Non-targeted LC-MS based metabolomics analysis of the urinary steroidal profile

The urinary steroidal fraction has been extensively explored as non-invasive alternative to monitor pathological conditions as well as to unveil the illicit intake of pseudo-endogenous anabolic steroids in sport. However, the majority of previous approaches involved the a priori selection of potentially relevant target analytes. Here we describe the non-targeted analysis of the urinary steroidal profiles. The workflow includes minimal sample pretreatment and normalization according to the specific gravity of urine, a 20 min reverse phase ultra-performance liquid chromatographic separation hyphenated to electrospray time-of-flight mass spectrometry. As initial validation, we analyzed a set of quality control urines spiked with glucurono- and sulfo-conjugated steroids at physiological ranges. We then applied the method for the analysis of samples collected after single transdermal administration of testosterone in hypogonadal men. The method allowed profiling of approximately three thousand metabolic features, including steroids of clinical and forensic relevance. It successfully identified metabolic pathways mostly responsible for groups clustering even in the context of high inter-individual variability and allowed the detection of currently unknown metabolic features correlating with testosterone administration. These outcomes set the stage for future studies aimed at implementing currently monitored urinary steroidal markers both in clinical and forensic analysis

Targeted Capture

This Article confronts one of the most difficult and contested questions in the debate about targeted killing that has raged in academic and policy circles over the last decade. Suppose that, in wartime, the target of a military strike may readily be neutralized through nonlethal means such as capture. Do the attacking forces have an obligation to pursue that nonlethal alternative? The Article defends the duty to employ less restrictive means (“LRM”) in wartime, and it advances several novel arguments in defense of that obligation. In contrast to those who look to external restraints--such as those imposed by international human rights law, U.S. constitutional law, or, indeed, the laws of war themselves--to check the operation of military necessity, I argue that the most plausible LRM obligation exists as a limitation embedded within the necessity principle itself. Indeed, the principle of military necessity supports not one, but two, related LRM restraints. The first restraint--virtually ignored yet highly relevant to contemporary debates--is a right reason requirement: it prohibits the killing of combatants for reasons unrelated to the pursuit of military advantage. Specifically, the necessity principle does not permit a preference for lethal force over capture when that preference is driven by considerations such as retributive justice, a desire to avoid due process obligations relating to capture and trial, raising morale, and diplomatic sensitivities. The second restraint--more familiar to the debate yet still deserving of further exploration--is objective in nature. It demands that lethal force benefit from a cognizable expectation of military advantage. The Article develops and defends these claims, engages both contrary and complementary viewpoints, and anticipates objections

Targeted Undersmoothing

This paper proposes a post-model selection inference procedure, called targeted undersmoothing, designed to construct uniformly valid confidence sets for a broad class of functionals of sparse high-dimensional statistical models. These include dense functionals, which may potentially depend on all elements of an unknown high-dimensional parameter. The proposed confidence sets are based on an initially selected model and two additionally selected models, an upper model and a lower model, which enlarge the initially selected model. We illustrate application of the procedure in two empirical examples. The first example considers estimation of heterogeneous treatment effects using data from the Job Training Partnership Act of 1982, and the second example looks at estimating profitability from a mailing strategy based on estimated heterogeneous treatment effects in a direct mail marketing campaign. We also provide evidence on the finite sample performance of the proposed targeted undersmoothing procedure through a series of simulation experiments

A Targeted Existence

Over the summer, I visited a friend from Gettysburg who was having a party. The party was fun for the first half, and I was having a good time, so I decided to stay the night instead of walk in the dark to the bus. This is what parents and educators and older sisters and women everywhere had taught me: stay with people you know; clutch your keys in your hand; don’t walk alone. I was staying with my friend from school; I was safe. [excerpt

Targeted matrix completion

Matrix completion is a problem that arises in many data-analysis settings where the input consists of a partially-observed matrix (e.g., recommender systems, traffic matrix analysis etc.). Classical approaches to matrix completion assume that the input partially-observed matrix is low rank. The success of these methods depends on the number of observed entries and the rank of the matrix; the larger the rank, the more entries need to be observed in order to accurately complete the matrix. In this paper, we deal with matrices that are not necessarily low rank themselves, but rather they contain low-rank submatrices. We propose Targeted, which is a general framework for completing such matrices. In this framework, we first extract the low-rank submatrices and then apply a matrix-completion algorithm to these low-rank submatrices as well as the remainder matrix separately. Although for the completion itself we use state-of-the-art completion methods, our results demonstrate that Targeted achieves significantly smaller reconstruction errors than other classical matrix-completion methods. One of the key technical contributions of the paper lies in the identification of the low-rank submatrices from the input partially-observed matrices.Comment: Proceedings of the 2017 SIAM International Conference on Data Mining (SDM

Targeted free energy perturbation

A generalization of the free energy perturbation identity is derived, and a computational strategy based on this result is presented. A simple example illustrates the efficiency gains that can be achieved with this method.Comment: 8 pages + 1 color figur

Immunogenicity of targeted lentivectors

To increase the safety and possibly efficacy of HIV-1 derived lentivectors (LVs) as an anti-cancer vaccine, we recently developed the Nanobody (Nb) display technology to target LVs to antigen presenting cells (APCs). In this study, we extend these data with exclusive targeting of LVs to conventional dendritic cells (DCs), which are believed to be the main cross-presenting APCs for the induction of a TH1-conducted antitumor immune response. The immunogenicity of these DC-subtype targeted LVs was compared to that of broad tropism, general APC-targeted and non-infectious LVs. Intranodal immunization with ovalbumin encoding LVs induced proliferation of antigen specific CD4(+) T cells, irrespective of the LVs' targeting ability. However, the cytokine secretion profile of the restimulated CD4(+) T cells demonstrated that general APC targeting induced a similar TH1-profile as the broad tropism LVs while transduction of conventional DCs alone induced a similar and less potent TH1 profile as the non-infectious LVs. This observation contradicts the hypothesis that conventional DCs are the most important APCs and suggests that the activation of other APCs is also meaningful. Despite these differences, all targeted LVs were able to stimulate cytotoxic T lymphocytes, be it to a lesser extent than broad tropism LVs. Furthermore this induction was shown to be dependent on type I interferon for the targeted and non-infectious LVs, but not for broad tropism LVs. Finally we demonstrated that the APC-targeted LVs were as potent in therapy as broad tropism LVs and as such deliver on their promise as safer and efficacious LV-based vaccines