The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI.

The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention

DNAJC12 deficiency: Mild hyperphenylalaninemia and neurological impairment in two siblings

Background: DNAJC12 co-chaperone protein deficiency has been recently described as a stand-alone metabolic disorder explaining many cases of mild hyperphenylalaninemia (HPA) that are not caused by variants in the PAH gene, which encodes for the hepatic enzyme phenylalanine hydroxylase (PAH), or inGCH1, PTS, QDPR, PCBD1 and DHPR, involved in tetrahydrobiopterin (BH4) biosynthesis and activity. Results: We describe two sisters born to consanguineous parents. The youngest sister (Patient 1), initially asymptomatic, tested positive at NewBorn Screening (NBS) for mild HPA. After variants in the PAH and BH4 related-genes were excluded, we performed DNAJC12 genetic analysis and found a previously described homozygous deletion [NM_021800.3: c.58_59del p.(Gly20Metfs*2)]. The older sister (Patient 2), homozygous for the same variant and exhibiting mild HPA, was diagnosed subsequently and presented with ataxia and repeated falls, upper limb dyskinesia, intentional tremor, and mild intellectual disability. Patient 1 was started on treatment with low Phenylalanine (Phe) diet, BH4, l-3,4-dihydroxyphenylalanine/carbidopa (L-DOPA) and 5-OH-Tryptophan, soon after diagnosis, and despite poor adherence to the dietary regimen, only manifested language impairment at last follow-up (age 5 years and 4 months). Patient 2, who started the same treatment at school age, experienced a minimal progression of neurological symptoms, with some improvement in her motor skills. Conclusions: These two new patients with DNAJC12-associated HPA, in addition to previous reports, point to DNAJC12 deficiency as a new metabolic syndrome that must be considered in patients with unexplained HPA

Manejo de plantas daninhas na cultura da mandioca no Agreste Alagoano.

bitstream/item/145863/1/CT-74.pd

On the solar origin of the 200 y Suess wiggles: Evidence from thermoluminescence in sea sediments

In order to understand the origin of the Suess wiggles, present in the tree ring 14C record, we have studied the thermoluminescence (TL) of a shallow-water Ionian sea core, in an attempt to provide a record of an indicator responding to the solar output more promptly than 14C in tree rings. The spectral content of the TL and radiocarbon records is very similar; neverthless, in addition to the 207 y Suess wave (A43.6% ), the TL record shows the second harmonic (103.5 y; A42.4% ), in phase with the envelope of the 11 y solar cycles. This result, obtained by different spectral methods, in particular by Superposition of Epochs (SE) and by Singular Spectrum Analysis (SSA), strongly supports the solar origin of the 200 y Suess wiggles

Ion channel-like activity of the antimicrobial peptide tritrpticin in planar lipid bilayers

The cationic peptide tritrpticin (VRRFPWWWPFLRR, Trp3) has a broad action spectrum, acting against Gram-positive and Gram-negative bacteria, as well as some fungi, while also displaying hemolytic activity. We have studied the behavior of Trp3 in planar lipid bilayers (or black lipid membrane-BLM) and were able to demonstrate its ion channel-like activity. Channel-like activity was observed in negatively charged azolectin BLM as a sudden appearance of discrete current fluctuations upon application of a constant voltage across the membrane. Trp3 formed large conductance channels (500-2000 pS) both at positive and negative potentials. in azolectin bilayers, the predominant ion-channel activity was characterized by very regular and discrete current steps (corresponding to openings) of uniform amplitude, which exhibited relatively long residence times (of the order of seconds). Occasionally, multiple conductance steps were observed, indicating the simultaneous presence of more than one open pore. in bilayers of zwitterionic diphytanoylphosphatidyl choline (DPhk) Trp3 also showed ion-channel activity, but in a much less frequent and less prominent way. Studies of ion selectivity indicated that Trp3 forms a cation-selective channel. These results should contribute to the understanding of the molecular interactions and mechanism of action of Trp3 in lipid bilayers and biological membranes. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.Univ São Paulo, Inst Chem, Dept Biochem, Struct Biol Lab, BR-05513970 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05389970 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04044020 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04044020 São Paulo, BrazilWeb of Scienc

Combined use of x-ray fluorescence microscopy, phase contrast imaging for high resolution quantitative iron mapping in inflamed cells

X-ray fluorescence microscopy (XRFM) is a powerful technique to detect and localize elements in cells. To derive information useful for biology and medicine, it is essential not only to localize, but also to map quantitatively the element concentration. Here we applied quantitative XRFM to iron in phagocytic cells. Iron, a primary component of living cells, can become toxic when present in excess. In human fluids, free iron is maintained at 10-18 M concentration thanks to iron binding proteins as lactoferrin (Lf). The iron homeostasis, involving the physiological ratio of iron between tissues/secretions and blood, is strictly regulated by ferroportin, the sole protein able to export iron from cells to blood. Inflammatory processes induced by lipopolysaccharide (LPS) or bacterial pathoge inhibit ferroportin synthesis in epithelial and phagocytic cells thus hindering iron export, increasing intracellular iron and bacterial multiplication. In this respect, Lf is emerging as an important regulator of both iron and inflammatory homeostasis. Here we studied phagocytic cells inflamed by bacterial LPS and untreated or treated with milk derived bovine Lf. Quantitative mapping of iron concentration and mass fraction at high spatial resolution is obtained combining X-ray fluorescence microscopy, atomic force microscopy and synchrotron phase contrast imaging

A 20 GHz bright sample for {\delta} > +72{\deg}: I. Catalogue

During 2010-2011, the Medicina 32-m dish hosted the 7-feed 18-26.5 GHz receiver built for the Sardinia Radio Telescope, with the goal to perform its commissioning. This opportunity was exploited to carry out a pilot survey at 20 GHz over the area for {\delta} > + 72.3{\deg}. This paper describes all the phases of the observations, as they were performed using new hardware and software facilities. The map-making and source extraction procedures are illustrated. A customised data reduction tool was used during the follow-up phase, which produced a list of 73 confirmed sources down to a flux density of 115 mJy. The resulting catalogue, here presented, is complete above 200 mJy. Source counts are in agreement with those provided by the AT20G survey. This pilot activity paves the way to a larger project, the K-band Northern Wide Survey (KNoWS), whose final aim is to survey the whole Northern Hemisphere down to a flux limit of 50 mJy (5{\sigma}).Comment: 10 pages, 10 figures. Accepted by MNRA