Structural Constraints Identified with Covariation Analysis in Ribosomal RNA

Covariation analysis is used to identify those positions with similar patterns of sequence variation in an alignment of RNA sequences. These constraints on the evolution of two positions are usually associated with a base pair in a helix. While mutual information (MI) has been used to accurately predict an RNA secondary structure and a few of its tertiary interactions, early studies revealed that phylogenetic event counting methods are more sensitive and provide extra confidence in the prediction of base pairs. We developed a novel and powerful phylogenetic events counting method (PEC) for quantifying positional covariation with the Gutell lab’s new RNA Comparative Analysis Database (rCAD). The PEC and MI-based methods each identify unique base pairs, and jointly identify many other base pairs. In total, both methods in combination with an N-best and helix-extension strategy identify the maximal number of base pairs. While covariation methods have effectively and accurately predicted RNAs secondary structure, only a few tertiary structure base pairs have been identified. Analysis presented herein and at the Gutell lab’s Comparative RNA Web (CRW) Site reveal that the majority of these latter base pairs do not covary with one another. However, covariation analysis does reveal a weaker although significant covariation between sets of nucleotides that are in proximity in the three-dimensional RNA structure. This reveals that covariation analysis identifies other types of structural constraints beyond the two nucleotides that form a base pair

A MAP6-Related Protein Is Present in Protozoa and Is Involved in Flagellum Motility

In vertebrates the microtubule-associated proteins MAP6 and MAP6d1 stabilize cold-resistant microtubules. Cilia and flagella have cold-stable microtubules but MAP6 proteins have not been identified in these organelles. Here, we describe TbSAXO as the first MAP6-related protein to be identified in a protozoan, Trypanosoma brucei. Using a heterologous expression system, we show that TbSAXO is a microtubule stabilizing protein. Furthermore we identify the domains of the protein responsible for microtubule binding and stabilizing and show that they share homologies with the microtubule-stabilizing Mn domains of the MAP6 proteins. We demonstrate, in the flagellated parasite, that TbSAXO is an axonemal protein that plays a role in flagellum motility. Lastly we provide evidence that TbSAXO belongs to a group of MAP6-related proteins (SAXO proteins) present only in ciliated or flagellated organisms ranging from protozoa to mammals. We discuss the potential roles of the SAXO proteins in cilia and flagella function

Chapter 19 Noise pollution and its impact on human health and the environment

This chapter deals with (1) the basic theory of sound propagation; (2) an overview of noise pollution problem in view of policy and standards by the World Health Organization, the United States, and the European Union; (3) noise exposure sources from aircraft, road traffic and railways, in-vehicle, work, and construction sites, and occupations, and households; (4) the noise pollution impact on human health and the biological environment; (5) modeling of regional noise-affected habitats in protected and unprotected land areas and the marine environment; (6) noise control measures and sustainability in view of sustainable building design, noise mapping, and control measures such as barriers and berms along roadsides, acoustic building materials, roadway vehicle noise source control, road surface, and pavement materials; and (7) environmental noise pollution management measures and their impact on human health

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Safety of temozolomide use in adult patients with renal dysfunction

PURPOSE: Temozolomide (TMZ), a cytotoxic DNA alkylating agent, is the main chemotherapy used for the treatment of high grade astrocytomas. The active alkylator, methylhydrazine, is not recovered in urine and thus renal function is not expected to affect clearance. Prescribing information for TMZ states pharmacokinetics have not been studied in adults with poor renal function, eGFR \u3c 36 mL/min/1.73 m(2). We reviewed our clinical experience with TMZ in patients with impaired renal function to evaluate safety of administering full dose TMZ. METHODS: The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with eGFR \u3c 60 mL/min/1.73 m(2) who received TMZ for treatment of high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphopenia hepatotoxicity, and number of TMZ cycles administered. Medical records of patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019 were accessed to identify cases for this study. RESULTS: Thirty-two patients were eligible for this study. Of the seven patients with eGFR \u3c 36 mL/min/1.73m(2), 38/39 cycles (97%) were completed without grade 3-4 thrombocytopenia. No patients experienced grade 3-4 neutropenia, and grade 3-4 lymphopenia occurred in 5 cycles (15%). One patient discontinued TMZ 7 days prior to completion of radiation due to thrombocytopenia. CONCLUSION: Hematologic toxicity in patients with severe renal dysfunction, eGFR \u3c 36 mL/min/1.73m(2), is similar to that of patients with normal renal function. Severe renal impairment does not preclude use of temozolomide, but cautious monitoring of blood counts is warranted

The highlight and underlying concepts of the PEC based covariation analysis in rCAD.

<p>A: data source; B: multi-dimensional data; C: mapping the substitutions; D: counting the positive and negative events.</p

Base pairs in the Bacterial 16S rRNA structure model that are identified with the helix extension method.

<p>Red: true positive base-pairs identified as the sum of PEC/JN-Best and MIxy/JN-Best methods, which are used as nucleation points in the helix extension Magenta: false positives in the nucleation pairs; Blue: true positive base-pairs identified with the helix-extension method; Yellow: false-positive pairs identified with the helix-extension method. Secondary base-pairs are represented by closed circles while tertiary base-pairs are represented by open circle and highlighted with arrows.</p

The flowchart of analysis in the identification of base-pairs and neighbor effects.

<p>The flowchart of analysis in the identification of base-pairs and neighbor effects.</p

The base pairs (true positives) identified by PEC/JN-Best and MI/JN-Best are plotted onto the <i>T. thermophiles</i> 16S rRNA secondary structure diagram.

<p>Red: base pairs only identified by PEC/JN-Best; Green: base pairs only identified by MI/JN-Best; Yellow: base pairs identified by both methods.</p