Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation

Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau’s ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.     

Analysis of the Origin and Dissemination of HIV-1 Subtype C in Bulgaria

HIV-1 subtype C is the most abundant strain of HIV-1 infections worldwide and was found in the first known patients diagnosed with HIV/AIDS in Bulgaria in 1986. However, there is limited information on the molecular-epidemiological characteristics of this strain in the epidemic of the country. In this study, we analyze the evolutionary history of the introduction and dissemination of HIV-1 subtype C in Bulgaria using global phylogenetic analysis, Bayesian coalescent-based approach, and molecular clock methods. All available samples with HIV-1 subtype C from individuals diagnosed with HIV/AIDS between 1986 and 2017 were analyzed. Men and women were equally represented, and 24.3% of patients reported being infected abroad. The global phylogenetic analysis indicated multiple introductions of HIV-1 subtype C from various countries of the world. The reconstruction of a Bayesian time-scaled phylogenies showed that several Bulgarian strains segregated together in clusters, while others were intermixed in larger clades containing strains isolated from both European and non-European countries. The time-scale of HIV-1 subtype C introductions in Bulgaria demonstrates the early introduction of these viruses in the country. Our in-depth phylogenetic and phylogeographic analyses are compatible with a scenario of multiple early introductions in the country followed by limited local distribution in the subsequent years. HIV-1 subtype C was introduced in the early years of the epidemic, originating from different countries of the world. Due to the comprehensive measures for prevention and control in the early years of the epidemic in Bulgaria, HIV-1 subtype C was not widely disseminated among the general population of the country.     

A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-β superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1^G93A transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-β superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1^G93A transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1^G93A transgenic mice. The improved function of SOD1^G93A transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-β pathway inhibitors to increase muscle strength in patients with ALS.     

Ten-year clinical laboratory follow-up after application of a symptom-based therapeutic strategy to patients with severe chronic aortic regurgitation of predominant rheumatic etiology

OBJECTIVES: This study was designed to assess the feasibility and the long-term results of a symptom-based strategy of aortic valve replacement in a Brazilian population with predominant rheumatic etiology. BACKGROUND: Optimal criteria for valve replacement in aortic regurgitation (AR) are still not entirely clear. The appearance of symptoms is an indication for surgery, but may be associated with myocardial damage. Although cardiac imaging data have provided a safer guide for such decisions, the use of symptom-based surgical indication has not been validated and might conceivably be better in populations with predominant rheumatic etiology and younger age. METHODS: Echocardiography and rest-exercise radionuclide ventriculography were performed in 75 patients with severe AR, age 28 +/- 9 years, over a period of 10 +/- 0.69 years. Thirty-seven patients developed symptoms and underwent aortic valve replacement surgery within six months. Thirty-eight patients remained asymptomatic and were managed medically. RESULTS: Survival was 100% in asymptomatic patients and 82% in symptomatic. Surgical treatment caused marked ventricular remodeling, with ventricular diameter involution and an improvement of rest-exercise ejection fraction percent variation. Multivariate analysis showed that the probability of developing symptoms within 10 years was 58% for a patient with a left ventricular end-diastolic diameter > or =70 mm and 76% for a patient with left ventricular end-systolic (LVESD) > or =50 mm. Logistic regression identified LVESD and age as the most predictive and specific, but not sensitive, indicators of symptom development. CONCLUSIONS: Application of a standardized therapeutic strategy to patients with severe AR and predominant rheumatic etiology resulted in 90.6% survival after 10 years of follow-up.     

Exonucleolytic degradation of RNA by p53 protein in cytoplasm

p53 in cytoplasm displays an intrinsic 3'-->5' exonuclease activity. To understand the significance of p53 exonuclease activity in cytoplasm, cytoplasmic extracts of various cell lines were examined for exonuclease activity with different single-stranded RNA (ssRNA) substrates. Using an in vitro RNA degradation assay, we observed in cytoplasmic extracts of LCC2 cells, expressing high levels of endogenous wtp53, an efficient 3'-->5' exonuclease activity with RNA substrates, removing the 3'-terminal nucleotides. Interestingly, RNA containing AU-rich sequences (ARE) is the permissive substrate for exonucleolytic degradation. Evidence that exonuclease function with RNA detected in cytoplasmic extracts is attributed to the p53 is supported by several facts: (1) this activity closely parallels with status and levels of endogenous cytoplasmic p53; (2) the endogenous exonuclease exerts identical RNA substrate specificity and excision profile characteristic for purified baculovirus-or bacterially-expressed wtp53s; (3) the exonuclease activity with ARE RNA is competed out by the presence of ss or double-stranded DNA substrate utilized by p53 protein in cytoplasm; (4) immunoprecipitation by specific anti-p53 antibodies markedly reduced the exonuclease activity with both RNA and DNA substrates; and (5) transfection of the wtp53, but not exonuclease-deficient mutant p53-R175H, into p53-null H1299 or HCT116 cells induced high levels of exonuclease activity with ARE RNA substrate in cytoplasm with characteristic excision profile. The efficient ARE RNA degradation correlates with the efficient binding of p53 to ARE RNA in cytoplasm. The possible role of p53 exonuclease activity in ARE-mRNA destabilization in cytoplasm, which may be important for expression of proteins that control cell growth and/or apoptosis is discussed.