Lentiviral Vectors Come of Age? Hurdles and Challenges in Scaling Up Manufacture

The pharmaceutical industry has been attracted to the gene therapy field and is starting to support clinical trials, establishing collaborative strategies to develop commercial products which in many cases are based on lentiviral vectors. The predictable widespread use of lentiviral vectors in next-generation gene therapy scenarios aimed at dealing with not only rare diseases raises important challenges and hurdles regarding their manufacture. The author reflects on this in the chapter on the state of the art in the manufacture of lentiviral vectors, addressing some current manufacturing processes, their achievements, and the uncertainties in ensuring a validated process capable of releasing consistent vector quality that meets global health authorities’ requirements. In summary, the proposal looks at the goals and challenges that must be addressed in manufacturing lentiviral vectors, in order to satisfy supply in the commercial stage, before we reach the next stage in gene therapy

Mass Exchange Dynamics of Surface and Subsurface Oil in Shallow-Water Transport

We formulate a model for the mass exchange between oil at and below the sea surface. This is a particularly important aspect of modeling oil spills. Surface and subsurface oil have different chemical and transport characteristics and lumping them together would compromise the accuracy of the resulting model. Without observational or computational constraints, it is thus not possible to quantitatively predict oil spills based upon partial field observations of surface and/or sub-surface oil. The primary challenge in capturing the mass exchange is that the principal mechanisms are on the microscale. This is a serious barrier to developing practical models for oil spills that are capable of addressing questions regarding the fate of oil at the large spatio-temporal scales, as demanded by environmental questions. We use upscaling to propose an environmental-scale model which incorporates the mass exchange between surface and subsurface oil due to oil droplet dynamics, buoyancy effects, and sea surface and subsurface mechanics. While the mass exchange mechanism detailed here is generally applicable to oil transport models, it addresses the modeling needs of a particular to an oil spill model [1]. This transport model is designed to capture oil spills at very large spatio-temporal scales. It accomplishes this goal by specializing to shallow-water environments, in which depth averaging is a perfectly good approximation for the flow, while at the same time retaining mass conservation of oil over the whole oceanic domain.Comment: 18 pages, 6 figure

A Chemokine Targets the Nucleus: Cxcl12-Gamma Isoform Localizes to the Nucleolus in Adult Mouse Heart

Chemokines are extracellular mediators of complex regulatory circuits involved principally in cell-to-cell communication. Most studies to date of the essential chemokine Cxcl12 (Sdf-1) have focused on the ubiquitously expressed secreted isoforms α and β. Here we show that, unlike these isoforms and all other known chemokines, the alternatively transcribed γ isoform is an intracellular protein that localizes to the nucleolus in differentiated mouse Cardiac tissue. Our results demonstrate that nucleolar transportation is encoded by a nucleolar-localization signal in the unique carboxy-terminal region of Sdf-1γ, and is competent both in vivo and in vitro. The molecular mechanism underlying these unusual chemokine properties involves cardiac-specific transcription of an mRNA containing a unique short-leader sequence lacking the signal peptide and translation from a non-canonical CUG codon. Our results provide an example of genome economy even for essential and highly conserved genes such as Cxcl12, and suggest that chemokines can exert tissue specific functions unrelated to cell-to-cell communication

Controllable direction of liquid jets generated by thermocavitation within a droplet.

A high-velocity fluid stream ejected from an orifice or nozzle is a common mechanism to produce liquid jets in inkjet printers or to produce sprays among other applications. In the present research, we show the generation of liquid jets of controllable direction produced within a sessile water droplet by thermocavitation. The jets are driven by an acoustic shock wave emitted by the collapse of a hemispherical vapor bubble at the liquid-solid/substrate interface. The generated shock wave is reflected at the liquid-air interface due to acoustic impedance mismatch generating multiple reflections inside the droplet. During each reflection, a force is exerted on the interface driving the jets. Depending on the position of the generation of the bubble within the droplet, the mechanical energy of the shock wave is focused on different regions at the liquid-air interface, ejecting cylindrical liquid jets at different angles. The ejected jet angle dependence is explained by a simple ray tracing model of the propagation of the acoustic shock wave inside the droplet

Efficient Exploration of Quantified Uncertainty in Granular Crystals

Granular crystals present unique nonlinear properties that support standing waves. These depend on precompression and impurities. Thus, they can be used for different applications such as impact and shock dissipation. There are different models which rely on reasonable approximations and assumptions. While experimental results show good agreement with theory, there are experimental errors that are not easily explained and are usually attributed to the approximations made and phenomena that are not accounted for. This might be the result of not quantifying the uncertainty, since variables like the grain size, position, mass and Young modulus, of each particle, are uncertain. Building a response surface is computationally expensive, because the underlying mapping to be learned is a high dimensional problem. This work presents a way of quantifying uncertainty in granular crystals in a computationally efficient way. To accomplish this, a low dimensional response surface is approximated through the method of active subspaces. Within this framework, special structure within the inputs is exploited to project it onto a lower dimensional manifold. The problem of subspace approximation is then treated as an optimization problem, with the use of the Bayesian Information Criterion (BIC). We treat the underlying function to be learned as a Gaussian Process and use Gaussian process regression to generate predictive distributions for test inputs. Distributions obtained through these methods, present a model for uncertainty propagation and could potentially be used to better understand the experimental errors for different models

Auxin and epigenetic regulation of SKP2B, an F-box that represses lateral root formation

In plants, lateral roots originate from pericycle founder cells that are specified at regular intervals along the main root. Here, we show that Arabidopsis (Arabidopsis thaliana) SKP2B (for S-Phase Kinase-Associated Protein2B), an F-box protein, negatively regulates cell cycle and lateral root formation as it represses meristematic and founder cell divisions. According to its function, SKP2B is expressed in founder cells, lateral root primordia and the root apical meristem. We identified a novel motif in the SKP2B promoter that is required for its specific root expression and auxin-dependent induction in the pericycle cells. Next to a transcriptional control by auxin, SKP2B expression is regulated by histone H3.1/H3.3 deposition in a CAF-dependent manner. The SKP2B promoter and the 59 end of the transcribed region are enriched in H3.3, which is associated with active chromatin states, over H3.1. Furthermore, the SKP2B promoter is also regulated by H3 acetylation in an auxin-and IAA14-dependent manner, reinforcing the idea that epigenetics represents an important regulatory mechanism during lateral root formation

Deviation from bulk in the pressure-temperature phase diagram of V2O3 thin films

We found atypical pressure dependence in the transport measurements of the metal to insulator transition (MIT) in epitaxial thin films of vanadium sesquioxide (V2O3). Three different crystallographic orientations and four thicknesses, ranging from 40 to 500 nm, were examined under hydrostatic pressures (P-h) of up to 1.5 GPa. All of the films at transition exhibited a four order of magnitude resistance change, with transition temperatures ranging from 140 to 165 K, depending on the orientation. This allowed us to build pressure-temperature phase diagrams of several orientations and film thicknesses. Interestingly, for pressures below 500 MPa, all samples deviate from bulk behavior and show a weak transition temperature (T-c) pressure dependence (dT(c)/dP(h) = 1.2 x 10(-2) +/- 0.3 x 10(-2) K/MPa), which recovers to bulklike behavior (3.9 x 10(-2) +/- 0.3 x 10(-2) K/MPa) at higher pressures. Furthermore, we found that pressurization leads to morphological but not structural changes in the films. This indicates that the difference in the thin film and bulk pressure-temperature phase diagrams is most probably due to pressure-induced grain boundary relaxation, as well as both plastic and elastic deformations in the film microstructure. These results highlight the difference between bulk and thin films behaviors

Fault Tolerant Control in a Semi-active Suspension

6 pagesInternational audienceA Fault Tolerant Control System (FTCS) in a Quarter of Vehicle (QoV ) model is proposed. The control law is time-varying using a Linear Parameter-Varying (LPV ) based controller, which includes two scheduling parameters. One parameter for monitoring the nonlinear behavior of the damper, and another for fault accommodation using a reference model obtained by a state observer of the normal operating regime. The QoV model represents a semi-active suspension, including an experimental magneto-rheological damper model. The FTCS is analyzed when the velocity sensor fails abruptly and the QoV model is susceptible to disturbances in the road pro le. Simulation results show the e ectiveness of the FTCS in terms of vehicle comfort, suspension detection and road holding in comparison with a conventional LPV based control system. In the FTCS, the comfort index based on the power spectral density is within the desirable bound (1.8) in all range of frequencies, once the sensor fault has occurred; while, the conventional control system deteriorates the comfort 54 %, specially at low frequencies (0-4 Hz). Additionally, the FTCS improves the road holding and suspension de ection indexes, 33% and 39% respectively, when the fault accommodation is considered

Diet cost and quality using the Healthy Eating Index-2015 in adults from urban and rural areas of Mexico

Objective: To assess the association between diet cost and quality by place of residence. Design: We analysed cross-sectional data of the National Health and Nutrition Survey-2012. Diet cost was estimated by linking dietary data, obtained from a 7-d SFFQ, with municipality food prices, which were derived from a national expenditure survey. Diet quality was assessed using the Healthy Eating Index-2015 (HEI-2015). Association between quintiles of diet cost and HEI-2015 was assessed using linear regression analysis. Settings: Mexico. Participants: 2438 adults (18-59 years). Results: Diet cost was positively associated with diet quality (HEI-2015) in urban but not in rural areas. Compared with quintile (Q1) of cost, the increment in diet quality score was 1 center dot 17 (95 % CI -0 center dot 06, 4 center dot 33) for Q2, 2 center dot 14 (95 % CI -0 center dot 06, 4 center dot 33) for Q3, 4 center dot 70 (95 % CI 2 center dot 62, 6 center dot 79) for Q4 and 6 center dot 34 (95 % CI 4 center dot 20, 8 center dot 49) for Q5 (P-trend < 0 center dot 001). Individuals in rural v. urban areas on average have higher quality diets at lower cost with higher intakes of whole grains and beans and lower intakes of Na, added sugars and saturated fats. Living in the South, being indigenous and having low socio-economic status were also associated with higher quality diets. Conclusions: Diet cost was positively associated with diet quality, but only in urban areas. Further studies are needed to understand the relation between diet cost and quality in rural areas. To improve overall diet quality in Mexico, strategies that aim to reduce the cost of high-quality diets should consider the heterogeneity by place of residence

Effects of oral capsaicinoids and capsinoids supplementation on resistance and high intensity interval training: A systematic review of randomized controlled trials

Oral capsaicinoids and capsinoids supplementation has been studied recently for a plausible ergogenic impact on sports performance. However, non-aggregated literature has focused on the impact of this substances in healthy humans’ performance. The aim of the present systematic review was to explore the effects of capsaicinoids and capsinoids on resistance training (RT) and HIIT exercise. Studies searches were performed in the PubMed/MEDLINE, Scopus and Web of Science electronic databases. Studies where healthy subjects consumed capsaicinoids or capsinoids acutely or chronically compared to placebo before a RT or HIIT intervention were included. The methodological quality of the included studies was assessed with PEDro checklist. A total of 7 excellent-good quality placebo-controlled trials (i.e., 5 RT and 2 HIIT experiments) were included. The most prevalent protocol used capsaicin (i.e., 6 capsacin and 1 capsiate studies) and acute (i.e., 5 of 7 interventions) supplementation designs. Positive effects were only noted for capsaicin in repetitions until failure (+14.4 to +21.7%), total weight lifted (+13.0 to +23.3%), perceived effort (-6.4%), fatigue index (+15.0%) and peak torque (+6.1%) compared to placebo. Neuromuscular HIIT variables (e.g., total and medium sprint time) were not highly affected by capsaicin except the time to reach 90% VO2 peak (+61.2%) and the number of efforts performed (+14.7%). Collectively, our findings suggest a positive effect of 12 mg of capsaicin on strength endurance, total weight lifted and perceived effort variables in healthy males after acute (i.e., 45 minutes pre-exercise) supplementation