Prestin is an anion transporter dispensable for mechanical feedback amplification in Drosophila hearing.

In mammals, the membrane-based protein Prestin confers unique electromotile properties to cochlear outer hair cells, which contribute to the cochlear amplifier. Like mammals, the ears of insects, such as those of Drosophila melanogaster, mechanically amplify sound stimuli and have also been reported to express Prestin homologs. To determine whether the D. melanogaster Prestin homolog (dpres) is required for auditory amplification, we generated and analyzed dpres mutant flies. We found that dpres is robustly expressed in the fly's antennal ear. However, dpres mutant flies show normal auditory nerve responses, and intact non-linear amplification. Thus we conclude that, in D. melanogaster, auditory amplification is independent of Prestin. This finding resonates with prior phylogenetic analyses, which suggest that the derived motor function of mammalian Prestin replaced, or amended, an ancestral transport function. Indeed, we show that dpres encodes a functional anion transporter. Interestingly, the acquired new motor function in the phylogenetic lineage leading to birds and mammals coincides with loss of the mechanotransducer channel NompC (=TRPN1), which has been shown to be required for auditory amplification in flies. The advent of Prestin (or loss of NompC, respectively) may thus mark an evolutionary transition from a transducer-based to a Prestin-based mechanism of auditory amplification

Relation of gallbladder function and Helicobacter pylori infection to gastric mucosa inflammation in patients with symptomatic cholecystolithiasis

Background. Inflammatory alterations of the gastric mucosa are commonly caused by Helicobacter pylori (Hp) infection in patients with symptomatic gallstone disease. However, the additional pathogenetic role of an impaired gallbladder function leading to an increased alkaline duodenogastric reflux is controversially discussed. Aim:To investigate the relation of gallbladder function and Hp infection to gastric mucosa inflammation in patients with symptomatic gallstones prior to cholecystectomy. Patients: Seventy-three patients with symptomatic gallstones were studied by endoscopy and Hp testing. Methods: Gastritis classification was performed according to the updated Sydney System and gallbladder function was determined by total lipid concentration of gallbladder bile collected during mainly laparoscopic cholecystectomy. Results: Fifteen patients revealed no, 39 patients mild, and 19 moderate to marked gastritis. No significant differences for bile salts, phospholipids, cholesterol, or total lipids in gallbladder bile were found between these three groups of patients. However, while only 1 out of 54 (< 2%) patients with mild or no gastritis was found histologically positive for Hp, this infection could be detected in 14 (74%) out of 19 patients with moderate to marked gastritis. Conclusion: Moderate to marked gastric mucosa inflammation in gallstone patients is mainly caused by Hp infection, whereas gallbladder function is not related to the degree of gastritis. Thus, an increased alkaline duodenogastric reflux in gallstone patients seems to be of limited pathophysiological relevance. Copyright (c) 2006 S. Karger AG, Basel

Biophysical suitability, economic pressure and land-cover change: a global probabilistic approach and insights for REDD+

There has been a concerted effort by the international scientific community to understand the multiple causes and patterns of land-cover change to support sustainable land management. Here, we examined biophysical suitability, and a novel integrated index of “Economic Pressure on Land” (EPL) to explain land cover in the year 2000, and estimated the likelihood of future land-cover change through 2050, including protected area effectiveness. Biophysical suitability and EPL explained almost half of the global pattern of land cover (R 2 = 0.45), increasing to almost two-thirds in areas where a long-term equilibrium is likely to have been reached (e.g. R 2 = 0.64 in Europe). We identify a high likelihood of future land-cover change in vast areas with relatively lower current and past deforestation (e.g. the Congo Basin). Further, we simulated emissions arising from a “business as usual” and two reducing emissions from deforestation and forest degradation (REDD) scenarios by incorporating data on biomass carbon. As our model incorporates all biome types, it highlights a crucial aspect of the ongoing REDD + debate: if restricted to forests, “cross-biome leakage” would severely reduce REDD + effectiveness for climate change mitigation. If forests were protected from deforestation yet without measures to tackle the drivers of land-cover change, REDD + would only reduce 30 % of total emissions from land-cover change. Fifty-five percent of emissions reductions from forests would be compensated by increased emissions in other biomes. These results suggest that, although REDD + remains a very promising mitigation tool, implementation of complementary measures to reduce land demand is necessary to prevent this leakage

Ram pressure feeding super-massive black holes

When supermassive black holes at the center of galaxies accrete matter (usually gas), they give rise to highly energetic phenomena named Active Galactic Nuclei (AGN). A number of physical processes have been proposed to account for the funneling of gas towards the galaxy centers to feed the AGN. There are also several physical processes that can strip gas from a galaxy, and one of them is ram pressure stripping in galaxy clusters due to the hot and dense gas filling the space between galaxies. We report the discovery of a strong connection between severe ram pressure stripping and the presence of AGN activity. Searching in galaxy clusters at low redshift, we have selected the most extreme examples of jellyfish galaxies, which are galaxies with long tentacles of material extending for dozens of kpc beyond the galaxy disk. Using the MUSE spectrograph on the ESO Very Large Telescope, we find that 6 out of the 7 galaxies of this sample host a central AGN, and two of them also have galactic-scale AGN ionization cones. The high incidence of AGN among the most striking jellyfishes may be due to ram pressure causing gas to flow towards the center and triggering the AGN activity, or to an enhancement of the stripping caused by AGN energy injection, or both. Our analysis of the galaxy position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another, yet unforeseen, possible mechanism for feeding the central supermassive black hole with gas.Comment: published in Nature, Vol.548, Number 7667, pag.30

High impact = high statistical standards? Not necessarily so.

What are the statistical practices of articles published in journals with a high impact factor? Are there differences compared with articles published in journals with a somewhat lower impact factor that have adopted editorial policies to reduce the impact of limitations of Null Hypothesis Significance Testing? To investigate these questions, the current study analyzed all articles related to psychological, neuropsychological and medical issues, published in 2011 in four journals with high impact factors: Science, Nature, The New England Journal of Medicine and The Lancet, and three journals with relatively lower impact factors: Neuropsychology, Journal of Experimental Psychology-Applied and the American Journal of Public Health. Results show that Null Hypothesis Significance Testing without any use of confidence intervals, effect size, prospective power and model estimation, is the prevalent statistical practice used in articles published in Nature, 89%, followed by articles published in Science, 42%. By contrast, in all other journals, both with high and lower impact factors, most articles report confidence intervals and/or effect size measures. We interpreted these differences as consequences of the editorial policies adopted by the journal editors, which are probably the most effective means to improve the statistical practices in journals with high or low impact factors

Identification of Domains and Amino Acids Essential to the Collagen Galactosyltransferase Activity of GLT25D1

Collagen is modified by hydroxylation and glycosylation of hydroxylysine residues. This glycosylation is initiated by the β1,O galactosyltransferases GLT25D1 and GLT25D2. The structurally similar protein cerebral endothelial cell adhesion molecule CEECAM1 was previously reported to be inactive when assayed for collagen glycosyltransferase activity. To address the cause of the absent galactosyltransferase activity, we have generated several chimeric constructs between the active human GLT25D1 and inactive human CEECAM1 proteins. The assay of these chimeric constructs pointed to a short central region and a large C-terminal region of CEECAM1 leading to the loss of collagen galactosyltransferase activity. Examination of the three DXD motifs of the active GLT25D1 by site-directed mutagenesis confirmed the importance of the first (amino acids 166–168) and second motif (amino acids 461–463) for enzymatic activity, whereas the third one was dispensable. Since the second DXD motif is incomplete in CEECAM1, we have restored the motif by introducing the substitution S461D. This change did not restore the activity of the C-terminal region, thereby showing that additional amino acids were required in this C-terminal region to confer enzymatic activity. Finally, we have introduced the substitution Q471R-V472M-N473Q-P474V in the CEECAM1-C-terminal construct, which is found in most animal GLT25D1 and GLT25D2 isoforms but not in CEECAM1. This substitution was shown to partially restore collagen galactosyltransferase activity, underlining its importance for catalytic activity in the C-terminal domain. Because multiple mutations in different regions of CEECAM1 contribute to the lack of galactosyltransferase activity, we deduced that CEECAM1 is functionally different from the related GLT25D1 protein

Articular cartilage mineralization in osteoarthritis of the hip

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to examine the frequency of articular cartilage calcification in patients with end-stage hip OA. Further, its impact on the clinical situation and the OA severity are analyzed.</p> <p>Methods</p> <p>Eighty patients with OA of the hip who consecutively underwent total hip replacement were prospectively evaluated, and 10 controls were included. The patients' X-rays were analyzed for the presence of articular cartilage mineralization. A Harris Hip Score (HHS) was preoperatively calculated for every patient.</p> <p>Slab specimens from the femoral head of bone and cartilage and an additional square centimeter of articular cartilage from the main chondral defect were obtained from each patient for analysis of mineralization by digital contact radiography (DCR). Histological grading was also performed. In a subset of 20 patients, minerals were characterized with an electron microscope (FE-SEM).</p> <p>Results</p> <p>Calcifications were seen in all OA cartilage and slab specimens using DCR, while preoperative X-rays revealed calcification in only 17.5%. None of the control cartilage specimens showed mineralization. There was a highly significant inverse correlation between articular cartilage calcification and preoperative HHS. Histological OA grade correlated positively with the amount of matrix calcification. FE-SEM analysis revealed basic calcium phosphate (BCP) as the predominant mineral; CPPD crystals were found in only two patients.</p> <p>Conclusions</p> <p>Articular cartilage calcification is a common event in osteoarthritis of the hip. The amount of calcification correlates with clinical symptoms and histological OA grade.</p

Essential Role of Cdc42 in Ras-Induced Transformation Revealed by Gene Targeting

The ras proto-oncogene is one of the most frequently mutated genes in human cancer. However, given the prevalence of activating mutations in Ras and its association with aggressive forms of cancer, attempts to therapeutically target aberrant Ras signaling have been largely disappointing. This lack of progress highlights the deficiency in our understanding of cellular pathways required for Ras-mediated tumorigenesis and suggests the importance of identifying new molecular pathways associated with Ras-driven malignancies. Cdc42 is a Ras-related small GTPase that is known to play roles in oncogenic processes such as cell growth, survival, invasion, and migration. A pan-dominant negative mutant overexpression approach to suppress Cdc42 and related pathways has previously shown a requirement for Cdc42 in Ras-induced anchorage-independent cell growth, however the lack of specificity of such approaches make it difficult to determine if effects are directly related to changes in Cdc42 activity or other Rho family members. Therefore, in order to directly and unambiguously address the role of Cdc42 in Ras-mediated transformation, tumor formation and maintenance, we have developed a model of conditional cdc42 gene in Ras-transformed cells. Loss of Cdc42 drastically alters the cell morphology and inhibits proliferation, cell cycle progression and tumorigenicity of Ras-transformed cells, while non-transformed cells or c-Myc transformed cells are largely unaffected. The loss of Cdc42 in Ras-transformed cells results in reduced Akt signaling, restoration of which could partially rescues the proliferation defects associated with Cdc42 loss. Moreover, disruption of Cdc42 function in established tumors inhibited continued tumor growth. These studies implicate Cdc42 in Ras-driven tumor growth and suggest that targeting Cdc42 is beneficial in Ras-mediated malignancies

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation