Minimotif Miner 4: a million peptide minimotifs and counting.

Minimotif Miner (MnM) is a database and web system for analyzing short functional peptide motifs, termed minimotifs. We present an update to MnM growing the database from ∼300 000 to >1 000 000 minimotif consensus sequences and instances. This growth comes largely from updating data from existing databases and annotation of articles with high-throughput approaches analyzing different types of post-translational modifications. Another update is mapping human proteins and their minimotifs to know human variants from the dbSNP, build 150. Now MnM 4 can be used to generate mechanistic hypotheses about how human genetic variation affect minimotifs and outcomes. One example of the utility of the combined minimotif/SNP tool identifies a loss of function missense SNP in a ubiquitylation minimotif encoded in the excision repair cross-complementing 2 (ERCC2) nucleotide excision repair gene. This SNP reaches genome wide significance for many types of cancer and the variant identified with MnM 4 reveals a more detailed mechanistic hypothesis concerning the role of ERCC2 in cancer. Other updates to the web system include a new architecture with migration of the web system and database to Docker containers for better performance and management. Weblinks:minimotifminer.org and mnm.engr.uconn.edu.

The Functional Human C-Terminome.

All translated proteins end with a carboxylic acid commonly called the C-terminus. Many short functional sequences (minimotifs) are located on or immediately proximal to the C-terminus. However, information about the function of protein C-termini has not been consolidated into a single source. Here, we built a new "C-terminome" database and web system focused on human proteins. Approximately 3,600 C-termini in the human proteome have a minimotif with an established molecular function. To help evaluate the function of the remaining C-termini in the human proteome, we inferred minimotifs identified by experimentation in rodent cells, predicted minimotifs based upon consensus sequence matches, and predicted novel highly repetitive sequences in C-termini. Predictions can be ranked by enrichment scores or Gene Evolutionary Rate Profiling (GERP) scores, a measurement of evolutionary constraint. By searching for new anchored sequences on the last 10 amino acids of proteins in the human proteome with lengths between 3-10 residues and up to 5 degenerate positions in the consensus sequences, we have identified new consensus sequences that predict instances in the majority of human genes. All of this information is consolidated into a database that can be accessed through a C-terminome web system with search and browse functions for minimotifs and human proteins. A known consensus sequence-based predicted function is assigned to nearly half the proteins in the human proteome. Weblink: http://cterminome.bio-toolkit.com.

Natural variability of minimotifs in 1092 people indicates that minimotifs are targets of evolution.

Since the function of a short contiguous peptide minimotif can be introduced or eliminated by a single point mutation, these functional elements may be a source of human variation and a target of selection. We analyzed the variability of ∼300 000 minimotifs in 1092 human genomes from the 1000 Genomes Project. Most minimotifs have been purified by selection, with a 94% invariance, which supports important functional roles for minimotifs. Minimotifs are generally under negative selection, possessing high genomic evolutionary rate profiling (GERP) and sitewise likelihood-ratio (SLR) scores. Some are subject to neutral drift or positive selection, similar to coding regions. Most SNPs in minimotif were common variants, but with minor allele frequencies generally <10%. This was supported by low substation rates and few newly derived minimotifs. Several minimotif alleles showed different intercontinental and regional geographic distributions, strongly suggesting a role for minimotifs in adaptive evolution. We also note that 4% of PTM minimotif sites in histone tails were common variants, which has the potential to differentially affect DNA packaging among individuals. In conclusion, minimotifs are a source of functional genetic variation in the human population; thus, they are likely to be an important target of selection and evolution.

Evaluation of calciotropic hormones in cats with odontoclastic resorptive lesions.

OBJECTIVE: To assess associations between epidemiologic and laboratory variables and calciotropic hormones in cats with odontoclastic resorptive lesions (ORLs). ANIMALS: 182 client-owned cats older than 1 year of age with oral disease. PROCEDURE: Information on medical history, behavior, living environment, and feeding management was assessed by use of a questionnaire. After induction of general anesthesia, oral examination was performed following standardized protocols and included dental probing and full-mouth radiography. Laboratory analyses included evaluation of FeLV-FIV status, serum biochemical analyses, CBC, urinalysis, and serum concentrations of intact parathyroid hormone (iPTH), parathyroid hormone-related peptide (PTHrP), 25-hydroxyvitamin D (25-OHD), free thyroxine (fT4), and ionized calcium (iCa). RESULTS: ORLs were identified in 72.5% of cats. Mandibular third premolars were the most commonly affected teeth. Cats with ORLs were significantly older (mean, 9.2 years) than cats without ORLs (mean, 6.6 years). Multivariate logistic regression analysis revealed that 25-OHD, urine specific gravity, jaw-opening reflex on probing, and missing teeth were significant variables, even after accounting for age. Cats with ORLs had significantly higher mean serum concentration of 25-OHD (112.4 nmol/L) and significantly lower mean urine specific gravity (1.0263), compared with cats without ORLs (89.8 nmol/L and 1.0366, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Results did not indicate associations between iPTH, PTHrP, or fT4 and development of ORLs. In affected cats, the importance of high serum 25-OHD and low urine specific gravity has not been determined.

Gingivostomatitis.

Gingivostomatitis (GS) with various patterns of disease may require antiviral therapy, steroids, laser fulguration, immunomodulation drugs, or nonsteroidal anti-inflammatory drugs. The use of cyclosporine as an immunomodulation drug has long-term benefits in reduction of the immunologic events that contribute to GS. Whole-mouth extraction or partial extraction (premolars and molars), with radiographic conformation that all root remnants have been removed, may be the most viable option in nonresponsive and or intractably painful stomatitis in noncompliant cats or dogs. Oral inflammation subsided after extraction without the need for further medication in approximately 70% of the cats from two studies with previous chronic unrelenting oral disease. The combination of immunomodulation with cyclosporine together with laser resection of proliferative tissue should be recommended if extraction of teeth is not desired. Removal of proliferative oral tissues by lasing (carbon dioxide laser) removes the tissue that maybe producing tissue antigens and the area where bacteria are sequestered. The use of anti-inflammatory medications is recommended in the management of GS. Therapeutic success is achieved when there is elimination of proliferative tissue and inflammation.