Scoring protein interaction decoys using exposed residues (SPIDER): a novel multibody interaction scoring function based on frequent geometric patterns of interfacial residues

Accurate prediction of the structure of protein-protein complexes in computational docking experiments remains a formidable challenge. It has been recognized that identifying native or native-like poses among multiple decoys is the major bottleneck of the current scoring functions used in docking. We have developed a novel multibody pose-scoring function that has no theoretical limit on the number of residues contributing to the individual interaction terms. We use a coarse-grain representation of a protein-protein complex where each residue is represented by its side chain centroid. We apply a computational geometry approach called Almost-Delaunay tessellation that transforms protein-protein complexes into a residue contact network, or an undirectional graph where vertex-residues are nodes connected by edges. This treatment forms a family of interfacial graphs representing a dataset of protein-protein complexes. We then employ frequent subgraph mining approach to identify common interfacial residue patterns that appear in at least a subset of native protein-protein interfaces. The geometrical parameters and frequency of occurrence of each "native" pattern in the training set are used to develop the new SPIDER scoring function. SPIDER was validated using standard "ZDOCK" benchmark dataset that was not used in the development of SPIDER. We demonstrate that SPIDER scoring function ranks native and native-like poses above geometrical decoys and that it exceeds in performance a popular ZRANK scoring function. SPIDER was ranked among the top scoring functions in a recent round of CAPRI (Critical Assessment of PRedicted Interactions) blind test of protein-protein docking methods.     

A Highlights from MBoC Selection: Slk19 clusters kinetochores and facilitates chromosome bipolar attachment

In all eukaryotic cells, DNA is packaged into multiple chromosomes that are linked to microtubules through a large protein complex called a kinetochore. Previous data show that the kinetochores are clustered together during most of the cell cycle, but the mechanism and the biological significance of kinetochore clustering are unknown. As a kinetochore protein in budding yeast, the role of Slk19 in the stability of the anaphase spindle has been well studied, but its function in chromosome segregation has remained elusive. Here we show that Slk19 is required for kinetochore clustering when yeast cells are treated with the microtubule-depolymerizing agent nocodazole. We further find that slk19Δ mutant cells exhibit delayed kinetochore capture and chromosome bipolar attachment after the disruption of the kinetochore–microtubule interaction by nocodazole, which is likely attributed to defective kinetochore clustering. In addition, we show that Slk19 interacts with itself, suggesting that the dimerization of Slk19 may mediate the interaction between kinetochores for clustering. Therefore Slk19 likely acts as kinetochore glue that clusters kinetochores to facilitate efficient and faithful chromosome segregation.     

The Association of Vitamin D Receptor Polymorphisms with Multiple Sclerosis in a Case-Control Study from Kuwait

Vitamin D deficiency is associated with several diseases including multiple sclerosis (MS). Several factors influence vitamin D levels and its optimal multi-function maintenance. Our objective was to assess quantifiable variables influencing vitamin D level and metabolism in MS patients from Kuwait. In a case-control study involving 50 MS patients, and 50 healthy control individuals for which plasma vitamin D levels, supplement use, vitamin D receptor (VDR) variants, and skin pigmentation indices were ascertained; we found overall vitamin D levels to be deficient in both groups, and supplement use to be common practice. VDR variants TaqI and BsmI associated with MS risk, and ApaI associated with low disease progression. VDR variant FokI associated with higher vitamin D levels in both groups. We conclude that several quantifiable variables related to vitamin D associate with MS suggesting a possible clinical immuno-modulatory application of vitamin D for MS patients in Kuwait.     

Health implications resulting from the timing of elective cesarean delivery

Background  

The literature is nearly unanimous in recommending elective cesarean delivery at 39 weeks of gestation because of the lower rates of neonatal respiratory complications compared to 38 weeks. However, elective cesarean delivery at 39 weeks or more may have maternal and other fetal consequences compared to delivery at 38 weeks, which are not always addressed in these studies.     

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

Gene targeting techniques have led to the phenotypic characterization of numerous genes; however, many genes show minimal to no phenotypic consequences when disrupted, despite many having highly conserved sequences. The standard explanation for these findings is functional redundancy. A competing hypothesis is that these genes have important ecological functions in natural environments that are not needed under laboratory settings. Here we discriminate between these hypotheses by competing mice (Mus musculus) whose Hoxb1 gene has been replaced by Hoxa1, its highly conserved paralog, against matched wild-type controls in seminatural enclosures. This Hoxb1^A1 swap was reported as a genetic manipulation resulting in no discernible embryonic or physiological phenotype under standard laboratory tests. We observed a transient decline in first litter size for Hoxb1^A1 homozygous mice in breeding cages, but their fitness was consistently and more dramatically reduced when competing against controls within seminatural populations. Specifically, males homozygous for the Hoxb1^A1 swap acquired 10.6% fewer territories and the frequency of the Hoxb1^A1 allele decreased from 0.500 in population founders to 0.419 in their offspring. The decrease in Hoxb1^A1 frequency corresponded with a deficiency of both Hoxb1^A1 homozygous and heterozygous offspring. These data suggest that Hoxb1 and Hoxa1 are more phenotypically divergent than previously reported and support that sub- and/or neofunctionalization has occurred in these paralogous genes leading to a divergence of gene function and incomplete redundancy. Furthermore, this study highlights the importance of obtaining fitness measures of mutants in ecologically relevant conditions to better understand gene function and evolution.     

Association between periodontitis and vitamin D status: A case-control study

Vitamin D deficiency and periodontitis are commonly prevalent among Saudi adults. However, the association between periodontitis and vitamin D status has not been well documented. This study aims to examine the association between periodontitis and vitamin D status among adults in the Albaha region of Saudi Arabia. A case-control study of 123 Saudi adults was conducted; 60 had severe or moderate periodontitis, and 63 were periodontally healthy. Data was collected by an online self-reported sociodemographic questionnaire. All participants then underwent a full periodontal examination. Blood samples were also provided to assess participants’ vitamin D statuses through serum levels of 25-hydroxyvitamin D (25(OH)D). A total of 60 cases and 63 controls matched for BMI (30.2 ± 4.86 kg/m²), age (40.01 ± 7.73 years), and sex (46.3% and 53.7% male and female, respectively) participated in the study. Mean levels of 25(OH)D were significantly lower in periodontitis participants than in controls (25.03 ± 8.55 ng/ml, 29.19 ± 12.82 ng/ml, p = 0.037, respectively). Lower odds of periodontitis were detected per unit of 25(OH)D level (OR 0.964, 95% CI; 0.931–0.999, p = 0.043). In conclusion, periodontitis is significantly associated with deficient and insufficient levels of vitamin D among Saudi adults in the Albaha region. Future longitudinal research with a larger sample size may be suggested to confirm these results.