Interplay of Mre11 Nuclease with Dna2 plus Sgs1 in Rad51-Dependent Recombinational Repair

The Mre11/Rad50/Xrs2 complex initiates IR repair by binding to the end of a double-strand break, resulting in 5′ to 3′ exonuclease degradation creating a single-stranded 3′ overhang competent for strand invasion into the unbroken chromosome. The nuclease(s) involved are not well understood. Mre11 encodes a nuclease, but it has 3′ to 5′, rather than 5′ to 3′ activity. Furthermore, mutations that inactivate only the nuclease activity of Mre11 but not its other repair functions, mre11-D56N and mre11-H125N, are resistant to IR. This suggests that another nuclease can catalyze 5′ to 3′ degradation. One candidate nuclease that has not been tested to date because it is encoded by an essential gene is the Dna2 helicase/nuclease. We recently reported the ability to suppress the lethality of a dna2Δ with a pif1Δ. The dna2Δ pif1Δ mutant is IR-resistant. We have determined that dna2Δ pif1Δ mre11-D56N and dna2Δ pif1Δ mre11-H125N strains are equally as sensitive to IR as mre11Δ strains, suggesting that in the absence of Dna2, Mre11 nuclease carries out repair. The dna2Δ pif1Δ mre11-D56N triple mutant is complemented by plasmids expressing Mre11, Dna2 or dna2K1080E, a mutant with defective helicase and functional nuclease, demonstrating that the nuclease of Dna2 compensates for the absence of Mre11 nuclease in IR repair, presumably in 5′ to 3′ degradation at DSB ends. We further show that sgs1Δ mre11-H125N, but not sgs1Δ, is very sensitive to IR, implicating the Sgs1 helicase in the Dna2-mediated pathway

Evans Syndrome in Childhood: Long Term Follow-Up and the Evolution in Primary Immunodeficiency or Rheumatological Disease

Evans syndrome (ES) is a rare but challenging condition, characterized by recurrent and refractory cytopenia episodes. Recent discoveries highlighted that an appropriate diagnostic workup is fundamental to identify an underlying immune dysregulation such as primary immunodeficiencies or a rheumatological disease. We hereby describe clinical features and laboratory results of 12 pediatric patients affected by ES referred to the Pediatric Onco-Hematology Unit of Bologna. Patients experienced a median of four acute episodes of cytopenia with 9 years as median age at the onset of symptoms. In 8/12 (67%) patients an underlying etiology, primary immunodeficiencies, or rheumatological disease was identified. In 4/12 children, other immune manifestations were associated (Thyroiditis, Celiac disease, Psoriasis, Vitiligo, Myositis, Membranoproliferative Glomerulonephritis). ES remained the primary diagnosis in four patients (33%). At a median follow-up time of 4 years, 5/12 (42%) patients revealed a chronic ITP, partially responsive to second line therapy. Immunoglobulin Replacement Therapy (IRT) was effective with a good hematological values control in three patients with a secondary ES (ALPS, CVID, and a patient with Rubinstein Taybi Syndrome and a progressive severe B cell deficiency with hypogammaglobulinemia). Our experience highlights that, in pediatric patients, ES is often only the first manifestation of an immunological or rheumatological disease, especially when cytopenias are persistent or resistant to therapy, with an early-onset or when are associated with lymphadenopathy

A kilobit hidden SNFS discrete logarithm computation

We perform a special number field sieve discrete logarithm computation in a 1024-bit prime field. To our knowledge, this is the first kilobit-sized discrete logarithm computation ever reported for prime fields. This computation took a little over two months of calendar time on an academic cluster using the open-source CADO-NFS software. Our chosen prime $p$ looks random, and $p--1$ has a 160-bit prime factor, in line with recommended parameters for the Digital Signature Algorithm. However, our p has been trapdoored in such a way that the special number field sieve can be used to compute discrete logarithms in $\mathbb{F}\_p^*$ , yet detecting that p has this trapdoor seems out of reach. Twenty-five years ago, there was considerable controversy around the possibility of back-doored parameters for DSA. Our computations show that trapdoored primes are entirely feasible with current computing technology. We also describe special number field sieve discrete log computations carried out for multiple weak primes found in use in the wild. As can be expected from a trapdoor mechanism which we say is hard to detect, our research did not reveal any trapdoored prime in wide use. The only way for a user to defend against a hypothetical trapdoor of this kind is to require verifiably random primes

ISO spectroscopy of gas and dust: from molecular clouds to protoplanetary disks

Observations of interstellar gas-phase and solid-state species in the 2.4-200 micron range obtained with the spectrometers on board the Infrared Space Observatory are reviewed. Lines and bands due to ices, polycyclic aromatic hydrocarbons, silicates and gas-phase atoms and molecules (in particular H2, CO, H2O, OH and CO2) are summarized and their diagnostic capabilities illustrated. The results are discussed in the context of the physical and chemical evolution of star-forming regions, including photon-dominated regions, shocks, protostellar envelopes and disks around young stars.Comment: 56 pages, 17 figures. To appear in Ann. Rev. Astron. Astrophys. 2004. Higher resolution version posted at http://www.strw.leidenuniv.nl/~ewine/araa04.pd

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal subregions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype

Localization-delocalization transition of a reaction-diffusion front near a semipermeable wall

The A+B --> C reaction-diffusion process is studied in a system where the reagents are separated by a semipermeable wall. We use reaction-diffusion equations to describe the process and to derive a scaling description for the long-time behavior of the reaction front. Furthermore, we show that a critical localization-delocalization transition takes place as a control parameter which depends on the initial densities and on the diffusion constants is varied. The transition is between a reaction front of finite width that is localized at the wall and a front which is detached and moves away from the wall. At the critical point, the reaction front remains at the wall but its width diverges with time [as t^(1/6) in mean-field approximation].Comment: 7 pages, PS fil

A novel long non-coding natural antisense RNA is a negative regulator of Nos1 gene expression

Long non-coding natural antisense transcripts (NATs) are widespread in eukaryotic species. Although recent studies indicate that long NATs are engaged in the regulation of gene expression, the precise functional roles of the vast majority of them are unknown. Here we report that a long NAT (Mm-antiNos1 RNA) complementary to mRNA encoding the neuronal isoform of nitric oxide synthase (Nos1) is expressed in the mouse brain and is transcribed from the non-template strand of the Nos1 locus. Nos1 produces nitric oxide (NO), a major signaling molecule in the CNS implicated in many important functions including neuronal differentiation and memory formation. We show that the newly discovered NAT negatively regulates Nos1 gene expression. Moreover, our quantitative studies of the temporal expression profiles of Mm-antiNos1 RNA in the mouse brain during embryonic development and postnatal life indicate that it may be involved in the regulation of NO-dependent neurogenesis

Social, environmental and psychological factors associated with objective physical activity levels in the over 65s

Objective: To assess physical activity levels objectively using accelerometers in community dwelling over 65 s and to examine associations with health, social, environmental and psychological factors. Design: Cross sectional survey. Setting: 17 general practices in Scotland, United Kingdom. Participants: Random sampling of over 65 s registered with the practices in four strata young-old (65–80 years), old-old (over 80 years), more affluent and less affluent groups. Main Outcome Measures: Accelerometry counts of activity per day. Associations between activity and Theory of Planned Behaviour variables, the physical environment, health, wellbeing and demographic variables were examined with multiple regression analysis and multilevel modelling. Results: 547 older people (mean (SD) age 79(8) years, 54% female) were analysed representing 94% of those surveyed. Accelerometry counts were highest in the affluent younger group, followed by the deprived younger group, with lowest levels in the deprived over 80 s group. Multiple regression analysis showed that lower age, higher perceived behavioural control, the physical function subscale of SF-36, and having someone nearby to turn to were all independently associated with higher physical activity levels (R2 = 0.32). In addition, hours of sunshine were independently significantly associated with greater physical activity in a multilevel model. Conclusions: Other than age and hours of sunlight, the variables identified are modifiable, and provide a strong basis for the future development of novel multidimensional interventions aimed at increasing activity participation in later life.Publisher PDFPeer reviewe

Bounding wide composite vector resonances at the LHC

In composite Higgs models (CHMs), electroweak precision data generically push colourless composite vector resonances to a regime where they dominantly decay into pairs of light top partners. This greatly attenuates their traces in canonical collider searches, tailored for narrow resonances promptly decaying into Standard Model final states. By reinterpreting the CMS same-sign dilepton (SS2$\ell$) analysis at the Large Hadron Collider (LHC), originally designed to search for top partners with electric charge $5/3$, we demonstrate its significant coverage over this kinematical regime. We also show the reach of the 13 TeV run of the LHC, with various integrated luminosity options, for a possible upgrade of the SS2$\ell$ search. The top sector of CHMs is found to be more fine-tuned in the presence of colourless composite resonances in the few TeV range.Comment: 9 pages, 5 figures. Minor corrections for publication in JHE