The KINETIC phase 2 randomized controlled trial of oral pamapimod-pioglitazone in non-critically ill COVID-19 inpatients.

The combination of pamapimod and pioglitazone (KIN001) has a synergetic antiviral, anti-inflammatory, and antifibrotic activity, which may prevent evolution toward COVID-19-associated severe respiratory failure. In a randomized, placebo-controlled, double-blind, phase 2, multicenter trial, 128 non-critically ill hospitalized patients with confirmed COVID-19 were treated with KIN001 or a placebo for 28 days. The proportion of patients alive and free of oxygen or respiratory support at the end of the therapy was lower than anticipated but not different in the two groups (KIN001 n = 19, 29%, placebo n = 21, 33%).

Ramipril Reduces Acylcarnitines and Distinctly Increases Angiotensin-Converting Enzyme 2 Expression in Lungs of Rats.

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is abundantly expressed in many organs. With respect to the role of circulating ACE2 and its receptor expression in the pathogenesis of the SARS-CoV-2 infection, it is still debated whether diseases such as hypertension or pharmacotherapies, including ACE inhibitors and angiotensin receptor blockers that affect ACE2 receptor expression, may modulate the severity and outcome of the coronavirus disease 2019 (COVID-19). We therefore tested the hypothesis that treatment with the ACE inhibitor Ramipril affects organ-specific ACE2 receptor mRNA and protein expression as well as the serum metabolome in BioBreeding (BB) rats.

A Descriptive analysis of urine drug screen results in patients with opioid use disorder managed in a primary care setting.

Background: Urine drug screening (UDS) is commonly used as part of treatment for opioid use disorder (OUD), including treatment with buprenorphine-naloxone for OUD in a primary care setting. Very little is known about the value of UDS, the optimum screening frequency in general, or its specific use for buprenorphine treatment in primary care. To address this question, we thought that in a stable population receiving buprenorphine-naloxone in the primary care setting it would be useful to know how often UDS yielded expected and unexpected results.

Leptin Receptor Compound Heterozygosity in Humans and Animal Models.

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones.

Effects of Whole-Body Adenylyl Cyclase 5 () Deficiency on Systemic Insulin Sensitivity and Adipose Tissue.

Genome-wide association studies have identified adenylyl cyclase type 5 () as candidate gene for diabetes-related quantitative traits and an increased risk of type 2 diabetes. Mice with a whole-body deletion of do not develop obesity, glucose intolerance and insulin resistance, have improved cardiac function and increased longevity. Here, we investigated knockout mice () to test the hypothesis that changes in adipose tissue (AT) may contribute to the reported healthier phenotype.

The -Cre-Model is Insufficient to Study Function in Adipose Tissue.

Developmental genes are important regulators of fat distribution and adipose tissue (AT) function. In humans, the expression of homeobox c9 () is significantly higher in subcutaneous compared to omental AT and correlates with body fat mass. To gain more mechanistic insights into the role of in AT, we generated -Cre-mediated knockout mice (AT).

A Human REPIN1 Gene Variant: Genetic Risk Factor for the Development of Nonalcoholic Fatty Liver Disease.

Objectives: We tested the hypothesis that a genetic deletion (Del) variant in the REPIN1 gene is associated with the severity of nonalcoholic fatty liver disease (NAFLD) in humans.

Methods: Sixty-three donors of liver biopsies from individuals with obesity and different degrees of NAFLD and fibrosis were screened for a Del REPIN1 gene variant and liver REPIN1 mRNA expression.

Results: In 8 homozygous Del carriers, we found significantly lower NAFLD activity and fibrosis scores compared with 55 wild-type allele carriers.

Metabolic effects of genetic variation in the human REPIN1 gene.

Background: Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue. The Repin1 resides within a quantitative trait locus (QTL) for body weight and triglyceride levels in the rat, and its hepatic deletion in mice results in improved insulin sensitivity and lower body weight. Here, we analyzed whether genetic variation within the Repin1 affects parameters of glucose and lipid metabolism.

Dysprosium electrodeposition from a hexaalkylguanidinium-based ionic liquid.

The rare-earth element dysprosium (Dy) is an important additive that increases the magnetocrystalline anisotropy of neodymium magnets and additionally prevents from demagnetizing at high temperatures. Therefore, it is one of the most important elements for high-tech industries and is mainly used in permanent magnetic applications, for example in electric vehicles, industrial motors and direct-drive wind turbines. In an effort to develop a more efficient electrochemical technique for depositing Dy on Nd-magnets in contrast to commonly used costly physical vapor deposition, we investigated the electrochemical behavior of dysprosium(iii) trifluoromethanesulfonate in a custom-made guanidinium-based room-temperature ionic liquid (RTIL).

Visible-Light-Driven Water Oxidation by a Molecular Manganese Vanadium Oxide Cluster.

Photosynthetic water oxidation in plants occurs at an inorganic calcium manganese oxo cluster, which is known as the oxygen evolving complex (OEC), in photosystem II. Herein, we report a synthetic OEC model based on a molecular manganese vanadium oxide cluster, [Mn4 V4 O17 (OAc)3 ](3-) . The compound is based on a [Mn4 O4 ](6+) cubane core, which catalyzes the homogeneous, visible-light-driven oxidation of water to molecular oxygen and is stabilized by a tripodal [V4 O13 ](6-) polyoxovanadate and three acetate ligands.

Titanium deposition from ionic liquids - appropriate choice of electrolyte and precursor.

In this study titanium isopropoxide was dissolved in 1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide (BMITFSI) and further in a custom-made guanidinium-based ionic liquid (N11N11NpipGuaTFSI). Electrochemical investigations were carried out by means of cyclic voltammetry (CV) and the initial stages of metal deposition were followed by in situ scanning tunneling microscopy (STM). For BMITFSI we found one large cathodic reduction peak at a potential of -1.

The single-chain anti-TNF-α antibody DLX105 induces clinical and biomarker responses upon local administration in patients with chronic plaque-type psoriasis.

It is not clear whether TNF-α antagonists used in the treatment of psoriasis need to act systemically, or whether local inhibition of skin-produced TNF-α would be sufficient to silence skin inflammation. To answer this question, we conducted two multicentre, double-blinded, randomized, placebo-controlled clinical trials with the novel single-chain anti-TNF-α-PENTRA(®) -antibody DLX105. Upon intra-dermal injection, DLX105 induced a mean local PASI decrease of 33% over baseline after 2 weeks of treatment, while the placebo response was only 12% (P = 0.

Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice.

Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to generate inducible conditional transgenic mouse models. Activation of ER signaling plays an important role in the regulation of adipose tissue (AT) metabolism. We therefore tested the hypothesis that tamoxifen administration causes changes in AT biology in vivo.

A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics: a European industry perspective.

There is much debate in the pharmaceutical industry on how to translate the current guidelines on immunogenicity testing for biotherapeutics into a testing strategy that suits the specific requirements of individual drug candidates. In this paper, member companies from the European immunogenicity platform (EIP) present a consensus view on the essential requirements for immunogenicity testing of a biotherapeutic throughout the various phases of drug development, to ensure patient safety and to enable successful market entry. Our aim is to open the debate and provoke discussion on this important topic which is unique to biotherapeutic drug development.

Modified constraint-induced movement therapy versus intensive bimanual training for children with hemiplegia - a randomized controlled trial.

Objective: To clarify whether modified constraint-induced movement therapy provides greater improvement than intensive bimanual training both for motor functions and spontaneous use of the paretic arm and hand in everyday life activities.

Design: Randomized controlled, single-blind trial.

Setting: Inpatient paediatric rehabilitation clinic.

The interfaces of Au(111) and Au(100) in a hexaalkyl-substituted guanidinium ionic liquid: an electrochemical and in situ STM study.

Five hexaalkylguanidinium-based ionic liquids have been synthesised, and based on their cyclic voltammograms the most suited one, N,N-dibutyl-N',N'-diethyl-N'',N''-dimethylguanidinium bis(trifluoromethylsulfonyl)imide, has been chosen for electrochemical studies. The surface interaction of this room-temperature ionic liquid with single crystalline gold surfaces (Au(100) and Au(111)) has been investigated using cyclic voltammetry, impedance spectroscopy and in situ scanning tunnelling microscopy (STM). The interfacial capacitance was found to be very low; STM measurements revealed the hex-reconstruction and herringbone reconstruction for Au(100) and for Au(111), respectively, at negative potentials; that is, at these potentials no hints for ad-structures of the cation could be found.

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.

Objective: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease.

Design: In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6.

Musical brains: a study of spontaneous and evoked musical sensations without external auditory stimuli.

Conclusions: Our observations confirm that musical sensations with no external stimuli, either spontaneous or evoked, occur in normal individuals and that a biological substrate can be demonstrated by brain single photon emission computed tomography (SPECT).

Objectives: There are individuals, usually musicians, who are seemingly able to evoke and/or have spontaneous musical sensations without external auditory stimuli. However, to date there is no available evidence to determine if it is feasible to have musical sensations without using external sensory receptors, or if there is a biological substrate for these sensations.

[KTP laser coagulation for xanthelasma palpebrarum].

Background: Xanthelasma palpebrarum is a benign skin disorder of unknown etiology appearing as one or multiple yellowish plaques around the eyelids. Hyperlipidemia, thyroid dysfunction, and diabetes mellitus are possible pathogenetic triggers. Removal of xanthelasma is desired for aesthetic reasons.

The human platelet membrane proteome reveals several new potential membrane proteins.

We present the first focused proteome study on human platelet membranes. Due to the removal of highly abundant cytoskeletal proteins a wide spectrum of known platelet membrane proteins and several new and hypothetical proteins were accessible. In contrast to other proteome studies we focused on prefractionation and purification of membranes from human platelets according to published protocols to reduce sample complexity and enrich interesting membrane proteins.

Design of selective peptidomimetic agonists for the human orphan receptor BRS-3.

New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay.

Identification and functional characterization of hemorphins VV-H-7 and LVV-H-7 as low-affinity agonists for the orphan bombesin receptor subtype 3.

1. The human orphan G-protein coupled receptor bombesin receptor subtype 3 (hBRS-3) was screened for peptide ligands by a Ca(2+)mobilization assay resulting in the purification and identification of two specific ligands, the naturally occurring VV-hemorphin-7 (VV-H-7) and LVV-hemorphin-7 (LVV-H-7), from human placental tissue. These peptides were functionally characterized as full agonists with unique specificity albeit low affinity for hBRS-3 compared to other bombesin receptors.

Systematic optimization of a lead-structure identities for a selective short peptide agonist for the human orphan receptor BRS-3.

The orphan receptor, human bombesin receptor subtype 3 (BRS-3) was assigned to the G-protein coupled bombesin receptor family because of its high sequence homology with the neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R). Since its pharmacology is stiIl unknown, new highly potent and selective tool-substances are needed, that may be able to elucidate its possible role in obesity and cancer. We have performed structure activity relationship studies on the high affinity peptide agonists [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, using their ability to mobilize intracellular calcium in BRS-3 transfected CHOGa-16 cells combined with receptor binding studies.

A novel gene encoding a putative transmembrane protein with two extracellular CUB domains and a low-density lipoprotein class A module: isolation of alternatively spliced isoforms in retina and brain.

We report herein the cDNA cloning of a novel retina and brain specific gene from mouse and human encoding a putative transmembrane protein with an N-terminal signal sequence and two conserved extracellular CUB domains followed by a single copy of the low-density lipoprotein class A (LDLa) module. The mouse and human genes, termed NETO1 (neuropilin and tolloid like-1), display sequence identities of 87% at the nucleotide and 95% at the protein level. The human NETO1 gene comprises 13 exons on chromosome 18q22-q23 and gives rise to three different mRNA isoforms.