Synthesis and Cellular Labeling of Caged Phosphatidylinositol Derivatives

Phosphatidylinositol (PI) is the biosynthetic precursor for seven phosphoinositides, important signaling lipids in cells. A membrane-permeant caged PI derivative featuring a photo-removable coumarinyl group masking the negative charge of the phosphate, as well as two enzymatically removable butyrate esters for increased lipophilicity and for preventing phosphate migration, were synthesized. Rapid cell entry and cellular labeling in fixed cells was demonstrated by a photo-cross-linkable diazirine followed by attachment of a fluorophore through click chemistry. Using this technique, we found that the multifunctional caged PI derivative resided predominantly at internal membranes but rapidly changed to the plasma membrane after uncaging. Accordingly, a preliminary proteomic analysis of the lipid–protein conjugates revealed that the two major PI transport proteins PITPα and β were prime targets of the photo-cross-linked PI derivative.     

DMT1 Inhibitors Kill Cancer Stem Cells by Blocking Lysosomal Iron Translocation

Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.     

Interpolation of nonlinear positive or order preserving operators on Banach lattices

Positivity - We study the relationship between exact interpolation spaces for positive, linear operators, for order preserving, Lipschitz continuous operators, and for positive...     

Crystalline Nitridophosphates by Ammonothermal Synthesis

Nitridophosphates are a well-studied class of compounds with high structural diversity. However, their synthesis is quite challenging, particularly due to the limited thermal stability of starting materials like P₃N₅. Typically, it requires even high-pressure techniques (e.g. multianvil) in most cases. Herein, we establish the ammonothermal method as a versatile synthetic tool to access nitridophosphates with different degrees of condensation. α-Li₁₀P₄N₁₀, β-Li₁₀P₄N₁₀, Li₁₈P₆N₁₆, Ca₂PN₃, SrP₈N₁₄, and LiPN₂ were synthesized in supercritical NH₃ at temperatures and pressures up to 1070 K and 200 MPa employing ammonobasic conditions. The products were analyzed by powder X-ray diffraction, energy dispersive X-ray spectroscopy, and FTIR spectroscopy. Moreover, we established red phosphorus as a starting material for nitridophosphate synthesis instead of commonly used and not readily available precursors, such as P₃N₅. This opens a promising preparative access to the emerging compound class of nitridophosphates.     

Theory of ion neutralisation scattering from surfaces

A method for the calculation of the probability of neutralisation of an ion, which is scattered from the surface of a solid is presented. It assumes the ion to move along a classical trajectory and solves for the time evolution operator for the electronic system. For one electron Hamiltonians the solution can be carried out exactly. Results are presented for scattering from a semi-infinite linear chain.     

A Particle-Mesh Method for the Shallow Water Equations Near Geostrophic Balance

In this paper we outline a new particle-mesh method for rapidly rotating shallow water flows based on a set of regularized equations of motion. The time-stepping method uses an operator splitting of the equations into an Eulerian gravity wave part and a Lagrangian advection part. An essential ingredient is the advection of absolute vorticity by means of translated radial basis functions. We show that this implies exact conservation of enstrophy. The method is tested on two model problems based on the qualitative features of the solutions obtained (i.e., dispersion or smoothness of potential vorticity contours) as well as on the increase in mean divergence level.     

The fixed points of the multivariate smoothing transform

Let \((\mathbf {T}_1, \mathbf {T}_2, \ldots )\) be a sequence of random \(d\times d\) matrices with nonnegative entries, and let Q be a random vector with nonnegative entries. Consider random vectors \(X\) with nonnegative entries, satisfying

$$\begin{aligned} X\mathop {=}\limits ^{{\mathcal {L}}}\sum _{i \ge 1} \mathbf {T}_i X_i + Q, \end{aligned}$$

(*)

where \(\mathop {=}\limits ^{{\mathcal {L}}}\) denotes equality of the corresponding laws, \((X_i)_{i \ge 1}\) are i.i.d. copies of \(X\) and independent of \((Q, \mathbf {T}_1, \mathbf {T}_2, \ldots )\). For \(d=1\), this equation, known as fixed point equation of the smoothing transform, has been intensively studied. Under assumptions similar to the one-dimensional case, we obtain a complete characterization of all solutions \(X\) to (*) in the non-critical case, and existence results in the critical case.

     

Scheduling products with subassemblies and changeover time

We revisit the problem, previously studied by Coffman et al, of scheduling products with two subassemblies on a common resource, where changeovers consume time, under the objective of flow-time minimization. We derive some previously unidentified structural properties that could be important to researchers working on similar batch scheduling problems. We show that there exists a series of base schedules from which optimal schedules can be easily derived. As these base schedules build on each other, they are easy to construct as well. We also show that the structure of these base schedules is such that batch sizes decrease over time in a well-defined manner. These insights about the general form of the schedules might also be important to practitioners wanting some intuition about the schedule structure that they are implementing.     

Combinatorial integral approximation

We are interested in structures and efficient methods for mixed-integer nonlinear programs (MINLP) that arise from a first discretize, then optimize approach to time-dependent mixed-integer optimal control problems (MIOCPs). In this study we focus on combinatorial constraints, in particular on restrictions on the number of switches on a fixed time grid. We propose a novel approach that is based on a decomposition of the MINLP into a NLP and a MILP. We discuss the relation of the MILP solution to the MINLP solution and formulate bounds for the gap between the two, depending on Lipschitz constants and the control discretization grid size. The MILP solution can also be used for an efficient initialization of the MINLP solution process. The speedup of the solution of the MILP compared to the MINLP solution is considerable already for general purpose MILP solvers. We analyze the structure of the MILP that takes switching constraints into account and propose a tailored Branch and Bound strategy that outperforms cplex on a numerical case study and hence further improves efficiency of our novel method.