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Background Intestinal microbial composition not only affects the health of the gut but also influences centrally mediated systems involved in mood, through the “gut-brain” axis, a bidirectional communication between gut microbiota and the brain. In this context, the modulation of intestinal microbiota and its metabolites through the administration of probiotics seems to represent a very promising approach in the treatment of the central nervous system alterations. Early postnatal life is a critical period during which the brain undergoes profound and essential modulations in terms of maturation and plasticity. Maternal separation (MS), i.e., the disruption of the mother–pup interaction, represents a pivotal paradigm in the study of stress-related mood disorders, by inducing persistent changes in the immune system, inflammatory processes, and emotional behavior in adult mammals. Results We conducted experiments to investigate whether sustained consumption of a multi-strain probiotic formulation by adult male mice could mitigate the effects of maternal separation. Our data demonstrated that the treatment with probiotics was able to totally reverse the anxiety- and depressive-like behavior; normalize the neuro-inflammatory state, by restoring the resting state of microglia; and finally induce a proneurogenic effect. Mice subjected to maternal separation showed changes in microbiota composition compared to the control group that resulted in permissive colonization by the administered multi-strain probiotic product. As a consequence, the probiotic treatment also significantly affected the production of SCFA and in particular the level of butyrate. Conclusion Gut microbiota and its metabolites mediate the therapeutic action of the probiotic mix on MS-induced brain dysfunctions. Our findings extend the knowledge on the use of probiotics as a therapeutic tool in the presence of alterations of the emotional sphere that significantly impact on gut microbiota composition. AdianNxLDM2uLY8oFPQcaD Video Abstract

The recent identification of a population of non-newly born, prenatally generated “immature” neurons in the layer II of the piriform cortex (cortical immature neurons, cINs), raises questions concerning their maintenance or depletion through the lifespan. Most forms of brain structural plasticity progressively decline with age, a feature that is particularly prominent in adult neurogenesis, due to stem cell depletion. By contrast, the entire population of the cINs is produced during embryogenesis. Then these cells simply retain immaturity in postnatal and adult stages, until they “awake” to complete their maturation and ultimately integrate into neural circuits. Hence, the question remains open whether the cINs, which are not dependent on stem cell division, might follow a similar pattern of age-related reduction, or in alternative, might leave a reservoir of young, undifferentiated cells in the adult and aging brain. Here, the number and features of cINs were analyzed in the mouse piriform cortex from postnatal to advanced ages, by using immunocytochemistry for the cytoskeletal marker doublecortin. The abundance and stage of maturation of cINs, along with the expression of other markers of maturity/immaturity were investigated. Despite a marked decrease in this neuronal population during juvenile stages, reminiscent of that observed in hippocampal neurogenesis, a small amount of highly immature cINs persisted up to advanced ages. Overall, albeit reducing in number with increasing age, we report that the cINs are present through the entire animal lifespan.

Background Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21 Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21 Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. Methods We designed a novel conditional p21 Waf1/Cip1 knock-out mouse model, in which the deletion of p21 Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. Results The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. Conclusions These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. We designed a novel conditional p21 knock-out mouse model, in which the deletion of p21 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

In the last few years, there is a general shift observable toward greener lubrication, fueled amongst others by policy initiatives such as the European Green Deal in consistency with the UN Sustainable Development Goals. At least 70 vol% of a lubricant is composed of a specific base oil, the rest is a variation of additives altering the lubricant properties (enhancing or suppressing existent base oil properties or adding new properties) to be operational for a particular field of application. So, in terms of sustainability, biodegradability, bioaccumulation, and toxicity the type of base oil plays a major role, which makes environmentally harmful petroleum-based lubricant formulations highly problematic for future applications. Hence, this leads to an ever-growing demand of environmentally friendly lubricant alternatives. Within the scope of this review lies the investigation of bio-based, bio-derived, and other sustainable lubricant components that could serve as promising replacements for conventional petroleum-based formulations, in accordance with the principles of green chemistry and tribology. As recycling is embraced by the term sustainability, waste-derived components of non-biological origin are also included in this work. An overview of studies on the tribological performance such as friction and wear properties of these sustainable and benign lubricant components is given.

ObjectivesTo develop predictive criteria for COVID-19-associated cytokine storm (CS), a severe hyperimmune response that results in organ damage in some patients infected with COVID-19. We hypothesised that criteria for inflammation and cell death would predict this type of CS.MethodsWe analysed 513 hospitalised patients who were positive for COVID-19 reverse transcriptase PCR and for ground-glass opacity by chest high-resolution CT. To achieve an early diagnosis, we analysed the laboratory results of the first 7 days of hospitalisation. We implemented logistic regression and principal component analysis to determine the predictive criteria. We used a ‘genetic algorithm’ to derive the cut-offs for each laboratory result. We validated the criteria with a second cohort of 258 patients.ResultsWe found that the criteria for macrophage activation syndrome, haemophagocytic lymphohistiocytosis and the HScore did not identify the COVID-19 cytokine storm (COVID-CS). We developed new predictive criteria, with sensitivity and specificity of 0.85 and 0.80, respectively, comprising three clusters of laboratory results that involve (1) inflammation, (2) cell death and tissue damage, and (3) prerenal electrolyte imbalance. The criteria identified patients with longer hospitalisation and increased mortality. These results highlight the relevance of hyperinflammation and tissue damage in the COVID-CS.ConclusionsWe propose new early predictive criteria to identify the CS occurring in patients with COVID-19. The criteria can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyperimmune response and possibly decrease mortality.

Aiming at exploring vascular components in multiple sclerosis (MS) with brain outflow disturbance, we combined transcriptome analysis in MS internal jugular vein (IJV) wall with WES in MS families with vertical transmission of disease. Main results were the differential expression in IJV wall of 16 MS-GWAS genes and of seven genes (GRIN2A, GRIN2B, IL20RB, IL26, PER3, PITX2, and PPARGC1A) not previously indicated by GWAS but encoding for proteins functionally interacting with MS candidate gene products. Strikingly, 22/23 genes have been previously associated with vascular or neuronal traits/diseases, nine encoded for transcriptional factors/regulators and six (CAMK2G, GRIN2A, GRIN2B, N1RD1, PER3, PPARGC1A) for circadian entrainment/rhythm components. Among the WES low-frequency (MAF ≤ 0.04) SNPs (n = 7) filtered in the 16 genes, the NR1D1 rs17616365 showed significantly different MAF in the Network for Italian Genomes affected cohort than in the 1000 Genome Project Tuscany samples. This pattern was also detected in five nonintronic variants (GRIN2B rs1805482, PER3 rs2640909, PPARGC1A rs2970847, rs8192678, and rs3755863) in genes coding for functional partners. Overall, the study proposes specific markers and low-frequency variants that might help (i) to understand perturbed biological processes in vascular tissues contributing to MS disease, and (ii) to characterize MS susceptibility genes for functional association with disease-pathways.

Over the years, an increasing proportion of metastatic prostate cancer patients has been found to experience an initial bone flare phenomenon under both standard therapies (androgen deprivation therapy, chemotherapy, radiotherapy, abiraterone, enzalutamide) and novel agents (immunotherapy, bone-targeting radioisotopes). The underlying biological mechanisms of the flare phenomenon are still elusive and need further clarification, particularly in relation to different types of treatment and their treatment response assessment. Flare phenomenon is often underestimated and, in some cases, can negatively affect clinical outcome. In cases with suspected bone flare, the treatment should be continued for a minimum of 12 more weeks before further decisions about efficacy can be taken. Physicians and patients should be aware of this effect to avoid unwarranted anxiety and inadequate early discontinuation of treatment. This review aims at highlighting new evidence on flare phenomenon arising after the introduction of new drugs extending across the biochemical, radiographic and clinical spectrum of the disease.