Modelling hemodynamics regulation in rats and dogs to facilitate drugs safety risk assessment.

Pharmaceutical companies routinely screen compounds for hemodynamics related safety risk. secondary pharmacology is initially used to prioritize compounds while studies are later used to quantify and translate risk to humans. This strategy has shown limitations but could be improved via the incorporation of molecular findings in the animal-based toxicological risk assessment.

Hydrophobic ion pairing as a novel approach to co-axial electrospraying of peptide-PLGA particles.

Electrospraying is a processing technique that has gained much interest to prepare polymeric particles. The technique operates at ambient temperature, thereby avoiding heat induced degradation of labile therapeutics (e.g.

A lipid-based delivery platform for thermo-responsive delivery of teriparatide.

Teriparatide (and analogue peptides) are the only FDA approved anabolic treatments for osteoporosis. Current therapies are administered as a daily subcutaneous injection, which limits patient adherence and clinical efficacy. To achieve the desired anabolic effect, a controlled delivery system must ensure a pulsatile release profile over a prolonged period.

Structural insights into i-motif DNA structures in sequences from the insulin-linked polymorphic region.

The insulin-linked polymorphic region is a variable number of tandem repeats region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of tandem repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression.

The WD Domain of Crucial for LC3-Associated Phagocytosis Is Not Required for Preserving Skin Barrier Function in Mice.

The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as a safeguard against extrinsic factors. Autophagy has been implicated in epidermal differentiation and in preserving skin homeostasis. LC3-associated phagocytosis (LAP) uses some but not all components of autophagy.

Circadian misalignment increases 24-hour acylated ghrelin in chronic shift workers: a randomized crossover trial.

Objective: Shift workers typically experience misalignment between their circadian system and behavioral/environmental cycles and have an increased risk for obesity. Experimental studies in non-shift workers have suggested that circadian misalignment can disrupt energy balance regulation. This study examined the impact of circadian misalignment in the most relevant population, i.

Using a multi-omic approach to investigate the mechanism of 12-bis-THA activity against .

is the causative agent of the tropical disease, melioidosis. It is intrinsically resistant to many antimicrobials and treatment requires an onerous regimen of intravenous and orally administered drugs. Relapse of disease and high rates of mortality following treatment are common, demonstrating the need for new anti- agents.

Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study.

Background: No pharmacological treatments are specifically indicated for painful small fibre neuropathy (SFN). CONVEY, a phase 2 enriched-enrolment study, evaluated the efficacy and safety of vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN.

Methods: CONVEY was a phase 2, multicentre, placebo-controlled, double-blind (DB), enriched-enrolment, randomised withdrawal study.

Actigraphy-Based Sleep Detection: Validation with Polysomnography and Comparison of Performance for Nighttime and Daytime Sleep During Simulated Shift Work.

Purpose: Actigraphy-based sleep detection algorithms were mostly validated using nighttime sleep, and their performance in detecting daytime sleep is unclear. We evaluated and compared the performance of Actiware and the Cole-Kripke algorithm (C-K) - two commonly used actigraphy-based algorithms - in detecting daytime and nighttime sleep.

Participants And Methods: Twenty-five healthy young adults were monitored by polysomnography and actigraphy during two in-lab protocols with scheduled nighttime and/or daytime sleep (within-subject design).

Identification of sugar-containing natural products that interact with i-motif DNA.

There are thousands of compounds shown to interact with G-quadruplex DNA, yet very few which target i-motif (iM) DNA. Previous work showed that tobramycin can interact with iM- DNA, indicating the potential for sugar-molecules to target these structures. Computational approaches indicated that the sugar-containing natural products baicalin and geniposidic acid had potential to target iM-DNA.

PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.

Introduction: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment.

Unanticipated daytime melatonin secretion on a simulated night shift schedule generates a distinctive 24-h melatonin rhythm with antiphasic daytime and nighttime peaks.

The daily rhythm of plasma melatonin concentrations is typically unimodal, with one broad peak during the circadian night and near-undetectable levels during the circadian day. Light at night acutely suppresses melatonin secretion and phase shifts its endogenous circadian rhythm. In contrast, exposure to darkness during the circadian day has not generally been reported to increase circulating melatonin concentrations acutely.

A multiscale sliding filament model of lymphatic muscle pumping.

The lymphatics maintain fluid balance by returning interstitial fluid to veins via contraction/compression of vessel segments with check valves. Disruption of lymphatic pumping can result in a condition called lymphedema with interstitial fluid accumulation. Lymphedema treatments are often ineffective, which is partially attributable to insufficient understanding of specialized lymphatic muscle lining the vessels.

OculoMotor Assessment Tool Test Procedure and Normative Data.

Significance: This study establishes normative data and a testing procedure for the oculomotor assessment tool. The oculomotor assessment tool standardizes visual targets for the Vestibular/OculoMotor Screening assessment and provides additional metrics that may aid in the differentiation between those with normal and those with abnormal oculomotor function potentially caused by a concussion.

Purpose: This study aimed to assess the oculomotor endurance of healthy participants with no self-reported history of concussions using the oculomotor assessment tool.

DNA G-Quadruplex and i-Motif Structure Formation Is Interdependent in Human Cells.

Guanine- and cytosine-rich nucleic acid sequences have the potential to form secondary structures such as G-quadruplexes and i-motifs, respectively. We show that stabilization of G-quadruplexes using small molecules destabilizes the i-motifs, and vice versa, indicating these gene regulatory controllers are interdependent in human cells. This has important implications as these structures are predominately considered as isolated structural targets for therapy, but their interdependency highlights the interplay of both structures as an important gene regulatory switch.

Circadian misalignment increases mood vulnerability in simulated shift work.

Night shift work can associate with an increased risk for depression. As night workers experience a 'misalignment' between their circadian system and daily sleep-wake behaviors, with negative health consequences, we investigated whether exposure to circadian misalignment underpins mood vulnerability in simulated shift work. We performed randomized within-subject crossover laboratory studies in non-shift workers and shift workers.

Enhanced selectivity, cellular uptake, and in vitro activity of an intrinsically fluorescent copper-tirapazamine nanocomplex for hypoxia targeted therapy in prostate cancer.

In the present work, a copper-tirapazamine (TPZ) nanocomplex [Cu(TPZ)] was synthesized for selective hypoxia-targeted therapy. The nanocomplex revealed a crystalline form, and exhibited higher lipophilicity, compared to TPZ. Furthermore, its stability was confirmed in different media, with minimum dissociation in serum (∼20% up to 72 h).

Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells.

Gastrin-releasing peptide is a member of the bombesin family of peptides. Its cognate receptor, gastrin releasing peptide receptor (GRPR), is widely expressed in cancers of the lung, pancreas and ovaries. Gastrin releasing peptide (GRP) is an autocrine growth factor in small cell lung cancer, which has very poor patient outcomes.

ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection.

Hematopoietic stem cells (HSCs) undergo rapid expansion in response to stress stimuli. Here we investigate the bioenergetic processes which facilitate the HSC expansion in response to infection. We find that infection by Gram-negative bacteria drives an increase in mitochondrial mass in mammalian HSCs, which results in a metabolic transition from glycolysis toward oxidative phosphorylation.

Sex differences in the circadian misalignment effects on energy regulation.

Shift work causes circadian misalignment and is a risk factor for obesity. While some characteristics of the human circadian system and energy metabolism differ between males and females, little is known about whether sex modulates circadian misalignment effects on energy homeostasis. Here we show-using a randomized cross-over design with two 8-d laboratory protocols in 14 young healthy adults (6 females)-that circadian misalignment has sex-specific influences on energy homeostasis independent of behavioral/environmental factors.

Understanding the Influence of a Bifunctional Polyethylene Glycol Derivative in Protein Corona Formation around Iron Oxide Nanoparticles.

Superparamagnetic iron oxide nanoparticles are one of the most prominent agents used in theranostic applications, with MRI imaging the main application assessed. The biomolecular interface formed on the surface of a nanoparticle in a biological medium determines its behaviour in vitro and in vivo. In this study, we have compared the formation of the protein corona on highly monodisperse iron oxide nanoparticles with two different coatings, dimercaptosuccinic acid (DMSA), and after conjugation, with a bifunctional polyethylene glycol (PEG)-derived molecule (2000 Da) in the presence of Wistar rat plasma.

Effects of circadian misalignment on cognition in chronic shift workers.

Shift work is associated with increased human operational errors, presumably due to the circadian timing system that inhibits optimal cognitive function during the night. Circadian misalignment, which is the misalignment between the circadian pacemaker and behavioral/environmental cycles, impairs cognitive performance in non-shift workers. However, it remains uncertain whether the adverse cognitive consequences of circadian misalignment are also observed in chronic shift workers.

Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides.

Novel alternatives to antibiotics are urgently needed for the successful treatment of antimicrobial resistant (AMR) infections. Experimental antibacterial oligonucleotide therapeutics, such as transcription factor decoys (TFD), are a promising approach to circumvent AMR. However, the therapeutic potential of TFD is contingent upon the development of carriers that afford efficient DNA protection against nucleases and delivery of DNA to the target infection site.