In silico tumor-targeting technologies for the evasion of acidity-induced multidrug resistance

The physiology of tumors is tied to MDR mechanisms that hamper chemotherapeutic effects, particularly passive membrane crossing compounds, like hydrophobic Lewis base drugs. Although the lysosomal entrapment phenomena remains to be fully understood, this pH-dependent MDR mechanism induces drug sequestration in the acidic lysosomal lumen. Overcoming the MDR requires multi-pronged therapies, which often overlook an ubiquitous tumor trait: the extracellular acidity of the tumor microenvironment (TME). To address this, pHLIP peptides have emerged as an acidity-selective technology for tumor-targeting drug delivery. We focused on refining our protocols with enhanced sampling techniques and tumor-like features to improve the predictive abilities of the CpHMD-L methodology and augment the realism of these biomolecular models, thus bridging the gap to in vivo and cellular conditions. The optimized protocol coupled the CpHMD-L method with a pHRE scheme, providing a robust baseline. Then, we applied the protocol to study the diverging therapeutic efficiency of the wt and an over-performing Var3 peptide. A novel implementation of a pH gradient CpHMD-L method successfully reproduced experimental performances, thus elucidating pivotal residues electrostatic networks that dictate peptides thermodynamic stability in TME conditions. A multi-peptide study highlighted the remarkable effects of permuting arginines in modulating the local vicinity of key aspartates. These findings heavily correlate with their tumor-targeting performance, supporting more rational and in silico-based approaches to peptide design. Finally, the pH-dependent mechanism of lysosomal entrapment was modelled, hinting at the important role of acidity in Lewis base drugs membrane intercalation. Additional pH-dependent permeability calculations, using a novel US-CpHMD method, identified the TME acidity as an additional MDR defense mechanism that impairs clinical efficiency. It also revealed an intrinsic flaw of these compounds, since they preferably target healthy cells. These findings have important implications in rational drug design, especially of conjugated therapies with pHLIP-like drug delivery systems to overcome these challenges

Asymptotics and stabilization for dynamic models of nonlinear beams

We prove that the von Kármán model for vibrating beams can be obtained as a singular limit of a modified Mindlin-Timoshenko system when the modulus of elasticity in shear k tends to infinity, provided a regularizing term through a fourth-order dispersive operator is added. We also show that the energy of solutions for this modified Mindlin-Timoshenko system decays exponentially, uniformly with respect to the parameter k, when suitable damping terms are added. As k → ∞ one deduces the uniform exponential decay of the energy of the von Kármán model

Asymptotic limits and stabilization for the 1D nonlinear Mindlin-Timoshenko system

This paper shows how the so called von Kármán model can be obtained as a singular limit of a modified Mindlin-Timoshenko system when the modulus of elasticity in shear k tends to infinity, provided a regularizing term through a fourth order dispersive operator is added. Introducing damping mechanisms, the authors also show that the energy of solutions for this modified Mindlin-Timoshenko system decays exponentially, uniformly with respect to the parameter k. As k → ∞, the authors obtain the damped von Kármán model with associated energy exponentially decaying to zero as well

Gold nanowires and the effect of impurities

Metal nanowires and in particular gold nanowires have received a great deal of attention in the past few years. Experiments on gold nanowires have prompted theory and simulation to help answer questions posed by these studies. Here we present results of computer simulations for the formation, evolution and breaking of very thin Au nanowires. We also discuss the influence of contaminants, such as atoms and small molecules, and their effect on the structural and mechanical properties of these nanowires

2007 Report of the ICES Study Group on Fisheries-Induced Adaptive Change (SGFIAC)

There is a growing body of scientific evidence indicating that fisheries can cause evolutionary responses over time periods as short as 1020 years, in particular in traits such as the onset of maturation. As these changes will most likely result in a reduction of the productivity of a fish stock, management objectives and (precautionary) reference points for sustainable exploitation need to be re-defined, and new objectives and reference points for managing fisheries-induced evolution need to be developed. Current knowledge allows for two generalisations. First, reducing harvest rates will almost always slow the rate and extent of fisheries-induced evolution in most life-history traits. Second, raising a stock's minimum size limit for exploitation well above the size range over which maturation occurs will slow down the rate of evolution in its maturation schedule. To go beyond these generic insights, "Evolutionary Impact Assessments" (EvoIAs) are proposed to quantify the effects of management measures, through the evolutionary response of specific stocks, on the utility functions defined by managers. The Study Group on Fisheries Induced Adaptive Change [SGFIAC] proposes to further develop this framework in dialogue with fisheries scientists and managers, with the aim of integrating the effects of fisheries-induced evolution into fisheries management advice. Developing EvoIAs in the context of suitable case studies is considered to be the most efficient way for making progress

LÍQUIDO FOLICULAR FRESCO OU CONGELADO NA PRODUÇÃO IN VITRO DE EMBRIÕES BOVINOS

A manutenção dos complexos cumulus-oócitos (CCO) em líquido folicular (LF) antes da sua maturação, além de visar a capacitação, viabiliza o transporte até o laboratório por ser de baixo custo, de fácil aquisição e o congelamento do LF permite seu armazenamento para futura utilização. Neste experimento avaliou-se o efeito do congelamento do LF obtido de folículos de 2-8mm e de folículos >8mm, sobre a taxa de produção embrionária. Oócitos foram aspirados de folículos de 2 a 8mm de ovários provenientes de abatedouro. No grupo controle (n=295) os CCO foram maturados por 24h. Nos tratamentos GF (n=297) e GC (n=282), os CCO foram mantidos por 6h a 30ºC em LF fresco ou congelado, respectivamente, de folículos >8mm. Já no tratamento PF(n=278) e PC (n=281), os CCO foram mantidos em LF fresco ou congelado, respectivamente, de folículos de 2-8mm. Posteriormente, os CCO dos tratamentos GF, GC, PF e PC foram maturados por 18h. Não houve efeito negativo do congelamento do líquido folicular e nem do tamanho dos folículos sobre as taxas de clivagem e produção embrionária em D7 e D9 (P>0,05). No entanto, o congelamento do LF de folículos de 2 a 8mm resultou em redução da taxa de eclosão e do número de células dos blastocistos. A manutenção de oócitos bovinos por 6h a 30ºC, antes da maturação, pode ser efetuada em líquido folicular de folículos >8mm, fresco ou congelado. Fresh or frozen follicular fluid in vitro bovine embryo production Abstract In addition to the capacitation, the maintenance of cumulus-oocyte complex (COC) in follicular fluid (FF) before maturation, allows the transport to the laboratory, being a practical and less expensive media. The FF can be stored after freezing to future use. Oocytes aspirated from bovine slaughterhouse ovaries, were used to evaluate the effect of maintaining the oocytes in fresh or frozen bovine FF (from 2-8mm and >8mm follicles) on the blastocyst rate. In the control group (n=259) the COC were matured for 24h. On treatments GF (n=297) and GC (n=282) the COC were held for 6h at 30°C in fresh or frozen FF from >8mm follicles, respectively. In treatments PF (n=278) and PC (n=281) the COC were held in fresh or frozen FF from 2-8mm follicles, respectively. Later, the COC from GF, GC, PF and PC were matured for 18h. The freezing process as well as the follicle size had no effect on the cleavage, D7 or D9 blastocyst rates (P>0,05). Nevertheless, the frozen FF from 2-8mm follicles resulted in a reduced hatching rate and lower ICM cells. Fresh or frozen follicular fluid of >8mm follicles could be used for a 6h transport of bovine oocytes before maturation for 18h

Histological and ultrastructural feature and nitrite production of caprine preantral follicles in vitro cultured in the presence or absence of serum

Avaliou-se o efeito da adição de diferentes tipos e concentrações de soro sobre o desenvolvimento e a sobrevivência de folículos ovarianos pré-antrais (FOPA) caprinos in vitro. Além disso, verificou-se a relação entre as concentrações de nitrito presentes no meio de cultivo e a viabilidade folicular. Cada par ovariano foi dividido em 29 fragmentos, sendo um destinado ao controle. Os fragmentos foram cultivados por um ou sete dias em meio essencial mínimo suplementado (MEM+) ou MEM+ com diferentes concentrações (10 ou 20%) de soro fetal bovino (SFB), soro de cabra em estro (SCE) ou soro de cabra em diestro (SCD). Na análise morfológica após sete dias, apenas o tratamento com 10% de SFB apresentou percentual de FOPA normais similar ao MEM+ (P>0,05). A análise ultra-estrutural dos folículos cultivados por sete dias com MEM+ ou MEM+ com 10% de SFB mostrou danos oocitários, porém células da granulosa normais. A análise do meio de cultivo revelou correlação positiva entre a viabilidade folicular e a produção de nitrito. A suplementação com soro não melhorou a viabilidade de FOPA e a concentração de nitrito no meio de cultivo funcionou como um indicador da viabilidade das células da granulosa de FOPA caprinos cultivados in vitro. ______________________________________________________________________________________________________________ ABSTRACTThe effect of the addition of different types and concentrations of sera on the viability and development of caprine preantal follicles (PAF) in vitro cultured was analyzed. In addition, it was evaluated the correlation between nitrite concentrations in culture medium and folicular viability. Each ovarian pair was divided in 29 fragments and one was used as control. The fragments were cultured for one or seven days in minimal essential medium (MEM+) or MEM+ with different concentrations of (10 or 20%) bovine fetal serum (BFS), estrous goat serum (EGS), or diestrous goat serum (DGS). After seven days, the morphological analysis showed that only the treatment with 10% BFS maintained the percentage of normal PAF similar to MEM+ (P>0.05). The ultrastructural analysis of follicles cultured for seven days in MEM+ or MEM+ with 10% BFS showed some oocyte damage, although the granulosa cells were normal. Analysis of culture medium revealed a positive correlation between follicular viability and nitrite production. Supplementation with serum did not improve the viability of PAF and nitrite levels in culture medium served as an indicator of viability of granulose cells from caprine PAF in vitro cultured

MMS Measurements of the Vlasov Equation: Probing the Electron Pressure Divergence Within Thin Current Sheets

We investigate the kinetic structure of electron‐scale current sheets found in the vicinity of the magnetopause and embedded in the magnetosheath within the reconnection exhaust. A new technique for computing terms of the Vlasov equation using Magnetospheric Multiscale (MMS) measurements is presented and applied to study phase space density gradients and the kinetic origins of the electron pressure divergence found within these current sheets. Crescent‐shaped structures in ∇⊥2fe give rise to bipolar and quadrupolar signatures in v·∇fe measured near the maximum ∇·Pe inside the current layers. The current density perpendicular to the magnetic field is strong (J⊥∼2 μA/m2), and the thickness of the current layers ranges from 3 to 5 electron inertial lengths. The electron flows supporting the current layers mainly result from the combination of E×B and diamagnetic drifts. We find nonzero J·E′ within the current sheets even though they are observed apart from typical diffusion region signatures.publishedVersio