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1.
Nature ; 573(7775): 578-581, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31554979

RESUMO

The widely accepted paradigm of Earth's geochemical evolution states that the successive extraction of melts from the mantle over the past 4.5 billion years formed the continental crust, and produced at least one complementary melt-depleted reservoir that is now recognized as the upper-mantle source of mid-ocean-ridge basalts1. However, geochemical modelling and the occurrence of high 3He/4He (that is, primordial) signatures in some volcanic rocks suggest that volumes of relatively undifferentiated mantle may reside in deeper, isolated regions2. Some basalts from large igneous provinces may provide temporally restricted glimpses of the most primitive parts of the mantle3,4, but key questions regarding the longevity of such sources on planetary timescales-and whether any survive today-remain unresolved. Kimberlites, small-volume volcanic rocks that are the source of most diamonds, offer rare insights into aspects of the composition of the Earth's deep mantle. The radiogenic isotope ratios of kimberlites of different ages enable us to map the evolution of this domain through time. Here we show that globally distributed kimberlites originate from a single homogeneous reservoir with an isotopic composition that is indicative of a uniform and pristine mantle source, which evolved in isolation over at least 2.5 billion years of Earth history-to our knowledge, the only such reservoir that has been identified to date. Around 200 million years ago, extensive volumes of the same source were perturbed, probably as a result of contamination by exogenic material. The distribution of affected kimberlites suggests that this event may be related to subduction along the margin of the Pangaea supercontinent. These results reveal a long-lived and globally extensive mantle reservoir that underwent subsequent disruption, possibly heralding a marked change to large-scale mantle-mixing regimes. These processes may explain why uncontaminated primordial mantle is so difficult to identify in recent mantle-derived melts.


Assuntos
Planeta Terra , Evolução Planetária , Fenômenos Geológicos , Radioisótopos/análise
2.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443165

RESUMO

The noble gas isotope systematics of ocean island basalts suggest the existence of primordial mantle signatures in the deep mantle. Yet, the isotopic compositions of lithophile elements (Sr, Nd, Hf) in these lavas require derivation from a mantle source that is geochemically depleted by melt extraction rather than primitive. Here, this apparent contradiction is resolved by employing a compilation of the Sr, Nd, and Hf isotope composition of kimberlites-volcanic rocks that originate at great depth beneath continents. This compilation includes kimberlites as old as 2.06 billion years and shows that kimberlites do not derive from a primitive mantle source but sample the same geochemically depleted component (where geochemical depletion refers to ancient melt extraction) common to most oceanic island basalts, previously called PREMA (prevalent mantle) or FOZO (focal zone). Extrapolation of the Nd and Hf isotopic compositions of the kimberlite source to the age of Earth formation yields a 143Nd/144Nd-176Hf/177Hf composition within error of chondrite meteorites, which include the likely parent bodies of Earth. This supports a hypothesis where the source of kimberlites and ocean island basalts contains a long-lived component that formed by melt extraction from a domain with chondritic 143Nd/144Nd and 176Hf/177Hf shortly after Earth accretion. The geographic distribution of kimberlites containing the PREMA component suggests that these remnants of early Earth differentiation are located in large seismically anomalous regions corresponding to thermochemical piles above the core-mantle boundary. PREMA could have been stored in these structures for most of Earth's history, partially shielded from convective homogenization.

3.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34074760

RESUMO

Globally distributed kimberlites with broadly chondritic initial 143Nd-176Hf isotopic systematics may be derived from a chemically homogenous, relatively primitive mantle source that remained isolated from the convecting mantle for much of the Earth's history. To assess whether this putative reservoir may have preserved remnants of an early Earth process, we report 182W/184W and 142Nd/144Nd data for "primitive" kimberlites from 10 localities worldwide, ranging in age from 1,153 to 89 Ma. Most are characterized by homogeneous µ182W and µ142Nd values averaging -5.9 ± 3.6 ppm (2SD, n = 13) and +2.7 ± 2.9 ppm (2SD, n = 6), respectively. The remarkably uniform yet modestly negative µ182W values, coupled with chondritic to slightly suprachondritic initial 143Nd/144Nd and 176Hf/177Hf ratios over a span of nearly 1,000 Mya, provides permissive evidence that these kimberlites were derived from one or more long-lived, early formed mantle reservoirs. Possible causes for negative µ182W values among these kimberlites include the transfer of W with low µ182W from the core to the mantle source reservoir(s), creation of the source reservoir(s) as a result of early silicate fractionation, or an overabundance of late-accreted materials in the source reservoir(s). By contrast, two younger kimberlites emplaced at 72 and 52 Ma and characterized by distinctly subchondritic initial 176Hf/177Hf and 143Nd/144Nd have µ182W values consistent with the modern upper mantle. These isotopic compositions may reflect contamination of the ancient kimberlite source by recycled crustal components with µ182W ≥ 0.

4.
Contrib Mineral Petrol ; 178(9): 64, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38617191

RESUMO

Despite the first-order importance of crystallisation-differentiation for arc magma evolution, several other processes contribute to their compositional diversity. Among them is the remelting of partly crystallised magmas, also known as cumulate melting or 'petrological cannibalism'. The impact of this process on the plutonic record is poorly constrained. We investigate a nepheline-normative dyke suite close to the Blumone gabbros, a large amphibole-gabbro unit of the Tertiary Southern Alpine Adamello igneous complex. The compositions of the studied dykes are characterised by low SiO2 (43-46 wt. %), MgO (5.0-7.2 wt. %), Ni (18-40 µg/g), and high Al2O3 (20.2-22.0 wt. %) contents. Phenocrystic plagioclase in these dykes exhibits major, trace, and Sr isotope compositions similar to Blumone cumulate plagioclase, suggesting a genetic link between the nepheline-normative dykes and the amphibole-gabbro cumulates. We tested this hypothesis by performing saturation experiments on a nepheline-normative dyke composition in an externally heated pressure vessel at 200 MPa between 975 and 1100 °C at fO2 conditions close to the Ni-NiO buffer. Plagioclase and spinel are near-liquidus phases at and above 1050 °C, contrasting with the typical near-liquidus olivine ± spinel assemblage in hydrous calc-alkaline basalts. The alkaline nature of the dykes results from the abundance of amphibole in the protolith, consistent with melting of amphibole-gabbro cumulates. We modelled the heat budget from the repeated injection of basaltic andesite into a partly crystallised amphibole-gabbro cumulate. The results of this model show that no more than 7% of the cumulate pile reaches temperatures high enough to produce nepheline-normative melts. We propose that such nepheline-normative dykes are a hallmark of hydrous cumulate melting in subvolcanic plumbing systems. Therefore, ne-normative dykes in arc batholiths may indicate periods with high magma fluxes. Supplementary Information: The online version contains supplementary material available at 10.1007/s00410-023-02047-3.

5.
Sensors (Basel) ; 23(12)2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37420632

RESUMO

We report on the development of scintillating bolometers based on lithium molybdate crystals that contain molybdenum that has depleted into the double-ß active isotope 100Mo (Li2100deplMoO4). We used two Li2100deplMoO4 cubic samples, each of which consisted of 45-millimeter sides and had a mass of 0.28 kg; these samples were produced following the purification and crystallization protocols developed for double-ß search experiments with 100Mo-enriched Li2MoO4 crystals. Bolometric Ge detectors were utilized to register the scintillation photons that were emitted by the Li2100deplMoO4 crystal scintillators. The measurements were performed in the CROSS cryogenic set-up at the Canfranc Underground Laboratory (Spain). We observed that the Li2100deplMoO4 scintillating bolometers were characterized by an excellent spectrometric performance (∼3-6 keV of FWHM at 0.24-2.6 MeV γs), moderate scintillation signal (∼0.3-0.6 keV/MeV scintillation-to-heat energy ratio, depending on the light collection conditions), and high radiopurity (228Th and 226Ra activities are below a few µBq/kg), which is comparable with the best reported results of low-temperature detectors that are based on Li2MoO4 using natural or 100Mo-enriched molybdenum content. The prospects of Li2100deplMoO4 bolometers for use in rare-event search experiments are briefly discussed.


Assuntos
Molibdênio , Rádio (Elemento) , Isótopos , Contagem de Cintilação/métodos , Lítio , Íons
6.
Amino Acids ; 48(3): 887-900, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26614437

RESUMO

Peptide-based antibiotics might help containing the rising tide of antimicrobial resistance. We developed SB056, a semi-synthetic peptide with a dimeric dendrimer scaffold, active against both Gram-negative and Gram-positive bacteria. Being the mechanism of SB056 attributed to disruption of bacterial membranes, we enhanced the amphiphilic profile of the original, empirically derived sequence [WKKIRVRLSA-NH2] by interchanging the first two residues [KWKIRVRLSA-NH2], and explored the effects of this modification on the interaction of peptide, both in linear and dimeric forms, with model membranes and on antimicrobial activity. Results obtained against Escherichia coli and Staphylococcus aureus planktonic strains, with or without salts at physiological concentrations, confirmed the added value of dendrimeric structure over the linear one, especially at physiological ionic strength, and the impact of the higher amphipathicity obtained through sequence modification on enhancing peptide performances. SB056 peptides also displayed intriguing antibiofilm properties. Staphylococcus epidermidis was the most susceptible strain in sessile form, notably to optimized linear analog lin-SB056-1 and the wild-type dendrimer den-SB056. Membrane affinity of all peptides increased with the percentage of negatively charged lipids and was less influenced by the presence of salt in the case of dendrimeric peptides. The analog lin-SB056-1 displayed the highest overall affinity, even for zwitterionic PC bilayers. Thus, in addition to electrostatics, distribution of charged/polar and hydrophobic residues along the sequence might have a significant role in driving peptide-lipid interaction. Supporting this view, dendrimeric analog den-SB056-1 retained greater membrane affinity in the presence of salt than den-SB056, despite the fact that they bear exactly the same net positive charge.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/metabolismo , Bactérias/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Testes de Sensibilidade Microbiana
7.
Science ; 385(6707): 452-455, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39052811

RESUMO

A long gamma-ray burst (GRB) is observed when the collapse of a massive star produces an ultrarelativistic outflow pointed toward Earth. Gamma-ray spectra of long GRBs are smooth, typically modeled by joint power-law segments describing a continuum, with no detected spectral lines. We report a significant (>6σ) narrow emission feature at ~10 mega-electron volts (MeV) in the spectrum of the bright GRB 221009A. Over 80 seconds, it evolves in energy (~12 to ~6 MeV) and in luminosity (~1.1 to <0.43 × 1050 erg second-1) but has a constant width of ~1 MeV. We interpret this feature as a blueshifted spectral line produced by the annihilation of electron-positron pairs, potentially in the same location responsible for emitting the brightest GRB pulses.

8.
Nat Commun ; 15(1): 5033, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866783

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m6A downregulation. Notably, cells expressing mutant FUS were characterized by higher m6A levels suggesting a possible link between m6A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Neurônios Motores , Proteína FUS de Ligação a RNA , Proteína FUS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Humanos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Grânulos Citoplasmáticos/metabolismo , Fibroblastos/metabolismo , Adenosina/metabolismo , Adenosina/análogos & derivados , Metiltransferases/metabolismo , Metiltransferases/genética , Mutação , Corpos de Inclusão/metabolismo , Grânulos de Estresse/metabolismo , Transcriptoma
9.
Nat Commun ; 14(1): 8150, 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38071371

RESUMO

Studies of ocean island basalts have identified a Prevalent Mantle (PREMA) component as a fundamental feature of mantle geochemical arrays; however, its origin and distribution are highly controversial, including its potential link to plumes sourced in low-shear-wave velocity provinces (LLSVPs) above the core-mantle boundary. In this study, we interrogate the compositional systematics of ~ 3500 Cenozoic oceanic and continental sodic basalts to provide insights into the origin and distribution of PREMA. We find that low-degree basaltic melts with high Nb concentrations located away from deep-mantle plumes have PREMA-like Sr-Nd-Hf isotopic signatures, implying that PREMA is highly fusible and not exclusively associated with LLSVPs. Geochemical modelling and mantle convection simulations indicate that PREMA could have been generated soon after Earth accretion, experiencing only minimal melting or enrichment, and then scattered throughout the upper mantle, rather than being the result of mixing between depleted and enriched mantle components.

10.
Biomedicines ; 11(7)2023 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-37509532

RESUMO

Circular RNAs (circRNAs), covalently closed RNAs that originate from back-splicing events, participate in the control of several processes, including those that occur in the development of pathological conditions such as cancer. Hereby, we describe circAFF1, a circular RNA overexpressed in alveolar rhabdomyosarcoma. Using RH4 and RH30 cell lines, a classical cell line models for alveolar rhabdomyosarcoma, we demonstrated that circAFF1 is a cytoplasmatic circRNA and its depletion impacts cell homeostasis favouring cell migration through the downregulation of genes involved in cell adhesion pathways. The presented data underline the importance of this circular RNA as a new partial suppressor of the alveolar rhabdomyosarcoma tumour progression and as a putative future therapeutic target.

11.
Nat Commun ; 14(1): 1898, 2023 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-37019933

RESUMO

N6-Methyladenosine (m6A) is well-known for controlling different processes of linear RNA metabolism. Conversely, its role in the biogenesis and function of circular RNAs (circRNAs) is still poorly understood. Here, we characterize circRNA expression in the pathological context of rhabdomyosarcoma (RMS), observing a global increase when compared to wild-type myoblasts. For a set of circRNAs, such an increase is due to the raised expression of the m6A machinery, which we also find to control the proliferation activity of RMS cells. Furthermore, we identify the RNA helicase DDX5 as a mediator of the back-splicing reaction and as a co-factor of the m6A regulatory network. DDX5 and the m6A reader YTHDC1 are shown to interact and to promote the production of a common subset of circRNAs in RMS. In line with the observation that YTHDC1/DDX5 depletion reduces RMS proliferation, our results provide proteins and RNA candidates for the study of rhabdomyosarcoma tumorigenicity.


Assuntos
RNA Circular , Rabdomiossarcoma , Humanos , RNA Circular/metabolismo , RNA/metabolismo , Splicing de RNA , Fatores de Processamento de RNA/metabolismo , Proteínas do Tecido Nervoso/metabolismo , RNA Helicases DEAD-box/metabolismo
12.
Nat Commun ; 14(1): 6999, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37919292

RESUMO

The diamond potential of kimberlites is difficult to assess due to several mantle and magmatic processes affecting diamond content. Traditionally, initial evaluations are based on the compositions of mantle-derived minerals (garnet, chromite, clinopyroxene), which allow an assessment of pressure-temperature conditions and lithologies suitable for diamond formation. Here we explore a complementary approach that considers the conditions of diamonds destruction by interaction with melts/fluids (metasomatism). We test the hypothesis that carbonate-rich metasomatism related to kimberlite melt infiltration into the deep lithosphere is detrimental to diamond preservation. Our results show that high diamond grades in kimberlites worldwide are exclusively associated with high-Mg/Fe olivine, which corresponds to mantle lithosphere minimally affected by kimberlite-related metasomatism. Diamond dissolution in strongly metasomatised lithosphere containing low-Mg/Fe olivine provides a causal link to the empirical associations between low diamond grades, abundant Ti-Zr-rich garnets and kimberlites with high Ti and low Mg contents. This finding show-cases olivine geochemistry as a viable tool in diamond exploration.

13.
Stem Cell Rev Rep ; 19(8): 2837-2851, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37605090

RESUMO

In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging. Recent studies suggest that the aged SVZ niche decreases the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that promote NSC quiescence. The transcription factors that mediate these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of NSPC cultures. Here, we further investigate its role as a candidate transcriptional regulator of neurogenic decline. We show that Dbx2 expression is downregulated by Epidermal Growth Factor receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines overexpressing Dbx2, we also show that this gene inhibits NSPC proliferation by hindering the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptomic networks modulated by Dbx2. Among the top hits, we report the downregulation of the molecular pathways implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a transcription factor relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.


Assuntos
Genes Homeobox , Neurogênese , Animais , Camundongos , Envelhecimento/genética , Divisão Celular , Neurogênese/genética , Neurônios , Fatores de Transcrição
14.
Biophys J ; 102(5): 1039-48, 2012 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-22404926

RESUMO

The novel antimicrobial peptide with a dimeric dendrimer scaffold, SB056, was empirically optimized by high-throughput screening. This procedure produced an intriguing primary sequence whose structure-function analysis is described here. The alternating pattern of hydrophilic and hydrophobic amino acids suggests the possibility that SB056 is a membrane-active peptide that forms amphiphilic ß-strands in a lipid environment. Circular dichroism confirmed that the cationic SB056 folds as ß-sheets in the presence of anionic vesicles. Lipid monolayer surface pressure experiments revealed unusual kinetics of monolayer penetration, which suggest lipid-induced aggregation as a membranolytic mechanism. NMR analyses of the linear monomer and the dendrimeric SB056 in water and in 30% trifluoroethanol, on the other hand, yielded essentially unstructured conformations, supporting the excellent solubility and storage properties of this compound. However, simulated annealing showed that many residues lie in the ß-region of the Ramachandran plot, and molecular-dynamics simulations confirmed the propensity of this peptide to fold as a ß-type conformation. The excellent solubility in water and the lipid-induced oligomerization characteristics of this peptide thus shed light on its mechanism of antimicrobial action, which may also be relevant for systems that can form toxic ß-amyloid fibrils when in contact with cellular membranes. Functionally, SB056 showed high activity against Gram-negative bacteria and some limited activity against Gram-positive bacteria. Its potency against Gram-negative strains was comparable (on a molar basis) to that of colistin and polymyxin B, with an even broader spectrum of activity than numerous other reference compounds.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/metabolismo , Bactérias/efeitos dos fármacos , Dendrímeros/metabolismo , Dimerização , Interações Hidrofóbicas e Hidrofílicas , Lipídeos de Membrana/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
15.
Antimicrob Agents Chemother ; 56(10): 5278-88, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22850525

RESUMO

Respiratory syncytial virus (RSV) interacts with cell surface heparan sulfate proteoglycans (HSPGs) to initiate infection. The interaction of RSV with HSPGs thus presents an attractive target for the development of novel inhibitors of RSV infection. In the present study, a minilibrary of linear, dimeric, and dendrimeric peptides containing clusters of basic amino acids was screened with the aim of identifying peptides able to bind HSPGs and thus block RSV attachment and infectivity. Of the compounds identified, the dendrimer SB105-A10 was the most potent inhibitor of RSV infectivity, with 50% inhibitory concentrations (IC(50)s) of 0.35 µM and 0.25 µM measured in Hep-2 and A549 cells, respectively. SB105-A10 was found to bind to both cell types via HSPGs, suggesting that its antiviral activity is indeed exerted by competing with RSV for binding to cell surface HSPGs. SB105-A10 prevented RSV infection when added before the viral inoculum, in line with its proposed HSPG-binding mechanism of action; moreover, antiviral activity was also exhibited when SB105-A10 was added postinfection, as it was able to reduce the cell-to-cell spread of the virus. The antiviral potential of SB105-A10 was further assessed using human-derived tracheal/bronchial epithelial cells cultured to form a pseudostratified, highly differentiated model of the epithelial tissue of the human respiratory tract. SB105-A10 strongly reduced RSV infectivity in this model and exhibited no signs of cytotoxicity or proinflammatory effects. Together, these features render SB105-A10 an attractive candidate for further development as a RSV inhibitor to be administered by aerosol delivery.


Assuntos
Antivirais/química , Antivirais/farmacologia , Dendrímeros/química , Heparitina Sulfato/química , Peptídeos/química , Peptídeos/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Linhagem Celular , Humanos
16.
Cell Mol Life Sci ; 68(13): 2255-66, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21598022

RESUMO

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/classificação , Membrana Celular/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/classificação
17.
Sci Adv ; 8(9): eabj1325, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35245120

RESUMO

Earth's carbon cycle is strongly influenced by subduction of sedimentary material into the mantle. The composition of the sedimentary subduction flux has changed considerably over Earth's history, but the impact of these changes on the mantle carbon cycle is unclear. Here, we show that the carbon isotopes of kimberlite magmas record a fundamental change in their deep-mantle source compositions during the Phanerozoic Eon. The 13C/12C of kimberlites before ~250 Ma preserves typical mantle values, whereas younger kimberlites exhibit lower and more variable ratios-a switch coincident with a recognized surge in kimberlite magmatism. We attribute these changes to increased deep subduction of organic carbon with low 13C/12C following the Cambrian Explosion when organic carbon deposition in marine sediments increased significantly. These observations demonstrate that biogeochemical processes at Earth's surface have a profound influence on the deep mantle, revealing an integral link between the deep and shallow carbon cycles.

18.
J Clin Med ; 11(6)2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35329824

RESUMO

Distal gastrectomy for benign gastroduodenal peptic disease has become rare, but it still represents a widely adopted procedure for advanced and, in some countries, even for early distal gastric cancer. Survival rates following surgery for gastric malignancy are constantly improving, hence the residual mucosa of the gastric stump is exposed for a prolonged period to biliopancreatic reflux and, possibly, to Helicobacter pylori (HP) infection. Biliopancreatic reflux and HP infection are considered responsible for gastritis and metachronous carcinoma in the gastric stump after oncologic surgery. For gastrectomy patients, in addition to eradication treatment for cases that are already HP positive, endoscopic surveillance should also be recommended, for prompt surveillance and detection in the residual mucosa of any metaplastic-atrophic-dysplastic features following surgery.

19.
Antimicrob Agents Chemother ; 55(7): 3231-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21576438

RESUMO

In response to the need for new antiviral agents, dendrimer-based molecules have been recognized as having a large number of potential therapeutic applications. They include peptide-derivatized dendrimers, which are hyperbranched synthetic well-defined molecules which consist of a peptidyl branching core and covalently attached surface functional peptides. However, few studies have addressed their applications as direct-acting antiviral agents. Here, we report on the ability of the peptide dendrimer SB105 and its derivative, SB105_A10, to directly inhibit herpes simplex virus 1 (HSV-1) and HSV-2 in vitro replication, with favorable selective indexes discerned for both compounds. An analysis of their mode of action revealed that SB105 and SB105_A10 prevent HSV-1 and HSV-2 attachment to target cells, whereas SB104, a dendrimer with a different amino acid sequence within the functional group and minimal antiviral activity, was ineffective in blocking HSV attachment. Moreover, both SB105 and SB105_A10 retained their ability to inhibit HSV adsorption at pH 3.0 and 4.0 and in the presence of 10% human serum proteins, conditions mimicking the physiological properties of the vagina, a potential therapeutic location for such compounds. The inhibition of HSV adsorption is likely to stem from the ability of SB105_A10 to bind to the glycosaminoglycan moiety of cell surface heparan sulfate proteoglycans, thereby blocking virion attachment to target cells. Finally, when combined with acyclovir in checkerboard experiments SB105_A10 exhibited highly synergistic activity. Taken together, these findings suggest that SB105 and SB105_A10 are promising candidates for the development of novel topical microbicides for the prevention of HSV infections.


Assuntos
Antivirais/química , Antivirais/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/fisiologia , Peptídeos/química , Animais , Antivirais/síntese química , Linhagem Celular , Chlorocebus aethiops , Dendrímeros/síntese química , Humanos , Concentração de Íons de Hidrogênio , Immunoblotting , Células Vero , Replicação Viral/efeitos dos fármacos
20.
Nat Commun ; 12(1): 6295, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728640

RESUMO

Oxygen isotope ratios in mantle-derived magmas that differ from typical mantle values are generally attributed to crustal contamination, deeply subducted crustal material in the mantle source or primordial heterogeneities. Here we provide an alternative view for the origin of light oxygen-isotope signatures in mantle-derived magmas using kimberlites, carbonate-rich magmas that assimilate mantle debris during ascent. Olivine grains in kimberlites are commonly zoned between a mantle-derived core and a magmatic rim, thus constraining the compositions of both mantle wall-rocks and melt phase. Secondary ion mass spectrometry (SIMS) analyses of olivine in worldwide kimberlites show a remarkable correlation between mean oxygen-isotope compositions of cores and rims from mantle-like 18O/16O to lower 'crustal' values. This observation indicates that kimberlites entraining low-18O/16O olivine xenocrysts are modified by assimilation of low-18O/16O sub-continental lithospheric mantle material. Interaction with geochemically-enriched domains of the sub-continental lithospheric mantle can therefore be an important source of apparently 'crustal' signatures in mantle-derived magmas.

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