Pollen Morphology and Boron Concentration in Floral Tissues as Factors Triggering Natural and GA-Induced Parthenocarpic Fruit Development in Grapevine

Parthenocarpic fruit development (PFD) reduces fruit yield and quality in grapevine. Parthenocarpic seedless berries arise from fruit set without effective fertilization due to defective pollen germination. PFD has been associated to micronutrient deficiency but the relation of this phenomenon with pollen polymorphism has not been reported before. In this work, six grapevine cultivars with different tendency for PFD and grown under micronutrient-sufficient conditions were analyzed to determine pollen structure and germination capability as well as PFD rates. Wide variation in non-germinative abnormal pollen was detected either among cultivars as well as for the same cultivar in different growing seasons. A straight correlation with PFD rates was found (R² = 0.9896), suggesting that natural parthenocarpy is related to defective pollen development. Such relation was not observed when PFD was analyzed in grapevine plants exposed to exogenous gibberellin (GA) or abscissic acid (ABA) applications at pre-anthesis. Increase (GA treatment) or reduction (ABA treatment) in PFD rates without significative changes in abnormal pollen was determined. Although these plants were maintained at sufficient boron (B) condition, a down-regulation of the floral genes VvBOR3 and VvBOR4 together with a reduction of floral B content in GA-treated plants was established. These results suggest that impairment in B mobility to reproductive tissues and restriction of pollen tube growth could be involved in the GA-induced parthenocarpy.     

Correlation of Hypertension and Proteinuria with Outcome in Elderly Bevacizumab-Treated Patients with Metastatic Colorectal Cancer

Background

Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab.

Patients and Methods

Patients ≥70 years of age received either capecitabine 1250 mg/m² bid days 1–14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m² bid days 1–14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m² day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS.

Results

In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P<0.0001). Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR.

Conclusion

This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab treatment and do not represent an independent prognostic factor.     

Polar Desolvation and Position 226 of Pancreatic and Neutrophil Elastases Are Crucial to their Affinity for the Kunitz-Type Inhibitors ShPI-1 and ShPI-1/K13L

The Kunitz-type protease inhibitor ShPI-1 inhibits human neutrophil elastase (HNE, K _i = 2.35·10⁻⁸ M) but does not interact with the porcine pancreatic elastase (PPE); whereas its P1 site variant, ShPI-1/K13L, inhibits both HNE and PPE (K _i = 1.3·10⁻⁹ M, and K _i = 1.2·10⁻⁸ M, respectively). By employing a combination of molecular modeling tools, e.g., structural alignment, molecular dynamics simulations and Molecular Mechanics Generalized-Born/Poisson-Boltzmann Surface Area free energy calculations, we showed that D226 of HNE plays a critical role in the interaction of this enzyme with ShPI-1 through the formation of a strong salt bridge and hydrogen bonds with K13 at the inhibitor’s P1 site, which compensate the unfavorable polar-desolvation penalty of the latter residue. Conversely, T226 of PPE is unable to establish strong interactions with K13, thereby precluding the insertion of K13 side-chain into the S1 subsite of this enzyme. An alternative conformation of K13 site-chain placed at the entrance of the S1 subsite of PPE, similar to that observed in the crystal structure of ShPI-1 in complex with chymotrypsin (PDB: 3T62), is also unfavorable due to the lack of stabilizing pair-wise interactions. In addition, our results suggest that the higher affinity of ShPI-1/K13L for both elastases mainly arises from the lower polar-desolvation penalty of L13 compared to that of K13, and not from stronger pair-wise interactions of the former residue with those of each enzyme. These results provide insights into the PPE and HNE inhibition and may contribute to the design of more potent and/or specific inhibitors toward one of these proteases.     

Maternal Mortality in Colombia in 2011: A Two Level Ecological Study

Objective

Maternal mortality reduction is a Millennium Development Goal. In Colombia, there is a large disparity in the maternal mortality ratio (MMR) between and into departments (states) and also between municipalities. We examined socioeconomics variables at the municipal and departmental levels which could be associated to the municipal maternal mortality in Colombia.

Methods

A multilevel ecology study was carried out using different national data sources in Colombia. The outcome variable was the MMR at municipal level in 2011 with multidimensional poverty at municipal and department level as the principal independent variables and other measures of the social and economic characteristics at municipal and departmental level were also considered explicative variables (overall fertility municipal rate, percentage of local rural population, health insurance coverage, per capita territorial participation allocated to the health sector, transparency index and Gini coefficient). The association between MMR and socioeconomic contextual conditions at municipal and departmental level was assessed using a multilevel Poisson regression model.

Results

The MMR in the Colombian municipalities was associated significantly with the multidimensional poverty (relative ratio of MMR: 3.52; CI 95%: 1.09-11.38). This association was stronger in municipalities from departments with the highest poverty (relative ratio of MMR: 7.14; CI 95%: 2.01-25.35). Additionally, the MMR at municipal level was marginally associated with municipally health insurance coverage (relative ratio of MMR: 0.99; CI 95%: 0.98-1.00), and significantly with transparency index at departmental level (relative ratio of MMR: 0.98; CI 95%: 0.97-0.99).

Conclusion

Poverty and transparency in a contextual level were associated with the increase of the municipal MMR in Colombia. The results of this study are useful evidence for informing the public policies discussion and formulation processes with a differential approach.     

Sleep Deprivation Induces Changes in Immunity in Trichinella spiralis-Infected Rats

Sleep is considered an important predictor of immunity. A lack of sleep may reduce immunity, which increases susceptibility to any type of infection. Moreover, sleep deprivation in humans produces changes in both, the percent of circulating immune cells (T cells and NK cells) and cytokine levels (IL-1, IFNγ, TNΦ-αα, IL-6 and IL-17). The aim of our study was to investigate whether sleep deprivation produces deregulation on immune variables during the immune response generated against the helminth parasite Trichinella spiralis. Because sleep deprivation is stressful per se, we designed another experiments to compared stress alone (consisting in movement restriction and single housing) with sleep deprivation, in both control (uninfected) and experimental (infected) rats. Our results demonstrate that the sleep deprivation and stress have a differential effect in mesenteric lymph nodes (MLN) and spleen. In uninfected rats sleep deprivation alone produces an increase in natural killer cells (NK+) and B cells (CD45+), accompanied by a decrease in cytotoxic T cells (CD3+CD8+) in spleen; while, in MLN, produces only an increase in natural killer cells (NK+). Both, SD and stress, produce an increased percentage of total T cells (CD3+) in spleen. In the MLN both are also associated to an increase in cytotoxic T cells (CD3+CD8+) and B cells (CD45+). In the spleens of parasitized rats, cell populations did not change. In spleens of both, sleep-deprived and stressed infected rats, we observed an increase in B cells (CD45+). In infected rats, sleep deprivation alone produced an increase in NK cells (NK+). In mesenteric node cell populations of parasitized rats, we observed a decrease in NK cells and an increase in T helper (CD4+) cells in both SD and stressed rats. Rats that were only subjected to stress showed a decrease in B cells (CD45+). These findings suggest that the immune response generated against infection caused by T. spiralis is affected when the sleep pattern is disrupted. These results support the notion that sleep is a fundamental process for an adequate and strong immune response generated against this parasite.     

Production of trichodiene by Trichoderma harzianum alters the perception of this biocontrol strain by plants and antagonized fungi

Trichothecenes are phytotoxic sesquiterpenic mycotoxins that can act as virulence factors in plant diseases. Harzianum A (HA) is a non‐phytotoxic trichothecene produced by Trichoderma arundinaceum. The first step in HA biosynthesis is the conversion of farnesyl diphosphate to trichodiene (TD), a volatile organic compound (VOC), catalysed by a sesquiterpene synthase encoded by the tri5 gene. Expression of tri5 in the biocontrol strain Trichoderma harzianum CECT 2413 resulted in production of TD in parallel with a reduction of ergosterol biosynthesis and an unexpected increase in the level of squalene. Transformants expressing tri5 displayed low chitinase activity and induced expression of Botrytis cinerea BOT genes, although their total antagonistic potential against phytopathogenic fungi was not reduced. VOCs released by the tri5‐transformant induced expression of tomato defence genes related to salicylic acid (SA), and TD itself strongly induced the expression of SA‐responsive genes and reduced the development of lateral roots. Together, these results suggest that TD acts as a signalling VOC in the interactions of Trichoderma with plants and other microorganisms by modulating the perception of this fungus to a given environment. Moreover, the TD ability to induce systemic defences indicates that complex trichothecene structures may not be necessary for inducing such responses.     

Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Background

Thyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood.A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes.

Results

Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events.

Conclusion

A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1372-0) contains supplementary material, which is available to authorized users.