Iterative similarity search programs, like psiblast, jackhmmer, and psisearch, are much more sensitive than pairwise similarity search methods like blast and ssearch because they build a position specific scoring model (a PSSM or HMM) that captures the pattern of sequence conservation characteristic to a protein family. But models are subject to contamination; once an unrelated sequence has been added to the model, homologs of the unrelated sequence will also produce high scores, and the model can diverge from the original protein family. Examination of alignment errors during psiblast PSSM contamination suggested a simple strategy for dramatically reducing PSSM contamination. psiblast PSSMs are built from the query-based multiple sequence alignment (MSA) implied by the pairwise alignments between the query model (PSSM, HMM) and the subject sequences in the library. When the original query sequence residues are inserted into gapped positions in the aligned subject sequence, the resulting PSSM rarely produces alignment over-extensions or alignments to unrelated sequences. This simple step, which tends to anchor the PSSM to the original query sequence and slightly increase target percent identity, can reduce the frequency of false-positive alignments more than 20-fold compared with psiblast and jackhmmer, with little loss in search sensitivity.
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http://dx.doi.org/10.1093/nar/gkw1207 | DOI Listing |
Mol Biol Cell
January 2025
Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
β-tubulin isotypes exhibit similar sequences but different activities, suggesting that limited sequence divergence is functionally important. We investigated this hypothesis for TUBB3/β3, a β-tubulin linked to aggressive cancers and chemoresistance in humans. We created mutant yeast strains with β-tubulin alleles that mimic variant residues in β3 and find that residues at the lateral interface are sufficient to alter microtubule dynamics and response to microtubule targeting agents.
View Article and Find Full Text PDFJAMA Cardiol
January 2025
Program of Medical and Population Genetics, Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard, Cambridge, Massachusetts.
Importance: Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood.
Objective: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk.
Mol Plant Microbe Interact
January 2025
Max Planck Institute for Biology Tübingen, Max-Planck Ring 5, Tuebingen, Germany, 72076;
Filamentous plant pathogens pose a severe threat to food security. Current estimates suggest up to 23% yield losses to pre- and post-harvest diseases and these losses are projected to increase due to climate change (Singh et al. 2023; Chaloner et al.
View Article and Find Full Text PDFDiscov Oncol
January 2025
Western Institute of Digital-Intelligent Medicine, 401329, Chongqing, China.
Background: The metabolism of stearoyl-GPE plays a key role in the liver metastasis of gastric cancer. This investigation delves into the mechanisms underlying the intricate tumor microenvironment (TME) heterogeneity triggered by stearoyl metabolism in gastric cancer with liver metastasis (LMGC), offering novel perspectives for LMGC.
Objective: Utilizing Mendelian randomization, we determined that stearoyl metabolism significantly contributes to the progression of gastric cancer (GC).
Methods Mol Biol
January 2025
Bioscience, Research and Early Development, Oncology, AstraZeneca, Cambridge, Cambridgeshire, UK.
A protocol for the preparation of tissue extracts for the targeted analysis ca. 150 polar metabolites, including those involved in central carbon metabolism, is described, using a reversed phase ion pair U(H)PLC-MS method. Data collection enabled in high-resolution mass spectrometry detection provides highly specific and sensitive acquisition of metabolic intermediates with wide range physicochemical properties and pathway coverage.
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