New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the ...highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.
Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance.The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV).Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.
p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally ...bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.
•CB-5083 is a potent and selective small-molecule inhibitor of the cancer target p97•CB-5083 induced a strong unfolded protein response leading to cancer cell death•CB-5083 has antitumor effects in vivo in multiple myeloma and solid tumor models
Anderson et al. characterize CB-5083 as a potent, selective, and orally bioavailable inhibitor of p97, a AAA-ATPase critical for regulating protein homeostasis pathways. CB-5083 activates the apoptotic arm of the unfolded protein response and has antitumor activity in several hematological and solid tumor models.
Background:
Although posterior medial meniscal root (PMMR) repairs are often successful, postoperative meniscal extrusion after a root repair has been identified as a potential clinical problem.
...Purpose/Hypothesis:
The purpose was to quantitatively evaluate the tibiofemoral contact mechanics and extent of meniscal extrusion after a PMMR repair. It was hypothesized that the addition of a centralization suture (into the posterior medial tibial plateau) would help restore normal joint load-bearing characteristics and restore the native amount of meniscal extrusion after a root tear. Furthermore, we hypothesized that the amount of meniscal extrusion would be greatest in loaded and flexed knees when measured at the posterior border of the medial collateral ligament (MCL).
Study Design:
Controlled laboratory study.
Methods:
Meniscal extrusion and tibiofemoral contact mechanics were measured using 3-dimensional digitization and pressure sensors in 10 nonpaired, human cadaveric knees. The PMMR of each knee was tested under 6 states: (1) intact; (2) type 2A PMMR tear; (3) anatomic transtibial pull-out root repair; (4) anatomic transtibial pull-out repair with centralization; (5) nonanatomic transtibial pull-out repair; and (6) nonanatomic transtibial pull-out repair with centralization, with randomization of the order of conditions 3 and 4, and 5 and 6. The testing protocol loaded knees with a 1000-N axial compressive force at 4 flexion angles (0°, 30°, 60°, 90°) in each state. Meniscal extrusion was measured with a 3-dimensional coordinate digitizer at 0° and 90° in both the loaded and unloaded states and calculated from the difference from the articular margin of the tibia to the periphery of the meniscus. Peak contact pressure, contact area, and total contact pressure were also recorded for all states at all flexion angles. Statistical analysis investigated the independent effects of flexion, state, and loading using 3 distinct 2-factor models.
Results:
Differences in the contact mechanics between repair techniques were most notable at higher flexion angles, demonstrating significantly higher average and peak contact pressures for nonanatomic repair states when compared with anatomic repairs with and without centralization (all P < .05). In unloaded knees at full extension, the magnitude of medial meniscal extrusion was significantly higher at the posterior border of the MCL compared with the posterior medial tibia (P < .001) and adjacent to the root attachment on the tibia locations (P < .001). Both anatomic repair states had no significant difference in the degree of extrusion when compared with the intact state.
Conclusion:
The anatomic transtibial pull-out root repair and the anatomic transtibial pull-out root repair with centralization techniques best restored contact mechanics of the knee and meniscal extrusion when compared with root tear and nonanatomic repair states at time zero. There were no significant differences in contact pressure or magnitude of extrusion between the anatomic repair state and the anatomic repair with centralization state. We found that extrusion is best measured in the coronal plane at the posterior border of the MCL for unloaded knees. However, the degree of extrusion increased as the knee was loaded and flexed to 90°.
Clinical Relevance:
When there are concerns about meniscal extrusion with a medial meniscal root repair, the addition of a centralization suture may be beneficial for patients in reducing pathologic meniscal extrusion and restoring joint contact mechanics.
The majority of pharmaceuticals are derived from natural products, bioactive compounds naturally synthesized by organisms to provide evolutionary advantages. Although the rich evolutionary history of ...eukaryotic algal species implicates a high potential for natural product-based drug discovery, it remains largely untouched. This study investigates 2762 putative biosynthetic gene clusters (BGCs) from 212 eukaryotic algal genomes. To analyze a vast set of structurally diverse BGCs, we employed comparative analysis based on the vectorization of biosynthetic domains, referred to as biosynthetic domain architecture (BDA). By characterizing core biosynthetic machineries through BDA, we identified key BDAs of modular BGCs in diverse eukaryotes and introduced 16 candidate modular BGCs with similar BDAs to previously validated BGCs. This study provides a global characterization of eukaryotic algal BGCs, offering an alternative to laborious manual curation for BGC prioritization.
Severe influenza infection has no effective treatment available. One of the key barriers to developing host-directed therapy is a lack of reliable prognostic factors needed to guide such therapy. ...Here, we use a network analysis approach to identify host factors associated with severe influenza and fatal outcome. In influenza patients with moderate-to-severe diseases, we uncover a complex landscape of immunological pathways, with the main changes occurring in pathways related to circulating neutrophils. Patients with severe disease display excessive neutrophil extracellular traps formation, neutrophil-inflammation and delayed apoptosis, all of which have been associated with fatal outcome in animal models. Excessive neutrophil activation correlates with worsening oxygenation impairment and predicted fatal outcome (AUROC 0.817-0.898). These findings provide new evidence that neutrophil-dominated host response is associated with poor outcomes. Measuring neutrophil-related changes may improve risk stratification and patient selection, a critical first step in developing host-directed immune therapy.
Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity ...remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.
Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain ...unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.
Biofouling is a prevalent issue in studies that involve prolonged implantation of electrochemical probes in the brain. In long-term fast-scan cyclic voltammetry (FSCV) studies, biofouling manifests ...as a shift in the peak oxidative potential of the background signal that worsens over days to weeks, diminishing sensitivity and selectivity to neurotransmitters such as dopamine. Using open circuit potential (OCP) measurements, scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDX), and electrochemical impedance spectroscopy (EIS), we examined the biofouling-induced events that occur due to electrode implantation. We determined that the FSCV background signal shift results from cathodic polarization of the Ag/AgCl-wire reference electrode and increased electrochemical impedance of both the Ag/AgCl-wire reference electrode and carbon-fiber working electrode. These events are likely caused collectively by immune response-induced electrode encapsulation. A headstage utilizing a three-electrode configuration, designed to compensate for the impedance component of biofouling, reduced the FSCV background signal shift in vivo and preserved dopamine sensitivity at artificially increased impedance levels in vitro. In conjunction with a stable reference electrode, this three-electrode configuration will be critical in achieving reliable neurotransmitter detection for the duration of long-term FSCV studies.
Background:
Recent biomechanical studies have identified sagittal plane posterior tibial slope as a potential risk factor for posterior cruciate ligament (PCL) injury because of its effects on the ...kinematics of the native and surgically treated knee. However, the literature lacks clinical correlation between primary PCL injuries and decreased posterior tibial slope.
Purpose/Hypothesis:
The purpose of this study was to retrospectively compare the amount of posterior tibial slope between patients with PCL injuries and age/sex-matched controls with intact PCLs. It was hypothesized that patients with PCL injuries would have a significantly decreased amount of posterior tibial slope when compared with patients without PCL injuries.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
Patients who underwent primary PCL reconstruction without anterior cruciate ligament injury between 2010 and 2017 by a single surgeon were retrospectively analyzed. Measurements of posterior tibial slope were performed with lateral radiographs of PCL-injured knees and matched controls without clinical or magnetic resonance imaging evidence of ligamentous injury. Mean values of posterior tibial slope were compared between the groups. Inter- and intrarater agreement was assessed for the tibial slope measurement technique via a 2-way random effects model to calculate the intraclass correlation coefficient (ICC).
Results:
In sum, 104 patients with PCL tears met the inclusion criteria, and 104 controls were matched according to age and sex. There were no significant differences in age (P = .166), sex (P = .345), or body mass index (P = .424) between the PCL-injured and control groups. Of the PCL tear cohort, 91 patients (87.5%) sustained a contact mechanism of injury, while 13 (12.5%) reported a noncontact mechanism of injury. The mean ± SD posterior tibial slopes were 5.7°± 2.1° (95% CI, 5.3°-6.1°) and 8.6°± 2.2° (95% CI, 8.1°-9.0°) for the PCL-injured and matched control groups, respectively (P < .0001). Subgroup analysis of the PCL-injured knees according to mechanism of injury demonstrated significant differences in posterior tibial slope between noncontact (4.6°± 1.8°) and contact (6.2°± 2.2°) injuries for all patients with PCL tears (P = .013) and among patients with isolated PCL tears (P = .003). The tibial slope measurement technique was highly reliable, with an ICC of 0.852 for interrater reliability and an ICC of 0.872 for intrarater reliability.
Conclusion:
A decreased posterior tibial slope was associated with patients with PCL tears as compared with age- and sex-matched controls with intact PCLs. Decreased tibial slope appears to be a risk factor for primary PCL injury. However, further clinical research is needed to assess if decreased posterior tibial slope affects posterior knee stability and outcomes after PCL reconstruction.
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The wetting of a solid by a liquid is a thermally-activated molecular rate process, which may be investigated by studying the temperature-dependence of the dynamic contact angle at ...standard experimental scales.
We use the plunging-tape method and a low-powered microscope to measure the dynamic contact angle of di-n-butyl phthalate (DBP) on poly(ethylene terephthalate) (PET) tape over a very wide speed range of 0.003–100 cm/s at 5 temperatures from 15 °C to 55 °C. The molecular-kinetic theory of dynamic wetting (the MKT) is then used to interpret the data, which span angles from 8° to near 180°.
The MKT successfully accounts for the temperature-dependence of the dynamic contact angle, yielding rational values for key parameters including the activation free energy of wetting. Arrhenius-like behavior is also demonstrated. These results would appear to confirm that, at the molecular-scale, dynamic wetting is a thermally-activated rate process and that the influence of temperature is not restricted simply to its effect on surface tension and viscosity. The data show a discontinuity at dynamic contact angles between 60° and 90° that implies a velocity-dependent change in the wetting mechanism. We attribute this to the chemical heterogeneity of the PET surface, which contains both polar and non-polar groups. The parameters obtained by applying the MKT suggest that the interactions of DBP with these groups determine, respectively, the dynamics observed below and above the transition. The sum of the activation free energies of wetting on either side of the transition is close to the total thermodynamic work of adhesion of DBP to PET.
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