SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.

Syngeneic Mouse Model of Glioblastoma: Intracranial Implantation of GL261 Cells.

Glioblastoma (GBM) is the most aggressive and prevalent primary brain malignancy in adults. Current treatments provide limited benefit, and thus, the median overall survival of GBM patients is only 15 months. GBM progression is highly dependent on its ability to evade immune response, so understanding the mechanisms behind GBM-driven immunosuppression seems crucial for designing more efficient therapies. Animal models of GBM constitute a convenient tool in glioma research, and several different approaches have been already developed to model this disease in vivo, including genetic and xenograft models. Here, we describe a murine syngeneic model of glioma which recapitulates many of the key features of human disease, including complex tumor microenvironment. We present an optimized protocol for stereotactic intracranial implantation of GL261 cells into C57BL/6 mice which results in tumor growth in the striatum. This model has been widely used to get insight into glioma biology, as well as in the studies aiming at the development and validation of new therapeutic approaches.

Everything on the right place ­ the role of VPS10P receptors in intracellular protein sorting / Wszystko na swoim miejscu ­ rola receptorów VPS10P w komórkowej segregacji bialek.

VPS10P (vacuolar protein sorting 10 protein) domain receptors consitute a family of sorting receptors which are responsible for directing their protein cargo into destined subcellular localization. Functions of VPS10P domain receptors have been well-described in neurons, where efficient sorting of proteins is crucial for cell viability. Dysfunctions in neuronal actions of VPS10P domain receptors are linked to disturbances in neuronal plasticity and development of neurodegenerative disorders. VPS10P domain receptors are also crucial for lipid metabolism, mainly through transport of lipolytic enzymes or influencing the uptake of lipoproteins by the cells. Emerging evidence suggests that VPS10P domain receptors can play important roles in immune response evoked by immune or glial cells. They are also key players in pathogenesis of cancers.

Comparative analysis of the effectiveness of the comprehensive antioedema therapy versus multilayer bandaging in lower limbs lymphoedema treatment.

INTRODUCTION: Treatment of patients with lymphoedema is time-consuming, labour-intensive, and is frequently associated with considerable costs. In Poland, patients with lower limb lymphoedema encounter major problems with access to the comprehensive antioedema therapy. In many cases treatment is limited only to the compression therapy alone or various forms of lymphatic drainage without compression support. This situation makes it difficult to obtain satisfactory treatment results. AIM: To compare the effects of lower limb lymphoedema treatment by means of the multilayer compression therapy alone and the comprehensive antioedema therapy. MATERIAL AND METHODS: Thirty-four women aged 50-80 years with stage 2 primary lymphoedema of the lower limbs were treated. The therapy was carried out at the Daily Rehabilitation Centre of the Palium Hospice in Poznan. The patients were treated for 2 weeks with the application of the multilayer compression therapy alone (group 1) or the comprehensive antioedema therapy (group 2). RESULTS: After 2 weeks, the volume of treated limbs decreased by 652.9 ±712.2 ml (15.9%) in group 1 and by 523.1 ±448.1 ml (11.2%) in group 2. The range of observed changes was comparable (p = 0.77). CONCLUSIONS: Although the oedema reduction was significant in both groups, no differences in the degree of the reduction were observed, which depends on the application of both therapeutic techniques. In the short-term treatment, no beneficial effect of the manual lymphatic drainage on the increase of the volume reduction of lower limbs affected by lymphoedema was observed.

S-Palmitoylation of Synaptic Proteins as a Novel Mechanism Underlying Sex-Dependent Differences in Neuronal Plasticity.

Although sex differences in the brain are prevalent, the knowledge about mechanisms underlying sex-related effects on normal and pathological brain functioning is rather poor. It is known that female and male brains differ in size and connectivity. Moreover, those differences are related to neuronal morphology, synaptic plasticity, and molecular signaling pathways. Among different processes assuring proper synapse functions are posttranslational modifications, and among them, S-palmitoylation (S-PALM) emerges as a crucial mechanism regulating synaptic integrity. Protein S-PALM is governed by a family of palmitoyl acyltransferases, also known as DHHC proteins. Here we focused on the sex-related functional importance of DHHC7 acyltransferase because of its S-PALM action over different synaptic proteins as well as sex steroid receptors. Using the mass spectrometry-based PANIMoni method, we identified sex-dependent differences in the S-PALM of synaptic proteins potentially involved in the regulation of membrane excitability and synaptic transmission as well as in the signaling of proteins involved in the structural plasticity of dendritic spines. To determine a mechanistic source for obtained sex-dependent changes in protein S-PALM, we analyzed synaptoneurosomes isolated from DHHC7-/- (DHHC7KO) female and male mice. Our data showed sex-dependent action of DHHC7 acyltransferase. Furthermore, we revealed that different S-PALM proteins control the same biological processes in male and female synapses.

The Impact of 12-Week Jaques-Dalcroze Eurhythmics Programme on the Dynamic Agility in Single-Dual-Task Conditions in Older Women: A Randomized Controlled Trial.

BACKGROUND: Progressive degenerative changes in the body of elderly people lead to a decrease in physical and mental fitness. Seniors have a problem with performing tasks that involve both physical and mental health at the same time. The risk of falls increases, the consequences of which in old age may be particularly dangerous. It was decided to investigate the impact of performing exercises involving both physical and mental spheres on the dynamic agility in older women. METHODS: 73 women (69.9 ± 3.2) were divided into two groups: intervention (IG, n = 34) and control (CG, n = 39). Individuals with IG participated in the Jaques-Dalcroze Eurhythmics exercise programme for 12 weeks, twice a week for 45 minutes each. Dynamic agility was determined by the Timed Up and Go test, which was conducted both in single-task (TUG_ST) and dual-task (TUG_DT) conditions, where the participant was simultaneously counting down from 60 every 3. The percentage difference between the results of both tests (dual-task cost, DTC) was also determined. Both groups had two measurement sessions: one week before the start of the exercise programme and one week after the end of exercise programme. RESULTS: After 12 weeks of exercise, IG participants obtained significantly better results in TUG_DT (p < 0.001) and DTC (p = 0.003) tests. During this time, CG participants had significantly worse results in TUG_DT (p < 0.001) and DTC (p < 0.001) tests. In the TUG_ST test, neither IG nor CG achieved a significant change in the result. In each test, a significant interaction between the group assignment and the measurement session was observed: TUG_ST: F = 11.523, η 2 P = 0.139, p = 0.001; TUG_DT: F = 60.227, η 2 P = 0.458, p < 0.001; DTC: F = 32.382, η 2 P = 0.313, p < 0.001. CONCLUSION: JDE exercises with a frequency of twice a week, for about 12 weeks, have a significant impact on the improvement of the dynamic agility control in women over 65 years of age.

The worldwide distribution of genetically and phylogenetically diverse Bacillus cereus isolates harbouring Bacillus anthracis-like plasmids.

Bacillus cereus is a close relative of B. anthracis, the causative agent of anthrax whose pathogenic determinants are located on pXO1 and pXO2 plasmids. Bacillus anthracis-like plasmids have been also noted among B. cereus, however, genetic features of B. cereus harbouring these elements remain largely undescribed, especially from the global perspective. Herein, we present the genetic polymorphism, population structure and phylogeny of B. cereus with pXO1-/pXO2-like plasmids originating from Argentina, Kazakhstan, Kenya and Poland. The plasmids were found in about 17% of the isolates, but their frequencies and expression of replicons differed within and between populations. In the multi-locus sequence typing, the bacteria exhibited high genetic polymorphism reflected by 116 sequencing types, including 84 singletons and 10 clonal complexes, which mainly consisted of isolates of the same origin. The phylogenetic analysis of pXO1-/pXO2-like positive B. cereus isolates revealed six independent clades; in certain clades individual populations predominated. Generally, B. cereus with pXO1-/pXO2-like plasmids did not indicate the genetic relationship with B. anthracis, and cannot be classified into an evolutionary independent anthrax line within the B. cereus group. Our report is of a crucial importance for discovering the genetic specificity and evolution of B. cereus bacilli.

One-day pulsed-field gel electrophoresis protocol for rapid determination of emetic Bacillus cereus isolates.

Bacillus cereus, the Gram-positive and spore-forming ubiquitous bacterium, may cause emesis as the result of food intoxication with cereulide, a heat-stable emetic toxin. Rapid determination of cereulide-positive B. cereus isolates is of highest importance due to consequences of this intoxication for human health and life. Here we present a 1-day pulsed-field gel electrophoresis for emetic B. cereus isolates, which allows rapid and efficient determination of their genomic relatedness and helps determining the source of intoxication in case of outbreaks caused by these bacilli.

Comparative analysis of quantitative reverse transcription real-time PCR and commercial enzyme imunoassays for detection of enterotoxigenic Bacillus thuringiensis isolates.

Entomopathogenic Bacillus thuringiensis is closely related to Bacillus cereus, a human pathogen known to cause emesis and diarrhea. Standard detection methods do not distinguish these bacilli. Hemolysin BL (hbl) and non-hemolytic enterotoxin (nhe) genes that encode, respectively, HBL and NHE enterotoxins, are known to be harbored in both bacterial species, suggesting that differentiation of these bacilli is clinically and epidemiologically relevant. In this study the reliability of quantitative reverse transcription real-time PCR (qRT-PCR) and enzyme immunoassays (EIAs) in detecting hbl and nhe transcripts and corresponding toxins in environmental B. thuringiensis isolates was assessed. At least one enterotoxin gene was present in each isolate, and nhe or hbl genes were found in 85% and 55% of the strains, respectively. Based on statistical analyses, both BCET-RPLA and Duopath detected HBL at similar levels, and TECRA and Duopath can be used interchangeably for the detection of NHE, although TECRA has significantly lower sensitivity than Duopath. Thus, as potential enterotoxic B. thuringiensis strains occur in the natural environment, and EIA results may not correspond with the presence of enterotoxin genes and their expression, we suggest that reliable interpretation will be significantly enhanced by including qRT-PCR to support inferences based on EIAs.