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Abstract Background The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability. Methods A mouse model with inducible deletion of the p53‐encoding gene, Trp53, in skeletal muscle was generated using the Cre‐loxP‐system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice. Results Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (−62,0%; P

Nanopore direct RNA sequencing (DRS) enables measurements of RNA modifications. Modification-free transcripts are a practical and targeted control for DRS, providing a baseline measurement for canonical nucleotides within a matched and biologically-derived sequence context. However, these controls can be challenging to generate and carry nanopore-specific nuances that can impact analyses. We produced DRS datasets using modification-free transcripts from in vitro transcription of cDNA from six immortalized human cell lines. We characterized variation across cell lines and demonstrated how these may be interpreted. These data will serve as a versatile control and resource to the community for RNA modification analyses of human transcripts.

Plant-growth-promoting bacteria (PGPB) have beneficial effects on plants. They can promote growth and enhance plant defense against abiotic stress and disease, and these effects are associated with changes in the plant metabolite profile. The research problem addressed in this study was the impact of inoculation with PGPB on the metabolite profile of Salicornia europaea L. across controlled and field conditions. Salicornia europaea seeds, inoculated with Brevibacterium casei EB3 and Pseudomonas oryzihabitans RL18, were grown in controlled laboratory experiments and in a natural field setting. The metabolite composition of the aboveground tissues was analyzed using GC–MS and UHPLC–MS. PGPB inoculation promoted a reconfiguration in plant metabolism in both environments. Under controlled laboratory conditions, inoculation contributed to increased biomass production and the reinforcement of immune responses by significantly increasing the levels of unsaturated fatty acids, sugars, citric acid, acetic acid, chlorogenic acids, and quercetin. In field conditions, the inoculated plants exhibited a distinct phytochemical profile, with increased glucose, fructose, and phenolic compounds, especially hydroxybenzoic acid, quercetin, and apigenin, alongside decreased unsaturated fatty acids, suggesting higher stress levels. The metabolic response shifted from growth enhancement to stress resistance in the latter context. As a common pattern to both laboratory and field conditions, biopriming induced metabolic reprogramming towards the expression of apigenin, quercetin, formononetin, caffeic acid, and caffeoylquinic acid, metabolites that enhance the plant’s tolerance to abiotic and biotic stress. This study unveils the intricate metabolic adaptations of Salicornia europaea under controlled and field conditions, highlighting PGPB’s potential to redesign the metabolite profile of the plant. Elevated-stress-related metabolites may fortify plant defense mechanisms, laying the groundwork for stress-resistant crop development through PGPB-based inoculants, especially in saline agriculture.

Background Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age‐related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age‐related arterial fibrotic remodeling and stiffening in 1‐year‐old mice. Methods and Results Treatment of in 1‐year‐old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse‐wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. Conclusions This study provides preclinical mechanistic evidence indicating that ARNI‐based interventions may counteract age‐related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.

RNA, DNA, and protein molecules are highly organized within three-dimensional (3D) structures in the nucleus. Although RNA has been proposed to play a role in nuclear organization, exploring this has been challenging because existing methods cannot measure higher-order RNA and DNA contacts within 3D structures. To address this, we developed RNA & DNA SPRITE (RD-SPRITE) to comprehensively map the spatial organization of RNA and DNA. These maps reveal higher-order RNA-chromatin structures associated with three major classes of nuclear function: RNA processing, heterochromatin assembly, and gene regulation. These data demonstrate that hundreds of ncRNAs form high-concentration territories throughout the nucleus, that specific RNAs are required to recruit various regulators into these territories, and that these RNAs can shape long-range DNA contacts, heterochromatin assembly, and gene expression. These results demonstrate a mechanism where RNAs form high-concentration territories, bind to diffusible regulators, and guide them into compartments to regulate essential nuclear functions.

Summary: During hypoxia, increases in cerebral blood flow maintain brain oxygen delivery. Here, we describe a mechanism of brain oxygen sensing that mediates the dilation of intraparenchymal cerebral blood vessels in response to reductions in oxygen supply. In vitro and in vivo experiments conducted in rodent models show that during hypoxia, cortical astrocytes produce the potent vasodilator nitric oxide (NO) via nitrite reduction in mitochondria. Inhibition of mitochondrial respiration mimics, but also occludes, the effect of hypoxia on NO production in astrocytes. Astrocytes display high expression of the molybdenum-cofactor-containing mitochondrial enzyme sulfite oxidase, which can catalyze nitrite reduction in hypoxia. Replacement of molybdenum with tungsten or knockdown of sulfite oxidase expression in astrocytes blocks hypoxia-induced NO production by these glial cells and reduces the cerebrovascular response to hypoxia. These data identify astrocyte mitochondria as brain oxygen sensors that regulate cerebral blood flow during hypoxia via release of nitric oxide.

PurposeMany rare ovarian cancer subtypes, such as small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), have poor prognosis due to their aggressive nature and resistance to standard platinum- and taxane-based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.Experimental designWe compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype, high-grade serous ovarian cancer (HGSC), to identify potential therapeutic targets. IHC of tissue microarrays was used as validation of arginosuccinate synthase (ASS1) deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient-derived xenograft mouse models representing SCCOHT.ResultsGlobal proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared with HGSC. Low ASS1 levels were validated through IHC in large patient cohorts. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 12 of 31 cases, and expressed in less than 5% of the tumor cells in 9 of 31 cases. ASS1-deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient-derived mouse xenograft model of SCCOHT, once-a-week treatment with ADI-PEG20 (30 mg/kg and 15 mg/kg) inhibited tumor growth in vivo.ConclusionsPreclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.

Abstract Background The prevalence of diabetes mellitus has risen considerably and currently affects more than 422 million people worldwide. Cardiovascular diseases including myocardial infarction and heart failure represent the major cause of death in type 2 diabetes (T2D). Diabetes patients exhibit accelerated aortic stiffening which is an independent predictor of cardiovascular disease and mortality. We recently showed that aortic stiffness precedes hypertension in a mouse model of diabetes (db/db mice), making aortic stiffness an early contributor to cardiovascular disease development. Elucidating how aortic stiffening develops is a pressing need in order to halt the pathophysiological process at an early time point. Methods To assess EndMT occurrence, we performed co-immunofluorescence staining of an endothelial marker (CD31) with mesenchymal markers (α-SMA/S100A4) in aortic sections from db/db mice. Moreover, we performed qRT-PCR to analyze mRNA expression of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. To identify the underlying mechanism by which EndMT contributes to aortic stiffening, we used aortas from db/db mice and diabetic patients in combination with high glucose-treated human umbilical vein endothelial cells (HUVECs) as an in vitro model of diabetes-associated EndMT. Results We demonstrate robust CD31/α-SMA and CD31/S100A4 co-localization in aortic sections of db/db mice which was almost absent in control mice. Moreover, we demonstrate a significant upregulation of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. As underlying regulator, we identified miR-132-3p as the most significantly downregulated miR in the micronome of db/db mice and high glucose-treated HUVECs. Indeed, miR-132-3p was also significantly downregulated in aortic tissue from diabetic patients. We identified Kruppel-like factor 7 (KLF7) as a target of miR-132-3p and show a significant upregulation of KLF7 in aortic sections of db/db mice and diabetic patients as well as in high glucose-treated HUVECs. We further demonstrate that miR-132-3p overexpression and KLF7 downregulation ameliorates EndMT in high glucose-treated HUVECs. Conclusions We demonstrate for the first time that EndMT contributes to aortic stiffening in T2D. We identified miR-132-3p and KLF7 as novel EndMT regulators in this context. Altogether, this gives us new insights in the development of aortic stiffening in T2D.

Abstract Background To compare the measurements obtained from the Orbscan II, IOLMaster 700, Pentacam AXL, and Castroviejo caliper and their effects on calculating the recommended implantable collamer lens (ICL) size and postoperative vault measurements. Methods This is a retrospective cross-sectional study of patients who underwent ICL surgery by a single surgeon from March 1, 2018 to July 31, 2021. Records were reviewed for the anterior chamber depth (ACD) and white-to-white (WTW) measurements obtained from the Orbscan II, IOLMaster 700, Pentacam AXL, and Castroviejo caliper (WTW only). These were used to calculate the recommended ICL size. The actual ICL size implanted, and vault measurements obtained one month postoperatively were also collected. Results One hundred seven eyes with a mean age of 27.9 ± 7.7 years were included in the study. Mean WTW measurements were significantly different between devices (P

The volatility of the labor market resulting from globalization, rapid technology changes, economic competition, and the impact of events such as the Covid-2019 Pandemic, demand from vocational psychology a more refined understanding of the processes individuals face while dealing with those new challenges and opportunities, especially in uncertain contexts. Theories such as Planned Happenstance address constructs such as career flexibility, an essential skill to recognize, create and use chance events as career opportunities. Furthermore, when fortuitous events and uncertain contexts are considered for career development, it becomes relevant to understand how subjective time perspective evolves, that is how the life events and career goals are projected, accessed, valued, and organized. Given this context, the objectives of the present study are to adapt and validate a Portuguese version of the Career Flexibility Inventory and to explore the possible relationships between career flexibility, time perspective, and variables inherent to the educational context. The Portuguese version of the Career Flexibility Inventory, the Time Perspective Inventory and a sociodemographic form were answered by 1,380 students from Portuguese higher education institutions. The results indicated that the Portuguese version of the CFI has an adequate three-factor structure with good reliability indices. Some limitations regarding psychometric validity show the importance of further research to improve the measure. However, the findings contribute to theoretically and operationally deepening discussions on the multidimensionality of Career Flexibility. The results regarding the relationships between time perspective and career flexibility seem to be in line with the theoretical indicators of the variables and support the formulated hypotheses, specifically, that future orientation presents a positive correlation with active adaptation; a negative correlation with wavering, and wavering presents a positive correlation with the negative future orientation. The results partially support the hypothesis of differences on time perspective and career flexibility among students with different academic grade averages and from diverse scientific areas of study. Finally, the study advances a theoretical reflection on the different nature of career flexibility dimensions and contributes to broadening and promoting theoretical and operational discussions on the relationships between time perspective and career flexibility, which are still incipient.

Photodynamic inactivation (PDI) is an emerging therapeutic approach that can effectively inactivate diverse microbial forms, including vegetative forms and spores, while preserving host tissues and avoiding the development of resistance to the photosensitization procedure. This study evaluates the antifungal and sporicidal photodynamic activity of two water-soluble amphiphilic tetra- and octa-β-substituted zinc(II) phthalocyanine (ZnPc) dyes with dimethylaminopyridinium groups at the periphery (ZnPcs 1, 2) and their quaternized derivatives (ZnPcs 1a, 2a). Tetra(1, 1a)- and octa(2, 2a)-β-substituted zinc(II) phthalocyanines were prepared and assessed as photosensitizers (PSs) for their effects on Fusarium oxysporum conidia. Antimicrobial photoinactivation experiments were performed with each PS at 0.1, 1, 10, and 20 µM under white light irradiation at an irradiance of 135 mW·cm–2, for 60 min (light dose of 486 J·cm−2). High PDI efficiency was observed for PSs 1a, 2, and 2a (10 µM), corresponding to inactivation until the method’s detection limit. PS 1 (20 µM) also achieved a considerable reduction of >5 log10 in the concentration of viable conidia. The quaternized PSs (1a, 2a) showed better PDI performance than the non-quaternized ones (1, 2), even at the low concentration of 1 µM, and a light dose of 486 J·cm−2. These cationic phthalocyanines are potent photodynamic drugs for antifungal applications due to their ability to effectively inactivate resistant forms, like conidia, with low concentrations and reasonable energy doses.

A crosslinked polymer from acrylamide (AM) and 1,3-divinyltetramethyldisiloxane was synthesized. The resulted polymer was characterized by NMR and FTIR-ATR. Their swelling and sealing capacity were assayed, and it was observed a percentage hydration of 1700% after 4 h of hydration and then, its hydration rate decreased, acquiring a maximum hydration of 2300% at 168 h.Also, the synthesized hydrogel was studied to evaluate his performance as loss control material (LCM) for petroleum industry. The performance in sand bed tester and High Pressure and high temperature (HPHT) cell essays, obtained at different pressures, demonstrated that the hydrogel is a good candidate for application as LCM. Additionally, it is combinable with additional particulate materials, showing synergy in their properties.

The mechanism of neurovascular coupling ensures that the brain energy supply is sufficient to meet demand. Here the authors show that in this mechanism CO2 plays an important role in neuronal activity-dependent regulation of local brain blood flow.

Aims This study investigated the bacterial communities in the rhizosphere of two traditional Portuguese olive cultivars, Cobrançosa and Negrinha de Freixo, in relation to soil properties. Additionally, we aimed to isolate and identify bacteria with potential for biocontrol and other plant growth-promoting traits from these rhizosphere communities. Methods and results Bacterial communities in the olive rhizosphere were investigated using a metabarcoding approach and the soil physicochemical properties of the olive groves were also analyzed. Higher bacterial richness was associated with Negrinha de Freixo growing in soil with high organic matter content and water-holding capacity. In contrast, the soils of the Cobrançosa grove presented higher pH and electric conductivity. Negrinha de Freixo rhizosphere was enriched with ASVs (Amplicon Sequence Variants) belonging to Bacillus, Gaiella, Acidothermus, Bradyrhizobium , and uncultured Xanthobacteraceae. On the other hand, the Cobrançosa rhizosphere was characterized by higher relative abundance of Streptomyces and Sphingomonas. Bacterial isolation from the rhizosphere and screening for plant growth-promoting activities were also performed. Six bacteria strains, predominantly Bacillus isolated from Negrinha de Freixo, demonstrated antagonistic activities against the olive fungal pathogen Colletotrichum gloeosporoides and other plant growth promotion (PGP) traits. Conclusions Our findings demonstrate that the structure of rhizosphere bacterial communities associated with olive trees is shaped by both plant cultivar and soil-related factors. The higher number of bacterial species in the rhizosphere of Negrinha de Freixo was related to a higher organic matter content and a greater abundance of isolates with plant growth promotion traits, particularly Bacillus strains. [ABSTRACT FROM AUTHOR]

Plant-growth-promoting bacteria (PGPB) have beneficial effects on plants. They can promote growth and enhance plant defense against abiotic stress and disease, and these effects are associated with changes in the plant metabolite profile. The research problem addressed in this study was the impact of inoculation with PGPB on the metabolite profile of Salicornia europaea L. across controlled and field conditions. Salicornia europaea seeds, inoculated with Brevibacterium casei EB3 and Pseudomonas oryzihabitans RL18, were grown in controlled laboratory experiments and in a natural field setting. The metabolite composition of the aboveground tissues was analyzed using GC–MS and UHPLC–MS. PGPB inoculation promoted a reconfiguration in plant metabolism in both environments. Under controlled laboratory conditions, inoculation contributed to increased biomass production and the reinforcement of immune responses by significantly increasing the levels of unsaturated fatty acids, sugars, citric acid, acetic acid, chlorogenic acids, and quercetin. In field conditions, the inoculated plants exhibited a distinct phytochemical profile, with increased glucose, fructose, and phenolic compounds, especially hydroxybenzoic acid, quercetin, and apigenin, alongside decreased unsaturated fatty acids, suggesting higher stress levels. The metabolic response shifted from growth enhancement to stress resistance in the latter context. As a common pattern to both laboratory and field conditions, biopriming induced metabolic reprogramming towards the expression of apigenin, quercetin, formononetin, caffeic acid, and caffeoylquinic acid, metabolites that enhance the plant's tolerance to abiotic and biotic stress. This study unveils the intricate metabolic adaptations of Salicornia europaea under controlled and field conditions, highlighting PGPB's potential to redesign the metabolite profile of the plant. Elevated-stress-related metabolites may fortify plant defense mechanisms, laying the groundwork for stress-resistant crop development through PGPB-based inoculants, especially in saline agriculture. [ABSTRACT FROM AUTHOR]

Colon tumors have a very complicated and poorly understood pathogenesis. Plant-based organic compounds might provide a novel source for cancer treatment with a sufficient novel mode of action. The objective of this study was to analyze and evaluate the efficacy of Aloe secundiflora’s (AS) methanolic extracts on the expression of CASPS9, 5-LOX, Bcl2, Bcl-xL, and COX-2 in colorectal cancer (CRC) management. Caco-2 cell lines were used in the experimental study. In the serial exhaustive extraction (SEE) method, methanol was utilized as the extraction solvent. Upon treatment of CASPS9 with the methanolic extracts, the expression of the genes was progressively upregulated, thus, dose-dependently increasing the rate of apoptosis. On the other hand, the expressions of 5-LOX, Bcl2, and Bcl-xL were variably downregulated in a dose-dependent manner. This is a unique novel study that evaluated the effects of AS methanolic extracts in vitro on CRC cell lines using different dosage concentrations. We, therefore, recommend the utilization of AS and the application of methanol as the extraction solvent of choice for maximum modulatory benefits in CRC management. In addition, we suggest research on the specific metabolites in AS involved in the modulatory pathways that suppress the development of CRC and potential metastases.

Background: Colorectal cancer is among the most common malignancy and the third prime cause of cancer-associated mortalities. Long-term inflammation of the colon can promote carcinogenesis by facilitating oxidative stress which enhances deoxyribonucleic acid damage resulting in the tumor initiation step. The existing chemotherapeutic options are often associated with adverse reactions and emergence of drug resistance. The carefully selected plants are cited to demonstrate anticancer properties as has been revealed in this review. Of significance, these plant species are widely available, especially in Africa Objective: The major goal was to present an updated comprehensive review of herbal plants used to treat colon cancer around the world. More specifically, the goal of this study was to analyse a group of selected plant species with proven efficacy, safety, and pharmacological effects on colon cancer models for further research. Methods: A systematic search of relevant literature was performed considering all the articles published until November 2021 through searching six library databases and a web search engine, Google scholar. It was created using MeSH terms and free text describing plant species and colorectal cancer. For subsequent investigation, all articles describing the use of medicinal plants to treat colorectal cancer and/or their pharmacological evaluation were maintained. The plant species investigated in this research for their pharmacotherapeutic effects were: Withania somnifera, Zingiber officinale, Moringa oleifera, Azadirachta indica and Aloe barbadensis. Results: The search yielded a total of 4803 papers published between the year 2000–2021 for further analysis. A total of 4726 articles (reports, reviews, and less relevant research papers) were excluded as they did not meet the inclusion criteria. A cumulative sum of 77 articles including research papers and reviews detailing in vivo and in vitro experiments of the specific plants of interest, with demonstrated activity met the inclusion criteria, and have been discussed in the present review. Conclusion: The pharmacological activities of the selected plant species have been demonstrated to inhibit cyclooxygenase 2, inhibit immunomodulation, suppress angiogenesis, inhibit proliferation, induce apoptosis, and reduction of oxidative stress with sufficient anti-colorectal cancer effects. These essential mechanisms make them befitting alternative options to synthetic chemotherapeutic options. In vivo studies are however encouraged in Moringa oleifera that has a significant gap identified through our search. In addition, more research is encouraged to document sufficient dose levels enough to elicit anti-colorectal cancer effects among the reviewed plants.

Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the normal cells are of utmost significance. A systematic review was conducted in screening for important literature was extensively performed by searching the Web of Science, Ovid, BMC Springer, Elsevier, Embase, and MEDLINE databases for optimum selectivity. Google Scholar was also used to supplement information. Pharmacotherapeutic biomolecules active against colon cancer carcinogenesis in Musa acuminata and Musa balbisiana (bananas), Punica granatum L (pomegranate), Glycine max (Soybean), Brassica oleracea L var. italica Plenck (Broccoli), and Hibiscus rosa-sinesis and Hibiscus sabdariffa (hibiscus) were evaluated. Signaling pathways like phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and nuclear factor-kappa B (NFκB) correlate the mediation of COX-2 expression. Increased levels of COX-2 are correlated with the occurrence and progression of colon cancer. Natural antioxidants in herbal plants including polyphenols and carotenoids inhibit the oxidation of lipids, proteins, and nucleic acids and thereby preventing the initiation of oxidizing chain reactions. These bioactive compounds should be considered an important dietary supplement.