We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with 4200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-c1 (PLCc1)-defective line was resistant. Jurkat cells showed a dosedependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca 2 þ flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca 2 þ chelators (BAPTA) and enhanced by Ca 2 þ effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCc1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies.

C-peptide (CP) has demonstrated unique beneficial effects in diabetic nephropathy (DN), but whether and how CP regulates NF-κB and its coactivator, p300, to suppress inducible iNOS and antagonize DN are unknown. iNOS expression, NF-κB nuclear translocation, colocalization and binding of NF-κB to p300, binding of NF-κB to the inos promoter, and the bound NF-κB, p300, and histone 3 lysine 9 acetylation (H3K9ac) at binding sites were measured in high glucose-stimulated mesangial cells. We evaluated pathologic changes, iNOS expression, NF-κB, and p300 contents in diabetic rats. We found that CP inhibited iNOS expression and notably prevented colocalization and binding of NF-κB and p300. CP prevented NF-κB from binding to the inos promoter, especially at the distal site, and reduced bound NF-κB, p300, and H3K9ac. N-terminal plus middle fragment could mostly mimic the antagonizing effects of CP against the pathologic changes of DN and equally suppresses renal iNOS expression as CP. In conclusion, CP prevented NF-κB from recruiting p300 and binding to the inos promoter, and decreased H3K9ac at the binding sites to suppress iNOS expression and antagonize DN, with the effect region identified as N-terminal plus middle fragment.-Li, Y., Li, X., He, K., Li, B., Liu, K., Qi, J., Wang, H., Wang, Y., Luo, W. C-peptide prevents NF-κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy.

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The effective detection of unmanned aerial vehicle (UAV) targets is of great significance to guarantee national military security and social stability. In recent years, with the development of communication and control technology, the movement of UAVs has become increasingly flexible and complex, presenting diverse trajectory forms and different motion models in different phases. The Gaussian mixture probability hypothesis density filter incorporating the linear Gaussian jump Markov system approach (LGJMS-GMPHD) provides an efficient method for tracking multiple maneuvering targets, as applied to the switching of motions between a set of models in a Markovian chain. However, in practice, the motion model parameters of targets are generally unknown and the model switching is uncertain. When the preset filtering model parameters are mismatched, the tracking performance is dramatically degraded. In this paper, within the framework of the LGJMS-GMPHD filter, a deep-learning-based multiple model tracking method is proposed. First, an adaptive turn rate estimation network is designed to solve the filtering model mismatch caused by unknown turn rate parameters in coordinate turn models. Second, a filter state modification network is designed to solve the large tracking errors in the maneuvering phase caused by uncertain motion model switching. Finally, based on simulations of multiple maneuvering targets in cluttered environments and experimental field data verification, it can be concluded that the proposed method has strong adaptability to multiple maneuvering forms and can effectively improve the tracking performance of targets with complex maneuvering motion.

Background Intramedullary spinal cord abscesses (ISCA) are rare, even more so in association with brain abscesses. Infective endocarditis is an uncommon cause of ISCA. In this case study, we report a patient with intramedullary abscesses and multiple brain abscesses due to subacute infective endocarditis. Case presentation A 54-year-old man presented with a 7-day history of head and neck pain and numbness in both lower limbs. Intramedullary abscess combined with multiple brain abscesses was diagnosed based on blood culture, head and spinal magnetic resonance imaging (MRI), contrast-enhanced MRI, and magnetic resonance spectroscopy. Echocardiography revealed vegetations on the mitral valve and severe mitral regurgitation, which the authors believe was caused by subacute infective endocarditis. With ceftriaxone combined with linezolid anti-infective therapy, the patient's symptoms and imaging was improved during follow-up. Conclusions This case hopes to raise the vigilance of clinicians for ISCA. When considering a patient with an ISCA, it is necessary to complete blood culture, MRI of the brain and spinal cord, and echocardiography to further identify whether the patient also has a brain abscess and whether the cause is infective endocarditis.