Association of a novel point mutation in MSH2 gene with familial multiple primary cancers

Background

Multiple primary cancers (MPC) have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues.

Methods

We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC.

Results

We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing) that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR) genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients.

Conclusion

Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome.

     

Mexican Arnica Anti–Inflammatory Action: Plant Age is Correlated with the Concentration of Anti–Inflammatory Sesquiterpenes in the Medicinal Plant <Emphasis Type="Italic">Heterotheca inuloides</Emphasis> Cass. (Asteraceae)<Superscript>1</Superscript>

Mexican Arnica Anti–Inflammatory Action: Plant Age Is Correlated with the Concentration of Anti–inflammatory Sesquiterpenes in the Medicinal Plant Heterotheca inuloides Cass. (Asteraceae). Mexican árnica (Heterotheca inuloides Cass.) is a widely used anti–inflammatory medicinal plant in Mexican folk medicine. Although it has been suggested that plant age, fertilization, and harvesting regime influence the concentration of secondary compounds affecting the therapeutic activity of the plant, the effect of these variables on the concentration of the Mexican árnica anti–inflammatory compounds was not known. We quantified anti–inflammatory sesquiterpenes (caryolan–1, 9β–diol, cadalen–15–oic acid, 7–hydroxycadalene, 4–hydroxy–2–isopropyl–4, 7–dimethyl–1[4H] naftalinone, 7–hydroxy–4αH–3, 4–dihydrocadalene, β–caryophyllene, and β–caryophyllene epoxide) in Mexican árnica plants subjected to fertilization and successive harvests of flowering stems, conditions that mimic the cultivation and harvesting for árnica in México. Fertilization and successive harvesting and their interaction had no significant effect on the concentration of anti–inflammatory compounds. However, the concentrations of these compounds were 60% higher in flowering stems from 15–month–old plants than in those from 4– or 8–month–old plants and was independent of the number of harvests and fertilization regime applied.     

Two new species of <Emphasis Type="Italic">Zercon</Emphasis> (Acari: Zerconidae) from Turkey

Two new species of zerconid mites, Zercon uludagicus sp. n. and Z. huseyini sp. n., from Turkey are described and illustrated. The similarities and differences between the species are discussed. The lists of the taxonomic diagnostic key to adults of Zercon species known from Turkey are also given.     

Water-soluble granules containing <Emphasis Type="Italic">Bacillus megaterium</Emphasis> for biological control of rice sheath blight: formulation,bacterial viability and efficacy testing

Endospores of B. megaterium were formulated in granule formulations with sodium alginate, lactose and polyvinylpyrrolidone (PVP K-30) by the wet granulation technique. The granule formulation exhibited good physical characteristics, such as high-water solubility and optimal viscosity, that would be suitable for spray application. The bacteria remained viable in the dry granule formulation at 10⁹ c.f.u./g after 24 months storage at room temperature. Under laboratory conditions, aqueous solutions of the formulation showed high activity against mycelial growth of R. solani (99.64 ± 0.14% mycelial inhibition). High viability of the bacterial antagonist on leaf sheath and leaf blade at day 7 after spraying with the formulation was observed (approximately 10⁶ c.f.u./g of plant). Application of an equivalent number of un-formulated endospores resulted in much loss of the bacterial endospores even 1 day after application. In a small pilot field study, an aqueous solution of the formulation (3%w/v) applied by spraying at days 1, 5 and 10 after pathogen inoculation of the rice plants was more effective in suppressing rice sheath blight disease than one application of a fungicide (Iprodione) at day 1. Additionally, rice plants sprayed with the aqueous solution of the granule formulation had higher panicle and whole kernel weights than those of fungicide-treated and control (untreated) plants.     

Restoration Strategies to Improve Connectivity for Golden-Headed Lion Tamarins (<Emphasis Type="Italic">Leontopithecus chrysomelas</Emphasis>) in the Bahian Atlantic Forest,Brazil

Habitat loss and fragmentation are the leading causes of biodiversity decline world-wide. Animals sensitive to fragmentation experience reduced dispersal, breeding opportunities, and genetic diversity, making them vulnerable to local extinction. Over the last few decades the Atlantic Forest of Brazil has been extremely fragmented, with only 11–16% of forest remaining. The Brazilian government and nongovernmental organizations have taken actions through legislation and conservation initiatives to restore forest. Using computer modeling, we compared how alternative forest restoration strategies could improve functional connectivity for golden-headed lion tamarins (Leontopithecus chrysomelas) in Southern Bahia, Brazil. Strategies differed by restoration configuration, including Within- and Across-Property approaches, and restoration amount (0–20% restoration). Increasing restoration amounts resulted in greater species functional connectivity, and Within-Property and Across-Property strategies both had significantly more connectivity than the Random strategy. We suggest restoration management consider the size and placement of restored forest, and that riparian forest be restored first to create dispersal corridors and reestablish essential ecosystem services. We further suggest the importance of forming canopy bridges across narrow sections of rivers during the early stages of the restoration process to promote increased connectivity of these newly restored areas. Our findings can aid managers and landowners in understanding the implications of different restoration strategies for highly arboreal, matrix-sensitive species.     

A recurrent neural model for proto-object based contour integration and figure-ground segregation

Visual processing of objects makes use of both feedforward and feedback streams of information. However, the nature of feedback signals is largely unknown, as is the identity of the neuronal populations in lower visual areas that receive them. Here, we develop a recurrent neural model to address these questions in the context of contour integration and figure-ground segregation. A key feature of our model is the use of grouping neurons whose activity represents tentative objects (“proto-objects”) based on the integration of local feature information. Grouping neurons receive input from an organized set of local feature neurons, and project modulatory feedback to those same neurons. Additionally, inhibition at both the local feature level and the object representation level biases the interpretation of the visual scene in agreement with principles from Gestalt psychology. Our model explains several sets of neurophysiological results (Zhou et al. Journal of Neuroscience, 20(17), 6594–6611 2000; Qiu et al. Nature Neuroscience, 10(11), 1492–1499 2007; Chen et al. Neuron, 82(3), 682–694 2014), and makes testable predictions about the influence of neuronal feedback and attentional selection on neural responses across different visual areas. Our model also provides a framework for understanding how object-based attention is able to select both objects and the features associated with them.     

Nitrogen fixing bacterial diversity in a tropical estuarine sediments

Microorganisms play a significant role in biogeochemical cycles, especially in the benthic and pelagic ecosystems. Role of environmental parameters in regulating the diversity, distribution and physiology of these microorganisms in tropical marine environment is not well understood. In this study, we have identified dinitrogen (N₂) fixing bacterial communities in the sediments by constructing clone libraries of nitrogenase (nifH) gene from four different stations in the Cochin estuary, along the southeastern Arabian Sea. N₂ fixing bacterial clones revealed that over 20 putative diazotrophs belong to alpha-, beta-, gamma-, delta- and epsilon- proteobacteria and firmicutes. Predominant genera among these were Bradyrhizobium sp. (α-proteobacteria), Dechloromonas sp. (β-proteobacteria); Azotobactor sp., Teredinibacter sp., Methylobacter sp., Rheinheimera sp. and Marinobacterium sp. (γ-proteobacteria); Desulfobacter sp., Desulfobulbus sp. and Desulfovibrio sp. (δ -proteobacteria); Arcobacter sp. and Sulfurospirillum sp. (ε-proteobacteria). Nostoc sp. was solely identified among the cyanobacterial phylotype. Nitrogen fixing Sulfate reducing bacteria (SRBs) such as Desulfobulbus sp., Desulfovibrio sp., Desulfuromonas sp., Desulfosporosinus sp., Desulfobacter sp., were also observed in the study. Most of the bacterial nifH sequences revealed that the identities of N₂ fixing bacteria were less than 95% similar to that available in the GenBank database, which suggested that the sequences were of novel N₂ fixing microorganisms. Shannon-Weiner diversity index of nifH gene ranged from 2.95 to 3.61, indicating an inflated diversity of N₂ fixing bacteria. Canonical correspondence analysis (CCA) implied positive correlation among nifH diversity, N₂ fixation rate and other environmental variables.     

Using the lymph fistula rat model to study the potentiation of GIP secretion by the ingestion of fat and glucose

Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin produced in the K cells of the intestine and secreted into the circulating blood following ingestion of carbohydrate- and fat-containing meals. GIP contributes to the regulation of postprandial insulin secretion and is essential for normal glucose tolerance. We have established a method of assaying GIP in response to nutrients using the intestinal lymph fistula model. Administration of Ensure, a mixed-nutrient liquid meal, stimulated a significant increase in intestinal lymphatic GIP levels that were approximately threefold those of portal plasma. Following the meal, lymph GIP peaked at 60 min (P < 0.001) and remained elevated for 4 h. Intraduodenal infusions of isocaloric and isovolumetric lipid emulsions or glucose polymer induced lymph GIP concentrations that were four and seven times the basal levels, respectively. The combination of glucose plus lipid caused an even greater increase of lymph GIP than either nutrient alone. In summary, these findings demonstrated that intestinal lymph contains high concentrations of GIP that respond to both enteral carbohydrate and fat absorption. The change in lymphatic GIP concentration is greater than the change observed in the portal blood. These studies allow the detection of GIP levels at which they exert their local physiological actions. The combination of glucose and lipid has a potentiating effect in the stimulation of GIP secretion. We conclude from these studies that the lymph fistula rat is a novel approach to study in vivo GIP secretion in response to nutrient feeding in conscious rats.