Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease.     

Histological and Micro-CT Evidence of Stigmatic Rostellum Receptivity Promoting Auto-Pollination in the Madagascan Orchid Bulbophyllum bicoloratum

Background

The rostellum, a projecting part of the gynostemium in orchid flowers, separates the anther(s) from the stigma and thus commonly prevents auto-pollination. Nonetheless, as a modified (usually distal) portion of the median stigma lobe, the rostellum has been frequently invoked of having re-gained a stigmatic function in rare cases of orchid auto-pollination. Here it is shown that a newly discovered selfing variant of Madagascan Bulbophyllum bicoloratum has evolved a modified rostellum allowing the penetration of pollen tubes from in situ pollinia.

Methods

Gynostemium micro-morphology and anatomy of selfing and outcrossing variants of B . bicoloratum was studied by using light and scanning electron microscopy and histological sections. Pollen tube growth in the selfing variant was further observed via X-ray computed microtomography (micro-CT), providing 3D reconstructions of floral tissues at a micron scale.

Findings

Selfing variants possess a suberect (‘displaced’) rostellum rather than the conventional, erect type. Very early in anthesis, the pollinia of selfers are released from the anther and slide down onto the suberect rostellum, where pollen tube growth preferentially occurs through the non-vascularized, i.e. rear (adaxial) and (semi-) lateral parts. This penetrated tissue is comprised of a thin layer of elongate and loosely arranged cells, embedded in stigmatic exudates, as also observed in the stigmatic cavity of both selfing and outcrossing variants.

Conclusions

Our results provide the first solid evidence of a stigmatic function for the rostellum in orchid flowers, thereby demonstrating for the first time the feasibility of the micro-CT technique for accurately visualizing pollen tube growth in flowering plants. Rostellum receptivity in B . bicoloratum probably uniquely evolved as an adaptation for reproductive assurance from an outcrossing ancestor possessing an erect (non-receptive) rostellum. These findings open up new avenues in the investigation of an organ that apparently re-gained its ‘primordial function’ of being penetrated by pollen tubes.     

Drivers of Wetland Conversion: a Global Meta-Analysis

Meta-analysis of case studies has become an important tool for synthesizing case study findings in land change. Meta-analyses of deforestation, urbanization, desertification and change in shifting cultivation systems have been published. This present study adds to this literature, with an analysis of the proximate causes and underlying forces of wetland conversion at a global scale using two complementary approaches of systematic review. Firstly, a meta-analysis of 105 case-study papers describing wetland conversion was performed, showing that different combinations of multiple-factor proximate causes, and underlying forces, drive wetland conversion. Agricultural development has been the main proximate cause of wetland conversion, and economic growth and population density are the most frequently identified underlying forces. Secondly, to add a more quantitative component to the study, a logistic meta-regression analysis was performed to estimate the likelihood of wetland conversion worldwide, using globally-consistent biophysical and socioeconomic location factor maps. Significant factors explaining wetland conversion, in order of importance, are market influence, total wetland area (lower conversion probability), mean annual temperature and cropland or built-up area. The regression analyses results support the outcomes of the meta-analysis of the processes of conversion mentioned in the individual case studies. In other meta-analyses of land change, similar factors (e.g., agricultural development, population growth, market/economic factors) are also identified as important causes of various types of land change (e.g., deforestation, desertification). Meta-analysis helps to identify commonalities across the various local case studies and identify which variables may lead to individual cases to behave differently. The meta-regression provides maps indicating the likelihood of wetland conversion worldwide based on the location factors that have determined historic conversions.     

Simulating the Evolution of the Human Family: Cooperative Breeding Increases in Harsh Environments

Verbal and mathematical models that consider the costs and benefits of behavioral strategies have been useful in explaining animal behavior and are often used as the basis of evolutionary explanations of human behavior. In most cases, however, these models do not account for the effects that group structure and cultural traditions within a human population have on the costs and benefits of its members'' decisions. Nor do they consider the likelihood that cultural as well as genetic traits will be subject to natural selection. In this paper, we present an agent-based model that incorporates some key aspects of human social structure and life history. We investigate the evolution of a population under conditions of different environmental harshness and in which selection can occur at the level of the group as well as the level of the individual. We focus on the evolution of a socially learned characteristic related to individuals'' willingness to contribute to raising the offspring of others within their family group. We find that environmental harshness increases the frequency of individuals who make such contributions. However, under the conditions we stipulate, we also find that environmental variability can allow groups to survive with lower frequencies of helpers. The model presented here is inevitably a simplified representation of a human population, but it provides a basis for future modeling work toward evolutionary explanations of human behavior that consider the influence of both genetic and cultural transmission of behavior.     

Stand-replacing wildfires alter the community structure of wood-inhabiting fungi in southwestern ponderosa pine forests of the USA

Increases in stand-replacing wildfires in the western USA have widespread implications for ecosystem carbon (C) cycling, in part because the decomposition of trees killed by fire can be a long-term source of CO₂ to the atmosphere. Knowledge of the composition and function of decay fungi communities may be important to understanding how wildfire alters C cycles. We assessed the effects of stand-replacing wildfires on the community structure of wood-inhabiting fungi along a 32-yr wildfire chronosequence. Fire was associated with low species richness for up to 4 yr and altered species composition relative to unburned forest for the length of the chronosequence. A laboratory incubation demonstrated that species varied in their capacity to decompose wood; Hypocrea lixii, an indicator of the most recent burn, caused the lowest decomposition rate. Our results show that stand-replacing wildfires have long-term effects on fungal communities, which may have consequences for wood decomposition and C cycling.     

The effect of harvest date and harvest method on the combustion characteristics of Miscanthus × giganteus

Miscanthus × giganteus is an energy crop with many attributes that make it a potential biofuel feedstock. This study examined the chemical composition of M. × giganteus stems cut at different dates throughout the spring harvest window (January, February and March) and either left in a swath or left flat in a thin layer on the ground and compared the composition to that of the standing crop collected on the same date in April (control). The research then examined the effect of cutting date on the chemical composition of whole plant M. × giganteus biomass (leaf and stem). The parameters examined in both parts of this experiment were lower heating value on a wet basis (LHV_WB), ash, chlorine, potassium, nitrogen, sulphur, carbon and hydrogen content. The range of values recorded for the parameters from both aspects of this trial were LHV_WB 4.84–11.87 MJ kg^?1; ash 1.44–1.97%; Cl 0.07–0.23%; K 0.15–0.32%; N 0.28–0.39%; S 0.13–0.19%; C 46.75–50.00%; H 5.76–6.09%. The length of time that the M. × giganteus remained in the field after cutting affected the LHV_WB (increased with time) of the stem biomass material. Cutting the biomass and leaving it in the field lowered the ash, Cl and C content of the stem material compared to that of the control which was cut and collected on the same date. No differences were observed for the other parameters. Date of harvest affected the LHV_WB, Cl and C content which all improved with later cutting dates. Thus, combustion quality can be improved by delaying the harvest date or by cutting the crop and leaving it in the field for a period prior to collection. Choosing the correct combination of time and harvest method can therefore improve biomass fuel quality.     

Connectivity Mapping for Candidate Therapeutics Identification Using Next Generation Sequencing RNA-Seq Data

The advent of next generation sequencing technologies (NGS) has expanded the area of genomic research, offering high coverage and increased sensitivity over older microarray platforms. Although the current cost of next generation sequencing is still exceeding that of microarray approaches, the rapid advances in NGS will likely make it the platform of choice for future research in differential gene expression. Connectivity mapping is a procedure for examining the connections among diseases, genes and drugs by differential gene expression initially based on microarray technology, with which a large collection of compound-induced reference gene expression profiles have been accumulated. In this work, we aim to test the feasibility of incorporating NGS RNA-Seq data into the current connectivity mapping framework by utilizing the microarray based reference profiles and the construction of a differentially expressed gene signature from a NGS dataset. This would allow for the establishment of connections between the NGS gene signature and those microarray reference profiles, alleviating the associated incurring cost of re-creating drug profiles with NGS technology. We examined the connectivity mapping approach on a publicly available NGS dataset with androgen stimulation of LNCaP cells in order to extract candidate compounds that could inhibit the proliferative phenotype of LNCaP cells and to elucidate their potential in a laboratory setting. In addition, we also analyzed an independent microarray dataset of similar experimental settings. We found a high level of concordance between the top compounds identified using the gene signatures from the two datasets. The nicotine derivative cotinine was returned as the top candidate among the overlapping compounds with potential to suppress this proliferative phenotype. Subsequent lab experiments validated this connectivity mapping hit, showing that cotinine inhibits cell proliferation in an androgen dependent manner. Thus the results in this study suggest a promising prospect of integrating NGS data with connectivity mapping.     

Very Long-Chain Acyl-CoA Synthetase 3: Overexpression and Growth Dependence in Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide. In the United States, only one in six lung cancer patients survives five years after diagnosis. These statistics may improve if new therapeutic targets are identified. We previously reported that an enzyme of fatty acid metabolism, very long-chain acyl-CoA synthetase 3 (ACSVL3), is overexpressed in malignant glioma, and that depleting glioblastoma cells of ACSVL3 diminishes their malignant properties. To determine whether ACSVL3 expression was also increased in lung cancer, we studied tumor histologic sections and lung cancer cell lines. Immunohistochemical analysis of normal human lung showed moderate ACSVL3 expression only in bronchial epithelial cells. In contrast, all of 69 different lung tumors tested, including adeno-, squamous cell, large cell, and small cell carcinomas, had robustly elevated ACSVL3 levels. Western blot analysis of lung cancer cell lines derived from these tumor types also had significantly increased ACSVL3 protein compared to normal bronchial epithelial cells. Decreasing the growth rate of lung cancer cell lines did not change ACSVL3 expression. However, knocking down ACSVL3 expression by RNA interference reduced cell growth rates in culture by 65–76%, and the ability of tumor cells to form colonies in soft agar suspension by 65–80%. We also conducted studies to gain a better understanding of the biochemical properties of human ACSVL3. ACSVL3 mRNA was detected in many human tissues, but the expression pattern differed somewhat from that of the mouse. The enzyme activated long- and very long-chain saturated fatty acid substrates, as well as long-chain mono- and polyunsaturated fatty acids to their respective coenzyme A derivatives. Endogenous human ACSVL3 protein was found in a punctate subcellular compartment that partially colocalized with mitochondria as determined by immunofluorescence microscopy and subcellular fractionation. From these studies, we conclude that ACSVL3 is a promising new therapeutic target in lung cancer.     

Antimicrobial Activity and Probable Mechanisms of Action of Medicinal Plants of Kenya: Withania somnifera,Warbugia ugandensis,Prunus africana and Plectrunthus barbatus

Withania somnifera, Warbugia ugandensis, Prunus africana and Plectrunthus barbatus are used traditionally in Kenya for treatment of microbial infections and cancer. Information on their use is available, but scientific data on their bioactivity, safety and mechanisms of action is still scanty. A study was conducted on the effect of organic extracts of these plants on both bacterial and fungal strains, and their mechanisms of action. Extracts were evaluated through the disc diffusion assay. Bacteria and yeast test strains were cultured on Mueller-Hinton agar and on Sabouraud dextrose agar for the filamentous fungi. A 0.5 McFarland standard suspension was prepared. Sterile paper discs 6 mm in diameter impregnated with 10 µl of the test extract (100 mg/ml) were aseptically placed onto the surface of the inoculated media. Chloramphenicol (30 µg) and fluconazole (25 µg) were used as standards. Discs impregnated with dissolution medium were used as controls. Activity of the extracts was expressed according to zone of inhibition diameter. MIC was determined at 0.78–100 mg/ml. Safety studies were carried using Cell Counting Kit 8 cell proliferation assay protocol. To evaluate extracts mechanisms of action, IEC-6 cells and RT-PCR technique was employed in vitro to evaluate Interleukin 7 cytokine. Investigated plants extracts have both bactericidal and fungicidal activity. W. ugandensis is cytotoxic at IC₅₀<50 µg/ml with MIC values of less than 0.78 mg/ml. Prunus africana shuts down expression of IL 7 mRNA at 50 µg/ml. W. somnifera has the best antimicrobial (1.5625 mg/ml), immunopotentiation (2 times IL 7 mRNA expression) and safety level (IC₅₀>200 µg/ml). Fractions from W. ugandensis and W. somnifera too demonstrated antimicrobial activity. Mechanisms of action can largely be attributed to cytotoxicity, Gene silencing and immunopotentiation. Use of medicinal plants in traditional medicine has been justified and possible mechanisms of action demonstrated. Studies to isolate and characterize the bioactive constituents continue.