Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan.

In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (ATM p. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.

Multifaceted framework for defining conservation units: An example from Atlantic salmon (Salmo salar) in Canada.

Conservation units represent important components of intraspecific diversity that can aid in prioritizing and protecting at-risk populations, while also safeguarding unique diversity that can contribute to species resilience. In Canada, identification and assessments of conservation units is done by the Committee on the Status of Endangered Wildlife in Canada (COSEWIC). COSEWIC can recognize conservation units below the species level (termed "designatable units"; DUs) if the unit has attributes that make it both discrete and evolutionarily significant. There are various ways in which a DU can meet criteria of discreteness and significance, and increasing access to "big data" is providing unprecedented information that can directly inform both criteria. Specifically, the incorporation of genomic data for an increasing number of non-model species is informing more COSEWIC assessments; thus, a repeatable, robust framework is needed for integrating these data into DU characterization. Here, we develop a framework that uses a multifaceted, weight of evidence approach to incorporate multiple data types, including genetic and genomic data, to inform COSEWIC DUs. We apply this framework to delineate DUs of Atlantic salmon (Salmo salar, L.), an economically, culturally, and ecologically significant species, that is also characterized by complex hierarchical population structure. Specifically, we focus on an in-depth example of how our approach was applied to a previously data limited region of northern Canada that was defined by a single large DU. Application of our framework with newly available genetic and genomic data led to subdividing this DU into three new DUs. Although our approach was developed to meet criteria of COSEWIC, it is widely applicable given similarities in the definitions of a conservation unit.

Inherent conflicts between reaction norm slope and plasticity indices when comparing plasticity: a conceptual framework and empirical test.

Phenotypic plasticity index (PI), the slope of reaction norm (K) and relative distances plasticity index (RDPI), the most commonly used estimators, have occasionally been found to generate different plasticity rankings between groups (species, populations, cultivars or genotypes). However, no effort has been made to determine how frequent this incongruence is, and the factors that influence the occurrence of the incongruence. To address these problems, we first proposed a conceptual framework and then tested the framework (its predictions) by reanalyzing 1248 sets of published data. Our framework reveals inherent conflicts between K and PI or RDPI when comparing plasticity between two groups, and the frequency of these conflicts increases with increasing inter-group initial trait difference and/or K values of the groups compared. More importantly, the estimators also affect the magnitude of the inter-group plasticity differences even when they do not change groups' plasticity rankings. The above-mentioned effects of plasticity estimators were confirmed by our empirical test using data from the literature, and the conflicts occur in 203 (16%) of the 1248 comparisons between K and indices, indicating that a considerable proportion of the comparative conclusions on plasticity in literature are estimator-dependent. The frequency of the conflicts is influenced by phylogenetic relatedness of the groups compared, being lower when comparing within relative to between species, but not by specific types of environments, traits and species. Our study indicates that care is needed to select estimator when comparing groups' plasticity, and that the conclusions in relevant literature should be treated with great caution.

Elucidation of Diverse Physico-Chemical Parameters in Mammalian Small Heat Shock Proteins: A Comprehensive Classification and Structural and Functional Exploration Using In Silico Approach.

Small heat shock proteins (sHSPs), often known as molecular chaperones, are most prevalent in nature. Under certain stress-induced conditions, these sHSPs act as an ATP-independent variation and thus prevent the inactivation of various non-native substrate proteins and their aggregation. They also assist other ATP-dependent chaperones in the refolding of these substrates. In the case of prokaryotes and lower eukaryotes, the chaperone functions of sHSPs can bind a wide range of cellular proteins but preferentially protect translation-related proteins and metabolic enzymes. Eukaryotes usually encode a larger number of sHSPs than those of prokaryotes. The chaperone functions of mammalian sHSPs are regulated by phosphorylation in cells and also by temperature. Their sHSPs have different sub-cellular compartments and cell/tissue specificity. The substrate proteins of mammalian sHSPs or eukaryotic sHSPs accordingly reflect their multi-cellular complexity. The sHSPs of animals play roles in different physiological processes as cell differentiation, apoptosis, and longevity. In this work, the characterization, location, tissue specificity, and functional diversity of sHSPs from seven different mammalian species with special emphasis on humans have been studied. Through this extensive work, a novel and significant attempt have been made to classify them based on their omnipresence, tissue specificity, localization, secondary structure, probable mutations, and evolutionary significance.

Computational analysis reveals a successive adaptation of multiple inositol polyphosphate phosphatase 1 in higher organisms through evolution.

Multiple inositol polyphosphate phosphatase 1 (Minpp1) in higher organisms dephosphorylates InsP6, the most abundant inositol phosphate. It also dephosphorylates less phosphorylated InsP5 and InsP4 and more phosphorylated InsP7 or InsP8. Minpp1 is classified as a member of the histidine acid phosphatase super family of proteins with functional resemblance to phytases found in lower organisms. This study took a bioinformatics approach to explore the extent of evolutionary diversification in Minpp1 structure and function in order to understand its physiological relevance in higher organisms. The human Minpp1 amino acid (AA) sequence was BLAST searched against available national protein databases. Phylogenetic analysis revealed that Minpp1 was widely distributed from lower to higher organisms. Further, we have identified that there exist four isoforms of Minpp1. Multiple computational tools were used to identify key functional motifs and their conservation among various species. Analyses showed that certain motifs predominant in higher organisms were absent in lower organisms. Variation in AA sequences within motifs was also analyzed. We found that there is diversification of key motifs and thus their functions present in Minpp1 from lower organisms to higher organisms. Another interesting result of this analysis was the presence of a glucose-1-phosphate interaction site in Minpp1; the functional significance of which has yet to be determined experimentally. The overall findings of our study point to an evolutionary adaptability of Minpp1 functions from lower to higher life forms.

Mixed asexual and sexual reproduction in the Indo-Pacific reef coral Pocillopora damicornis.

Pocillopora damicornis is one of the best studied reef-building corals, yet it's somewhat unique reproductive strategy remains poorly understood. Genetic studies indicate that P. damicornis larvae are produced almost exclusively parthenogenetically, and yet population genetic surveys suggest frequent sexual reproduction. Using microsatellite data from over 580 larvae from 13 colonies, we demonstrate that P. damicornis displays a mixed reproductive strategy where sexual and asexual larvae are produced simultaneously within the same colony. The majority of larvae were parthenogenetic (94%), but most colonies (10 of the 13) produced a subset of their larvae sexually. Logistic regression indicates that the proportion of sexual larvae varied significantly with colony size, cycle day, and calendar day. In particular, the decrease in sexual larvae with colony size suggests that the mixed reproductive strategy changes across the life of the coral. This unique shift in reproductive strategy leads to increasingly asexual replications of successful genotypes, which (in contrast to exclusive parthenogens) have already contributed to the recombinant gene pool.

Species of Gonostomum and Paragonostomum (Ciliophora, Hypotrichida, Oxytrichidae) from the Valley of Flowers, India, with descriptions of Gonostomum singhii sp nov, Paragonostomum ghangriai sp nov and Paragonostomum minuta sp nov.

Soil samples taken from the Valley of Flowers, a component of the Nanda Devi Biosphere Reserve in the Himalayan regions of India showed the presence of twenty two free living species of ciliates. There is a preponderance of species which exhibit oral ciliature and ontogenesis in the Gonostomum pattern. Of the four species of the genus Gonostomum, three viz., G affine, G gonostomoida and G kuehnelti are similar to described species; Gonostomum singhii is new. The two species of genus Paragonostomum viz., P minuta and P ghangriai are new. The three new species are described in the present paper. All these species show prominent hypertrophied ciliary structures. Their paroral membranes reveal characteristic differences with respect to their position, number of constituent cilia and the distance between adjacent cilia. It is proposed that such species specific features of the paroral membrane have a bearing in exercising different food organism preferences as they co-exist at many sites. This single factor has possibly played an important role in species diversification of this group of hypotrichs in this isolated habitat.