Can molecular cell biology explain chromosome motions?

<p>Abstract</p> <p>Background</p> <p>Mitotic chromosome motions have recently been correlated with electrostatic forces, but a lingering "molecular cell biology" paradigm persists, proposing binding and release proteins or molecular geometries for force generation.</p> <p>Results</p> <p>Pole-facing kinetochore plates manifest positive charges and interact with negatively charged microtubule ends providing the motive force for poleward chromosome motions by classical electrostatics. This conceptual scheme explains dynamic tracking/coupling of kinetochores to microtubules and the simultaneous depolymerization of kinetochore microtubules as poleward force is generated.</p> <p>Conclusion</p> <p>We question here why cells would prefer complex molecular mechanisms to move chromosomes when direct electrostatic interactions between known bound charge distributions can accomplish the same task much more simply.</p

Divergence of AMP Deaminase in the Ice Worm Mesenchytraeus solifugus (Annelida, Clitellata, Enchytraeidae)

Glacier ice worms, Mesenchytraeus solifugus and related species, are the largest glacially obligate metazoans. As one component of cold temperature adaptation, ice worms maintain atypically high energy levels in an apparent mechanism to offset cold temperature-induced lethargy and death. To explore this observation at a mechanistic level, we considered the putative contribution of 5′ adenosine monophosphate deaminase (AMPD), a key regulator of energy metabolism in eukaryotes. We cloned cDNAs encoding ice worm AMPD, generating a fragment encoding 543 amino acids that included a short N-terminal region and complete C-terminal catalytic domain. The predicted ice worm AMPD amino acid sequence displayed conservation with homologues from other mesophilic eukaryotes with notable exceptions. In particular, an ice worm-specific K188E substitution proximal to the AMP binding site likely alters the architecture of the active site and negatively affects the enzyme's activity. Paradoxically, this would contribute to elevated intracellular ATP levels, which appears to be a signature of cold adapted taxa

A Glutamine-Rich Factor Affects Stem Cell Genesis in Leech

Leech embryogenesis is a model for investigating cellular and molecular processes of development. Due to the unusually large size of embryonic stem cells (teloblasts: 50–300 μm) in the glossiphoniid leech, Theromyzon tessulatum, and the presence of identifiable stem cell precursors (proteloblasts), we previously isolated a group of genes upregulated upon stem cell birth. In the current study, we show that one of these genes, designated Theromyzon proliferation (Tpr), is required for normal stem cell genesis; specifically, transient Tpr knockdown experiments conducted with antisense oligonucleotides and monitored by semiquantitative RT-PCR, caused abnormal proteloblast proliferation leading to embryonic death, but did not overtly affect neuroectodermal or mesodermal stem cell development once these cells were born. Tpr encodes a large glutamine-rich (∼34%) domain that shares compositional similarity with strong transcriptional enhancers many of which have been linked with trinucleotide repeat disorders (e.g., Huntington's)

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma

BackgroundProteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis.MethodsExome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis.ResultsThe most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9—22.3, p = 5.42*10−7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10−6).ConclusionsWe identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations

The Alcohol Dehydrogenase System in the Xylose-Fermenting Yeast Candida maltosa

The alcohol dehydrogenase (ADH) system plays a critical role in sugar metabolism involving in not only ethanol formation and consumption but also the general "cofactor balance" mechanism. Candida maltosa is able to ferment glucose as well as xylose to produce a significant amount of ethanol. Here we report the ADH system in C. maltosa composed of three microbial group I ADH genes (CmADH1, CmADH2A and CmADH2B), mainly focusing on its metabolic regulation and physiological function.Genetic analysis indicated that CmADH2A and CmADH2B tandemly located on the chromosome could be derived from tandem gene duplication. In vitro characterization of enzymatic properties revealed that all the three CmADHs had broad substrate specificities. Homo- and heterotetramers of CmADH1 and CmADH2A were demonstrated by zymogram analysis, and their expression profiles and physiological functions were different with respect to carbon sources and growth phases. Fermentation studies of ADH2A-deficient mutant showed that CmADH2A was directly related to NAD regeneration during xylose metabolism since CmADH2A deficiency resulted in a significant accumulation of glycerol.Our results revealed that CmADH1 was responsible for ethanol formation during glucose metabolism, whereas CmADH2A was glucose-repressed and functioned to convert the accumulated ethanol to acetaldehyde. To our knowledge, this is the first demonstration of function separation and glucose repression of ADH genes in xylose-fermenting yeasts. On the other hand, CmADH1 and CmADH2A were both involved in ethanol formation with NAD regeneration to maintain NADH/NAD ratio in favor of producing xylitol from xylose. In contrast, CmADH2B was expressed at a much lower level than the other two CmADH genes, and its function is to be further confirmed

Magna Carta, the Rule of Law and the Limits on Government

This paper surveys the legal tradition that links Magna Carta with the modern concepts of the rule of law and the limits on government. It documents that the original understanding of the rule of law included substantive commitments to individual freedom and limited government. Then, it attempts at explaining how and why such commitments were lost to a formalist interpretation of the rule of law from 1848 to 1939. The paper concludes by arguing how a revival of the substantive commitments of the rule of law is central in a project of reshaping modern states

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice