The evaluation of PIK3CA gene variation and serum PI3K level in breast cancer risk and prognosis in Turkish population

Objectives The PI3K (Phosphatidylinositol 3-kinase) is the member of lipid kinase family that plays important roles in tumorigenesis, cancer development and cell proliferation. In our study, we aimed to investigate the relationships between breast cancer risk and prognosis with PIK3CA rs6443624 (C>A) intron region gene polymorphism and serum PI3K levels. Methods A total of 61-patients with breast cancer and 101 controls were included to the study. PIK3CA polymorphism was detected by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique. Serum PI3K levels were measured by Enzyme-Linked Immuno Sorbent Assay (ELISA). Results PIK3CA (C>A) gene polymorphism genotype and allele distributions were no significant in cases and controls (p>0.05). The serum PI3K levels of breast cancer patients were found significantly higher than the control groups (p=0.033). There were not significant association between PIK3CA (C>A) gene polymorphism and clinic and prognostic parameters in our study group. We also evaluated serum PI3K levels in the term of tumor progression, but we did not observe any significant data. Conclusions We suggest that serum PI3K levels may play role in breast cancer risk and larger patient groups may have clinical value in assessment of the genetic risk and tumor progression of breast cancer.

Whole Genome Sequencing Illuminates the Developmental Signatures of Human Language Ability

Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis - and how it compares to that of more general cognitive functioning - remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals, who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few "language genes".

A new species of the genus Tylototriton (Urodela, Salamandridae) from western Thailand

We describe a new species of the newt genus Tylototriton from Umphang Wildlife Sanctuary, Tak Province, western Thailand based on molecular and morphological evidence and named here as Tylototriton umphangensissp. nov. The new species is assigned to the subgenus Tylototriton and differs from other species in having dark-brown to blackish-brown body and limbs, truncate snout, prominent antero-medial ends of the expansion of the dentary bones, laterally protruding quadrate regions, indistinct and small rib nodules, a well-segmented vertebral ridge, and rough dorsolateral bony ridges, which are steeper anterior, and curved medially at the posterior ends. The molecular data show that Tylototriton umphangensissp. nov. differs from T. uyenoi sensu stricto by a 5% genetic sequence divergence of the mitochondrial NADH dehydrogenase subunit 2 region gene. The new species and T. uyenoi are both endemic to Thailand, distributed along the Northwest Thai (Dawna) Uplands of Indochina. To clarify the species boundary between Tylototriton umphangensissp. nov. and T. uyenoi, additional field research is needed in adjacent areas. Tylototriton umphangensissp. nov. is restricted to evergreen hill forests in Umphang Wildlife Sanctuary. We suggest that the new species should be classified as Endangered (EN) in the IUCN Red List.

Novel Insights Into the Genetic Population Connectivity of Transient Whale Sharks (Rhincodon typus) in Pacific Panama Provide Crucial Data for Conservation Efforts

The whale shark (Rhincodon typus) is an endangered and highly migratory species, of which solitary individuals or aggregations are observed in oceans worldwide and for which conservation efforts are hindered by a lack of comprehensive data on genetic population connectivity. Tissue samples were collected from wandering whale sharks in Pacific Panama to determine genetic diversity, phylogeographic origin, and possible global and local connectivity patterns using a 700–800 bp fragment of the mitochondrial control region gene. Genetic diversity among samples was high, with five new haplotypes and nine polymorphic sites identified among the 15 sequences. Haplotype diversity (Hd = 0.83) and nucleotide diversity (π = 0.00516) were similar to those reported in other studies. Our sequences, in particular haplotypes PTY1 and PTY2, were similar to those previously reported in the Arabian Gulf and the Western Indian Ocean populations (a novel occurrence in the latter case). Haplotypes PTY3, PTY4, and PTY5 were similar to populations in Mexico and the Gulf of California. In contrast, the only populations to which our Panamanian sequences were genetically dissimilar were those from the Atlantic Ocean. The absence of reference sequences in GenBank from southern sites in the Eastern Tropical Pacific, such as Galapagos (Ecuador), Gorgona and Malpelo Islands (Colombia), and Coco Island (Costa Rica), reduced our capacity to genetically define regional patterns. Genetic differentiation and connectivity were also assessed using an analysis of molecular variance (AMOVA), which showed a similar population structure (five groups) to the neighbor-joining tree. Other population features based on neutrality tests, such as Tajima’s D and Fu’s Fs statistics, showed positive values for Panama of 0.79 and 1.61, respectively. Positive values of these statistics indicate a lack of evidence for population expansion among the sampled individuals. Our results agree with previous reports suggesting that whale sharks can travel over long distances and that transboundary conservation measures may be effective for species protection.

The transcriptome of rat hippocampal subfields

The hippocampus comprises several neuronal populations such as CA1, CA2, CA3, and the dentate gyrus (DG), which present different neuronal origins, morphologies, and molecular mechanisms. Laser capture microdissection (LCM) allows selectively collecting samples from target regions and eliminating unwanted cells to obtain more specific results. LCM of hippocampus neuronal populations coupĺed with RNA-seq analysis has the potential to allow the exploration of the molecular machinery unique to each of these subfields. Previous RNA-seq investigation has already provided a molecular blueprint of the hippocampus, however, there is no RNA-seq data specific for each of the rat hippocampal regions. Serial tissue sections covering the hippocampus were produced from frozen brains of adult male Wistar rats, and the hippocampal subfields CA1, CA2, CA3, and DG were identified and isolated by LCM. Total RNA was extracted from samples, and cDNA libraries were prepared and run on a HiSeq 2500 platform. Reads were aligned using STAR, and the DESeq2 statistics package was used to estimate gene expression. We found evident segregation of the transcriptomic profile from different regions of the hippocampus and the expression of known, as well as novel, specific marker genes for each region. Gene ontology enrichment analysis of CA1 subfield indicates an enrichment of actin regulation and postsynaptic membrane AMPA receptors genes indispensable for long-term potentiation. CA2 and CA3 transcripts were found associated with the increased metabolic processes. DG expression was enriched for ribosome and spliceosome, both required for protein synthesis and maintenance of cell life. The present findings contribute to a deeper understanding of the differences in the molecular machinery expressed by the rat hippocampal neuronal populations, further exploring underlying mechanisms responsible for each subflied specific functions.

Targeting Bruton’s Tyrosine Kinase in CLL

Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with TP53 aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Distinct target selectivity of individual BTKis confer differences in target-mediated as well as off-target adverse effects. Disease progression on covalent BTKis, driven by histologic transformation or selective expansion of BTK and PLCG2 mutated CLL clones, remains a major challenge in the field. Fixed duration combination regimens and reversible BTKis with non-covalent binding chemistry hold promise for the prevention and treatment of BTKi-resistant disease.

effect of diet composition, a probiotic and a symbiotic treatment on the ileal microbiota composition of one-week-old broiler chickens

A healthy microbiota present in the small intestine contributes significantly to small intestinal function, including digestion, nutrient absorption and health. The current study investigated the effects of a prebiotic, a probiotic and a symbiotic supplementation on ileal microbiota composition of broilers at 7 days of age. In a total of 574 male Ross 308 day-old chickens were divided into four groups using six replicate pens and 24 chickens per pen. A maise-soybean based control diet (C), a control diet supplemented with probiotics (Broilact; Br), a control diet supplemented with symbiotic (inulin, yeast, Bacillus subtilis; Sy) and a wheat based diet supplemented with wheat bran (W) were formulated. On day 7 of life, two chickens per pen were slaughtered and ileal chymus samples were collected. For microbiota analysis 16S rRNA (V3-V4 region) gene targeted Illumina MiSeq sequencing was used. Feeding all diets supplemented increased the diversity to varying degrees compared to the control (C) diet (p=0.006). As a conclusion, all supplementation substantially influenced ileal microbiota of broiler chickens at an early age. All these results could offer some information for the future study on the relationship between early intestinal microbiota and the compounds of the feed.

Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1

Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.