Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing

Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.

Genetic testing in neurology exploiting next generation sequencing:state of art

Next generations sequencing (NGS) is definitely one of the most revolutionary technology of the last years in genetic and medical field (Kricka and Di Resta, 2013). It brought important changes in genetic testing of inherited human disorders, in particular in neurological Mendelian forms, such as inherited neuropathies, ataxias or monogenic form of epilepsy, where “diagnostic odyssey” is quite common.

Testicular volume in infertile versus fertile white-European men: a case-control investigation in the real-life setting

Testicular volume(TV)is considered a good clinical marker of hormonal and spermatogenic function.Accurate reference values for TV measures in infertile and fertile men are lacking.We aimed to assess references values for TV in white-European infertile men and fertile controls.We analyzed clinical and laboratory data from 1940(95.0%)infertile men and 102(5.0%)fertile controls.Groups were matched by age using propensity score weighting.TV was assessed using a Prader orchidometer(PO).Circulating hormones and semen parameters were investigated in every male.Descriptive statistics,Spearman's correlation,and logistic regression models tested potential associations between PO-estimated TV values and clinical variables.Receiver operating characteristic(ROC)curves were used to find TV value cutoffs for oligoasthenoteratozoospermia(OAT)and nonobstructive azoospermia(NOA)status in infertile men.The median testicular volume was smaller in infertile than that of fertile men(15.0 ml vs 22.5 ml;P<0.001).TV positively correlated with total testosterone,sperm concentration,and progressive sperm motility(all P≤0.001)in infertile men.At multivariable logistic regression analysis,infertile status(P<0.001)and the presence of left varicocele(P<0.001)were associated with TV<15 ml.Testicular volume thresholds of 15 ml and 12 ml had a good predictive ability for detecting OAT and NOA status,respectively.In conclusion,infertile men have smaller testicular volume than fertile controls.TV positively correlated with total testosterone,sperm concentration,and progressive motility in infertile men,which was not the case in the age-matched fertile counterparts.