Platelet inventory management with demand and supply uncertainty and variable pricing considerations.

Managing the inventory of blood is a crucial operation in hospitals owing to its significance in medical treatment. At the same time, blood is characterized by unique attributes, such as perishability and the unpredictable nature of its supply and demand. While models have been developed to optimize the said process, gaps in literature exist in terms of considering the possibility of variable pricing and extensively accounting for uncertainties in the supply chain. In this light, the present study proposes a stochastic multi-period mixed integer linear programming cost minimization model that determines the optimal inventory plan for a hospital purchasing platelets, assuming that prices fluctuate along with the blood center's supply. To implement uncertain supply and demand, the model considers a discrete set of scenarios for each parameter. A study was performed, and the results indicate a promising direction as inventory costs decreased relative to models without the new considerations.

CTL Clonotypes with Higher TCR Affinity Have Better Ability to Reduce the HIV Latent Reservoir.

The success of the shock and kill strategy for the HIV cure depends both on the reactivation of the latent reservoir and on the ability of the immune system to eliminate infected cells. As latency reversal alone has not shown any impact in the size of the latent reservoir, ensuring that effector CTLs are able to recognize and kill HIV-infected cells could contribute to reservoir reduction. In this study, we investigated which functional aspects of human CTLs are associated with a better capacity to kill HIV-infected CD4+ T cells. We isolated Gag- and Nef-specific CTL clones with different TCR sequences from the PBMC of donors in acute and chronic infection. High-affinity clonotypes that showed IFN-γ production preserved even when the CD8 coreceptor was blocked, and clones with high Ag sensitivity exhibited higher efficiency at reducing the latent reservoir. Although intrinsic cytotoxic capacity did not differ according to TCR affinity, clonotypes with high TCR affinity showed a better ability to kill HIV-infected CD4+ T cells obtained from in vivo-infected PBMC and subjected to viral reactivation. Strategies aiming to specifically boost and maintain long-living memory CTLs with high TCR affinity in vivo prior to latency-reversing treatment might improve the efficacy of the shock and kill approach to reduce the latent reservoir.

Modeling HIV-1 Latency Using Primary CD4+ T Cells from Virally Suppressed HIV-1-Infected Individuals on Antiretroviral Therapy.

The low frequency of latently HIV-infected cells in vivo limits the testing of potential HIV cure strategies using cells from successfully suppressed individuals. To date, primary cell models of latency use cells infected in vitro Primary CD4+ T cell models carrying an individual's endogenous HIV reservoir that recapitulate in vivo conditions of HIV latency are still outstanding. We developed a primary CD4+ T cell model of HIV latency derived from memory CD4+ T cells isolated from virally suppressed HIV-infected individuals that recapitulates HIV-1 latency and viral reactivation events. This model is based on the expansion of primary CD4+ T cells up to 300-fold in cell number. These cells reestablish a resting state without active virus production after extended culture and maintain a stable number of total HIV proviruses. The ability of these cells to respond to various classes of latency-reversing agents is similar to that of ex vivo CD4+ T cells directly isolated from blood. Importantly, viral outgrowth assays confirmed the ability of these expanded cells to produce replication-competent endogenous virus. In sum, this model recapitulates ex vivo viral reactivation conditions, captures the variability between individuals with different HIV reservoirs, and provides large numbers of cells for testing multiple agents from a single donor. The use of this novel model will allow accurate exploration of novel cure approaches aimed either at promoting viral reactivation or maintaining sustained latency.IMPORTANCE Primary cell models of HIV latency have been very useful to identify mechanisms contributing to HIV latency and to evaluate potential HIV cure strategies. However, the current models utilize in vitro infection with exogenous virus that does not fully recapitulate virus reactivation profiles of endogenous HIV in in vivo-infected CD4+ T cells. In contrast, obtaining sufficient amounts of CD4+ T cells from HIV-infected individuals to interrogate the HIV reservoir in vitro requires leukapheresis. In the model we propose here, in vitro expansion and extended culture of primary CD4+ T cells isolated from virally suppressed HIV-infected individuals enable obtaining large numbers of cells harboring endogenous latent HIV reservoirs without performing leukapheresis. This model captures the variability of HIV reservoirs seeded in different individuals and should be useful to evaluate future HIV cure strategies.

Using Constrained-INC for Large-Scale Gene Tree and Species Tree Estimation.

Incremental tree building (INC) is a new phylogeny estimation method that has been proven to be absolute fast converging under standard sequence evolution models. A variant of INC, called Constrained-INC, is designed for use in divide-and-conquer pipelines for phylogeny estimation where a set of species is divided into disjoint subsets, trees are computed on the subsets using a selected base method, and then the subset trees are combined together. We evaluate the accuracy of INC and Constrained-INC for gene tree and species tree estimation on simulated datasets, and compare it to similar pipelines using NJMerge (another method that merges disjoint trees). For gene tree estimation, we find that INC has very poor accuracy in comparison to standard methods, and even Constrained-INC(using maximum likelihood methods to compute constraint trees) does not match the accuracy of the better maximum likelihood methods. Results for species trees are somewhat different, with Constrained-INC coming close to the accuracy of the best species tree estimation methods, while being much faster; furthermore, using Constrained-INC allows species tree estimation methods to scale to large datasets within limited computational resources. Overall, this study exposes the benefits and limitations of divide-and-conquer strategies for large-scale phylogenetic tree estimation.