An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis.

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitors. The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis.

Genetic mapping of species differences via in vitro crosses in mouse embryonic stem cells.

Discovering the genetic changes underlying species differences is a central goal in evolutionary genetics. However, hybrid crosses between species in mammals often suffer from hybrid sterility, greatly complicating genetic mapping of trait variation across species. Here, we describe a simple, robust, and transgene-free technique to generate "in vitro crosses" in hybrid mouse embryonic stem (ES) cells by inducing random mitotic cross-overs with the drug ML216, which inhibits the DNA helicase Bloom syndrome (BLM). Starting with an interspecific F1 hybrid ES cell line between the Mus musculus laboratory mouse and Mus spretus (∼1.5 million years of divergence), we mapped the genetic basis of drug resistance to the antimetabolite tioguanine to a single region containing hypoxanthine-guanine phosphoribosyltransferase (Hprt) in as few as 21 d through "flow mapping" by coupling in vitro crosses with fluorescence-activated cell sorting (FACS). We also show how our platform can enable direct study of developmental variation by rederiving embryos with contribution from the recombinant ES cell lines. We demonstrate how in vitro crosses can overcome major bottlenecks in mouse complex trait genetics and address fundamental questions in evolutionary biology that are otherwise intractable through traditional breeding due to high cost, small litter sizes, and/or hybrid sterility. In doing so, we describe an experimental platform toward studying evolutionary systems biology in mouse and potentially in human and other mammals, including cross-species hybrids.

Pregnancy Reduces Il33+ Hybrid Progenitor Accumulation in the Aged Mammary Gland.

Aging increases breast cancer risk while an early first pregnancy reduces a woman's life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary epithelial cells (MECs), but the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a differentiated cell state. Importantly, we uncover a minority population of Il33-expressing hybrid MECs with high cellular potency that accumulate in aged nulliparous mice but is significantly reduced in aged parous mice. Functionally, IL33 treatment of basal, but not luminal, epithelial cells from young mice phenocopies aged nulliparous MECs and promotes formation of organoids with Trp53 knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated loss of lineage integrity in the basal layer through a decrease in Il33+ hybrid MECs, potentially contributing to pregnancy-induced breast cancer protection.

Deep data mining reveals variable abundance and distribution of microbial reproductive manipulators within and among diverse host species.

Bacterial symbionts that manipulate the reproduction of their hosts are important factors in invertebrate ecology and evolution, and are being leveraged for host biological control. Infection prevalence restricts which biological control strategies are possible and is thought to be strongly influenced by the density of symbiont infection within hosts, termed titer. Current methods to estimate infection prevalence and symbiont titers are low-throughput, biased towards sampling infected species, and rarely measure titer. Here we develop a data mining approach to estimate symbiont infection frequencies within host species and titers within host tissues. We applied this approach to screen ~32,000 publicly available sequence samples from the most common symbiont host taxa, discovering 2,083 arthropod and 119 nematode infected samples. From these data, we estimated that Wolbachia infects approximately 44% of all arthropod and 34% of all nematode species, while other reproductive manipulators only infect 1-8% of arthropod and nematode species. Although relative titers within hosts were highly variable within and between arthropod species, a combination of arthropod host species and Wolbachia strain explained approximately 36% of variation in Wolbachia titer across the dataset. To explore potential mechanisms for host control of symbiont titer, we leveraged population genomic data from the model system Drosophila melanogaster. In this host, we found a number of SNPs associated with titer in candidate genes potentially relevant to host interactions with Wolbachia. Our study demonstrates that data mining is a powerful tool to detect bacterial infections and quantify infection intensities, thus opening an array of previously inaccessible data for further analysis in host-symbiont evolution.

Importance of Assessing Compliance with Conservative Treatment of Primary Hyperoxaluria Type 1: A Case Report of a Patient with I244T/c.969-3C>G Mutation.

INTRODUCTION: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited disorder that progresses to end-stage renal disease. Patients experience excessive urinary oxalate excretion, which causes nephrocalcinosis and recurrent urolithiasis. When the glomerular filtration rate declines, calcium oxalate accumulates in extrarenal tissues, causing end-organ damage. More than 190 responsible mutations have been documented, with some genotype-phenotype differences reported. Regardless of the genetic basis, prompt diagnosis and treatment are decisive for the long-term outcome. If the condition advances to chronic kidney disease stage 4 or 5, a combined liver-kidney transplant should be considered. CASE PRESENTATION: We describe a 5-month-old asymptomatic female patient with bilateral diffuse nephrocalcinosis and nephrolithiasis. Laboratory and genetic findings confirmed PH1. She was promptly administered conservative treatment consisting of high fluid intake, calcium oxalate crystallization inhibitors, and pyridoxine. Nephrocalcinosis and urolithiasis disappeared after 2 years of treatment. As far as we know, this is a unique case of a patient with an I244T/null mutation diagnosed after the neonatal period and with normal renal function, who remained asymptomatic during an 18-year follow-up. This case is also unique because of the long-term therapeutic success. DISCUSSION: Physicians need a high level of suspicion to diagnose this rare disease. It has been previously demonstrated that early conservative treatment improves long-term outcomes, averting preemptive transplant during childhood. This case report emphasizes the importance of encouraging compliance with this approach, reinforces the need for good physician-patient communication, and raises awareness of the problems that might arise during conservative PH1 treatment.

On the Distribution of Tract Lengths During Adaptive Introgression.

Admixture is increasingly being recognized as an important factor in evolutionary genetics. The distribution of genomic admixture tracts, and the resulting effects on admixture linkage disequilibrium, can be used to date the timing of admixture between species or populations. However, the theory used for such prediction assumes selective neutrality despite the fact that many famous examples of admixture involve natural selection acting for or against admixture. In this paper, we investigate the effects of positive selection on the distribution of tract lengths. We develop a theoretical framework that relies on approximating the trajectory of the selected allele using a logistic function. By numerically calculating the expected allele trajectory, we also show that the approach can be extended to cases where the logistic approximation is poor due to the effects of genetic drift. Using simulations, we show that the model is highly accurate under most scenarios. We use the model to show that positive selection on average will tend to increase the admixture tract length. However, perhaps counter-intuitively, conditional on the allele frequency at the time of sampling, positive selection will actually produce shorter expected tract lengths. We discuss the consequences of our results in interpreting the timing of the introgression of EPAS1 from Denisovans into the ancestors of Tibetans.

Bulk pollen sequencing reveals rapid evolution of segregation distortion in the male germline of Arabidopsis hybrids.

Genes that do not segregate in heterozygotes at Mendelian ratios are a potentially important evolutionary force in natural populations. Although the impacts of segregation distortion are widely appreciated, we have little quantitative understanding about how often these loci arise and fix within lineages. Here, we develop a statistical approach for detecting segregation distorting genes from the comprehensive comparison of whole genome sequence data obtained from bulk gamete versus somatic tissues. Our approach enables estimation of map positions and confidence intervals, and quantification of effect sizes of segregation distorters. We apply our method to the pollen of two interspecific F1 hybrids of Arabidopsis lyrata and A. halleri and we identify three loci across eight chromosomes showing significant evidence of segregation distortion in both pollen samples. Based on this, we estimate that novel segregation distortion elements evolve and achieve high frequencies within lineages at a rate of approximately one per 244,000 years. Furthermore, we estimate that haploid-acting segregation distortion may contribute between 10% and 30% of reduced pollen viability in F1 individuals. Our results indicate haploid acting factors evolve rapidly and dramatically influence segregation in F1 hybrid individuals.

Estimating the Timing of Multiple Admixture Pulses During Local Ancestry Inference.

Admixture, the mixing of genetically distinct populations, is increasingly recognized as a fundamental biological process. One major goal of admixture analyses is to estimate the timing of admixture events. Whereas most methods today can only detect the most recent admixture event, here, we present coalescent theory and associated software that can be used to estimate the timing of multiple admixture events in an admixed population. We extensively validate this approach and evaluate the conditions under which it can successfully distinguish one- from two-pulse admixture models. We apply our approach to real and simulated data of Drosophila melanogaster We find evidence of a single very recent pulse of cosmopolitan ancestry contributing to African populations, as well as evidence for more ancient admixture among genetically differentiated populations in sub-Saharan Africa. These results suggest our method can quantify complex admixture histories involving genetic material introduced by multiple discrete admixture pulses. The new method facilitates the exploration of admixture and its contribution to adaptation, ecological divergence, and speciation.

Docência voluntária na aposentadoria: transição entre o trabalho e o não trabalho / Voluntary teaching in retirement: a transition between work and non-work / Docencia voluntaria en la jubilación: transición entre el trabajo y el no trabajo

A atividade docente em instituições públicas federais possui particularidades que repercutem no momento da aposentadoria desses profissionais, levando muitos a permanecerem exercendo suas atividades de forma voluntária ao se aposentarem. O presente estudo foi desenvolvido com oito professores aposentados que permanecem em atividade profissional via adesão ao trabalho voluntário na Universidade Federal de Santa Catarina (UFSC). Evidenciou-se que a escolha por essa permanência se vincula ao significado atribuído ao trabalho docente e que tanto fatores de ordem pessoal quanto externos aos sujeitos influenciam tal decisão. Os resultados encontrados indicaram que a continuidade do exercício profissional docente se configura como forma de manutenção do modo habitual de viver e principalmente como uma transição em direção à desvinculação total das atividades desenvolvidas. Embora aposentados, os docentes exercem a docência voluntária como estratégia de bridge employment em direção ao desligamento definitivo do trabalho e da instituição.

The teaching activity in federal public institutions has peculiarities that reflect in the moment of these professionals' retirement, making many of them keep doing their teaching activities voluntarily when they retire. This study was developed along with eight retired professors who have remained in professional activity by means of doing volunteer work for Universidade Federal de Santa Catarina. It has been evidenced that the choice for this permanence is connected to the meaning given to teaching work and that personal facts, as well as external facts, influence such decision. The results found indicate that remaining in the teaching professional exercise is a way of keeping the usual way of living and mainly as a transition towards the total disconnecting from the developed activities. Although retired, the professors do volunteer teaching as a strategy of bridge employment towards the definitive disconnection from work and from the institution.

La actividad docente en instituciones públicas federales tienen particularidades que influencian en el momento de es os profesionales retirase, llevan do muchos a permaneceren ejerciendo sus actividades de enseñanza de manera voluntaria. Este estudio fue desarrollado junto a 8 (ocho) profesores jubilados que permanecen en actividad profesional a través de la adhesión al trabajo voluntario en la Universidad Federal de Santa Catarina. Se ha evidenciado que la elección de esa permanencia se vincula al significado atribuido al trabajo docente y tal cual factores de orden personal como factores externos a los sujetos influencian tal decisión. Los resultados encontrados indicaran que la continuidad del ejercicio profesional de docencia se configura como forma de manutención de la manera habitual de vivir y principalmente como una transición en dirección a la desvinculación total de las actividades ejercidas. A pesar de jubilados, los docentes ejercen la docencia voluntaria como estrategia de bridge employment en dirección al alejamiento del trabajo y de la institución.

Revisão da literatura latino-americana sobre aposentadoria e trabalho: perspectivas psicológicas / Review of latin american literature on retirement and work: psychological perspectives / Revisión de la literatura bibliográfica latinoamericana sobre jubilación y trabajo: perspectivas psicológicas

Este estudo teve como objetivo realizar revisão da literatura sobre aposentadoria e trabalho, a partir de perspectivas psicológicas, com base em artigos publicados em periódicos brasileiros e latino-americanos. Para tal, foi realizada a busca em três bases de dados eletrônicas (SciELO, LILACS e PePSIC), sem restrição de data inicial, com publicações até junho de 2016. Foram utilizados os termos "aposentadoria" e "trabalho" e suas versões em inglês e espanhol. Considerando os 42 artigos selecionados para análise, observou-se um significativo aumento do número de estudos sobre o tema nos últimos anos, com predominância de estudos empíricos - caracterizados como relatos de pesquisa - tanto qualitativos quanto quantitativos, sobretudo a respeito do tema "preparação para a aposentadoria". Destacou-se a necessidade da diversificação nas abordagens e dos métodos de pesquisa e intervenção sobre o tema na América Latina, a fim de favorecer a confiabilidade e abrangência dos resultados alcançados.

This study aimed to perform a literature review on retirement and work, from psychological perspectives, based on articles published in Brazilian and Latin American journals. For this purpose, a search in three electronic databases (SciELO, LILACS, and PePSIC) was made, regardless of initial date, for publications dated until June 2014, using the Portuguese-language terms for "retirement" and "work", and their versions in English and Spanish. Considering the 42 articles selected for analysis, a significant increase in the number of studies on the subject was observed in recent years, with a predominance of empirical qualitative and quantitative studies characterized as research reports, especially on the topic of "Preparation for Retirement". The need is emphasized for diversifying the theoretical approaches and methods of research and intervention on the subject, in Latin America, to promote the reliability and completeness of results.

Este estudio tuvo como objetivo realizar una revisión de la literatura bibliográfica latinoamericana sobre jubilación y trabajo, desde una perspectiva psicológica, con base en artículos publicados en revistas brasileñas y latinoamericanas. Para tanto, se hizo una búsqueda en tres bases de datos electrónicos (SciELO, LILACS y PePSIC) sin restricción de fecha inicial, y publicados hasta junio de 2016. Fueron utilizados los términos "jubilación" y "trabajo" y sus versiones en inglés y español. Considerando los 42 artículos seleccionados para el análisis, se observó un aumento significativo del número de estudios sobre el referido tema en los últimos años, predominantemente de los estudios empíricos, caracterizados como informes de investigación, cualitativos y cuantitativos, especialmente respecto del tema "Preparación para la jubilación". Hay la necesidad de diversificar los enfoques y métodos de investigación e intervención concerniente al tema en Latinoamérica, para facilitar la confiabilidad y el abarcamiento de los resultados.

Coworking como modalidade e espaço de trabalho: uma análise bibliométrica / Coworking as working mode and space: A bibliometric analysis

Coworking é a modalidade de trabalho na qual profissionais de diferentes áreas sem local fixo de trabalho buscam ampliar sua rede de contatos, compartilhando espaço e serviços de escritório. Considerando essa realidade, o artigo apresenta resultados de análise bibliométrica sobre o tema coworking, a qual objetivou identificar estudos e seus enfoques no trato da temática. Foram analisados oito artigos, identificados por meio de busca sistematizada em bases de dados, a qual possibilitou identificar as áreas do conhecimento que vêm estudando o coworking, a metodologia de pesquisa utilizada, os períodos das publicações e seus países de origem. Os resultados foram categorizados conforme a abordagem relacionada ao tema. Os artigos identificados foram produzidos na França, Inglaterra, Estados Unidos, Austrália, Alemanha e Espanha, e publicados majoritariamente em 2012, sendo, em sua maioria, oriundos da área de informática. Predominaram estudos de abordagem qualitativa, associando o tema coworking a relações de trabalho, a novas formas de trabalho, ao espaço físico, ao perfil dos coworkers e à responsabilidade social.

Coworking is the working mode in which professionals from different areas without fixed workplace seek to expand their networking by sharing the same space and business services. Considering this fact, the article presents results of a bibliometric analysis on the coworking subject which aimed to identify studies and their approaches in the treatment of this theme. Eight articles were analyzed, identified through systematic search in databases, which enabled us to identify the areas of knowledge that have been studying coworking, research methodology used, periods of publications, and the countries of origin of the studies. Results were divided into categories according to the related approach to the subject. The articles identified were produced in France, England, USA, Australia, Germany, and Spain, and were published mainly in 2012, coming mostly from the computer science area. Studies conducted through qualitative approach predominated, associating the theme coworking to labor relations, new ways of working, physical space, profile of coworkers, and social responsibility.