Large phenotype jumps in biomolecular evolution

By defining the phenotype of a biopolymer by its active three-dimensional shape, and its genotype by its primary sequence, we propose a model that predicts and characterizes the statistical distribution of a population of biopolymers with a specific phenotype, that originated from a given genotypic sequence by a single mutational event. Depending on the ratio g0 that characterizes the spread of potential energies of the mutated population with respect to temperature, three different statistical regimes have been identified. We suggest that biopolymers found in nature are in a critical regime with g0 in the range 1-6, corresponding to a broad, but not too broad, phenotypic distribution resembling a truncated Levy flight. Thus the biopolymer phenotype can be considerably modified in just a few mutations. The proposed model is in good agreement with the experimental distribution of activities determined for a population of single mutants of a group I ribozyme.Comment: to appear in Phys. Rev. E; 7 pages, 6 figures; longer discussion in VII, new fig.

Sindrome fibromialgica : un caso clinico

La Sindrome Fibromialgica (SFM) \ue8 una malattia che colpisce i muscoli causando tensione muscolare e che si manifesta principalmente con le seguenti sensazioni: iperalgesia, rigidit\ue0, astenia e affaticamento. La diagnosi clinica non \ue8 sempre agevole poich\ue9 non esistono indagini di laboratorio che permettano l\u2019identificazione certa della malattia. Gli studi di neuro-imaging mostrano che la SFM sia legata ad una disfunzione cerebrale che non permette la corretta elaborazione del dolore, tuttavia non \ue8 chiaro se questa disfunzione ne sia causa o effetto. \uc8 indubbio per\uf2 che i fattori psicologici influiscano in maniera significativa sulla sintomatologia dolorosa. Il caso clinico proposto \ue8 riferito ad una paziente (A.) affetta da SFM inviata presso il Servizio di Psicoterapia del Dipartimento di Salute Mentale, Fondazione IRCSS Ca\u2019 Granda Ospedale Maggiore Policlinico di Milano. La paziente effettua una valutazione clinico-diagnostica al baseline (T0) che prevede la somministrazione della seguente batteria testale: Interviste Cliniche Semi-Strutturate per diagnosi secondo DSM-IV TR (SCID I e II), Hamilton Rating scale for Depression and Anxiety (HAM-D e HAM-A), Tema Relazionale Conflittuale Centrale (CCRT), Toronto Alexithymia Scale (TAS-20), Symptom Checklist (SCL-90-R) ed Inventory of Interpersonal Problems (IIP-127). Tale valutazione ha evidenziato un quadro psicopatologico caratterizzato da incapacit\ue0 di individuare e mentalizzare i propri stati emotivi e tendenza alla somatizzazione. In considerazione di quanto emerso e dei dati anamnestici della paziente, viene proposta una psicoterapia psicodinamica breve (STPP), della durata di 9 mesi, finalizzata al conseguimento di una maggiore consapevolezza di s\ue8 e delle proprie emozioni attraverso un focus centrato sul miglioramento delle relazioni interpersonali. Al termine del percorso psicoterapico la paziente esegue una valutazione follow-up (T1) con la medesima batteria testale utilizzata al T0. Le valutazioni al T1 non mostrano variazioni psicopatologiche clinicamente significative, tuttavia la paziente riferisce un vissuto soggettivo positivo, riportando la percezione di un miglioramento della sintomatologia algica cronica derivante da una maggior individuazione delle proprie sensazioni somatiche. Verranno illustrati brani delle sedute psicoterapeutiche per approfondire le principali tematiche cliniche

Rothmund-Thomson syndrome: Insights from new patients on the genetic variability underpinning clinical presentation and cancer outcome

Biallelic mutations in RECQL4 gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic RECQL4 variants by in silico predictions and transcripts analyses. Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient #38 is heterozygous for c.2412_2414del, no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype

Differential signature of the centrosomal MARK4 isoforms in glioma

Background: MAP/microtubule affinity-regulating kinase 4 (MARK4) is a serine-threonine kinase expressed in two spliced isoforms, MARK4L and MARK4S, of which MARK4L is a candidate for a role in neoplastic transformation. Methods: We performed mutation analysis to identify sequence alterations possibly affecting MARK4 expression. We then investigated the MARK4L and MARK4S expression profile in 21 glioma cell lines and 36 tissues of different malignancy grades, glioblastoma-derived cancer stem cells (GBM CSCs) and mouse neural stem cells (NSCs) by real-time PCR, immunoblotting and immunohistochemistry. We also analyzed the sub-cellular localisation of MARK4 isoforms in glioma and normal cell lines by immunofluorescence. Results: Mutation analysis rules out sequence variations as the cause of the altered MARK4 expression in glioma. Expression profiling confirms that MARK4L is the predominant isoform, whereas MARK4S levels are significantly decreased in comparison and show an inverse correlation with tumour grade. A high MARK4L/MARK4S ratio also characterizes undifferentiated cells, such as GBM CSCs and NSCs. Accordingly, only MARK4L is expressed in brain neurogenic regions. Moreover, while both MARK4 isoforms are localised to the centrosome and midbody in glioma and normal cells, the L isoform exhibits an additional nucleolar localisation in tumour cells. Conclusions: The observed switch towards MARK4L suggests that the balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. Moreover, the MARK4L nucleolar localisation in tumour cells features this MARK4 isoform as a nucleolus-associated tumour marker