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Numerous p53 missense mutations possess gain-of-function activities. Studies in mouse models have demonstrated that the stabilization of p53 R172H (R175H in human) mutant protein, by currently unknown factors, is a prerequisite for its oncogenic gain-of-function phenotype such as tumour progression and metastasis. Here we show that MDM2-dependent ubiquitination and degradation of p53 R175H mutant protein in mouse embryonic fibroblasts is partially inhibited by increasing concentration of heat shock protein 70 (HSP70/HSPA1-A). These phenomena correlate well with the appearance of HSP70-dependent folding intermediates in the form of dynamic cytoplasmic spots containing aggregate-prone p53 R175H and several molecular chaperones. We propose that a transient but recurrent interaction with HSP70 may lead to an increase in mutant p53 protein half-life. In the presence of MDM2 these pseudoaggregates can form stable amyloid-like structures, which occasionally merge into an aggresome. Interestingly, formation of folding intermediates is not observed in the presence of HSC70/HSPA8, the dominant-negative K71S variant of HSP70 or HSP70 inhibitor. In cancer cells, where endogenous HSP70 levels are already elevated, mutant p53 protein forms nuclear aggregates without the addition of exogenous HSP70. Aggregates containing p53 are also visible under conditions where p53 is partially unfolded: 37°C for temperature-sensitive variant p53 V143A and 42°C for wild-type p53. Refolding kinetics of p53 indicate that HSP70 causes transient exposure of p53 aggregate-prone domain(s). We propose that formation of HSP70- and MDM2-dependent protein coaggregates in tumours with high levels of these two proteins could be one of the mechanisms by which mutant p53 is stabilized. Moreover, sequestration of p73 tumour suppressor protein by these nuclear aggregates may lead to gain-of-function phenotypes.

In this paper, hydrochars and pyrochars were produced at 260 °C under different residence times (2 and 4 h) using anaerobic digested sewage sludge (SSL) as initial feedstock. The effect of reaction time on the fuel properties of hydrochars and pyrochars was evaluated. Moreover, the combustion kinetics of raw SSL and the derived pyrochars and hydrochars without coal blending were determined at two different air flows (20 and 90 mL/min) and compared. In the same conditions, the yield of hydrochar was significantly lower than that of pyrochar, confirming the different reaction pathways followed in each process. The results showed hydrochars have lower carbon recovery and energy yield than pyrochars, making the latter more suitable for energy purposes. The thermogravimetric combustion study showed that both thermochemical treatments increased the ignition temperature but decreased the burnout temperature, which results in higher stability during handling and storage. However, raw SSL is better for combustion than hydrochar according to the combustibility index. In addition, the kinetic study showed that the activation energy of the combustion of biochars, especially pyrochar, is lower than that of raw SSL, which is advantageous for their combustion.

Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers. In our studies, we used a rat model of temporal lobe epilepsy. An epileptogenic insult was status epilepticus evoked by stimulation of the left lateral nucleus of the amygdala. Next, animals were continuously video and EEG monitored for 3 months. Blood was collected at 14, 30, 60, and 90 days after stimulation. Blood plasma was separated and miRNA levels were analyzed. We compared miRNA levels between sham-operated and stimulated animals, and between animals with high and low numbers of seizures. We propose three miRNAs that could be biomarkers of epilepsy: miR-671, miR-9a-3p and miR-7a-5p. According to us, miR-206-5p is a potential biomarker of epileptogenesis, and miR-221-3p is a potential biomarker of epilepsy severity. We think that these five miRNAs can be considered in the future as potential treatment targets.

5‐hydroxymethylfurfural (HMF) is the object of extensive research in recent times. The challenge in the industrial production of HMF is the choice of cheap, hexose feedstock. This study compares continuous HMF synthesis from hexoses—fructose and glucose, and biomass—Miscanthus × giganteus and chicory roots. The experiments were conducted in technical‐scale biorefinery (TRL 6/7). In the first stage, optimal conditions for the production of HMF from hexoses were selected using sulfuric acid as a catalyst in an aqueous medium. The following conditions were chosen for fructose: temperature of 200°C, the reaction time of 18 min, and pH = 2, and for glucose: 210°C, 18 min, and pH = 3. Under these conditions, the HMF yield was 56.5 mol% (39.6 wt.%) from fructose and 18.1 mol% (12.6 wt.%) from glucose. From the biomass, the HMF yields were 36.7 and 16.2 wt.% for miscanthus and chicory roots, respectively. Some results from the conversion of biomass solutions are unexpected and show a need for further investigations. This work has demonstrated the capacity to produce HMF from biomass as part of an environmentally friendly process in a biorefinery. Further research in this field and process optimization will be a step forward in the sustainable production of bioplastics. Agricultural biomass may be a promising feedstock for the production of platform chemicals such as 5‐hydroxymethylfurfural (HMF). For this purpose, miscanthus and forced chicory roots can be used. HMF production from biomass requires two steps, first obtaining carbohydrates and then their subsequent hydrothermal dehydration. Effective implementation of this process creates hope for the development of biorefineries.

Hydrochar is a very interesting product from agricultural and food production residues. Unfortunately, severe conditions for complete conversion of lignocellulosic biomass is necessary, especially compared to the conversion of sugar compounds. The goal of this work is to improve the conversion of internal carbohydrates by application of a two-steps process, by acid addition and slightly higher water content. A set of experiments at different temperatures (180, 200, and 220 °C), reaction times (2 and 4 h), and moisture contents (80% and 90%) was performed to characterize the solid (high heating value (HHV), elemental) and liquid product phase. Afterwards, acid addition for a catalyzed hydrolysis reaction during hydrothermal carbonization (HTC) and a two-steps reaction (180 and 220 °C) were tested. As expected, a higher temperature leads to higher C content of the hydrochar and a higher fixed carbon (FC) content. The same effect was found with the addition of acids at lower temperatures. In the two-steps reaction, a primary hydrolysis step increases the conversion of internal carbohydrates. Higher water content has no significant effect, except for increasing the solubility of ash components.

Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered “hallmarks of cancer”. In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein–protein interactions, and more.

Minimally invasive surgery is the method of choice in endometrial cancer. Experience in procedures assisted by a robotic system is growing rapidly. One of the new bipolar ones is a Vessel Sealer, with sealing and cutting function. The aim of the study was to compare robotic surgery assisted with the da Vinci X system with use of the Vessel Sealer or without it. The study included 25 patients with high-risk endometrial cancer after completed pelvic and paraaortic lymphadenectomy with mean age 60.07 ± 10.67 (range 34.69–83.23) years divided into two groups: one with use of the Vessel Sealer; the second one only with monopolar scissors and subdivided by one-site versus dual docking. Duration of the operation was significantly associated with previous surgery ( p  < 0.005). Use of the Vessel Sealer was associated with lower blood loss during surgery ( p  < 0.05). The number of removal pelvic lymph nodes was higher in case of Vessel Sealer with no relation to BMI. Experience in robotic surgery allowed for shortened operation time and led to better outcomes. The Vessel Sealer used in robotic surgery appears to reduce blood loss during surgery and operation time, especially in the case of previous surgery, however, it increases costs of the procedure.

Methyl CpG binding domain 3 (Mbd3) protein belongs to the MBD family of proteins and is responsible for reading the DNA methylation pattern. Our previous study revealed increased levels of Nucleosome Remodeling and Deacetylase (NuRD) complex proteins, including Mbd3, in the brains of epileptic animals. The present study investigated whether the Mbd3 protein level determines the seizure threshold. We demonstrate that seizures induced by pentylenetetrazole (PTZ) cause a transient, brain area-specific increase in Mbd3 protein levels in the entorhinal cortex and amygdala. Overexpression of Mbd3 in the amygdala using AAV decreased anxiety, increased excitability in the open-field test, and accelerated epileptogenesis in the PTZ-kindling model. In vitro, mRNA profiling using RNA-seq in a model of magnesium deficiency-induced epileptiform discharges revealed complex, time- and state-specific changes in gene expression. Genes regulated by Mbd3 overexpression were associated with the Wnt and Notch pathways, potassium channel function, and GABAB receptor signaling. Our findings indicate that increased Mbd3 expression has pro-epileptic properties and contributes to the regulation of multiple pathways potentially involved in seizure development. Significantly, seizures themselves transiently elevate Mbd3 levels, suggesting a potential vicious circle that may aggravate disease progression. Targeting the pro-epileptic effects of Mbd3 could therefore represent a novel therapeutic approach in epilepsy.

Gain-of-function (GOF) mutations in the TP53 gene lead to acquisition of new functions by the mutated tumor suppressor p53 protein. A number of the over-represented 'hot spot' mutations, including the ones in codons 175, 248 or 273, convey GOF phenotypes. Such phenotypes may include resistance to chemotherapeutics or changes in motility and invasiveness. Whereas the prevalent notion is that the acquisition of the p53 GOF phenotype translates into poorer prognosis for the patient, the analysis of a human somatic p53 mutations dataset demonstrated earlier tumor onset, but decreased frequency and altered location of metastases in patients with the p53-R248Q allele. Therefore, the GOF activities of p53-R248Q and p53-D281G were analyzed in triple negative breast cancer MDA-MB-231 and lung adenocarcinoma H1299 cell lines with regard to invasive and metastatic traits. The expression of p53-D281G increased the motility and invasiveness of the lung cancer cells, but not those of the breast cancer cells. In contrast, the expression of p53-R248Q decreased the motility and invasiveness of the breast and lung cancer cells in a p53 transactivation-dependent manner. The intravenous xenotransplantation of MDA-MB-231 cells expressing p53-R248Q into zebrafish embryos resulted in an alteration of the distribution of cancer cells in the body of the fish. In p53-R248Q-expressing H1299 cells a decrease in the expression of TCF8/ZEB1 and N-cadherin was observed, suggesting partial mesenchymal-to-epithelial transition. In the two cell lines expressing p53-R248Q a decrease was noted in the expression of myosin light chain 2, a protein involved in actomyosin-based motility. To the best of our knowledge, the present study is one of only few reports demonstrating the mutated p53 GOF activity resulting in a decrease of a malignant trait in human cancer.

Background/Objectives: Although considerable progress has been made in understanding lateral ankle sprains (LAS) and chronic ankle instability (CAI), recurrent injury rates remain high. This highlights the need to explore additional contributors such as comprehensive lower-limb gait analysis, including multisegmented foot models and proximal joint kinematics and strength. This study aimed to assess multisegmented foot and lower-limb kinematics throughout the gait cycle in individuals with CAI compared to healthy controls. Additionally, associations between hip abductor strength and frontal plane ankle kinematics were examined. Methods: Fifty males (25 with CAI and 25 healthy controls) participated in this cross-sectional study. Gait analysis was conducted using a BTS SMART 3D motion capture system to assess multisegmented foot and proximal joint kinematics. Isometric hip strength was measured using a Biodex dynamometer. Statistical Parametric Mapping (SPM) was used to assess group differences, and correlations were calculated between hip abductor strength and ankle kinematics. Results: The CAI group demonstrated significantly greater calcaneus abduction relative to the shank in the transverse plane between 88% and 93% of the gait cycle (MD = −3.50°, 95% CI [−5.60, −1.40], d = −0.95, p = 0.037). No other statistically significant between-group differences in hip, knee, or foot segment kinematics were detected. Furthermore, correlations between hip abductor strength and ankle frontal plane kinematics were not significant. Conclusions: Males with CAI demonstrated altered rearfoot kinematics in the transverse plane during the terminal swing phase. The multisegmented foot model was valuable in detecting subtle deviations and emphasized the importance of including the swing phase. Hip abductor strength was not associated with ankle kinematics, suggesting that its potential role in CAI may involve other mechanisms. These findings may support clinical gait assessment and rehabilitation planning by highlighting the importance of evaluating all foot segments and the entire lower limb, rather than focusing solely on the ankle joint. Segment-specific deviations, particularly those emerging during the swing phase, may help guide targeted interventions aimed at improving foot positioning in males with CAI.