Ngk1 kinase‐mediated N‐acetylglucosamine metabolism promotes UDP‐GlcNAc biosynthesis in Saccharomyces cerevisiae

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Ngk1 kinase-mediated N-acetylglucosamine metabolism promotes UDP-GlcNAc biosynthesis in Saccharomyces cerevisiae

We uncovered a novel pathway of N-acetylglucosamine (GlcNAc) metabolism for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) biosynthesis via Ngk1 kinase in Saccharomyces cerevisiae. GlcNAc phosphorylation by Ngk1 promotes UDP-GlcNAc synthesis and compensates for the hexosamine pathway, a known pathway for UDP-GlcNAc synthesis. The increased synthesis of UDP-GlcNAc by Ngk1 enhances chitin production.


N-acetylglucosamine (GlcNAc) is an important structural component of the cell wall chitin, N-glycans, glycolipids, and GPI-anchors in eukaryotes. GlcNAc kinase phosphorylates GlcNAc into GlcNAc-6-phosphate, a precursor of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) that serves as a substrate for glycan synthesis. Although GlcNAc kinase is found widely in organisms ranging from microorganisms to mammals, it has never been found in the model yeast Saccharomyces cerevisiae. Here, we demonstrate the presence of GlcNAc metabolism for UDP-GlcNAc biosynthesis in S. cerevisiae through Ngk1, a GlcNAc kinase we discovered previously. The overexpression or deletion of Ngk1 in the presence of GlcNAc affected the amount of both UDP-GlcNAc and chitin, suggesting that GlcNAc metabolism via Ngk1 promotes UDP-GlcNAc synthesis. Our data suggest that the Ngk1-mediated GlcNAc metabolism compensates for the hexosamine pathway, a known pathway for UDP-GlcNAc synthesis.

Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro‐inflammation cues

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Abstract

Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging methods that can detect chronic inflammatory features to identify pre-cancerous and cancerous angiogenic changes in tissue microenvironments. This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative experimental preclinical and human clinical studies using these imaging methods provide biological and clinical relevance to cutaneous field carcinogenesis in altered tissue microenvironments in the apparently normal epidermis and dermis. Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options.

Mobile health technologies in an interventional hybrid study on actinic keratosis: Results from an early phase randomized controlled trial investigating the safety and efficacy of a cytosolic phospholipase A2 inhibitor gel in photodamaged skin

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Abstract

Hybrid trials are a new trend in dermatological research that leverage mobile health technologies to decentralize a subset of clinical trial elements and thereby reduce the number of in-clinic visits. In a Phase I/IIa randomized controlled hybrid trial, the safety and efficacy of an anti-proliferative and anti-inflammatory drug inhibiting cytosolic phospholipase A2 (AVX001) was tested using 1%, 3% or vehicle gel in 60 patients with actinic keratosis (AK) and assessed in-clinic as well as remotely. Over the course of 12 weeks, patients were assessed in-clinic at baseline, end of treatment (EOT) and end of study (EOS), as well as 9 times remotely on a weekly to biweekly basis. Safety outcomes comprising local skin reactions (LSR; 0–5), adverse events (AE) and cosmesis, were graded in-clinic and remotely using patient-obtained smartphone photographs (PSPs) and questionnaires; efficacy was assessed in-clinic based on clinically visible clearance of AK target area of >50%. A total of 55 participants (91.7%) completed the treatment course. The average submission rate of PSPs was high (≥85%), of which 93% were of sufficient quality. No serious AE were reported and only two experienced temporary LSR >2 (scale 0–4) and cosmesis remained stable throughout the study. Based on the mild AE and LSR profile, daily application of AVX001 gel for 1 month appears safe, tolerable, and cosmetically acceptable for use in patients with AK. At EOT, AVX001 achieved a subtle treatment response with clearance of AK target area of >50% in 18% of patients. Remote and in-clinic assessments of LSRs were in high agreement, suggesting that the use of mobile health technologies in early-phase hybrid studies of AK does not compromise patient safety.

Lithium chloride promotes mesenchymal‐epithelial transition in murine cutaneous wound healing via inhibiting CXCL9 and IGF2

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Abstract

Cutaneous wound healing is a challenge in plastic and reconstructive surgery. In theory, cells undergoing mesenchymal transition will achieve re-epithelialization through mesenchymal-epithelial transition at the end of wound healing. But in fact, some pathological stimuli will inhibit this biological process and result in scar formation. If mesenchymal-epithelial transition can be activated at the corresponding stage, the ideal wound healing may be accomplished. Two in vivo skin defect mouse models and dermal-derived mesenchymal cells were used to evaluate the effect of lithium chloride in wound healing. The mesenchymal-epithelial transition was detected by immunohistochemistry staining. In vivo, differentially expressed genes were analysed by transcriptome analyses and the subsequent testing was carried out. We found that lithium chloride could promote murine cutaneous wound healing and facilitate mesenchymal-epithelial transition in vivo and in vitro. In lithium chloride group, scar area was smaller and the collagen fibres are also orderly arranged. The genes related to mesenchyme were downregulated and epithelial mark genes were activated after intervention. Moreover, transcriptome analyses suggested that this effect might be related to the inhibition of CXCL9 and IGF2, subsequent assays demonstrated it. Lithium chloride can promote mesenchymal-epithelial transition via downregulating CXCL9 and IGF2 in murine cutaneous wound healing, the expression of IGF2 is regulated by β-catenin. It may be a potential promising therapeutic drug for alleviating postoperative scar and promoting re-epithelialization in future.

Symptomatic brain metastases in melanoma

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Abstract

Although clinical outcomes in metastatic melanoma have improved in recent years, the morbidity and mortality of symptomatic brain metastases remain challenging. Response rates and survival outcomes of patients with symptomatic melanoma brain metastases (MBM) are significantly inferior to patients with asymptomatic disease. This review focusses upon the specific challenges associated with the management of symptomatic MBM, discussing current treatment paradigms, obstacles to improving clinical outcomes and directions for future research.

Flock health planning: How to move from a plan to a reflective planning process in Northern Irish sheep flocks?

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Flock health planning: How to move from a plan to a reflective planning process in Northern Irish sheep flocks?

This is a predominantly qualitative study of the beliefs and behaviours of sheep farmers, and their veterinarians, from across Northern Ireland, surrounding their flock health plans and flock health planning process. Sheep farmers participating saw their health plan as a static, physical document rather than an ongoing continuous cycle of improvement. Veterinarians saw potential to improve flock health if they could engage farmers and develop an income stream from the work. Farmers and veterinarians concurred that incentivising engagement and support in implementation of the agreed plans was key to drive flock health planning forward.


Abstract

Flock health planning has been advocated as part of a wider drive within livestock production for veterinarians and farmers to adopt a prevention-focused approach to veterinary medicine. This approach has, at its core, a cyclical process of assessment, evaluation, action and re-assessment, and is documented, at least in summary, in a health plan (HP). The HP has become a defining pillar of farm quality assurance schemes (QASs), introduced to address calls for greater transparency and accountability in food production. There is limited current information on the attitudes and behaviours surrounding flock HPs in the sheep sector and the barriers to greater involvement in an active process of continual improvement through reflective flock health planning. This study aims to address these issues with reference to the national flock in Northern Ireland. A mixed-methods approach was used to explore farmers' and veterinarians' opinions and behaviours related to QASs and HP, with data obtained through an online scoping questionnaire, semi-structured interviews with 27 farmers and 15 veterinarians, and discussion groups with farmers and veterinarians. No evidence of a positive association between a farm having a HP and implementation of 12 industry-recommended flock health activities was identified using the Fisher's exact test. Farmers reported a reluctance to pay for veterinary advice while some veterinarians reported a lack of time to develop HPs for farmers, and sheep-related work generally. Farmers predominantly saw the HP as a static, physical document, which had limited impact on their management practices, rather than a proactive, reflective and collaborative planning process. Veterinarians tasked with completing HPs felt restricted by limited knowledge of on-farm practices, flock production data and a lack of confidence in the accuracy of on-farm medicine records. This led some to believe that the HPs may fail to address critical issues. A new approach to engage farmers and veterinarians together in active flock health planning needs to be developed. This will need a sustainable delivery plan. Then the focus can be shifted towards ongoing reflective health planning to drive change for the betterment of sheep health and welfare.

Phenological coding of Crambe abyssinica Hochst. according to the BBCH system

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Phenological coding of Crambe abyssinica Hochst. according to the BBCH system

In the present study, a proposed scale of the phenological growth stages of crambe was applied according to the Biologische Bundesanstalt Bundessortenamt und Chemische Industrie coding system was applied.


Abstract

Crambe (Crambe abyssinica Hochst.) is an oilseed crop domesticated in the Mediterranean region that is becoming increasingly important worldwide. Crambe is now considered as an alternative to bioenergy crops and oleochemicals, because of its ability to acclimatise under inhospitable conditions. Despite the interest in the agronomic characteristics and applications of this crop, research on crambe is still scarce and has focused only on production, taking into account the phenological stages of this species. Therefore, a single criterion for quantifying the phenology of the species can be a useful tool for both researchers and growers. In the present study, a proposed scale of the phenological growth stages of crambe was applied according to the BBCH (Biologische Bundesanstalt, Bundessortenamt und Chemische Industrie) coding system. The phenological stages were described using the one- and two-digit decimal coding of the BBCH system and corresponded to stage 0: germination; stage 1: leaf development; stage 2: lateral sprout formation; stage 5: inflorescence emergence; stage 6: flowering; stage 8: fruit ripening and stage 9: senescence. Growth stages 3 and 4 (main stem elongation and development of collectable vegetative parts, respectively) have been omitted. Figures have been included to illustrate the main stages, and plant growth has been represented by a technical botanical illustration. The BBCH system has been effective in providing phenological data on crambe, allowing for better growing management of the crop under varying climatic conditions, as well as contributing to the standardisation of research methods on the species.