SUMMARY The shelterin complex plays both positive and negative roles in telomerase regulation. While shelterin prevents the checkpoint kinases ATM and ATR from fully activating DNA damage responses at telomeres, those kinases are also required for telomere maintenance. In fission yeast, cells lacking both Tel1 (ATM ortholog) and Rad3 (ATR ortholog) fail to recruit telomerase to telomeres, and survive by circularizing chromosomes. However, the critical telomere substrate(s) of Tel1ATM/Rad3ATR remained unknown. Here, we show that Tel1ATM/Rad3ATR-dependent phosphorylation of the shelterin subunit Ccq1 on Thr93 is essential for telomerase association with telomeres. In addition, we show that the telomerase subunit Est1 interacts directly with the phosphorylated Thr93 of Ccq1 to ensure telomere maintenance. The shelterin subunits Taz1, Rap1 and Poz1 (previously established inhibitors of telomerase) were also found to negatively regulate Ccq1 phosphorylation. These findings establish Tel1ATM/Rad3ATR-dependent Ccq1 Thr93 phosphorylation as a critical regulator of telomere maintenance in fission yeast.

INTRODUCTION: Endocarditis caused by Lactobacilli species is rare and usually manifests in patients with severe comorbidities, congenital heart disease, or prosthetic valves. Lactobacilli species are gram-positive coccobacilli mostly found in the gastrointestinal tract flora. Current literature shows an association of this bacterium with the use of probiotics. We hypothesize a possible association between acute cholecystitis and the occurrence of Lactobacillus endocarditis in a patient with no history of use of probiotics. CASE DESCRIPTION/METHODS: A 75-year-old female with a history of Birt-Hogg-Dube Syndrome with multiple spontaneous pneumothoraxes, COPD, aortic stenosis status post prosthetic aortic valve (AV) replacement, presented with acute respiratory failure and septic shock. She was diagnosed with acute cholecystitis, severe aortic regurgitation, and found to have lactobacillus bacteremia. We started her on empiric antibiotic coverage and later switched to penicillin G and gentamicin following three positive blood cultures for Lactobacillus paracasei. A transesophageal echocardiogram showed vegetation with emerging severe aortic regurgitation, degeneration, and perforation of AV leaflet when compared with echocardiogram one year ago. A CT-thorax demonstrated pan lobular emphysema with large cysts and pneumatoceles at the lung bases. Bacteremia persisted for two weeks after initiation of antibiotic therapy. Treatment with penicillin G and gentamicin was deemed necessary for up to 4 weeks after definitive surgical treatment. However, the patient's severe lung condition complicated preoperative clearance, and she was transferred to a specialized center for open-heart AV replacement. DISCUSSION: Very few cases of Lactobacillus endocarditis are reported in the literature. A handful of studies describe some implicated pathogenesis of the Lactobacillus in the blood as induced by cholecystitis. Other studies suggest that the increased presence of Lactobacillus in the respiratory tract in cases of severe lung pathology can lead to hematogenous dissemination to the heart valves. However, the association between Lactobacillus species and prosthetic valve material (and implication with endocarditis) is currently well-established. All things considered, and despite the lack of histopathology, we suggest that the source of Lactobacillus was likely the acute cholecystitis, and the presence of lung comorbidities and prosthetic AV further exacerbated the patient's condition.

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This study examines the utility of neural networks for extracting useful information from the diastolic heart sounds associated with coronary occlusions. It has been widely reported that coronary stenoses produce sounds due to the turbulent blood flow in these vessels. These compIex and highly attenuated signals taken from recordings made in both soundproof and noisy rooms were detected and analyzed to provide feature set based on linear prediction coefficients by using the Autoregressive (AR) after Adaptive Line Enhancement (ALE) method.In order to further explore the extraction of the useful information regarding the complex diastolic heart sounds assoicated with coronary artery disease, the analysis of the diastolic heart sounds was approached using neural networks since neural networks are potentially capable of partitioning the signal space into arbitrarily complex decision regions.