Vascular endothelial growth factor and related molecules in acute lung injury.

VEGFs and their receptors have been implicated in the regulation of vascular permeability in many organ systems, including the lung. Increased permeability and interstitial and pulmonary edema are prominent features of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Extrapolating data from other organ systems and animal experiments have suggested that overexpression of VEGF functions primarily as proinjurious molecules in the lung. Recent data, from animal models as well as from patients with ARDS, have shown decreased levels of VEGF in the lung. The role of VEGF and related molecules in ALI/ARDS is, therefore, controversial: what has become clear is that there are many unique features in the regulation of pulmonary vascular permeability and in VEGF expression in the lung. In this review, we explore a growing body of literature looking at the expression and function of VEGF and related molecules in different models of ALI and in patients with ALI/ARDS. Novel evidence points to a potential role of VEGF in promoting repair of the alveolar-capillary membrane during recovery from ALI/ARDS. Understanding the role of VEGF in this disease process is crucial for developing new therapeutic strategies for ALI/ARDS.     

Factors influencing limit values for pine needle litter decomposition: a synthesis for boreal and temperate pine forest systems

We synthesized available data for decomposition of pine (Pinus) needle litter in pine forests to determine the litter chemical characteristics and climate factors that explained variation in the limit value, i.e. the level of accumulated mass loss at which the decomposition process either continues at a very low rate or possibly stops. Our data base included 56 separate studies on decomposition of pine needle litter, spanning Scots pine, lodgepole pine, Aleppo pine, stone pine and white pine, mainly incubated at the site of collection. Studies had 5 to 19 samplings, on average 10, and the decomposition was followed to a mass loss ranging from 47 to 83%, on average 67%. The periods from 3.0 to 5.4 years, on average 3.9 years, were of sufficient duration to allow estimates of limit values of decomposition. We used a linear mixed model with regression effects to relate limit values to potential explanatory variables, namely the sites’ long-term mean annual temperature (MAT) and mean annual precipitation (MAP) and to substrate-chemistry factors. Regarding the latter, we explored two models; one that included initial concentrations of water solubles, lignin, N, P, K, Ca, Mg, and Mn and one that included only lignin, N, Ca, and Mn to focus on those nutrients known to influence lignin degradation. Using backward elimination significant explanatory variables were determined. For litter decomposed in its site of origin we found the limit value to depend mainly on the initial concentration of Mn, with higher Mn concentrations resulting in higher accumulated mass loss. Thus, litter with higher Mn reached a higher limit value and left a smaller stable fraction. This is likely due to the fact that Mn is an essential component of ligninolytic enzymes important for degrading litter in the later stages of decomposition. Manganese has received little attention in decomposition studies to date. Given its significance in this synthesis, the role of Mn in influencing variation in the late stages of decomposition among ecosystems and among litters of other genera besides Pinus deserves further attention.     

Quantitative Organization of GABAergic Synapses in the Molecular Layer of the Mouse Cerebellar Cortex

In the cerebellar cortex, interneurons of the molecular layer (stellate and basket cells) provide GABAergic input to Purkinje cells, as well as to each other and possibly to other interneurons. GABAergic inhibition in the molecular layer has mainly been investigated at the interneuron to Purkinje cell synapse. In this study, we used complementary subtractive strategies to quantitatively assess the ratio of GABAergic synapses on Purkinje cell dendrites versus those on interneurons. We generated a mouse model in which the GABA_A receptor α1 subunit (GABA_ARα1) was selectively removed from Purkinje cells using the Cre/loxP system. Deletion of the α1 subunit resulted in a complete loss of GABA_AR aggregates from Purkinje cells, allowing us to determine the density of GABA_AR clusters in interneurons. In a complementary approach, we determined the density of GABA synapses impinging on Purkinje cells using α-dystroglycan as a specific marker of inhibitory postsynaptic sites. Combining these inverse approaches, we found that synapses received by interneurons represent approximately 40% of all GABAergic synapses in the molecular layer. Notably, this proportion was stable during postnatal development, indicating synchronized synaptogenesis. Based on the pure quantity of GABAergic synapses onto interneurons, we propose that mutual inhibition must play an important, yet largely neglected, computational role in the cerebellar cortex.     

Biosensors and molecular imaging

The increase in the understanding of the physical and functional properties of the biological material, from the cellular level down to single molecules, owes its success to the development of suitable high-sensitivity platforms to image the biomaterial and analyze its response to specific stimuli. Imaging has indeed reached molecular capabilities, thanks to optical or magnetic markers [1], to the atomic force microscopy (AFM) in surface reconstruction [2], and is nearing success in three-dimensional (3-D) reconstruction thanks to X-ray holography [3].     

Reconstructing past ecological networks: the reconfiguration of seed-dispersal interactions after megafaunal extinction

The late Quaternary megafaunal extinction impacted ecological communities worldwide, and affected key ecological processes such as seed dispersal. The traits of several species of large-seeded plants are thought to have evolved in response to interactions with extinct megafauna, but how these extinctions affected the organization of interactions in seed-dispersal systems is poorly understood. Here, we combined ecological and paleontological data and network analyses to investigate how the structure of a species-rich seed-dispersal network could have changed from the Pleistocene to the present and examine the possible consequences of such changes. Our results indicate that the seed-dispersal network was organized into modules across the different time periods but has been reconfigured in different ways over time. The episode of megafaunal extinction and the arrival of humans changed how seed dispersers were distributed among network modules. However, the recent introduction of livestock into the seed-dispersal system partially restored the original network organization by strengthening the modular configuration. Moreover, after megafaunal extinctions, introduced species and some smaller native mammals became key components for the structure of the seed-dispersal network. We hypothesize that such changes in network structure affected both animal and plant assemblages, potentially contributing to the shaping of modern ecological communities. The ongoing extinction of key large vertebrates will lead to a variety of context-dependent rearranged ecological networks, most certainly affecting ecological and evolutionary processes.     

CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers

Tumor growth is allowed by its ability to escape immune system surveillance. An important role in determining tumor evasion from immune control might be played by tumor-infiltrating regulatory lymphocytes. This study was aimed at characterizing phenotype and function of CD8+ CD28- T regulatory cells infiltrating human cancer. Lymphocytes infiltrating primitive tumor lesion and/or satellite lymph node from a series of 42 human cancers were phenotypically studied and functionally analyzed by suppressor assays. The unprecedented observation was made that CD8+ CD28- T regulatory lymphocytes are almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4+ CD25+ T regulatory lymphocytes associate with CD8+ CD28- T regulatory cells so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant. The infiltration of regulatory T cells seems tumor related, being present in metastatic but not in metastasis-free satellite lymph nodes; it likely depends on both in situ generation (via cytokine production) and recruitment from the periphery (via chemokine secretion). Collectively, these results have pathogenic relevance and implication for immunotherapy of cancer.     

Molecular Characterization of Microbial Population Dynamics during Sildenafil Citrate Degradation

Little is known about pharmaceutical and personal care products pollutants (PPCPs), but there is a growing interest in how they might impact the environment and microbial communities. The widespread use of Viagra (sildenafil citrate) has attracted great attention because of the high usage rate, the unpredictable disposal and the unknown potential effects on wildlife and the environment. Until now information regarding the impact of Viagra on microbial community in water environment has not been reported. In this research, for the first time, the genetic profile of the microbial community, developing in a Viagra polluted water environment, was evaluated by means of the 16S and 18S rRNA genes, for bacteria and fungi, respectively, amplified by polymerase chain reaction (PCR) and separated using the denaturing gradient gel electrophoresis (DGGE) technique. The DGGE results revealed a complex microbial community structure with most of the population persisting throughout the experimental period. DNA sequences from bands observed in the different denaturing gradient gel electrophoresis profiles exhibited the highest degree of identity to uncultured bacteria and fungi found previously mainly in polluted environmental and treating bioreactors. Biotransformation ability of sildenafil citrate by the microbial pool was studied and the capability of these microorganisms to detoxify a polluted water ecosystem was assessed. The bacterial and fungal population was able to degrade sildenafil citrate entirely. Additionally, assays conducted on Daphnia magna, algal growth inhibition assay and cell viability determination on HepG2 human cells showed that biotransformation products obtained from the bacterial growth was not toxic. The higher removal efficiency for sildenafil citrate and the lack of toxicity by the biotransformation products obtained showed that the microbial community identified here represented a composite population that might have biotechnological relevance to retrieve sildenafil citrate contaminated sites.     

Adipoparacrinology--vascular periadventitial adipose tissue (tunica adiposa) as an example

Human adipose tissue is partitioned into two large depots (subcutaneous and visceral), and many small depots associated with internal organs, e.g. heart, blood vessels, major lymph nodes, pancreas, prostate gland and ovaries. Since the adipose 'Big Bang' led to the discovery of leptin (Zhang, Proenca, Maffei, Barone, Leopold and Friedman, Nature 1994;372:425-32), adipose tissue has been seen not merely as a lipid store, but as a secretory - endocrine and paracrine - organ, particularly in the pathogenesis of a number of diseases. Accordingly, two major sub-fields of adipobiology have emerged, viz. adipoendocrinology and adipoparacrinology, the latter herein being illustrated by PAAT (periadventitial adipose tissue) in vascular walls. A long-standing paradigm holds that the vascular wall consists of three coats, tunica intima, tunica media and tunica adventitia. It is now imperative that 'to further elucidate vascular function, we should no longer, as hitherto, separate adventitia and PAAT from the vascular wall, but keep them attached and in place, and subject to thorough examination' (Chaldakov, Fiore, Ghenev, Stankulov and Aloe, Int Med J 2000;7:43-9; Chaldakov, Stankulov and Aloe, Atherosclerosis 2001;154:237-8; Chaldakov GN, Stankulov IS, Fiore M, Ghenev PI and Aloe L, Atherosclerosis 2001;159:57-66). From the available data, we propose that it is time to rethink about vascular wall composition, and suggest that the PAAT may be considered the fourth and outermost vascular coat, hence, tunica adiposa (regarding the proximal segment of coronary artery, it is the innermost part of the EAT (epicardial adipose tissue) situated around the coronary adventitia). Its significance in the pathogenesis and therapy of CMDs (cardiometabolic diseases), particularly atherosclerosis and hypertension, requires further basic, translational and clinical studies.