A stochastic model for the stepwise motion in actomyosin dynamics

A jump-diffusion process is proposed to describe the displacements performed by single myosin heads along actin filaments during the rising phases. The process consists of the superposition of a Wiener and a jump process, with jumps originated by sequences of Poisson-distributed energy-supplying pulses. In a previous paper, the amplitude of the jumps was described by a mixture of two Gaussian distributions. To embody the effects of ATP hydrolysis, we now refine such a model by assuming that the jumps' amplitude is described by a mixture of three Gaussian distributions. This model has been inspired by the experimental data of T. Yanagida and his co-workers concerning observations at single molecule processes level.Comment: 9 pages, 4 figure

Permanent diabetes mellitus in the first year of life

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Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies

Sickle cell disease (SCD) is due to a mutation in the O-globin gene causing production of the toxic sickle hemoglobin (HbS; ex2OS2). Transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vectors (LVs) expressing an anti-sickling O-globin (OAS) is a promising treatment; however, it is only partially effective, and patients still present elevated HbS levels. Here, we developed a bifunctional LV expressing OAS3-globin and an artificial microRNA (amiRNA) specifically downregulating OS-globin expression with the aim of reducing HbS levels and favoring OAS3 incorporation into Hb tetramers. Efficient transduction of SCD HSPCs by the bifunctional LV led to a substantial decrease of OS-globin transcripts in HSPC-derived erythroid cells, a significant reduction of HbS+ red cells, and effective correction of the sickling phenotype, outperforming OAS gene addition and BCL11A gene silencing strategies. The bifunctional LV showed a standard integration profile, and neither HSPC viability, engraftment, and multilineage differentiation nor the erythroid transcriptome and miRNAome were affected by the treatment, confirming the safety of this therapeutic strategy. In conclusion, the combination of gene addition and gene silencing strategies can improve the efficacy of current LV-based therapeutic approaches without increasing the mutagenic vector load, thus representing a novel treatment for SCD

Testing of optimal filters for gravitational wave signals: An experimental implementation

We have implemented likelihood testing of the performance of an optimal filter within the online analysis of AURIGA, a sub-Kelvin resonant-bar gravitational wave detector. We demonstrate the effectiveness of this technique in discriminating between impulsive mechanical excitations of the resonant-bar and other spurious excitations. This technique also ensures the accuracy of the estimated parameters such as the signal-to-noise ratio. The efficiency of the technique to deal with non-stationary noise and its application to data from a network of detectors are also discussed

Optimal management of constipation associated with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common chronic functional disorder of the gastrointestinal tract, meanly characterized by recurrent abdominal pain or discomfort and altered bowel habit. It is a complex disorder involving biological, environmental, and psychosocial factors. The diagnosis is achieved according to the Rome III criteria provided that organic causes have been excluded. Although IBS does not constitute a life-threatening condition, it has a remarkable prevalence and profoundly reduces the quality of life with burdening socioeconomic costs. One of the principal concerns about IBS is the lack of effective therapeutic options. Up to 40% of patients are not satisfied with any available medications, especially those suffering from chronic constipation. A correct management of IBS with constipation should evolve through a global approach focused on the patient, starting with careful history taking in order to assess the presence of organic diseases that might trigger the disorder. Therefore, the second step is to examine lifestyle, dietary habits, and psychological status. On these bases, a step-up management of disease is recommended: from fiber and bulking agents, to osmotic laxative drugs, to new molecules like lubiprostone and linaclotide. Although new promising tools for relief of bowel-movement-related symptoms are being discovered, a dedicated doctor\u2013patient relationship still seems to be the key for succes

Initial operation of the International Gravitational Event Collaboration

The International Gravitational Event Collaboration, IGEC, is a coordinated effort by research groups operating gravitational wave detectors working towards the detection of millisecond bursts of gravitational waves. Here we report on the current IGEC resonant bar observatory, its data analysis procedures, the main properties of the first exchanged data set. Even though the available data set is not complete, in the years 1997 and 1998 up to four detectors were operating simultaneously. Preliminary results are mentioned.Comment: 8 pages, 2 figures, 3 tables; Proceeding of the GWDAW'99. Submitted to the International Journal of Modern Physic

Performance of Delta4 Phantom+ using Flattening-Filter and Flattening Filter-Free beams

EnThe goal of this study was to evaluate the performances of the new pre-treatment system Delta4 Phantom+ in terms of a stable and sensitive tool for achieving a reliable verification. Delta4+ was evaluated for verification with 6FFFMV beams using static beam arrangement. The accelerator output was monitored with the ionization chamber. The device was tested for dose-rate dependence, linearity and stability using its daily output correction. The response of Delta4+ was evaluated for energy 6FFFMV, measuring the gamma index of four Volumetric Modulated Arc Therapy (VMAT) plan. The response of Delta4+ as a function of accelerator dose rate is in agreement with the ionization chamber with a difference smaller than 0,1%. The output is constant for different MU. VMAT plan analysis show values within 98,3%-100% with a threshold of 3%-3mm, while with a threshold of 2%-2mm the values are within 93,5%-97,5%. Delta4+ is an accurate device. For all the measurements made, uncertainties below 1% were obtained.ItLo scopo di questo studio è stato quello di valutare la risposta in termini di stabilità e sensibilità del nuovo sistema pre-trattamento Delta4 Phantom+. La risposta del sistema è stato studiata utilizzando fasci di fotoni da 6MVsenza filtro di flattening (6FFFMV). L'output dell'acceleratore è stato monitorato con una camera a ionizzazione. La dipendenza dal dose rate, la linearità e la stabilità sono state verificate utilizzando il fattore di correzione giornaliera fornito dal sistema. La risposta è stata verificata su 4 piani di trattamento con tecnica VMAT. La risposta del Delta4+ al variare del dose rate è in accordo con quella della camera a ionizzazione con una scarto minore dello 0.1%. La risposta al variare delle UM è costante con una differenza entro lo 0.4%. L'analisi dei piani VMAT mostra valori di indice gamma per soglia 3%-3mm compresi tra 98.3%-100%, mentre per 2%-2mm i valori sono tra 93,5%-97,5%. Il Delta4+ risulta essere un sistema accurato in quanto l'incertezza ottenuta su tutte le misure non supera l'1%

Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

: Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the -200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy - even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies

Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: an Italian multicenter study

OBJECTIVE— To estimate the prevalence of biopsy-confirmed celiac disease in Italian children and adolescents with type 1 diabetes and to assess whether age at onset of type 1 diabetes is independently associated with diagnosis of celiac disease. RESEARCH DESIGNANDMETHODS— The study group was a clinic-based cohort of children and adolescents with type 1 diabetes cared for in 25 Italian centers for childhood diabetes. Yearly screening for celiac disease was performed using IgA/IgG anti-gliadin and IgA anti-endomysium antibodies. RESULTS— Of the 4,322 children and adolescents (age 11.8 4.2 years) identified with type 1 diabetes, biopsy-confirmed celiac disease was diagnosed in 292 (prevalence 6.8%, 95% confidence interval [CI] 6.0 –7.6), with a higher risk seen in girls than in boys (odds ratio [OR] 1.93, 1.51–2.47). In 89% of these, diabetes was diagnosed before celiac disease. In logistic regression analyses, being younger at onset of diabetes, being female, and having a diagnosis of a thyroid disorder were independently associated with the risk of having diabetes and celiac disease. In comparison with subjects who were older than 9 years at onset of diabetes, subjects who were younger than 4 years at onset had an OR of 3.27 (2.20–4.85). CONCLUSIONS— We have provided evidence that 1) the prevalence of biopsy-confirmed celiac disease in children and adolescents with type 1 diabetes is high (6.8%); 2) the risk of having both diseases is threefold higher in children diagnosed with type 1 diabetes at age 4 years than in those age 9 years; and 3) girls have a higher risk of having both diseases than boys