Showing papers by "University of Florence published in 2006"
TL;DR: The relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate is discussed and some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior is described.
Abstract: Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.
5,897 citations
TL;DR: The tumor–node–metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference is reported.
Abstract: The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor–node–metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients.
1,424 citations
TL;DR: The findings suggest that the beneficial effect on graft‐versus‐host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of M SCs by T cell– derived IFN‐γ.
Abstract: Mesenchymal stem cells (MSCs) inhibit the proliferation of HLA-unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4+ and CD8+ T lymphocytes, as well as of natural killer (NK) cells, whereas they do not have an effect on the proliferation of B lymphocytes. The antiproliferative effect of MSCs was not associated with any effect on the expression of cell-activation markers, induction of cell apoptosis, or mimicry/enhancement of T regulatory cell activity. The suppressive activity of MSCs was not contact-dependent and required the presence of interferon (IFN)-gamma produced by activated T cells and NK cells. Accordingly, even activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN-gamma. The suppressive effect of IFN-gamma was related to its ability to stimulate the production by MSCs of indoleamine 2,3-dioxygenase activity, which in turn inhibited the proliferation of activated T or NK cells. These findings suggest that the beneficial effect on graft-versus-host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of MSCs by T cell- derived IFN-gamma.
1,204 citations
TL;DR: It is demonstrated here that SA‐β‐gal activity is expressed from GLB1, the gene encoding lysosomal β‐D‐galactosidase, the activity of which is typically measured at acidic pH 4.5.
Abstract: Replicative senescence limits the proliferation of somatic cells passaged in culture and may reflect cellular aging in vivo. The most widely used biomarker for senescent and aging cells is senescence-associated beta-galactosidase (SA-beta-gal), which is defined as beta-galactosidase activity detectable at pH 6.0 in senescent cells, but the origin of SA-beta-gal and its cellular roles in senescence are not known. We demonstrate here that SA-beta-gal activity is expressed from GLB1, the gene encoding lysosomal beta-D-galactosidase, the activity of which is typically measured at acidic pH 4.5. Fibroblasts from patients with autosomal recessive G(M1)-gangliosidosis, which have defective lysosomal beta-galactosidase, did not express SA-beta-gal at late passages even though they underwent replicative senescence. In addition, late passage normal fibroblasts expressing small-hairpin interfering RNA that depleted GLB1 mRNA underwent senescence but failed to express SA-beta-gal. GLB1 mRNA depletion also prevented expression of SA-beta-gal activity in HeLa cervical carcinoma cells induced to enter a senescent state by repression of their endogenous human papillomavirus E7 oncogene. SA-beta-gal induction during senescence was due at least in part to increased expression of the lysosomal beta-galactosidase protein. These results also indicate that SA-beta-gal is not required for senescence.
905 citations
TL;DR: The present bioinformatic research proposes a strategy to answer the question of how many and which proteins encoded in the human genome may require zinc for their physiological function by a combination of approaches, which include searching in the proteome for the zinc-binding patterns that are obtained from all available X-ray data.
Abstract: Metalloproteins are proteins capable of binding one or more metal ions, which may be required for their biological function, or for regulation of their activities or for structural purposes. Genome sequencing projects have provided a huge number of protein primary sequences, but, even though several different elaborate analyses and annotations have been enabled by a rich and ever-increasing portfolio of bioinformatic tools, metal-binding properties remain difficult to predict as well as to investigate experimentally. Consequently, the present knowledge about metalloproteins is only partial. The present bioinformatic research proposes a strategy to answer the question of how many and which proteins encoded in the human genome may require zinc for their physiological function. This is achieved by a combination of approaches, which include: (i) searching in the proteome for the zinc-binding patterns that, on their turn, are obtained from all available X-ray data; (ii) using libraries of metal-binding protei...
884 citations
TL;DR: Patients with hematologic malignancies are currently at higher risk of IFI caused by molds than by yeasts, and the incidence of I FI is highest among patients with acute myeloid leukemia.
Abstract: BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the incidence and outcome of invasive fungal infections (IFI) in patients with hematologic malignancies. DESIGN AND METHODS: This was a retrospective cohort study of patients admitted between 1999 and 2003 to 18 hematology wards in Italy. Each participating center provided information on all patients with newly diagnosed hematologic malignancies admitted during the survery period and on all episodes of IFI experienced by these patients. RESULTS: The cohort was formed of 11,802 patients with hematologic malignacies: acute leukemia (myeloid 3012, lymphoid 1173), chronic leukemia (myeloid 596, lymphoid 1104), lymphoma (Hodgkin's 844, non-Hodgkin's 3457), or multiple myeloma (1616). There were 538 proven or probable IFI (4.6%); 373 (69%) occurred in patients with acute myeloid leukemia. Over half (346/538) were caused by molds (2.9%), in most cases Aspergillus spp. (310/346). The 192 yeast infections (1.6%) included 175 cases of candidemia. Overall and IFI-attributable mortality rates were 2% (209/11802) and 39% (209/538), respectively. The highest IFI-attributable mortality rates were associated with zygomycosis (64%) followed by fusariosis (53%), aspergillosis (42%), and candidemia (33%). INTERPRETATION AND CONCLUSIONS: Patients with hematologic malignancies are currently at higher risk of IFI caused by molds than by yeasts, and the incidence of IFI is highest among patients with acute myeloid leukemia. Aspergillus spp are still the most common pathogens, followed by Candida spp. Other agents are rare. The attributable mortality rate for aspergillosis has dropped from 60-70% to approximately 40%. Candidemia-related mortality remains within the 30-40% range reported in literature although the incidence has decreased.
844 citations
TL;DR: In the lanthanide-containing phthalocyanine complexes reported in the literature the ligand environment induces a large splitting of the ground Jmanifold, whereas in SMMs large-spin ground states arising from magnetic interactions between the metal centers of the cluster can enhance the weaker single-ion.
Abstract: The study of paramagnetic metal-ion aggregates has been of increasing interest since the observation that such molecules can exhibit magnetic memory effects. Termed singlemolecule magnets or SMMs, the important factors leading to such properties derive from the combination of a large ground-state spin and a large magnetic anisotropy of the Ising (easy-axis) type. Studies have largely been based on transition-metal compounds since they typically exhibit both of the aforementioned features. The incorporation of lanthanides into these complexes has been investigated to take advantage of the potentially large number of unpaired f-electrons available. However, very little work has been done to date on purely lanthanide-based systems. The origin of SMM behavior in lanthanide-containing compounds is more complicated than that of d-block transition-metal ions since there is likely to be a significant orbital component. In the lanthanide-containing phthalocyanine complexes reported in the literature the ligand environment induces a large splitting of the ground Jmanifold, whereas in SMMs large-spin ground states arising from magnetic interactions between the metal centers of the cluster can enhance the weaker single-ion
770 citations
TL;DR: This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.
Abstract: Regenerative medicine represents a critical clinical goal for patients with ESRD, but the identification of renal adult multipotent progenitor cells has remained elusive. It is demonstrated that in human adult kidneys, a subset of parietal epithelial cells (PEC) in the Bowman’s capsule exhibit coexpression of the stem cell markers CD24 and CD133 and of the stem cell–specific transcription factors Oct-4 and BmI-1, in the absence of lineage-specific markers. This CD24 + CD133 + PEC population, which could be purified from cultured capsulated glomeruli, revealed self-renewal potential and a high cloning efficiency. Under appropriate culture conditions, individual clones of CD24 + CD133 + PEC could be induced to generate mature, functional, tubular cells with phenotypic features of proximal and/or distal tubules, osteogenic cells, adipocytes, and cells that exhibited phenotypic and functional features of neuronal cells. The injection of CD24 + CD133 + PEC but not of CD24 − CD133 − renal cells into SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different portions of the nephron. More important, treatment of acute renal failure with CD24 + CD133 + PEC significantly ameliorated the morphologic and functional kidney damage. This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.
686 citations
TL;DR: Evidence that up- or down-regulation of the multiple membrane transporters, target enzymes, enzymes involved in the metabolism of gemcitabine and alterations in the apoptotic pathways may confer sensitivity/resistance to this drug has been provided in experimental models and more recently in the clinical setting.
628 citations
TL;DR: In patients undergoing cancer surgery, VTE is the most common cause of death at 30 days after surgery, and a remarkable proportion of events occurring late after surgery is found.
Abstract: Summary Background Data: The epidemiology of venous thromboembolism (VTE) after cancer surgery is based on clinical trials on VTE prophylaxis that used venography to screen deep vein thrombosis (DVT). However, the clinical relevance of asymptomatic venography-detected DVT is unclear, and the population of these clinical trials is not necessarily representative of the overall cancer surgery population. Objective: The aim of this study was to evaluate the incidence of clinically overt VTE in a wide spectrum of consecutive patients undergoing surgery for cancer and to identify risk factors for VTE. Methods: @RISTOS was a prospective observational study in patients undergoing general, urologic, or gynecologic surgery. Patients were assessed for clinically overt VTE occurring up to 30 5 days after surgery or more if the hospital stay was longer than 35 days. All outcome events were evaluated by an independent Adjudication Committee. Results: A total of 2373 patients were included in the study: 1238 (52%) undergoing general, 685 (29%) urologic, and 450 (19%) gynecologic surgery. In-hospital prophylaxis was given in 81.6% and postdischarge prophylaxis in 30.7% of the patients. Fifty patients (2.1%) were adjudicated as affected by clinically overt VTE (DVT, 0.42%; nonfatal pulmonary embolism, 0.88%; death 0.80%). The incidence of VTE was 2.83% in general surgery, 2.0% in gynecologic surgery, and 0.87% in urologic surgery. Forty percent of the events occurred later than 21 days from surgery. The overall death rate was 1.72%; in 46.3% of the cases, death was caused by VTE. In a multivariable analysis, 5 risk factors were identified: age above 60 years (2.63, 95% confidence interval, 1.21‐5.71), previous VTE (5.98, 2.13‐16.80), advanced cancer (2.68, 1.37‐5.24), anesthesia lasting more than 2 hours (4.50, 1.06‐19.04), and bed rest longer than 3 days (4.37, 2.45‐7.78). Conclusions: VTE remains a common complication of cancer surgery, with a remarkable proportion of events occurring late after surgery. In patients undergoing cancer surgery, VTE is the most common cause of death at 30 days after surgery.
620 citations
TL;DR: It is concluded that BDNF but not NT‐4 is required for the environmental induction of neurogenesis, and failure to up‐regulate BDNF accompanied the lack of a neurogenic response in enriched BDNF heterozygous mice.
Abstract: Neurogenesis continues to occur in the adult mammalian hippocampus and is regulated by both genetic and environmental factors. It is known that exposure to an enriched environment enhances the number of newly generated neurons in the dentate gyrus. However, the mechanisms by which enriched housing produces these effects are poorly understood. To test a role for neurotrophins, we used heterozygous knockout mice for brain-derived neurotrophic factor (BDNF+/-) and mice lacking neurotrophin-4 (NT-4-/-) together with their wild-type littermates. Mice were either reared in standard laboratory conditions or placed in an enriched environment for 8 weeks. Animals received injections of the mitotic marker bromodeoxyuridine (BrdU) to label newborn cells. Enriched wild-type and enriched NT-4-/- mice showed a two-fold increase in hippocampal neurogenesis as assessed by stereological counting of BrdU-positive cells in the dentate gyrus and double labelling for BrdU and the neuronal marker NeuN. Remarkably, this enhancement of hippocampal neurogenesis was not seen in enriched BDNF+/- mice. Failure to up-regulate BDNF accompanied the lack of a neurogenic response in enriched BDNF heterozygous mice. We conclude that BDNF but not NT-4 is required for the environmental induction of neurogenesis.
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TL;DR: In this paper, the authors use a matching estimator to show that Temporary Work Agency (TWA) assignments can be an effective springboard to permanent employment, and propose a simulation-based sensitivity analysis, which highlights that only for one of these two regions their results are robust to specific failures of the CIA.
Abstract: The diffusion of Temporary Work Agency (TWA) jobs originated a harsh policy debate and ambiguous empirical evidence. Results for the US, based on quasi-experimental evidence, suggest that a TWA assignment decreases the probability of finding a stable job, while results for Europe, based on the Conditional Independence Assumption (CIA), typically reach opposite conclusions. Using data for two Italian regions, we use a matching estimator to show that TWA assignments can be an effective springboard to permanent employment. We also propose a simulation-based sensitivity analysis, which highlights that only for one of these two regions our results are robust to specific failures of the CIA. We conclude that European studies based on the CIA should not be automatically discarded, but should be put under the scrutiny of a sensitivity analysis like the one we propose.
TL;DR: An overview of zinc usage by archaeal, bacterial, and eukaryotic organisms is obtained and the proportionality constant of Eukaryota (8.8%) is significantly higher than that observed in Bacteria and Archaea (from 5% to 6%).
Abstract: Zinc is one of the metal ions essential for life, as it is required for the proper functioning of a large number of proteins. Despite its importance, the annotation of zinc-binding proteins in gene banks or protein domain databases still has significant room for improvement. In the present work, we compiled a list of known zinc-binding protein domains and of known zinc-binding sequence motifs (zinc-binding patterns), and then used them jointly to analyze the proteome of 57 different organisms to obtain an overview of zinc usage by archaeal, bacterial, and eukaryotic organisms. Zinc-binding proteins are an abundant fraction of these proteomes, ranging between 4% and 10%. The number of zinc-binding proteins correlates linearly with the total number of proteins encoded by the genome of an organism, but the proportionality constant of Eukaryota (8.8%) is significantly higher than that observed in Bacteria and Archaea (from 5% to 6%). Most of this enrichment is due to the larger portfolio of regulatory proteins in Eukaryota.
TL;DR: Continuous chemical proxy data spanning the last eight glacial cycles from the Dome C Antarctic ice core constrain winter sea-ice extent in the Indian Ocean, Southern Ocean biogenic productivity and Patagonian climatic conditions and observe large glacial–interglacial contrasts in iron deposition, which is infer reflects strongly changing Patagonia conditions.
Abstract: Sea ice and dust flux increased greatly in the Southern Ocean during the last glacial period. Palaeorecords provide contradictory evidence about marine productivity in this region, but beyond one glacial cycle, data were sparse. Here we present continuous chemical proxy data spanning the last eight glacial cycles (740,000 years) from the Dome C Antarctic ice core. These data constrain winter sea-ice extent in the Indian Ocean, Southern Ocean biogenic productivity and Patagonian climatic conditions. We found that maximum sea-ice extent is closely tied to Antarctic temperature on multi-millennial timescales, but less so on shorter timescales. Biological dimethylsulphide emissions south of the polar front seem to have changed little with climate, suggesting that sulphur compounds were not active in climate regulation. We observe large glacial-interglacial contrasts in iron deposition, which we infer reflects strongly changing Patagonian conditions. During glacial terminations, changes in Patagonia apparently preceded sea-ice reduction, indicating that multiple mechanisms may be responsible for different phases of CO2 increase during glacial terminations. We observe no changes in internal climatic feedbacks that could have caused the change in amplitude of Antarctic temperature variations observed 440,000 years ago.
TL;DR: The findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.
Abstract: The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.
TL;DR: The CHIANTI atomic database as mentioned in this paper contains atomic energy levels, wavelengths, radiative transition probabilities, and collisional excitation data for a large number of ions of astrophysical interest.
Abstract: The CHIANTI atomic database contains atomic energy levels, wavelengths, radiative transition probabilities, and collisional excitation data for a large number of ions of astrophysical interest. CHIANTI also includes a suite of IDL routines to calculate synthetic spectra and carry out plasma diagnostics. Version 5 has been released, which includes several new features, as well as new data for many ions. The new features in CHIANTI are as follows: the inclusion of ionization and recombination rates to individual excited levels as a means to populate atomic levels; data for Kα and Kβ emission from Fe II to Fe XXIV; new data for high-energy configurations in Fe XVII to Fe XXIII; and a complete reassessment of level energies and line identifications in the X-ray range, multitemperature particle distributions, and photoexcitation from any user-defined radiation field. New data for ions already in the database, as well as data for ions not present in earlier versions of the database, are also included. Version 5 of CHIANTI represents a major improvement in the calculation of line emissivities and synthetic spectra in the X-ray range and expands and improves theoretical spectra calculations in all other wavelength ranges.
TL;DR: In this paper, four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the minimal supersymmetric standard model (MSSM).
Abstract: The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the Minimal Supersymmetric standard model (MSSM). The data of the four collaborations are statistically combined and examined for their consistency with the background hypothesis and with a possible Higgs boson signal. The combined LEP data show no significant excess of events which would indicate the production of Higgs bosons. The search results are used to set upper bounds on the cross-sections of various Higgs-like event topologies. The results are interpreted within the MSSM in a number of “benchmark” models, including CP-conserving and CP-violating scenarios. These interpretations lead in all cases to large exclusions in the MSSM parameter space. Absolute limits are set on the parameter cosβ and, in some scenarios, on the masses of neutral Higgs bosons.
TL;DR: There are consistent, albeit moderate, correlations between the progression of cognitive impairment and increasing brain lesion load and brain atrophy in MS, and among clinical predictors, incipient cognitive decline seems to be the major risk factor for further deterioration in the short-term.
TL;DR: The first family of rare-earth-based single chain magnets is presented and both static and dynamic magnetic properties of the whole family are reported.
Abstract: The first family of rare-earth-based single chain magnets is presented. Compounds of general formula [M(hfac)3(NITPhOPh)], where M = Eu, Gd, Tb, Dy, Ho, Er, or Yb, and PhOPh is the nitronyl-nitroxide radical (2,4'-benzoxo-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), have been structurally characterized and found to be isostructural. The characterization of both static and dynamic magnetic properties of the whole family is reported. Dy, Tb, and Ho compounds display slow relaxation of the magnetization, and ac susceptibility shows a thermally activated regime with energy barriers of 69, 45, and 34 K for Dy, Tb, and Ho compounds, respectively, while only a frequency-dependent susceptibility is observed for Er below 2.0 K. In Gd and Yb derivatives, antiferromagnetic interactions dominate. The pre-exponential factors differ by about 4 orders of magnitude. Finite size effects, due to naturally occurring defects, affect the static and dynamic properties of the compounds differently.
Durham University1, University of Helsinki2, University of Wisconsin-Madison3, University of Rochester4, University of Catania5, Weizmann Institute of Science6, University of Warsaw7, University of Southampton8, CERN9, Lawrence Livermore National Laboratory10, Indian Institute of Science11, University of Montpellier12, Spanish National Research Council13, University of Zurich14, ETH Zurich15, Stanford University16, Northwestern University17, University of Pittsburgh18, Carleton University19, University of Hamburg20, Moscow State University21, University of Florida22, Paul Scherrer Institute23, University of Würzburg24, Imperial College London25, Florida State University26, University of Florence27, University of Bonn28, University at Buffalo29, RWTH Aachen University30, University of Sheffield31, University of California, Irvine32, Laboratoire d'Annecy-le-Vieux de physique des particules33, Brookhaven National Laboratory34, Argonne National Laboratory35, University of Bergen36, University of Mainz37, Centers for Medicare and Medicaid Services38, Lancaster University39, University of California, Santa Cruz40, University of Copenhagen41, University of Tokyo42, Austrian Academy of Sciences43, University of Manchester44, University College London45, University of Edinburgh46, University of California, Davis47, University of California, Berkeley48, University of Glasgow49, University of Barcelona50, Max Planck Society51, University of Chicago52, University of Turin53, Royal Holloway, University of London54, Kobe University55, University of Oslo56, Kyoto University57
TL;DR: In this paper, the authors discuss the possible interplay between the Large Hadron Collider (LHC) and the International e(+)e(-) Linear Collider (ILC) in testing the Standard Model and in discovering and determining the origin of new physics.
TL;DR: Heat wave effects were apparent in simple time-series models but were reduced in multilag nonlinear models and small when compared with the overall summertime mortality burden of heat.
Abstract: BACKGROUND: Mortality during sustained periods of hot weather is generally regarded as being in excess of what would be predicted from smooth temperature-mortality gradients estimated using standard time-series regression models. However, the evidence for an effect of continuous days of exceptional heat ("heat wave effect") is indirect. In addition, because some interventions may be triggered only during forecasted heat waves, it would be helpful to know what fraction of all heat-related deaths falls during these specific periods and what fraction occurs throughout the remainder of the summer. METHODS: Extended time-series data sets of daily mortality counts in 3 major European cities (London, 28 years of data; Budapest, 31 years; Milan, 18 years) were examined in relation to hot weather using a generalized estimating equations approach. We modeled temperature and specific heat wave terms using a variety of specifications. RESULTS: With a linear effect of same-day temperature above an identified threshold, an additional "heat wave" effect of 5.5% was observed in London (95% confidence interval = 2.2 to 8.9), 9.3% in Budapest (5.8 to 13.0), and 15.2% in Milan (5.7 to 22.5). Heat wave effects were reduced slightly when we relaxed the linear assumption and these effects were reduced substantially when temperature was modeled as an average value of lags 0 to 2 days. In London, fewer than half of all heat-related deaths could be attributed to identified heat wave periods. In Milan and Budapest, the fraction was less than one fifth. CONCLUSIONS: Heat wave effects were apparent in simple time-series models but were reduced in multilag nonlinear models and small when compared with the overall summertime mortality burden of heat. Reduction of the overall heat burden requires preventive measures in addition to those that target warnings and responses uniquely to heat waves.
TL;DR: In this article, the transverse-momentum distribution of generic high-mass systems (lepton pairs, vector bosons, Higgs particles, etc) produced in hadron collisions is considered, and all-order resummation of the logarithmically-enhanced contributions in QCD perturbation theory is investigated.
TL;DR: The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self‐antigen recognition and dangerous autoimmune reactions, and regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery.
Abstract: The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self-antigen recognition and dangerous autoimmune reactions Therefore, regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery The control of self-reactive T cells occurs through a process of negative selection that results in apoptosis of T cells showing high affinity for self-peptides expressed at the thymic level by means of promiscuous gene expression Self-reactive T cells escaped to negative selection are controlled in the periphery by other regulatory mechanisms, the most important being natural Foxp3+ T regulatory (Treg) cells Regulation is also required to control excessive effector T cell responses against exogenous antigens, when they become dangerous for the body Three types of effector T cells have been recognized: T helper 1 (Th1) cells, which are protective against intracellular bacteria; Th2 cells, which play some role in the protection against nematodes, but are responsible for allergic reactions; Th17 cells, which are probably effective in the protection against extracellular bacteria, but also play a role in the amplification of autoimmune disorders Abnormal or excessive Th effector responses are regulated by different mechanisms Redirection or immune deviation of Th1- or Th2-dominated responses is provided by cytokines [interferon-gamma (IFN-gamma) vs interleukin-4 (IL-4)] produced by the same cell types and by the CXCR3-binding chemokines CXCL4 and CXCL10 Moreover, both Th1 and Th2 responses can be suppressed by adaptive Treg cells through contact-dependent mechanisms and/or the production of IL-10 and transforming growth factor-beta (TGF-beta) Finally, TGF-beta1 can promote the development of both Th17 effector and adaptive Treg cells, while the contemporaneous production of IL-6 contributes to the development of Th17 cells, but inhibits Treg cells The development of Th17 cells is also down-regulated by IL-4 produced by Th2 cells and by IFN-gamma produced by Th1 cells
TL;DR: This data indicates that n‐3 long‐chain polyunsaturated fatty acids (n‐3 PUFA) as peroxisome proliferator‐activated receptor‐α ligands in improving non‐alcoholic fatty liver disease (NAFLD) in rodents is feasible in humans, although data in humans is still lacking.
Abstract: SUMMARY Background Recent studies suggest a role of n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) as peroxisome proliferator-activated receptor-a ligands in improving non-alcoholic fatty liver disease (NAFLD) in rodents. However, data in humans are still lacking. Aim
TL;DR: In this article, the authors proposed to jointly consider absolute daily returns, daily high-low range and daily realized volatility to develop a forecasting model based on their conditional dynamics, which is consistent and asymptotically normal under a wide range of specifications for the error density function.
TL;DR: Skin-directed therapies are the most appropriate option for early-stage MF/SS and most patients can look forward to a normal life expectancy.
TL;DR: In this paper, a detailed study of chemical freeze-out in p-p, C-C, Si-Si, and Pb-Pb collisions at beam momenta of 158A GeV was presented.
Abstract: We present a detailed study of chemical freeze-out in p-p, C-C, Si-Si, and Pb-Pb collisions at beam momenta of 158A GeV as well as Pb-Pb collisions at beam momenta of 20A, 30A, 40A, and 80A GeV. By analyzing hadronic multiplicities within the statistical hadronization model, we studied the parameters of the source as a function of the number of participating nucleons and the beam energy. We observe a nice smooth behavior of temperature, baryon chemical potential, and strangeness under-saturation parameter as a function of energy and nucleus size. Interpolating formulas are provided which allow us to predict the chemical freeze-out parameters in central collisions at center-of-mass energies $\sqrt{s}{}_{\mathit{NN}}\ensuremath{\gtrsim}4.5$ GeV and for any colliding ions. Specific discrepancies between data and the model emerge in particle ratios in Pb-Pb collisions at beam energies between 20A and 40A GeV which cannot be accounted for in the considered model schemes.
TL;DR: Selective CA IX inhibitors could prove useful for elucidating the role of CA IX in hypoxic cancers, for controlling the pH imbalance in tumor cells and for developing diagnostic or therapeutic applications for tumor management.
TL;DR: The results of these studies, combined with the increasing information available in the scientific literature on this and other crayfish species, will help to understand invasions in this taxon and make predictions about the identity of futurecrayfish invaders.
Abstract: The red swamp crayfish, Procambarus clarkii, native to northeastern Mexico and southcentral USA, is today the dominant macroinvertebrate in several European countries. While the first introduction of this species into Spain is well-documented, little is known about its pathways of invasion and the reason for its rapid spread in several European countries. Study of the biology of the species has revealed a number of properties that makes this crayfish a successful invader. Procambarus clarkii exhibits properties characteristic of an r-selected species, including early maturity at small body size, rapid growth rates, large numbers of offspring at a given parental size, and relatively short life spans. It is also plastic in its life cycle, able to disperse widely in the habitat and to tolerate environmental extremes. It displays generalist and opportunistic feeding habits, consuming macrophytes and preying on amphibians. Procambarus clarkii can also replace indigenous crayfish by a combination of mechanisms,...
TL;DR: Clinical trials of retroviral vectors containing drug resistance genes have established that the approach is safe and are now being designed to address the therapeutically relevant issues, and the development of transcriptional regulators appears promising.
Abstract: Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. One of the underlying mechanisms of MDR is cellular overproduction of P-glycoprotein (P-gp) which acts as an efflux pump for various anticancer drugs. P-gp is encoded by the MDR1 gene and its overexpression in cancer cells has become a therapeutic target for circumventing multidrug resistance. A potential strategy is to co-administer efflux pump inhibitors, although such reversal agents might actually increase the side effects of chemotherapy by blocking physiological anticancer drug efflux from normal cells. Although many efforts to overcome MDR have been made using first and second generation reversal agents comprising drugs already in current clinical use for other indications (e.g. verapamil, cyclosporine A, quinidine) or analogues of the first-generation drugs (e.g. dexverapamil, valspodar, cinchonine), few significant advances have been made. Clinical trials with third generation modulators (e.g. biricodar, zosuquidar, and laniquidar) specifically developed for MDR reversal are ongoing. The results however are not encouraging and it may be that the perfect reverser does not exist. Other approaches to multidrug resistance reversal have also been considered: encapsulation of anthracyclines in liposomes or other carriers which deliver these drugs selectively to tumor tissues, the use of P-gp targeted antibodies such as UIC2 or the use of antisense strategies targeting the MDR1 messenger RNA. More recently, the development of transcriptional regulators appears promising. Also anticancer drugs that belong structurally to classes of drugs extruded from cells by P-gp but that are not substrates of this drug transporter may act as potent inhibitors of MDR tumors (e.g. epothilones, second generation taxanes). Taking advantage of MDR has also been studied. Bone marrow suppression, one of the major side effects of cancer chemotherapy, can compromise the potential of curative and palliative chemotherapy. It is conceivable that drug resistance gene transfer into bone marrow stem cells may be able to reduce or abolish chemotherapy-induced myelosuppression and facilitate the use of high dose chemotherapy. Clinical trials of retroviral vectors containing drug resistance genes have established that the approach is safe and are now being designed to address the therapeutically relevant issues.