A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were ...shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg–1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg–1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg–1.
Theoretical calculations are performed using the Vienna Ab-initio simulation package (VASP) to understand the mechanisms that control the adsorption of Ampyra drug on the different crystallographic ...planes of β-cristobalite: the hydroxylated (111) and (100) surfaces. The Ampyra-silica interaction is most favored on the (100) surface where the entire ring of the molecule interacts with the surface while on the (111) face, lesser exchange and fewer non-polar atoms are involved. Calculations show that the interactions mainly occur at the interface between the Ampyra and the closest silanol groups, according to the formation of the H-bonding interactions. The results indicate that the H-bonds have an important influence on the adsorption of the Ampyra. In consequence, adsorption on the (111) surface is observed to a lesser extent than on the (100) surface according the smaller hydroxyl density.
DFT calculations are performed to understand the mechanisms that control the adsorption of Ampyra drug on the different crystallographic planes of β-cristobalite: the hydroxylated (111) and (100) surfaces.
Cerebral malaria, a major cause of death during malaria infection, is characterised by the sequestration of infected red blood cells (IRBC) in brain microvessels. Most of the molecules implicated in ...the adhesion of IRBC on endothelial cells (EC) are already described; however, the structure of the IRBC/EC junction and the impact of this adhesion on the EC are poorly understood. We analysed this interaction using human brain microvascular EC monolayers co-cultured with IRBC. Our study demonstrates the transfer of material from the IRBC to the brain EC plasma membrane in a trogocytosis-like process, followed by a TNF-enhanced IRBC engulfing process. Upon IRBC/EC binding, parasite antigens are transferred to early endosomes in the EC, in a cytoskeleton-dependent process. This is associated with the opening of the intercellular junctions. The transfer of IRBC antigens can thus transform EC into a target for the immune response and contribute to the profound EC alterations, including peri-vascular oedema, associated with cerebral malaria.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding biochemical mechanisms and changes associated with disease conditions and, therefore, development of improved clinical treatments, is relying increasingly on various biochemical mapping ...and imaging techniques on tissue sections. However, it is essential to be able to ascertain whether the sampling used provides the full biochemical information relevant to the disease and is free from artefacts. A multi-modal micro-spectroscopic approach, including FTIR imaging and PIXE elemental mapping, has been used to study the molecular and elemental profile within cryofixed and formalin-fixed murine brain tissue sections. The results provide strong evidence that amino acids, carbohydrates, lipids, phosphates, proteins and ions, such as Cl(-) and K(+), leach from tissue sections into the aqueous fixative medium during formalin fixation of the sections. Large changes in the concentrations and distributions of most of these components are also observed by washing in PBS even for short periods. The most likely source of the chemical species lost during fixation is the extra-cellular and intra-cellular fluid of tissues. The results highlight that, at best, analysis of formalin-fixed tissues gives only part of the complete biochemical "picture" of a tissue sample. Further, this investigation has highlighted that significant lipid peroxidation/oxidation may occur during formalin fixation and that the use of standard histological fixation reagents can result in significant and differential metal contamination of different regions of tissue sections. While a consistent and reproducible fixation method may be suitable for diagnostic purposes, the findings of this study strongly question the use of formalin fixation prior to spectroscopic studies of the molecular and elemental composition of biological samples, if the primary purpose is mechanistic studies of disease pathogenesis.
Cerebral malaria (CM) is a major life-threatening complication of
Plasmodium falciparum infection. The nature of the pathogenetic processes leading to the cerebral complications is poorly understood. ...Mouse models of this condition have provided insight into the key events in pathogenesis, including those that occur before clinical symptoms are seen. Some T helper 1 (Th1) cytokines (e.g. interferon-γ, lymphotoxin and tumour necrosis factor) have been implicated in driving the immunopathological process leading to CM, whereas some Th2 cytokines (e.g. interleukin-10, transforming growth factor-β) appear to oppose this process. Upregulation of leukocyte adhesion molecules on the cerebral microvascular endothelium appears to be an important component of the proinflammatory actions of the cytokines. Activation of platelets in the cerebral microcirculation could also be a key event in CM. Furthermore, recent evidence has emerged indicating that cytokines might influence biochemical pathways in the brain that, in turn, could determine the outcome of CM.
Extracellular vesicles (EVs) are lipid‐membrane enclosed nanoparticles that play significant roles in health and disease. EVs are abundant in body fluids and carry an array of molecules (proteins, ...lipids, nucleic acids and glycans) that reflect the identity and activity of their cell‐of‐origin. While the advent of high throughput omics technologies has allowed in‐depth characterisation of EV compositions, how these molecular species are spatially distributed within EV structures is not well appreciated. This is particularly true of the EV surface where a plethora of molecules are reported to be both integral and peripherally associated to the EV membrane. This coronal layer or ‘atmosphere’ that surrounds the EV membrane contributes to a large, highly interactive and dynamic surface area that is responsible for facilitating EV interactions with the extracellular environment. The EV coronal layer harbours surface molecules that reflect the identity of parent cells, which is likely a highly valuable property in the context of diagnostic liquid biopsies. In this review, we describe the current understanding of the mechanical, electrostatic and molecular properties of the EV surface that offer significant biomarker potential and contribute to a highly dynamic interactome.
Flash card Lung Ultrasound and COVID-19 Segura-Grau, E
Revista española de anestesiología y reanimación,
2020 Jun - Jul, 20200601, Letnik:
67, Številka:
6
Journal Article
Highlights • Feed restriction increases circulating leptin A (LepA) and hepatic lepa and leptin receptor ( lepr ) mRNA levels, suggesting enhanced LepA sensitivity and production is fundamental to ...promoting catabolic processes during the adaptive stress response associated with low nutrient availability. • Recombinant tilapia leptin A (rtLepA) upregulates hepatic insulin like growth factors, igf-1 and igf-2 , and growth hormone receptors, ghr1 and ghr2, suggesting the hormone may act locally to enhance GH sensitivity and IGF production. • Hypophysectomy (Hx) increases lepa mRNA in the tilapia and growth hormone (GH) replacement restores levels to that in intact animals. • Physiological doses of GH suppress lepa and lepr in cultured hepatocytes while higher hormone dosages stimulate lepa, suggesting GH is a negative modulator of LepA production. • Physiological concentrations of rtLepA act to suppress pituitary GH gene expression, but has little effect on GH secretion in vitro , indicating leptin may modulate GH cell function in fishes.
Multiple sclerosis (MS) is a disease in which the immune system damages components of the central nervous system (CNS), leading to the destruction of myelin and the formation of demyelinating ...plaques. This often occurs in episodic "attacks" precipitated by the transmigration of leukocytes across the blood-brain barrier (BBB), and repeated episodes of demyelination lead to substantial losses of axons within and removed from plaques, ultimately leading to progressive neurological dysfunction. Within leukocyte populations, macrophages and T and B lymphocytes are the predominant effectors. Among current immunotherapies, oral cladribine's impact on lymphocytes is well characterised, but little is known about its impact on other leukocytes such as monocytes and dendritic cells (DCs). The aim of this study was to determine the transmigratory ability of monocyte and DC subsets in healthy subjects and untreated and cladribine-treated relapse-remitting MS (RRMS) patients using a well-characterised model of the BBB. Peripheral blood mononuclear cells from subjects were added to an in vitro transmigration assay to assess cell migration. Our findings show that while prior treatment with oral cladribine inhibits the migration of intermediate monocytes, it has no impact on the transmigration of DC subsets. Overall, our data indicate a previously unrecognised role of cladribine on intermediate monocytes, known to accumulate in the brain active MS lesions.
Abstract
Background
The experiences and perceived support needs of harm reduction workers in the USA have been understudied. While previous research has explored staff burnout and role-related ...stress, there is a research gap around potential supports for staff wellbeing and individual longevity in their roles. This is especially critical given the growing overdose crisis and the need for sustainable harm reduction programming. Thus, we sought to describe the experiences of harm reduction staff and identify the perceived support that could empower harm reduction staff to successfully navigate their roles.
Methods
Purposive sampling methods were used to recruit harm reduction staff working in Connecticut. Seventeen semi-structured, one-on-one interviews were conducted between December 2022 and March 2023. Participants were asked about their experiences with role-related stressors and supports. Informed by the Social-Ecological Model, transcripts were coded using both inductive and deductive codes, and themes were developed using thematic analysis approaches.
Results
Study participants described their experiences working in harm reduction and the numerous ways they already are or could be receiving support in their roles. These experiences were organized into eight themes according to the levels of the Social-Ecological Model. At the individual level, participants explained that support could help them navigate the variability of the physical environment, boundary setting, and self-care. Relationships between clients and co-workers were both identified as means of support at the interpersonal level, helping participants navigate difficult situations and feelings of stress. At the organizational level, study participants explained how they look to their organization to provide sufficient support by way of training, staffing, compensation, and benefits. Additionally, participants stressed the importance of having supervisors who valued their work and provided emotional support. Lastly, at the community level, participants discussed how support was needed to help them navigate complex systems while working with a stigmatized population in an often-stigmatized field.
Conclusions
To best support harm reduction staff in their day-to-day roles, our findings underscore the need for support on multiple levels. Future research could explore how the provision of support to harm reduction staff impacts not only staff perceptions of support but also the success of clients accessing harm reduction services.
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