Water-Peptide Site-Specific Interactions: A Structural Study on the Hydration of Glutathione

AbstractWater-peptide interactions play an important role in determining peptide structure and function. Nevertheless, a microscopic description of these interactions is still incomplete. In this study we have investigated at the atomic scale length the interaction between water and the tripeptide glutathione. The rationale behind this work, based on the combination between a neutron diffraction experiment and a computer simulation, is twofold. It extends previous studies on amino acids, addressing issues such as the perturbation of the water network brought by a larger biomolecule in solution. In addition, and more importantly, it seeks a possible link between the atomic length scale description of the glutathione-water interaction with the specific biological functionality of glutathione, an important intracellular antioxidant. Results indicate a rather weak hydrogen bond between the thiol (-SH) group of cysteine and its first neighbor water molecule. This -SH group serves as a proton donor, is responsible for the biological activity of glutathione, and it is involved in the formation of glutathione disulfide, the oxidized form of glutathione. Moreover, the hydration shell of the chemically identical carboxylate group on the glutamic acid residue and on the glycine residue shows an intriguing different spatial location of water molecules and coordination numbers around the two CO2− groups

Synaptic Adhesion Molecules Regulate the Integration of New Granule Neurons in the Postnatal Mouse Hippocampus and their Impact on Spatial Memory.

Postnatal hippocampal neurogenesis induces network remodeling and may participate to mechanisms of learning. In turn, the maturation and survival of newborn neurons is regulated by their activity. Here, we tested the effect of a cell-autonomous overexpression of synaptic adhesion molecules on the maturation and survival of neurons born postnatally and on hippocampal-dependent memory performances. Families of adhesion molecules are known to induce pre- and post-synaptic assembly. Using viral targeting, we overexpressed three different synaptic adhesion molecules, SynCAM1, Neuroligin-1B and Neuroligin-2A in newborn neurons in the dentate gyrus of 7- to 9-week-old mice. We found that SynCAM1 increased the morphological maturation of dendritic spines and mossy fiber terminals while Neuroligin-1B increased spine density. In contrast, Neuroligin-2A increased both spine density and size as well as GABAergic innervation and resulted in a drastic increase of neuronal survival. Surprisingly, despite increased neurogenesis, mice overexpressing Neuroligin-2A in new neurons showed decreased memory performances in a Morris water maze task. These results indicate that the cell-autonomous overexpression of synaptic adhesion molecules can enhance different aspects of synapse formation on new neurons and increase their survival. Furthermore, they suggest that the mechanisms by which new neurons integrate in the postnatal hippocampus conditions their functional implication in learning and memory

Single-cell RNA sequencing identifies a paracrine interaction that may drive oncogenic notch signaling in human adenoid cystic carcinoma

Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling have been implicated in ACC pathophysiology, but in vivo descriptions of these two programs in human tumors and investigation into their active coordination remain incomplete. We utilize single-cell RNA sequencing to profile human head and neck ACC, including a comparison of primary ACC with a matched local recurrence. We define expression heterogeneity in these rare tumors, uncovering diversity in myoepithelial and luminal cell expression. We find differential expression of Notch ligands DLL1, JAG1, and JAG2 in myoepithelial cells, suggesting a paracrine interaction that may support oncogenic Notch signaling. We validate this selective expression in three published cohorts of patients with ACC. Our data provide a potential explanation for the biphasic nature of low- and intermediate-grade ACC and may help direct new therapeutic strategies against these tumors

A new medical record proposal to the prognostic risk assessment for mronj in oncologic patients: “Sapienza head and neck unit” proposal

Medication-related osteonecrosis of the jaw (MRONJ) is an adverse event associated with antiresorptive and antiangiogenic drugs. The use of these drugs in the treatment of cancer patients with bone metastasis is necessary and standardized in the literature. A multidisciplinary approach for the patient’s management is strongly recommended. Therefore, it should be necessary to integrate the path of these subjects with a dedicated dental screening in order to first assess the individual risk of developing a MRONJ, and then to plan dental treatments and oral hygiene sessions, and finally to schedule a follow-up to intercept and treat early osteonecrosis. The aim of this manuscript is to propose a new simple medical report to evaluate patients affected by metastatic bone cancer in order to reduce the risk of developing MRONJ

Estabilidade e resistência de agregados de Latossolo Vermelho-Escuro cultivado com sucessão milho-adubo verde

Latosols (oxisols) under cerrado vegetation in their natural condition present, in general, high structural stability due mainly to the performance of aluminum and iron oxides and organic matter. In the Cerrado region, however, the practice of burning cultural residues and the excessive use of harrow during soil preparation is very common, mainly the plowing harrow, which pulverizes the soil with consequent weakness and destruction of soil structure. This study aimed to evaluate the resistance of aggregates of a cerrado phase, clayey texture, Dark-Red Latosol (Oxisol) to simulated raindrop impact as well as the geometrical average diameter of aggregates of this soil under different green manure-corn succession systems and under native cerrado. The tested green manure species were Crotalaria juncea, Cajanus cajan, Mucuna aterrima, Brachiaria ruziziensis and Canavalia ensiformis, cultivated in rotation with corn (cv. Pioneer 3072), during two years. The native cerrado presented larger and more stable aggregates, and it was necessary higher kinectic energy for disrupting them. In the green manure systems, brachiaria showed higher aggregation action than the leguminous species. The simulated raindrop impact method presented good performance, leading to better distinction among the treatments in relation to the aggregates stability method.Os Latossolos do cerrado em seu estado natural caracterizam-se, em geral, pela elevada estabilidade estrutural causada principalmente pela atuação dos óxidos de alumínio e de ferro e matéria orgânica. Entretanto, na região dos Cerrados é bastante frequente a prática da queima dos restos culturais e do uso excessivo de grades no preparo do solo, especialmente a grade aradora, que pulveriza o solo com o consequente enfraquecimento e destruição da estrutura. Objetivou-se com este estudo avaliar a resistência de agregados de Latossolo Vermelho-Escuro, textura argilosa, fase cerrado, ao impacto de gotas de chuva simulada e o diâmetro médio geométrico dos agregados deste solo sob sistemas de sucessão de diferentes adubos verdes-milho e sob cerrado nativo. As espécies de adubos verdes testadas foram Crotalaria juncea, Cajanus cajan, Mucuna aterrima, Brachiaria ruziziensis e Canavalia ensiformis, cultivadas na entressafra do milho (cv. Pioneer 3072), durante dois anos. O cerrado nativo apresentou agregados maiores e mais estáveis, sendo necessária maior energia cinética para destruí-los. Nos sistemas de adubos verdes, a braquiária mostrou maior ação agregante que as leguminosas. O método do impacto de gotas de chuva simulada apresentou boa performance, proporcionando maior discriminação entre os tratamentos em relação ao método de estabilidade de agregados

Adenosine A2A receptors modulate BDNF both in normal conditions and in experimental models of Huntington’s disease

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances synaptic transmission and regulates neuronal proliferation and survival. Functional interactions between adenosine A2A receptors (A2ARs) and BDNF have been recently reported. In this article, we report some recent findings from our group showing that A2ARs regulate both BDNF functions and levels in the brain. Whereas BDNF (10 ng/ml) increased the slope of excitatory postsynaptic field potentials (fEPSPs) in hippocampal slices from wild-type (WT) mice, it was completely ineffective in slices taken from A2AR knock-out (KO) mice. Furthermore, enzyme immunoassay studies showed a significant reduction in hippocampal BDNF levels in A2AR KO vs. WT mice. Having found an even marked reduction in the striatum of A2AR KO mice, and as both BDNF and A2ARs have been implicated in the pathogenesis of Huntington’s disease (HD), an inherited striatal neurodegenerative disease, we then evaluated whether the pharmacological blockade of A2ARs could influence striatal levels of BDNF in an experimental model of HD-like striatal degeneration (quinolinic acid-lesioned rats) and in a transgenic mice model of HD (R6/2 mice). In both QA-lesioned rats and early symptomatic R6/2 mice (8 weeks), the systemic administration of the A2AR antagonist SCH58261 significantly reduced striatal BDNF levels. These results indicate that the presence and the tonic activation of A2ARs are necessary to allow BDNF-induced potentiation of synaptic transmission and to sustain a normal BDNF tone. The possible functional consequences of reducing striatal BDNF levels in HD models need further investigation