Multi-scale mechanistic modelling of the host defence in invasive aspergillosis reveals leucocyte activation and iron acquisition as drivers of infection outcome

Aspergillus species are ubiquitous environmental moulds, with spores inhaled daily by most humans. Immunocompromised hosts can develop an invasive infection resulting in high mortality. There is, therefore, a pressing need for host-centric therapeutics for this infection. To address it, we created a multi-scale computational model of the infection, focused on its interaction with the innate immune system and iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the siderophore secretion rate seems to be an essential prerequisite for the establishment of the infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability and impaired leucocyte activation lead to a high conidial germination rate. Similarly, in neutropenic hosts, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leucocyte activation and high siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth, iron acquisition and leucocyte activation as critical determinants of the fate of the infection.     

亚利桑那州立大学沃尔特·克朗凯特新闻与大众传播学院

为了振兴凤凰城市中心,亚利桑那州为亚利桑那州立大学的一个新建项目举办了几次跨越"毕业领奖台"的优秀设计.楼高6层,20,903m<'2>(295,000平方英尺)的沃尔特·克朗凯特新闻与大众传播学院建筑是其中快速设计、各方协力实施的典范.该建筑由建筑师Ehrlich、HDR建筑公司和和总承包商SUNDT建设公司通力合作,创造了在二十二个月内完成设计并交付使用的记录.     

Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies

The goal of this study was to investigate the functional organization of the subpallidal-->accumbens direct and indirect feedback loops by both anatomical and electrophysiological methods. The results of the dextran-conjugated rhodamine injections into the subpallidal area has shown three distinct projections: (1) a substantial pathway from the subpallidal area to the ventral tegmental area, (2) a more diffuse rostral projection from the subpallidal area to the core area of the nucleus accumbens, and (3) a sparse pathway projecting rostrodorsally from the subpallidal area toward the thalamic regions. Electrical or chemical stimulation of the subpallidal region, which was studied by the axonal tracer, evoked inhibitory responses in the majority (60 and 80%, respectively) of the accumbens and ventral tegmental area neurons in a standard extracellular recording study. Less than 1/3 of the accumbens or ventral tegmental area cells showed an increase in the mean firing rate. The majority (77.5%) of all responded neurons had a latency of less than 10 ms. Furthermore, injection of glutamate into the subpallidal area not only altered the firing pattern of the accumbens neurons, but also attenuated their excitatory responses elicited by the electrical stimulation of the ventral subiculum. Our results indicate that the subpallidal area plays a predominantly inhibitory role in the ventral tegmental area-accumbens-subpallidal circuitry, presumably by its GABAergic projections, and may also modulate subicular input into the nucleus accumbens.     

Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections

Members of the semaphorin family have been implicated in mediating axonal guidance in the nervous system by their ability to collapse growth cones and to function as chemorepellents. The present findings show that recombinant Semaphorin D has similar effects on cortical axons and, in addition, inhibits axonal branching. In contrast, semaphorin E acts as an attractive guidance signal for cortical axons. Attractive effects were only observed when growth cones encountered increasing concentrations or a patterned distribution of Semaphorin E, but not when they are exposed to uniform concentrations of this molecule. Specific binding sites for Semaphorin D and Semaphorin E were present on cortical fibers both in vitro and in vivo at the time when corticofugal projections are established. In situ hybridization analysis revealed that the population of cortical neurons used in our experiments express neuropilin-1 and neuropilin-2, which are essential components of receptors for the class III semaphorins. Moreover, semD mRNA was detected in the ventricular zone of the neocortex whereas semE mRNA was restricted to the subventricular zone. Taken together, these results indicate that semaphorins are bifunctional molecules whose effects depend on their spatial distribution. The coordinated expression of different semaphorins, together with their specific activities on cortical axons, suggests that multiple guidance signals contribute to the formation of precise corticofugal pathways.     

Dimer acid structures: Cyclic structures of clay catalyzed dimers of normal linoleic acid, 9-cis, 12-cis-Octadecadienoic acid

The clay catalyzed dimer of linoleic acid has been examined by mass spectrometry of the unhydrogenated, the partially hydrogenated and completely hydrogenated dimer. The results show that monocyclic, bicyclic and tricyclic structures are present. Monocyclic structures predominate, bicyclic structures are also prominent, and tricyclic structures are relatively minor. The monocyclic structure is believed to arise from a Diels-Alder type addition reaction. The bicyclic structure may result from a free radical coupling followed by intramolecular ring closure. The monocyclic structure in the unhydrogenated dimer appears to be mostly a benzene ring with saturated and unsaturated side-chains. It probably is formed by hydrogen transfer from the Diels-Alder cyclohexene structure first formed. Little, if any, of the Diels-Alder dimer structure as such is present. The catalytic linoleate dimer has a higher ratio of monocyclic to bicyclic dimer than does the noncatalytic (thermal) dimer made from normal (nonconjugated) linoleate, while the thermal dimer of a conjugatedtrans-trans linoleate is exclusively monocyclic. It is suggested that the clay catalyzes conjugation and hence favors the Diels-Alder reaction, and then catalyzes hydrogen transfer to aromatize the cyclohexene ring.     

RELATION OF COEFFICIENT OF EXPANSION TO IMPACT RESISTANCE OF PORCELAIN ENAMELS*

The tentative standard impact test procedure, adopted by the Porcelain Enamel Institute, was used to test and compare cylinders coated with several experimental and commercial enamels. The important facts noted were (1) the effect of cubic thermal expansion on the impact resistance, (2) the importance of the ground coat to the resistance of any one cover enamel, and (3) the wide variation between cover enamels in resistance to impact.     

A DYNAMIC,ADAPTIVE, LOCALLY CONSERVATIVE,AND NONCONFORMING SOLUTION STRATEGY FOR TRANSPORT PHENOMENA IN CHEMICAL ENGINEERING

A family of discontinuous Galerkin (DG) methods are formulated and applied to chemical engineering problems. They are the four primal discontinuous Galerkin schemes for space discretization: symmetric interior penalty Galerkin, Oden-Babu?ka-Baumann DG formulation, nonsymmetric interior penalty Galerkin, and incomplete interior penalty Galerkin. Numerical examples of DG to solve typical chemical engineering problems, including a diffusion-convection-reaction system in a catalytic particle, a problem of heat transfer in a fixed bed, and flow and contaminant transport simulations in porous media, are presented. This article highlights the substantial advantages of DG on adaptive mesh modification over traditional methods. In particular, we propose and investigate the dynamic mesh modification strategy for DG guided by mathematically sound a posteriori error estimators.     

ON THE MOMENT COEFFICIENT CALCULATION OF A ROTATING DISK IN A TURBULENT FLUID FLOW

Mixing in co-rotating sinusoidal cavity flows is studied with period, T, and phase shift, a, as parameters. Notice that the main obstacle to uniform mixing is the existence of stable :ower periodic orbits, mixing windows, where uniform mixing takes place, are found in the T— a space u:iing bifurcation analysis. The main advantage of this method is a great saving of the computation time.     

Soil nutrient maps of Sub-Saharan Africa: assessment of soil nutrient content at 250 m spatial resolution using machine learning

Spatial predictions of soil macro and micro-nutrient content across Sub-Saharan Africa at 250 m spatial resolution and for 0–30 cm depth interval are presented. Predictions were produced for 15 target nutrients: organic carbon (C) and total (organic) nitrogen (N), total phosphorus (P), and extractable—phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg), sulfur (S), sodium (Na), iron (Fe), manganese (Mn), zinc (Zn), copper (Cu), aluminum (Al) and boron (B). Model training was performed using soil samples from ca. 59,000 locations (a compilation of soil samples from the AfSIS, EthioSIS, One Acre Fund, VitalSigns and legacy soil data) and an extensive stack of remote sensing covariates in addition to landform, lithologic and land cover maps. An ensemble model was then created for each nutrient from two machine learning algorithms—random forest and gradient boosting, as implemented in R packages ranger and xgboost—and then used to generate predictions in a fully-optimized computing system. Cross-validation revealed that apart from S, P and B, significant models can be produced for most targeted nutrients (R-square between 40–85%). Further comparison with OFRA field trial database shows that soil nutrients are indeed critical for agricultural development, with Mn, Zn, Al, B and Na, appearing as the most important nutrients for predicting crop yield. A limiting factor for mapping nutrients using the existing point data in Africa appears to be (1) the high spatial clustering of sampling locations, and (2) missing more detailed parent material/geological maps. Logical steps towards improving prediction accuracies include: further collection of input (training) point samples, further harmonization of measurement methods, addition of more detailed covariates specific to Africa, and implementation of a full spatio-temporal statistical modeling framework.