A separable non-remainder of

We prove that there is a compact separable continuum that (consistently) is not a remainder of the real line.

     

Pro-Inflammatory Interactions of Dolutegravir with Human Neutrophils in an In Vitro Study

There is increasing awareness of an association between the uptake of the HIV integrase inhibitor, dolutegravir, in first-line antiretroviral regimens with unusual weight gain and development of the metabolic syndrome, particularly in African women. Although seemingly unexplored, the development of systemic inflammation linked to the putative pro-inflammatory activity of dolutegravir represents a plausible pathophysiological mechanism of this unusual weight gain. This possibility was explored in the current study undertaken to investigate the effects of dolutegravir (2.5–20 μg/mL) on several pro-inflammatory activities of neutrophils isolated from the blood of healthy, adult humans. These activities included the generation of reactive oxygen species (ROS), degranulation (elastase release) and alterations in the concentrations of cytosolic Ca²⁺ using chemiluminescence, spectrophotometric and fluorimetric procedures, respectively. Exposure of neutrophils to dolutegravir alone resulted in the abrupt, dose-related, and significant (p < 0.0039–p < 0.0022) generation of ROS that was attenuated by the inclusion of the Ca²⁺-chelating agent, EGTA, or inhibitors of NADPH oxidase (diphenyleneiodonium chloride, DPI), phospholipase C (U733122), myeloperoxidase (sodium azide) and phosphoinositol-3-kinase (wortmannin). In addition, exposure to dolutegravir augmented the release of elastase by stimulus-activated neutrophils. These pro-inflammatory effects of dolutegravir on neutrophils were associated with significant, rapid, and sustained increases in the concentrations of cytosolic Ca²⁺ that appeared to originate from the extracellular compartment, seemingly consistent with an ionophore-like property of dolutegravir. These findings are preliminary and necessitate verification in the clinical setting of HIV infection. Nevertheless, given the complex link between inflammation and obesity, these pro-inflammatory interactions of dolutegravir with neutrophils may contribute to unexplained weight gain, possibly via the development of insulin resistance.     

Optimal vehicle suspension characteristics for increased structural fatigue life

Heavy off-road vehicle suspension systems face unique challenges. The ride comfort versus handling compromise in these vehicles has been frequently investigated using mathematical optimisation. Further challenges exist due to the large variations in vehicle sprung mass. A passive suspension system can only provide optimal isolation at a single payload. The designer of such a suspension system must therefore make a compromise between designing for a fully-laden or unladen payload state. This work deals with suspension optimisation for vehicle structural life. The paper mainly addresses two questions: (1) What are the suspension characteristics required to ensure optimal isolation of the vehicle structure from road loads? and (2) If such optimal suspension characteristics can be found, how sensitive are they to changes in vehicle payload? The study aims to answer these questions by examining a Land Rover Defender 110 as test vehicle. An experimentally validated non-linear seven degree-of-freedom mathematical model of the test vehicle is constructed for the use in sensitivity studies. Mathematical optimisation is performed using the model in order to find the suspension characteristics for optimal structural life for the vehicle under consideration. Sensitivity studies are conducted to determine the robustness of the optimal characteristics and their sensitivity to vehicle payload variation. Recommendations are made for suspension characteristic selection for optimal structural life.     

Exact results for noise power spectra in linear biochemical reaction networks

We present a simple method for determining the exact noise power spectra and related statistical properties for linear chemical reaction networks. The method is applied to reaction networks which are representative of biochemical processes such as gene expression. We find, for example, that a post-translational modification reaction can reduce the noise associated with gene expression. Our results also indicate how to coarse grain networks by the elimination of fast reactions. In this context we have discovered a breakdown of the sum rule which relates the noise power spectrum to the total noise. The breakdown can be quantified by a sum rule deficit, which is found to be universal, and can be attributed to the high-frequency noise in the fast reactions.     

Short synthesis of functionalized pentalongin derivatives using pyridinium ylid chemistry

3-Substituted pentalongin derivatives possessing an acetal function at C-1 were synthesized by cyclization of acylmethylnaphthoquinones. The latter naphthoquinones were prepared starting from 2-dioxolanylnaphthoquinone by means of both a stoichiometric and a catalytic method deploying various pyridinium ylids.     

A new subcontinuum of

We present a method for describing all indecomposable subcontinua of . This method enables us to construct in a new subcontinuum of .

We also show that the nontrivial layers of standard subcontinua can be described by our method. This allows us to construct a layer with a proper dense -subset and bring the number of (known) nonhomeomorphic subcontinua of to 14.

     

ω* has (almost) no continuous images

We prove that the following statement follows from the Open Colouring Axiom (OCA): ifX is locally compactσ-compact but not compact and if its Čech-Stone remainderX* is a continuous image ofω*, thenX is the union ofω and a compact set. It follows that the remainders of familiar spaces like the real line or the sum of countably many Cantor sets need not be continuous images ofω*.     

In Vitro Evaluation of the Squaramide-Conjugated Fibroblast Activation Protein Inhibitor-Based Agents AAZTA5.SA.FAPi and DOTA.SA.FAPi

Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA^5m.SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [⁶⁸Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA⁵ chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA⁵.SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of the complexes were characterized and compared with those of DOTA.SA.FAPi. AAZTA⁵.SA.FAPi and its derivatives labelled with non-radioactive isotopes demonstrated similar excellent inhibitory potencies compared to the previously published SA.FAPi ligands, i.e., sub-nanomolar IC₅₀ values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA⁵.SA.FAPi compared to the corresponding DOTA analogue at ambient temperature. Especially, scandium-44 labeling with the AAZTA derivative resulted in higher specific activities. Both DOTA.SA.FAPi and AAZTA⁵.SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP.