Abstract
Although Candida albicans remains the main cause of candidiasis, in recent years a significant number of infections has been attributed to non-albicans Candida (NAC) species, including ...Candida krusei. This epidemiological change can be partly explained by the increased resistance of NAC species to antifungal drugs. C. krusei is a diploid, dimorphic ascomycetous yeast that inhabits the mucosal membrane of healthy individuals. However, this yeast can cause life-threatening infections in immunocompromised patients, with hematologic malignancy patients and those using prolonged azole prophylaxis being at higher risk. Fungal infections are usually treated with five major classes of antifungal agents which include azoles, echinocandins, polyenes, allylamines, and nucleoside analogues. Fluconazole, an azole, is the most commonly used antifungal drug due to its low host toxicity, high water solubility, and high bioavailability. However, C. krusei possesses intrinsic resistance to this drug while also rapidly developing acquired resistance to other antifungal drugs. The mechanisms of antifungal resistance of this yeast involve the alteration and overexpression of drug target, reduction in intracellular drug concentration and development of a bypass pathway. Antifungal resistance menace coupled with the paucity of the antifungal arsenal as well as challenges involved in antifungal drug development, partly due to the eukaryotic nature of both fungi and humans, have left researchers to exploit alternative therapies. Here we briefly review our current knowledge of the biology, pathophysiology and epidemiology of a potential multidrug-resistant fungal pathogen, C. krusei, while also discussing the mechanisms of drug resistance of Candida species and alternative therapeutic approaches.
Fungal co-infections, especially with Aspergillus and Candida species, are prevalent in hospitalised COVID-19 patients, and could influence patient outcomes and hamper treatment efforts. However, ...information about and elucidation of the causal relationship between fungal co-infections and COVID-19 disease outcomes or severity in patients are still lacking. Such information, if and when available, will help facilitate appropriate case management.
Remote sensing delivers multimodal and -temporal data from the Earth's surface. In order to cope with these multidimensional data sources and to make the most of them, image fusion is a valuable ...tool. It has developed over the past few decades into a usable image processing technique for extracting information of higher quality and reliability. As more sensors and advanced image fusion techniques have become available, researchers have conducted a vast amount of successful studies using image fusion. However, the definition of an appropriate workflow prior to processing the imagery requires knowledge in all related fields - i.e. remote sensing, image fusion and the desired image exploitation processing. From the findings of this research it can be seen that the choice of the appropriate technique, as well as the fine-tuning of the individual parameters of this technique, is crucial. There is still a lack of strategic guidelines due to the complexity and variability of data selection, processing techniques and applications. This paper gives an overview on the state-of-the-art in remote sensing image fusion including sensors and applications. Putting research results in image fusion from the past 15 years into a context provides a new view on the subject and helps other researchers to build their innovation on these findings. Recommendations of experts help to understand further needs to achieve feasible strategies in remote sensing image fusion.
CRISPR/Cas9 based systems have emerged as versatile platforms for precision genome editing in a wide range of organisms. Here we have developed powerful CRISPR/Cas9 tools for marker-based and ...marker-free genome modifications in Penicillium chrysogenum, a model filamentous fungus and industrially relevant cell factory. The developed CRISPR/Cas9 toolbox is highly flexible and allows editing of new targets with minimal cloning efforts. The Cas9 protein and the sgRNA can be either delivered during transformation, as preassembled CRISPR-Cas9 ribonucleoproteins (RNPs) or expressed from an AMA1 based plasmid within the cell. The direct delivery of the Cas9 protein with in vitro synthesized sgRNA to the cells allows for a transient method for genome engineering that may rapidly be applicable for other filamentous fungi. The expression of Cas9 from an AMA1 based vector was shown to be highly efficient for marker-free gene deletions.
Background
Early life adversity (ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease ...susceptibility remains poorly understood.
Methods
Utilizing a porcine early weaning stress (EWS) model to mimic ELA, we investigated the long‐term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia.
Key Results
Juvenile and adult EWS pigs exhibited chronic, functional diarrhea (EWS 43.6% vs late wean control(LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male‐C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1‐2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co‐localization with neuronal ganglia were observed in both Male‐C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male‐C pigs.
Conclusions and Inferences
These data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male‐C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders (FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA.
This study demonstrates that early weaning stress in piglets induces lasting alterations in GI function that mimic some of the key features of human FGID's including chronic functional diarrhea, intestinal permeability, and enhanced mast cell activity and localization with enteric nerves. Potential sex differences were evident as females pigs exhibited a more severe clinical and pathophysiological EWS phenotype compared with Male‐C pigs. Therefore the EWS porcine model holds promise as a preclinical translational model for studying the pathophysiology of FGIDs such as IBS‐D that are associated with early life adversity.
BACKGROUND
Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist i.e. polycystic ovary syndrome (PCOS), obesity and ...congenital adrenal hyperplasia. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS.
METHODS
To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity.
RESULTS
The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood.
CONCLUSIONS
Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.
In ticks, the digestion of blood occurs intracellularly and proteolytic digestion of hemoglobin takes place in a dedicated type of lysosome, the digest vesicle, followed by transfer of the heme ...moiety of hemoglobin to a specialized organelle that accumulates large heme aggregates, called hemosomes. In the present work, we studied the uptake of fluorescent metalloporphyrins, used as heme analogs, and amitraz, one of the most regularly used acaricides to control cattle tick infestations, by Rhipicephalus (Boophilus) microplus midgut cells. Both compounds were taken up by midgut cells in vitro and accumulated inside the hemosomes. Transport of both molecules was sensitive to cyclosporine A (CsA), a well-known inhibitor of ATP binding cassette (ABC) transporters. Rhodamine 123, a fluorescent probe that is also a recognized ABC substrate, was similarly directed to the hemosome in a CsA-sensitive manner. Using an antibody against conserved domain of PgP-1-type ABC transporter, we were able to immunolocalize PgP-1 in the digest vesicle membranes. Comparison between two R. microplus strains that were resistant and susceptible to amitraz revealed that the resistant strain detoxified both amitraz and Sn-Pp IX more efficiently than the susceptible strain, a process that was also sensitive to CsA. A transcript containing an ABC transporter signature exhibited 2.5-fold increased expression in the amitraz-resistant strain when compared with the susceptible strain. RNAi-induced down-regulation of this ABC transporter led to the accumulation of metalloporphyrin in the digestive vacuole, interrupting heme traffic to the hemosome. This evidence further confirms that this transcript codes for a heme transporter. This is the first report of heme transport in a blood-feeding organism. While the primary physiological function of the hemosome is to detoxify heme and attenuate its toxicity, we suggest that the use of this acaricide detoxification pathway by ticks may represent a new molecular mechanism of resistance to pesticides.
•Caenorhabditis elegans is a model to study PUFA/oxylipin production and function.•It shares many aspects of PUFA synthesis with mammals.•There are differences in oxylipin synthesis between mammals ...and C. elegans.•PUFA composition can be easily manipulated to study their roles.
Polyunsaturated fatty acids (PUFAs) exhibit a diverse range of important biological functions in most biological systems. These PUFAs can be oxygenated via enzymatic or free radical-mediated reactions to form bioactive oxygenated lipid mediators termed oxylipins. Eicosanoids are broad class of oxylipins that are transient and locally synthesized signalling molecules, including prostaglandins, leukotrienes, lipoxins and thromboxanes, which mediate various physiological responses, such as inflammation. In addition to arachidonic acid-derived eicosanoids, current developments in lipidomic methodologies have brought attention to vast number of oxylipins produced from other PUFAs, including omega-3. Although, the molecular mechanisms of how PUFAs and oxylipins contribute to majority of the fundamental biological processes are largely unclear, a model organism Caenorhabditis elegans remains a powerful model for exploring lipid metabolism and functions of PUFAs and oxylipins. For instance, the ability of C. elegans to modify fatty acid composition with dietary supplementation and genetic manipulation enables the dissection of the roles of omega-3 and omega-6 PUFAs in many biological processes that include aging, reproduction, and neurobiology. However, much remains to be elucidated concerning the roles of oxylipins, but thus far, C. elegans is well-known for the synthesis of vast set of cytochrome (CYP) eicosanoids. These CYP eicosanoids are extremely susceptible to changes in the relative bioavailability of the different PUFAs, thus providing a better insight into complex mechanisms connecting essential dietary fatty acids to various biological processes. Therefore, this review provides an overview of the synthesis and function of PUFAs and oxylipins in mammals. It also focusses on what is known regarding the production of PUFAs and oxylipins in C. elegans and their functions.
PDF
