Genetically dissecting the meiotic checkpoint active during prophase I in female mice

Females have a non-renewable number of gametes at birth. These oocytes are extremely sensitive to environmental factors that generate DNA damage. Oocyte death due to DNA damage can result in infertility and ovarian failure. In contrast to postnatal oocytes, at earlier stages of gametogenesis these cells withstand hundreds of developmentally programmed DNA breaks (DSBs). During the first meiotic division these DSBs promote synapsis (homologous chromosomes pairing), and recombination, which are both essential for sexual reproduction and environmental fitness. However, DSB repair and synapsis need to occur in a timely manner, or the quality of the gametes becomes compromised. The mechanisms that guarantee oocyte quality were hypothesized to operate through two independent pathways: one that surveys DNA integrity, and the other synapsis. However, I present experimental evidence that oocytes defective for either DNA repair or synapsis are eliminated by the same DNA damage response. Furthermore, through the detailed analysis of DNA repair dynamics, I provide evidence that the protein HORMAD2, which localizes to unsynapsed chromosomes, regulates DSB-repair. I hypothesize that HORMAD2 interferes with repair by preventing broken DNA from using the sister chromatid as a repair template. This “block to sister-chromatid repair” (BSCR) assures that the homologous chromosome is the substrate of choice. Whereas BSCR guarantees homologous recombination, it also prevents unsynapsed chromosomes from fixing DSBs. Thus, failure to synapse will result in persistent DSBs. Since DNA damage causes oocyte death postnatally, unsynapsed chromosome will trigger the DNA damage checkpoint. Through the understanding of this checkpoint, I was able to test if the transient inhibition of the DNA damage checkpoint protein (CHK2) prevents oocyte death. My finding that oocyte death was prevented, and fertility was preserved, provides evidence that chemically protecting oocyte from DNA damaging agents is a viable clinical approach. This result will hopefully translate into a treatment to delay ovarian failure. Taken together these results have implications on our current understanding of the prophase I checkpoint. TEACHING AS RESEARCH My interest in improving teaching strategies led me to research the qualitative outcome of using a novel teaching tool during the laboratory section of a histology course. I tested an interactive response system (IRS) as formative assessment tool. I found that IRS results in a positive experience, however my study was not able to detect quantitative difference on students’ grades was detected

Primordial Black Hole Evaporation and Spontaneous Dimensional Reduction

Several different approaches to quantum gravity suggest the effective dimension of spacetime reduces from four to two near the Planck scale. In light of such evidence, this letter re-examines the thermodynamics of primordial black holes (PBHs) in specific lower-dimensional gravitational models. Unlike in four dimensions, \done-D black holes radiate with power P \sim \Mbh^2, while it is known no $(2+1)-$D (BTZ) black holes can exist in a non-anti-deSitter universe. This has important relevance to the PBH population size and distribution, and consequently on cosmological evolution scenarios. The number of PBHs that have evaporated to present day is estimated, assuming they account for all dark matter. Entropy conservation during dimensional transition imposes additional constraints. If the cosmological constant is non-negative, no black holes can exist in the $(2+1)$-dimensional epoch, and consequently a $(1+1)$-dimensional black hole will evolve to become a new type of remnant. Although these results are conjectural and likely model-dependent, they open new questions about the viability of PBHs as dark matter candidates.Comment: 20 pp, 1 figure; title changed and discussion significantly expanded; to appear in Phys. Lett.

Meralgia paresthetica by compression from a modeling girdle

Meralgia paresthetica is characterized by pain, paresthesia or burning sensation, and reduction of tactile and pain sensitivity in the anterolateral surface of the thigh. This disability is caused by a neuropathy of the lateral femoral cutaneous nerve (LFCN). Conservative treatment is often successful at relieving the symptoms in the majority of patients. We describe the case of a 44-year-old patient who presented with these symptoms caused by postoperative use of a surgical girdle after aesthetic surgery

A modular RNA delivery system comprising spherical nucleic acids built on endosome-escaping polymeric nanoparticles

Nucleic acid therapeutics require delivery systems to reach their targets. Key challenges to be overcome include avoidance of accumulation in cells of the mononuclear phagocyte system and escape from the endosomal pathway. Spherical nucleic acids (SNAs), in which a gold nanoparticle supports a corona of oligonucleotides, are promising carriers for nucleic acids with valuable properties including nuclease resistance, sequence-specific loading and control of receptor-mediated endocytosis. However, SNAs accumulate in the endosomal pathway and are thus vulnerable to lysosomal degradation or recycling exocytosis. Here, an alternative SNA core based on diblock copolymer PMPC25–PDPA72 is investigated. This pH-sensitive polymer self-assembles into vesicles with an intrinsic ability to escape endosomes via osmotic shock triggered by acidification-induced disassembly. DNA oligos conjugated to PMPC25–PDPA72 molecules form vesicles, or polymersomes, with DNA coronae on luminal and external surfaces. Nucleic acid cargoes or nucleic acid-tagged targeting moieties can be attached by hybridization to the coronal DNA. These polymeric SNAs are used to deliver siRNA duplexes against C9orf72, a genetic target with therapeutic potential for amyotrophic lateral sclerosis, to motor neuron-like cells. By attaching a neuron-specific targeting peptide to the PSNA corona, effective knock-down is achieved at doses of 2 particles per cell

Obtaining the structure factors for an epitaxial film using Cu X-ray radiation

Determining atomic positions in thin films by X-ray diffraction is, at present, a task reserved for synchrotron facilities. Here an experimental method is presented which enables the determination of the structure factor amplitudes of thin films using laboratory-based equipment (Cu K[alpha] radiation). This method was tested using an epitaxial 130 nm film of CuMnAs grown on top of a GaAs substrate, which unlike the orthorhombic bulk phase forms a crystal structure with tetragonal symmetry. From the set of structure factor moduli obtained by applying this method, the solution and refinement of the crystal structure of the film has been possible. The results are supported by consistent high-resolution scanning transmission electron microscopy and stoichiometry analyses

Análise das possíveis diferenças entre contratantes e contratados em terceirização de serviços de software segundo a métrica de análise de ponto de função

This study on which this article is based analyzed possible differences in the outsourcing contracts for the development of information systems – IS on the basis of the metric of the Function Points Analysis – FPA. Thus, an evaluation instrument was developed to analyze its most relevant aspects. The next step consisted of the analysis of contracts and of interviews with IS specialists. Finally, the considerations of the latter, allied to the specific literature on contracts, resulted in an instrument similar to a Likert scale with 16 assertions, applied in a sample of 82 respondents who had FPA certification or worked in contract management. The scale was validated through the method of exploratory factorial analysis of the main components. Furthermore, a discriminating analysis of three different characteristics of the sample respondents in relation to the factors generated by the factorial analysis was made, which did not show significant differences. In the analysis of the differences between the categorical variables of the respondents and the assertions, only two assertions presented significant differences with regard to the party in the contract and the nature of the work (assertion 15 in the two aspects and assertion 11 only with regard to the party in the contract). As far as the time of experience in the function is concerned, no significant difference was identified in any of the assertions. In terms of conclusion, the study identified the need for clarity and objectivity in the contracts and software services, as well as the need for a better definition of the stakeholders in relation to their roles in the negotiations. Key words: metric of software, function point analysis, software outsourcing contracts, measurement of attitudes, multivariate data analysis.O objetivo deste estudo é a avaliação das possíveis diferenças nos contratos de terceirização para o desenvolvimento de sistemas de informação – SI, baseada em métricas de Análise de Pontos de Função – APF. Assim sendo, foi desenvolvido um instrumento de avaliação que analisasse seus aspectos mais relevantes. Procedeu-se, então, à análise de contratos e à realização de entrevistas com especialistas da área. Por fim, as considerações destes, aliadas à literatura específica de contratos, resultaram em um instrumento do tipo escala de Likert com 16 assertivas, aplicado em uma amostra de 82 respondentes que possuem certificação de APF ou que atuam na gestão de contratos. A escala foi validada através do método de análise fatorial exploratória baseada nos componentes principais. Também, procedeu-se à análise discriminante de três características dos sujeitos em relação aos fatores gerados na análise fatorial, que não apresentou diferenças significativas. Da análise das diferenças entre as variáveis categóricas dos respondentes e as assertivas, somente duas assertivas apresentaram diferenças significativas com relação à parte no contrato e natureza do trabalho (assertiva 15, nos dois aspectos e assertiva 11, somente com relação à parte no contrato). Com relação ao tempo de experiência na função, não se identificou diferença significativa em nenhuma das assertivas. Pela conclusão do estudo constata-se a necessidade de clareza e objetividade nos contratos e dos serviços de software, assim como a necessidade de maior definição dos envolvidos quanto aos seus papéis nas negociações. Palavras-chave: métrica de software, análise de ponto de função, contratos de terceirização, mensuração de atitudes, análise multivariada de dados

Análise das possíveis diferenças entre contratantes e contratados em terceirização de serviços de software segundo a métrica de análise de ponto de função

This study on which this article is based analyzed possible differences in the outsourcing contracts for the development of information systems – IS on the basis of the metric of the Function Points Analysis – FPA. Thus, an evaluation instrument was developed to analyze its most relevant aspects. The next step consisted of the analysis of contracts and of interviews with IS specialists. Finally, the considerations of the latter, allied to the specific literature on contracts, resulted in an instrument similar to a Likert scale with 16 assertions, applied in a sample of 82 respondents who had FPA certification or worked in contract management. The scale was validated through the method of exploratory factorial analysis of the main components. Furthermore, a discriminating analysis of three different characteristics of the sample respondents in relation to the factors generated by the factorial analysis was made, which did not show significant differences. In the analysis of the differences between the categorical variables of the respondents and the assertions, only two assertions presented significant differences with regard to the party in the contract and the nature of the work (assertion 15 in the two aspects and assertion 11 only with regard to the party in the contract). As far as the time of experience in the function is concerned, no significant difference was identified in any of the assertions. In terms of conclusion, the study identified the need for clarity and objectivity in the contracts and software services, as well as the need for a better definition of the stakeholders in relation to their roles in the negotiations. Key words: metric of software, function point analysis, software outsourcing contracts, measurement of attitudes, multivariate data analysis.O objetivo deste estudo é a avaliação das possíveis diferenças nos contratos de terceirização para o desenvolvimento de sistemas de informação – SI, baseada em métricas de Análise de Pontos de Função – APF. Assim sendo, foi desenvolvido um instrumento de avaliação que analisasse seus aspectos mais relevantes. Procedeu-se, então, à análise de contratos e à realização de entrevistas com especialistas da área. Por fim, as considerações destes, aliadas à literatura específica de contratos, resultaram em um instrumento do tipo escala de Likert com 16 assertivas, aplicado em uma amostra de 82 respondentes que possuem certificação de APF ou que atuam na gestão de contratos. A escala foi validada através do método de análise fatorial exploratória baseada nos componentes principais. Também, procedeu-se à análise discriminante de três características dos sujeitos em relação aos fatores gerados na análise fatorial, que não apresentou diferenças significativas. Da análise das diferenças entre as variáveis categóricas dos respondentes e as assertivas, somente duas assertivas apresentaram diferenças significativas com relação à parte no contrato e natureza do trabalho (assertiva 15, nos dois aspectos e assertiva 11, somente com relação à parte no contrato). Com relação ao tempo de experiência na função, não se identificou diferença significativa em nenhuma das assertivas. Pela conclusão do estudo constata-se a necessidade de clareza e objetividade nos contratos e dos serviços de software, assim como a necessidade de maior definição dos envolvidos quanto aos seus papéis nas negociações. Palavras-chave: métrica de software, análise de ponto de função, contratos de terceirização, mensuração de atitudes, análise multivariada de dados

A multistep process for the dispersal of a Y chromosomal lineage in the Mediterranean area

Tn this work we focus on a microsatellite-defined Y-chromosomal lineage (network 1.2) identified by us and reported in previous studies, whose geographic distribution and antiquity appear to be compatible with the Neolithic spread of farmers. Here, we set network 1.2 in the Y-chromosomal phylogenetic tree, date it with respect to other lineages associated with the same movements by other authors, examine its diversity by means of tri- and tetranucleotide loci and discuss the implications hi reconstructing the spread of this group of chromosomes in the Mediterranean area. Our results define a tripartite phylogeny wit-bin HG 9 (Rosser et al. 2000) with the deepest branching defined by alleles T (Haplogroup Eu 10) or G (Haplogroup Eu9) at M172 (Semino et al. 2000), and a subsequent branching within Eu9 defined by network 1.2. Population distributions of HG 9 and network 1.2 show that their occurrence in the surveyed area is not due to the spread of people from a single parental population but, rather, to a process punctuated by at least two phases. Our data identify the wide area of the Balkans, Aegean and Anatolia as the possible homeland harbouring the largest variation within network 1.2. The use of recently proposed tests based on the stepwise mutation model suggests that its spread was associated to a population expansion, xvith a high rate of male gene flow in the Turkish Greek area