Impact of droughts on the carbon cycle in European vegetation : a probabilistic risk analysis using six vegetation models

Peer reviewedPublisher PD

The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis

Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFβ-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFβ stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFβ promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFβ-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis

Resection of the liver for colorectal carcinoma metastases - A multi-institutional study of long-term survivors

In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized. © 1988 American Society of Colon and Rectal Surgeons

The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis. METHODS: JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP. RESULTS: The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFβ)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFβ. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2. CONCLUSION: We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models

The Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence.

BACKGROUND: The neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. There are only two anti-parasitic drugs available to treat this disease, benznidazole and nifurtimox. Thus it is important to identify and validate new drug targets in Trypanosoma cruzi, the causative agent. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx). This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: To assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if it is essential for virulence, we generated null mutants by targeted gene disruption. Loss of activity was associated with increased sensitivity to exogenous hydrogen peroxide, but had no effect on susceptibility to the front-line Chagas disease drug benznidazole. This suggests that increased oxidative stress in the ER does not play a significant role in its mechanism of action. Homozygous knockouts could proceed through the entire life-cycle in vitro, although they exhibited a significant decrease in their ability to infect mammalian cells. To investigate virulence, we exploited a highly sensitive bioluminescence imaging system which allows parasites to be monitored in real-time in the chronic stage of murine infections. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism in vivo. CONCLUSIONS/SIGNIFICANCE: TcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in establishment or maintenance of chronic infections, and should therefore not be considered a priority for drug design

First finds of Prunus domestica L. in Italy from the Phoenician and Punic periods (6th-2nd centuries BC)

Abstract During the archaeological excavations in the Phoenician and Punic settlement of Santa Giusta (Oristano, Sardinia, Italy), dating back to the 6th–2nd centuries bc, several Prunus fruitstones (endocarps) inside amphorae were recovered. The exceptional state of preservation of the waterlogged remains allowed morphometric measurements to be done by image analysis and statistical comparisons made with modern cultivated and wild Prunus samples collected in Sardinia. Digital images of modern and archaeological Prunus fruitstones were acquired with a flatbed scanner and analysed by applying image analysis techniques to measure 26 morphometric features. By applying stepwise linear discriminant analysis, a morphometric comparison was made between the archaeological fruitstones of Prunus and the modern ones collected in Sardinia. These analyses allowed identification of 53 archaeological fruitstones as P. spinosa and 11 as P. domestica. Moreover, the archaeological samples of P. spinosa showed morphometric similarities in 92.5% of the cases with the modern P. spinosa samples currently growing near the Phoenician and Punic site. Likewise, the archaeological fruitstones identified as P. domestica showed similarities with the modern variety of P. domestica called Sanguigna di Bosa which is currently cultivated near the village of Bosa. Currently, these findings represent the first evidence of P. domestica in Italy during the Phoenician and Punic periods. Keywords Archaeobotany · Image analysis · Morphometric features · Prunus · Sardini

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Number of necessary training examples for Neural Networks with different number of trainable parameters

In this work, the network complexity should be reduced with a concomitant reduction in the number of necessary training examples. The focus thus was on the dependence of proper evaluation metrics on the number of adjustable parameters of the considered deep neural network. The used data set encompassed Hematoxylin and Eosin (H&E) colored cell images provided by various clinics. We used a deep convolutional neural network to get the relation between a model’s complexity, its concomitant set of parameters, and the size of the training sample necessary to achieve a certain classification accuracy. The complexity of the deep neural networks was reduced by pruning a certain amount of filters in the network. As expected, the unpruned neural network showed best performance. The network with the highest number of trainable parameter achieved, within the estimated standard error of the optimized cross-entropy loss, best results up to 30% pruning. Strongly pruned networks are highly viable and the classification accuracy declines quickly with decreasing number of training patterns. However, up to a pruning ratio of 40%, we found a comparable performance of pruned and unpruned deep convolutional neural networks (DCNN) and densely connected convolutional networks (DCCN)