Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases

The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.

Amyotrophic lateral sclerosis disease burden:doing better at getting better

Amyotrophic lateral sclerosis(ALS)is classified as a multigenic,multifactorial,and heterogeneous neurodegenerative/neuroinflammatory disease that slays especially upper and lower motor neurons controlling voluntary muscle activity.After the insurgence that is characterized by typical symptoms such as weakness in the limbs and muscle twitches,the disease rapidly evolves into progressive muscle atrophy,paralysis,and lastly death occurring by respiratory failure usually within 2-4 years of diagnosis.

International study of the Complex Stress Reaction Syndrome:Implications for transdiagnostic clinical practice

BACKGROUND The debate regarding diagnostic classification systems in psychiatry(categorial vs dimensional systems)has essential implications for the diagnosis,prevention and treatment of stress reactions.We previously found a unique pattern of stress reaction in a study executed during the coronavirus disease 2019 pandemic using large representative samples in two countries,and termed it the Complex Stress Reaction Syndrome(CSRS).AIM To investigate CSRS,Type A(psychiatric symptoms,spanning anxiety,depression,stress symptoms,and posttraumatic stress disorder(PTSD)),with or without long-coronavirus disease(COVID)residuals(CSRS,Type B,neuropsychiatric symptoms spanning cognitive deficits and fatigue,excluding systemic symptoms).Our two-tailed hypothesis was that CSRS is a condition related to an unrecognized type of stress reaction in daily life in the general population(Type A)or that it is related to the severe acute respiratory syndrome coronavirus 2 infection and its long-COVID residuals(Type B).METHODS 977 individuals in four continents(North America,Europe,Australia and the Middle East)completed the online study questionnaire in six languages using the Qualtrics platform.The study was managed by six teams in six countries that promoted the study on social media.The questionnaire assessed anxiety,depression,stress symptoms and PTSD(CSRS,Type A),cognitive deficits and fatigue(CSRS,Type B).The data were analyzed using Proportion Analyses,Multivariate Analysis of Co-Variance(MANCOVA),linear regression analyses and validated clinical cutoff points.RESULTS The results of the Proportion Analyses showed that the prevalence of 4 symptoms spanning anxiety,depression,stress symptoms,and PTSD was significantly higher than the most prevalent combinations of fewer symptoms across 4 continents,age groups,and gender.This supports the transdiagnostic argument embedded in the CSRS(Type A).The same pattern of results was found in infected/recovered individuals.The prevalence of the 4 psychiatric symptoms combination was significantly greater than that of 5 and 6 symptoms,when adding cognitive deficits and fatigue,respectively.MANCOVA showed a significant three-way interaction(age×gender×continent).Further analyses showed that the sources of this three-way interaction were threefold relating to two sub-populations at-risk:(1)Individuals that self-identified as non-binary gender scored significantly higher on all 4 psychiatric symptoms of the CSRS,Type A at young age groups(<50 years old)in North America compared to(self-identified)women and men located in the 4 continents studied,and to other ages across the adult life span;and(2)This pattern of results(CSRS,Type A)was found also in women at young ages(<40 years old)in North America who scored higher compared to men and women in other continents and other ages.Linear regression analyses confirmed the MANCOVA results.CONCLUSION These results show a combined mental health risk factor related to stress reactivity,suggesting that the CSRS is sensitive to populations at risk and may be applied to future identification of other vulnerable sub-populations.It also supports the transdiagnostic approach for more accurate prevention and treatment.Time will tell if such transdiagnostic syndromes will be part of the discussions on the next revisions of the traditional classification systems or whether the crisis in psychiatry further evolves.

Probiotics to counteract biofilm-associated infections: promising and conflicting data

Altered bowel flora is currently thought to play a role in a variety of disease conditions, and the use of Bifidobacterium spp. and Lactobacillus spp. as probiotics has been demonstrated to be health-promoting, even if the success of their administration depends on the applied bacterial strain（s） and the targeted disease. In the last few decades, specific probiotics have been shown to be effective in the treatment or the prevention of acute viral gastroenteritis, pediatric post-antibiotic-associated diarrhea, some pediatric allergic disorders, necrotizing enterocolitis in preterm infants, inflammatory bowel diseases and postsurgical pouchitis. The potential application of probiotics is continuously widening, with new evidence accumulating to support their effect on the prevention and treatment of other disease conditions, including several oral diseases, such as dental caries, periodontal diseases and oral malodor, as well as genitourinary and wound infections. Considering the increasingly widespread ability of pathogens to generate persistent biofilm-related infections, an even more attractive proposal is to administer probiotics to prevent or counteract biofilm development.The response of biofilm-based oral, intestinal, vaginal and wound infections to probiotics treatment will be reviewed here in light of the most recent results obtained in this field.

Insights from human sleep research on neural mechanisms of Alzheimer’s disease

Alzheimer's disease(AD)is considered as the major cause of dementia and affects about 50 million people in world population,with an expected increase of 27%in the coming decades,as reported by the most recent AD statistics.The fast-growing empirical evidence is highlighting the close relationship between sleep and AD since the preclinical stage of the disease,pointing to an important role of sleep in the occurrence and progression of AD.

What good is the reserve? A translational perspective for the managing of cognitive decline

The concept of reserve appears in the neurological literature in the 1940s arising from the observation that there is no linear relationship between neurological damage and severity of the clinical symptoms.Basically,this concept sustains that the experiences pursued during life-span enrich the brain by making it more resilient to neuronal damage.However,in the last three decades the reserve concept has become very popular in the scientific field,mainly associated with the pathophysiological mechanisms underlying the Alzheimer’s Disease(AD)(Serra et al.,2018;Stern et al.,2018).

Is it possible to develop a cerebellar reserve?

The concept of neural plasticity accounts for the now well clarified brain ability to react to internal and external stimuli by transforming its structure and function.The translation of whatever experience in specific electrical signals that run through our neural networks induces a number of plastic changes at both functional and structural levels.

CD44v8-10 is a marker for malignant traits and a potential driver of bone metastasis in a subpopulation of prostate cancer cells

Objective:Bone metastasis is a clinically important outcome of prostate carcinoma(PC).We focused on the phenotypic and functional characterization of a particularly aggressive phenotype within the androgen-independent bone metastasis-derived PC3 cell line.These cells,originated from the spontaneous conversion of a CD44-negative subpopulation,stably express the CD44 v8-10 isoform(CD44 v8-10 pos)and display stem cell-like features and a marked invasive phenotype in vitro that is lost upon CD44 v8-10 silencing.Methods:Flow cytometry,enzyme-linked immunoassay,immunofluorescence,and Western blot were used for phenotypic and immunologic characterization.Real-time quantitative polymerase chain reaction and functional assays were used to assess osteomimicry.Results:Analysis of epithelial–mesenchymal transition markers showed that CD44 v8-10 pos PC3 cells surprisingly display epithelial phenotype and can undergo osteomimicry,acquiring bone cell phenotypic and behavioral traits.Use of specific si RNA evidenced the ability of CD44 v8-10 variant to confer osteomimetic features,hence the potential to form bone-specific metastasis.Moreover,the ability of tumors to activate immunosuppressive mechanisms which counteract effective immune responses is a sign of the aggressiveness of a tumor.Here we report that CD44 v8-10 pos cells express programmed death ligand 1,a negative regulator of anticancer immunity,and secrete exceptionally high amounts of interleukin-6,favoring osteoclastogenesis and immunosuppression in bone microenvironment.Notably,we identified a novel pathway activated by CD44 v8-10,involving tafazzin(TAZ)and likely the Wnt/TAZ axis,known to play a role in upregulating osteomimetic genes.Conclusions:CD44 v8-10 could represent a marker of a more aggressive bone metastatic PC population exerting a driver role in osteomimicry in bone.A novel link between TAZ and CD44 v8-10 is also shown.

A longitudinal study in atypical Cri-du chat profile: A single case report

Background: Cri-du-Chat Syndrome (CdCS) is a rare genetic disorder characterized by a severe mental delay, minimal verbal abilities and severe learning difficulties. Methods: Here, we report two neuropsychological assessments of an Italian girl (FS) with CdCS who was affected by a moderate mental delay. The first assessment was made at 2.3 years and second at 6.5 years. Results: Her cognitive profile was characterized by a discrepancy between social-communicative and visual-motor skills. Specifically, her linguistic skills were better than her ability to copy a drawing or play with a set of building blocks. FS showed good lexical competence in both comprehension and production. Differently, her grammatical skills (i.e. comprehension and production) were somewhat defective. Conclusion: The FS’s case, due to her moderate mental delay and her preserved linguistic skills, allowed investigating some aspects of this syndrome never explored before.

小胶质细胞控制成年小鼠海马中的谷氨酸能突触

小胶质细胞是调节大脑突触发育和可塑性的重要细胞类型,但其影响突触的正常功能的机制尚不清楚。在本研究中,我们通过PLX5622造成小胶质细胞耗竭,并观察其对成年野生型小鼠海马CA3-CA1突触的影响。在小胶质细胞耗竭后,与树突棘密度降低相关的自发和诱发谷氨酸能活动的减少,出现未成熟突触特征以及突触的可塑性提高。小胶质细胞耗竭的小鼠在新物体识别任务的获取方面表现出缺陷。海马星形胶质细胞出现增生,但并没有神经炎症反应。在Cx3cr1-/-小鼠中,PLX不能导致海马出现上述改变。这说明CX3CL1/CX3CR1轴在小胶质细胞对突触功能的控制中有重要作用。PLX5622停用后,小胶质细胞的重新增殖,海马突触恢复,小鼠的学习功能也出现恢复。综上所述,小胶质细胞对维持成人大脑的突触的正常功能用重要的作用,去除小胶质细胞会导致谷氨酸能突触组织和活动的可逆变化。

Lipid catabolism and mitochondrial uncoupling are stimulated in brown adipose tissue of amyotrophic lateral sclerosis mouse models

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease typically leading to death within 5 years from symptom onset. ALS familial forms are associated with mutations in several genes, including Superoxide Dismutase 1 (SOD1) and Fused in Sarcoma (FUS). Although genes linked to ALS participate in disparate biological processes, ALS genetic variants largely trigger shared pathogenic events such as oxidative stress, protein aggregation and defects in RNA processing. Moreover, ALS patients show systemic hypermetabolism that leads to increased energy expenditure at rest and thus weight loss during the disease course.1 ALS hypermetabolic phenotype and weight loss have been extensively characterized in mice bearing the G93A substitution in SOD1 protein (SOD1-G93A), which exhibit skeletal-muscle metabolic reprogramming before disease onset.

Stem/progenitor cells in fetuses and newborns:overview of immunohistochemical markers

Microanatomy of the vast majority of human organs at birth is characterized by marked differences as compared toadult organs, regarding their architecture and the cell types detectable at histology. In preterm neonates, thesedifferences are even more evident, due to the lower level of organ maturation and to ongoing cell differentiation.One of the most remarkable finding in preterm tissues is the presence of huge amounts of stem/progenitor cells inmultiple organs, including kidney, brain, heart, adrenals, and lungs. In other organs, such as liver, the completelydifferent burden of cell types in preterm infants is mainly related to the different function of the liver duringgestation, mainly focused on hematopoiesis, a function that is taken by bone marrow after birth. Our preliminarystudies showed that the antigens expressed by stem/progenitors differ significantly from one organ to the next.Moreover, within each developing human tissue, reactivity for different stem cell markers also changes duringgestation, according with the multiple differentiation steps encountered by each progenitor during development. Abetter knowledge of stem/progenitor cells of preterms will allow neonatologists to boost preterm organmaturation, favoring the differentiation of the multiple cells types that characterize each organ in at term neonates.