ALA in hamsters, the involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor-kappa B (NF-κB), which are activated in response to oxidative stress. From 12 h post-infection the ALA was visible, haematoxylin-eosin and Masson's trichrome stains were consistent with these observations, and alanine aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase serum activities were increased too. At 48 h after infection, liver glycogen content was significantly reduced. Western blot analyses showed that 4-Hydroxy-2-nonenal peaked at 12 h, while glycogen synthase kinase-3ß, cleaved caspase-3, pNF-κB, interleukin-1ß and tumour necrosis factor-α were overexpressed from 12 to 48 h post-infection. Otherwise, Nrf2 and superoxide dismutase-1, decreased at 48 h and catalase declined at 36 and 48 h. Furthermore, heme oxygenase-1 was increased at 12 and 24 h and decreased to normal levels at 36 and 48 h. These findings suggest for the first time that the host antioxidant system of Nrf2 is influenced during ALA.

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells.

Genetic alterations that reduce the function of the immunoregulatory cytokine IL-10 contribute to colitis in mouse and man. Myeloid cells such as macrophages (MΦs) and dendritic cells (DCs) play an essential role in determining the relative abundance of IL-10 versus inflammatory cytokines in the gut. As such, using small molecules to boost IL-10 production by DCs-MΦs represents a promising approach to increase levels of this cytokine specifically in gut tissues. Toward this end, we screened a library of well-annotated kinase inhibitors for compounds that enhance production of IL-10 by murine bone-marrow-derived DCs stimulated with the yeast cell wall preparation zymosan. This approach identified a number of kinase inhibitors that robustly up-regulate IL-10 production including the Food and Drug Administration (FDA)-approved drugs dasatinib, bosutinib, and saracatinib that target ABL, SRC-family, and numerous other kinases. Correlating the kinase selectivity profiles of the active compounds with their effect on IL-10 production suggests that inhibition of salt-inducible kinases (SIKs) mediates the observed IL-10 increase. This was confirmed using the SIK-targeting inhibitor HG-9-91-01 and a series of structural analogs. The stimulatory effect of SIK inhibition on IL-10 is also associated with decreased production of the proinflammatory cytokines IL-1ß, IL-6, IL-12, and TNF-α, and these coordinated effects are observed in human DCs-MΦs and anti-inflammatory CD11c(+) CX3CR1(hi) cells isolated from murine gut tissue. Collectively, these studies demonstrate that SIK inhibition promotes an anti-inflammatory phenotype in activated myeloid cells marked by robust IL-10 production and establish these effects as a previously unidentified activity associated with several FDA-approved multikinase inhibitors.

Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.

We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure-activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50=0.10µM) and solubility (79µM in PBS), and it was designated as probe ML312.

Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.

A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure-activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50=17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278.

Direct-bandgap light-emitting germanium in tensilely strained nanomembranes.

Silicon, germanium, and related alloys, which provide the leading materials platform of electronics, are extremely inefficient light emitters because of the indirect nature of their fundamental energy bandgap. This basic materials property has so far hindered the development of group-IV photonic active devices, including diode lasers, thereby significantly limiting our ability to integrate electronic and photonic functionalities at the chip level. Here we show that Ge nanomembranes (i.e., single-crystal sheets no more than a few tens of nanometers thick) can be used to overcome this materials limitation. Theoretical studies have predicted that tensile strain in Ge lowers the direct energy bandgap relative to the indirect one. We demonstrate that mechanically stressed nanomembranes allow for the introduction of sufficient biaxial tensile strain to transform Ge into a direct-bandgap material with strongly enhanced light-emission efficiency, capable of supporting population inversion as required for providing optical gain.

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.

Discovery of small-molecule modulators of the Sonic Hedgehog pathway.

The Hedgehog signaling pathway is involved in the development of multicellular organisms and, when deregulated, can contribute to certain cancers, among other diseases. The molecular characterization of the pathway, which has been enabled by small-molecule probes targeting its components, remains incomplete. Here, we report the discovery of two potent, small-molecule inhibitors of the Sonic Hedgehog (Shh) pathway, BRD50837 and BRD9526. Both compounds exhibit stereochemistry-based structure-activity relationships, a feature suggestive of a specific and selective interaction of the compounds with as-yet-unknown cellular target(s) and made possible by the strategy used to synthesize them as members of a stereochemically and skeletally diverse screening collection. The mechanism-of-action of these compounds in some ways shares similarities to that of cyclopamine, a commonly used pathway inhibitor. Yet, in other ways their mechanism-of-action is strikingly distinct. We hope that these novel compounds will be useful probes of this complex signaling pathway.

The effect of caffeic acid phenethyl ester analogues in a modified resistant hepatocyte model.

We present a study of the chemoprotective effects of two caffeic acid phenethyl ester (CAPE)-related structures: LQM717 and LQM706. The modified resistant hepatocyte model in rats was used to study the chemoprevention of these CAPE analogues, which are inexpensive and easily obtained. In the liver cancer model used, we detected extensive necrosis and lipid peroxidation after 24 h, many altered hepatic foci, putatively preneoplastic lesions with γ-glutamyl transpeptidase staining after 30 days, and liver tumors at 12 months. We tested the effect of the CAPE analogues on necrosis, lipid peroxidation, proliferation, p65 activation, altered hepatic foci, and tumors. Both compounds exerted protective effects on lipid peroxidation, necrosis, cell proliferation, p65 activation, and preneoplastic lesions. Rats under a carcinogenic protocol showed a 52, 71.74, and 51.6% decrease in the number of preneoplastic nodules when pretreated with CAPE, LQM706, and LQM717, respectively. At 12 months after carcinogenic treatment, eight of eight rats developed liver cancer, whereas in the group of rats that received pretreatment with CAPE, LQM706, or LQM717, 62.5, 83.3, or 42.85%, respectively, had tumors. In conclusion, LQM717 has the potential to enhance chemoprotection activity much better than CAPE by markedly reducing the formation of liver cancers in this model, and this is a compound that is easy to obtain.

Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.

A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.

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.

Discovery of a new molecular probe ML228: an activator of the hypoxia inducible factor (HIF) pathway.

Hypoxia and ischemia are linked to several serious public health problems that affect most major organ systems. Specific examples include diseases of the cardiovascular, pulmonary, renal, neurologic, and musculoskeletal systems. The most significant pathway for cellular response to hypoxia is the hypoxia inducible factor (HIF) pathway. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. A high-throughput cell-based HIF-mediated gene reporter screen was carried out using the NIH's Molecular Libraries Small Molecule Repository to identify activators of the HIF pathway. This communication describes the subsequent medicinal chemistry optimization of a triazine scaffold that led to the identification of the new molecular probe ML228. A discussion of HIF activation SAR within this chemotype as well as detailed in vitro characterization of the probe molecule is presented here.

Identification of a selective small molecule inhibitor of breast cancer stem cells.

A high-throughput screen (HTS) with the National Institute of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) compound collection identified a class of acyl hydrazones to be selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP).

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.