Protein Subcellular Relocalization Increases the Retention of Eukaryotic Duplicate Genes

Abstract Gene duplication is widely accepted as a key evolutionary process, leading to new genes and novel protein functions. By providing the raw genetic material necessary for functional expansion, the mechanisms that involve the retention and functional diversification of duplicate genes are one of the central topics in evolutionary and comparative genomics. One proposed source of retention and functional diversification is protein subcellular relocalization (PSR). PSR postulates that changes in the subcellular location of eukaryotic duplicate proteins can positively modify function and therefore be beneficial to the organism. As such, PSR would promote retention of those relocalized duplicates and result in significantly lower death rates compared with death rates of nonrelocalized duplicate pairs. We surveyed both relocalized and nonrelocalized duplicate proteins from the available genomes and proteomes of 59 eukaryotic species and compared their relative death rates over a Ks range between 0 and 1. Using the Cox proportional hazard model, we observed that the death rates of relocalized duplicate pairs were significantly lower than the death rates of the duplicates without relocalization in most eukaryotic species examined in this study. These observations suggest that PSR significantly increases retention of duplicate genes and that it plays an important, but currently underappreciated, role in the evolution of eukaryotic genomes

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Abstract Background Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome. Methods To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc−) is upregulated in Mecp2-null glia when compared to WT, the role of Xc− in the uptake of NAC and l-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan. Results We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc− was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc− for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival. Conclusions These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT

Correction to: Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Abstract After publication of the article [1], it has been brought to our attention that an author’s name has been formatted incorrectly

Selected Transesophageal Echocardiographic Parameters of Left Ventricular Diastolic Function Predict Length of Stay Following Coronary Artery Bypass Graft—A Prospective Observational Study

(1) Importance: Abnormal left ventricular (LV) diastolic function, with or without a diagnosis of heart failure, is a common finding that can be easily diagnosed by intra-operative transesophageal echocardiography (TEE). The association of diastolic function with duration of hospital stay after coronary artery bypass (CAB) is unknown. (2) Objective: To determine if selected TEE parameters of diastolic dysfunction are associated with length of hospital stay after coronary artery bypass surgery (CAB). (3) Design: Prospective observational study. (4) Setting: A single tertiary academic medical center. (5) Participants: Patients with normal systolic function undergoing isolated CAB from September 2017 through June 2018. (6) Exposures: LV function during diastole, as assessed by intra-operative TEE prior to coronary revascularization. (7) Main Outcomes and Measures: The primary outcome was duration of postoperative hospital stay. Secondary intermediate outcomes included common postoperative cardiac, respiratory, and renal complications. (8) Results: The study included 176 participants (mean age 65.2 ± 9.2 years, 73% male); 105 (60.2%) had LV diastolic dysfunction based on selected TEE parameters. Median time to hospital discharge was significantly longer for subjects with selected parameters of diastolic dysfunction (9.1/IQR 6.6–13.5 days) than those with normal LV diastolic function (6.5/IAR 5.3–9.7 days) (p < 0.001). The probability of hospital discharge was 34% lower (HR 0.66/95% CI 0.47–0.93) for subjects with diastolic dysfunction based on selected TEE parameters, independent of potential confounders, including a baseline diagnosis of heart failure. There was a dose–response relation between severity of diastolic dysfunction and probability of discharge. LV diastolic dysfunction based on those selected TEE parameters was also associated with postoperative cardio-respiratory complications; however, these complications did not fully account for the relation between LV diastolic dysfunction and prolonged length of hospital stay. (9) Conclusions and Relevance: In patients with normal systolic function undergoing CAB, diastolic dysfunction based on selected TEE parameters is associated with prolonged duration of postoperative hospital stay. This association cannot be explained by baseline comorbidities or common post-operative complications. The diagnosis of diastolic dysfunction can be made by TEE