With Strings Attached: Grandparent-provided child care, fertility, and female labour market outcomes

Grandparents are regular providers of free child care. Similar to any other form of child care, availability of grandparent-provided child care affects fertility and labor market decisions of women positively. We find that women in Germany, residing close to parents or in-laws are more likely to have children and that as mothers they are more likely to hold a regular part- or fulltime job. However, different from any other type of child care, for individuals to enjoy grandparent-provided child care on a regular basis, residence choices must coincide with those of parents or in-laws. Thus while living close provides access to free child care, it imposes costly spatial restrictions. We find that hourly wages of mothers residing close to parents or in-laws are lower compared to those residing further away, and having relatives taking care of ones' children increases the probability of having to commute. We build a general equilibrium model of residence choice, fertility decisions, and female labor force participation that can account for the relationships between grandparent-provided child care, fertility and female labor market outcomes. We simulate our model to analyze how women's decisions on residence, fertility, and labor force participation change under distinct scenarios regarding availability of grandparent-provided child care and different family policies

With strings attached: grandparent-provided child care, fertility, and female labor market outcomes

Grandparents are regular providers of free child care. Similar to any other form of child care, availability of grandparent-provided child care affects fertility and labor market decisions of women positively. We find that women in Germany, residing close to parents or in-laws are more likely to have children and that as mothers they are more likely to hold a regular part-or fulltime job. However, different from any other type of child care, for individuals to enjoy grandparent-provided child care on a regular basis, residence choices must coincide with those of parents or in-laws. Thus while living close provides access to free child care, it imposes costly spatial restrictions. We find that hourly wages of mothers residing close to parents or in-laws are lower compared to those residing further away, and having relatives taking care of ones' children increases the probability of having to commute. We build a general equilibrium model of residence choice, fertility decisions, and female labor force participation that can account for the relationships between grandparent-provided child care, fertility and female labor market outcomes. We simulate our model to analyze how women's decisions on residence, fertility, and labor force participation change under distinct scenarios regarding availability of grandparent provided childcare and different family policies

Arsenophonus, an emerging clade of intracellular symbionts with a broad host distribution

<p>Abstract</p> <p>Background</p> <p>The genus <it>Arsenophonus </it>is a group of symbiotic, mainly insect-associated bacteria with rapidly increasing number of records. It is known from a broad spectrum of hosts and symbiotic relationships varying from parasitic son-killers to coevolving mutualists.</p> <p>The present study extends the currently known diversity with 34 samples retrieved mainly from hippoboscid (Diptera: Hippoboscidae) and nycteribiid (Diptera: Nycteribiidae) hosts, and investigates phylogenetic relationships within the genus.</p> <p>Results</p> <p>The analysis of 110 <it>Arsenophonus </it>sequences (incl. <it>Riesia </it>and <it>Phlomobacter</it>), provides a robust monophyletic clade, characterized by unique molecular synapomorphies. On the other hand, unstable inner topology indicates that complete understanding of <it>Arsenophonus </it>evolution cannot be achieved with 16S rDNA. Moreover, taxonomically restricted <it>Sampling </it>matrices prove sensitivity of the phylogenetic signal to sampling; in some cases, <it>Arsenophonus </it>monophyly is disrupted by other symbiotic bacteria. Two contrasting coevolutionary patterns occur throughout the tree: parallel host-symbiont evolution and the haphazard association of the symbionts with distant hosts. A further conspicuous feature of the topology is the occurrence of monophyletic symbiont lineages associated with monophyletic groups of hosts without a co-speciation pattern. We suggest that part of this incongruence could be caused by methodological artifacts, such as intragenomic variability.</p> <p>Conclusion</p> <p>The sample of currently available molecular data presents the genus <it>Arsenophonus </it>as one of the richest and most widespread clusters of insect symbiotic bacteria. The analysis of its phylogenetic lineages indicates a complex evolution and apparent ecological versatility with switches between entirely different life styles. Due to these properties, the genus should play an important role in the studies of evolutionary trends in insect intracellular symbionts. However, under the current practice, relying exclusively on 16S rRNA sequences, the phylogenetic analyses are sensitive to various methodological artifacts that may even lead to description of new <it>Arsenophonus </it>lineages as independent genera (e.g. <it>Riesia </it>and <it>Phlomobacter</it>). The resolution of the evolutionary questions encountered within the <it>Arsenophonus </it>clade will thus require identification of new molecular markers suitable for the low-level phylogenetics.</p

Impact of molecular methods in the analysis of the invasiveness of Streptococcus pneumoniae

[eng] This doctoral thesis proves the necessity of applying molecular techniques in direct sample for a more accurate study of the Invasive Disease Potential (IDP) of Streptococcus pneumoniae and for its epidemiological surveillance. These methods allow a better detection and serotype identification of the pneumococcal population in both Invasive Pneumococcal Disease (IPD) and nasopharyngeal carriers. However, to better understand the behavior of the different serotypes a complete analysis of the clonal types of pneumococci (invasive and carriers) should be also performed. In the first two studies the IDP of pneumococcal serotypes found in our pediatric population was estimated. In the first study, traditional methods based only in culture were used for both the detection of Streptococcus pneumoniae and the identification of the capsular type; while in the second study, the same estimation was performed but this time adding molecular techniques in direct sample for both the detection and serotyping. When comparing the results of both studies, the addition of molecular techniques in direct sample doubled the number of pneumococci identified causing IPD, and in the nasopharynx of healthy children. The great increase in the pneumococcus detection revealed a different distribution of the serotypes circulating in the population of the area, when compared with the data that had been obtained only by culture, which was translated in a huge impact in the IDP of these serotypes. In the carrier’s population an important proportion in the increase of serotypes that were able to be identified in carriers was due to the detection of multiple colonies in one sample, with up to four different serotypes distinguished in the same sample. The analysis of the carriers’ population also revealed a rate of co-colonization of 26.4% in the children population of our area. The better estimation of the ranking order of the most common serotypes in IPD and in the nasopharynx also allowed a more accurate analysis of the effects of PCV7 in the study time period. The results from the third study provided additional information about the invasive disease potential of serotypes causing IPD in our area due to the clonal study of invasive strains. In addition, it provided information about the evolution of serotypes causing disease after the introduction of PCV13 in 2010, in both children and adults. Although the most common serotypes found in the study were still PCV13 serotypes (with a special concern for the increase of the ST156 serotype 14), probably due to the low vaccine coverage in our area, a significant decrease was observed. In contrast, a significant increase in the proportion of non-PCV13 serotypes was revealed. Worth mentioning, is the increase experienced by serotype 12F (in high association with ST989) and, when analyzed by age groups, the increase of serotype 24F in children less than 2 years old (the major clone being the multi drug resistant ST230). But most importantly was the data obtained in the serotypes analysis of their clonal composition. Despite the capsule is the most important factor in virulence, strains expressing the same serotype but belonging to different clonal types has been found to present different invasiveness. Certain clonal types may present some characteristics that are likely to be advantageous for invasiveness, like antibiotic resistance. The study of the genetic population of the serotypes offers a more complete knowledge of the pneumococcal invasiveness, explains temporal trends and differences in geographical areas, and provides useful information for the prediction of which serotypes could be replacing the ones included in the vaccines. For a better interpretation of the pneumococcal behavior, the analysis of the clonal types associated with a serotype should be performed along with the capsular identification.[cat] Aquesta tesis doctoral demostra la necessitat d’aplicar tècniques moleculars en mostra directa per a poder realitzar un estudi més acurat del potencial invasiu de Streptococcus pneumoniae, i per a la seva vigilància epidemiològica. Aquests mètodes permeten una millor detecció i un millor serotipatge de la població pneumocòccica, tant en la malaltia pneumocòccica invasiva (MPI) com en els portadors nasofaringis. Tot i això, per realment entendre millor el comportament dels diferents serotips també s’hauria de realitzar un anàlisi complet dels tipus clonals que presenten els pneumococs (tant en malaltia com en portadors). Als dos primers estudis es va calcular el potencial invasiu dels serotips pneumocòccics trobats en la població pediàtrica de Catalunya (Espanya). Al primer estudi es van utilitzar mètodes tradicionals basats en el cultiu tant per la detecció de Streptococcus pneumoniae com per la identificació del tipus capsular; mentre que en el segon estudi, es va realitzar el mateix anàlisi però en aquest cas afegint les tècniques moleculars en mostra directa tant per la detecció com pel serotipatge. Al comparar els resultats d’ambdós estudis, l’addició de les tècniques moleculars en mostra directa va duplicar el número de pneumococs identificats causant MPI i presents a la nasofaringe de nens sans. Aquesta millora en la detecció del pneumococ també es va traduir en un gran impacte en el càlcul del potencial invasiu d’aquest serotips. En la població de portadors la capacitat de detectar múltiples colònies en una mateixa mostra va tenir un paper rellevant en l’increment de serotips que es van poder identificar en el segon estudi. Els resultats del tercer estudi van aportar informació addicional sobre el potencial invasiu dels serotips causant MPI a la nostra àrea gràcies a l’estudi clonal de les soques invasives. A més, van aportar informació sobre l’evolució dels serotips causant malaltia després de la introducció de la PCV13 al 2010, tant en nens com en adults. L’anàlisi dels tipus clonals sent expressats pels serotips pneumocòccics podria explicar perquè alguns tipus capsulars que es troben normalment colonitzant asimptomàticament han experimentat un canvi en la seva invasivitat convertint-se en les principals causes de la MPI

Monoclonal Antibodies for Non-Hodgkin's Lymphoma: State of the Art and Perspectives

Monoclonal antibodies have been the most successful therapeutics ever brought to cancer treatment by immune technologies. The use of monoclonal antibodies in B-cell Non-Hodgkin's lymphomas (NHL) represents the greatest example of these advances, as the introduction of the anti-CD20 antibody rituximab has had a dramatic impact on how we treat this group of diseases today. Despite this success, several questions about how to optimize the use of monoclonal antibodies in NHL remain open. The best administration schedules, as well as the optimal duration of rituximab treatment, have yet to be determined. A deeper knowledge of the mechanisms underlying resistance to rituximab is also necessary in order to improve the activity of this and of similar therapeutics. Finally, new antibodies and biological agents are entering the scene and their advantages over rituximab will have to be assessed. We will discuss these issues and present an overview of the most significant clinical studies with monoclonal antibodies for NHL treatment carried out to date

Systems medicine in colorectal cancer: from a mathematical model toward a new type of clinical trial

Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial level. Our model allows for the inclusion of the unique molecular profiles of each individual patient's tumor. While existing clinical guidelines are well established, dynamic modeling may be used for future targeted combination therapies, which may progressively become part of clinical practice within the near future. WIREs Syst Biol Med 2016, 8:314\u2013336. doi: 10.1002/wsbm.1342. For further resources related to this article, please visit the WIREs website

Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer

Background & aims: there are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer. Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients, but also within tumors. We have explored intratumor heterogeneity at the epigenetic level, due to its dynamic nature. We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors. Methods: we determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases, obtained from 2 hospitals in Spain. We also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses. Results: we observed differences in DNA methylation among the 3 tumor sections; regions of tumor−host interface differed the most from the other tumor sections. Interestingly, tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When we calculated individual coefficients to quantify heterogeneity, we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival (log-rank P = .037) and short time of overall survival (log-rank P = .026) in patients with locoregional colorectal cancer. Conclusions: in an analysis of 79 colorectal tumors, we found significant heterogeneity in patterns of DNA methylation within each tumor; the level of heterogeneity correlates with times of relapse-free and overall survival

Grb7 Upregulation Is a Molecular Adaptation to HER2 Signaling Inhibition Due to Removal of Akt-Mediated Gene Repression

The efficacy of anti-HER2 therapeutics, such as lapatinib and trastuzumab, is limited by primary and acquired resistance. Cellular adaptations that allow breast cancer cell to survive prolonged HER2 inhibition include de-repression of the transcription factor FOXO3A with consequent estrogen receptor activation, and/or increased HER3 signaling. Here, we used low-density arrays, quantitative PCR, and western blotting to determine how HER2 signaling inhibition with lapatinib or PI3K inhibitors affects the expression of genes involved in breast cancer metastatic spread and overall prognosis. Retroviral transgenesis was used to express constitutively active forms of Akt in the HER2+ breast cancer cell line SKBR3, and Grb7 in MCF7 cells. Specific gene silencing was obtained by siRNAs transfection. A murine BT474 xenograft cancer model was used to assess the effect of lapatinib on gene expression in vivo. We found that lapatinib induces upregulation of Grb7, an adaptor protein involved in receptor tyrosine kinase signaling and promoting cell survival and cell migration. Grb7 upregulation induced by lapatinib was found to occur in cancer cells in vitro and in vivo. We demonstrate that Grb7 upregulation is recreated by PI3K inhibitors while being prevented by constitutively active Akt. Thus, Grb7 is repressed by PI3K signaling and lapatinib-mediated Akt inhibition is responsible for Grb7 de-repression. Finally, we show that Grb7 removal by RNA-interference reduces breast cancer cell viability and increases the activity of lapatinib. In conclusion, Grb7 upregulation is a potentially adverse consequence of HER2 signaling inhibition. Preventing Grb7 accumulation and/or its interaction with receptor tyrosine kinases may increase the benefit of HER2-targeting drugs

Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.

Prolonged seizures (status epilepticus, SE) can cause neuronal death within brain regions such as the hippocampus. This may contribute to impairments in cognitive functioning and trigger or exacerbate epilepsy. Seizure-induced neuronal death is mediated, at least in part, by apoptosis-associated signaling pathways. Indeed, mice lacking certain members of the potently proapoptotic BH3-only subfamily of Bcl-2 proteins are protected against hippocampal damage caused by status epilepticus. The recently identified BH3-only protein Bcl-2-modifying factor (Bmf) normally interacts with the cytoskeleton, but upon certain cellular stresses, such as loss of extracellular matrix adhesion or energy crisis, Bmf relocalizes to mitochondria, where it can promote Bax activation and mitochondrial dysfunction. Although Bmf has been widely reported in the hematopoietic system to exert a proapoptotic effect, no studies have been undertaken in models of neurological disorders. To examine whether Bmf is important for seizure-induced neuronal death, we studied Bmf induction after prolonged seizures induced by intra-amygdala kainic acid (KA) in mice, and examined the effect of Bmf-deficiency on seizures and damage caused by SE. Seizures triggered an early (1-8 h) transcriptional activation and accumulation of Bax in the cell death-susceptible hippocampal CA3 subfield. Bmf mRNA was biphasically upregulated beginning at 1 h after SE and returning to normal by 8 h, while again being found elevated in the hippocampus of epileptic mice. Bmf upregulation was prevented by Compound C, an inhibitor of adenosine monophosphate-activated protein kinase, indicating Bmf expression may be induced in response to bioenergetic stress. Bmf-deficient mice showed normal sensitivity to the convulsant effects of KA, but, surprisingly, displayed significantly more neuronal death in the hippocampal CA1 and CA3 subfields after SE. These are the first studies investigating Bmf in a model of neurologic injury, and suggest that Bmf may protect neurons against seizure-induced neuronal death in vivo