Do seismic waves and fluid flow sense the same permeability?

We study the discrepancy between the effective flow permeability and the effective seismic permeability, that is, the effective permeability controlling seismic attenuation due to wave-induced fluid flow, in 2D rock samples having mesoscopic heterogeneities and in the presence of strong permeability fluctuations. In order to do so, we employ a numerical oscillatory compressibility test to determine attenuation and velocity dispersion due to wave-induced fluid flow in these kinds of media and compare the responses with those obtained by replacing the heterogeneous permeability field by constant values, including the average permeability as well as the effective flow permeability of the sample. The latter is estimated in a separate upscaling procedure by solving the steady-state flow equation in the rock sample under study. Numerical experiments let us verify that attenuation levels are less significant and the attenuation peak gets broader in the presence of such strong permeability fluctuations. Moreover, we observe that for very low frequencies the effective seismic permeability is similar to the effective flow permeability, while for very high frequencies it approaches the arithmetic average of the permeability field.

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.

Alzheimer disease: curly fibers and tangles in organs other than brain.

The filamentous brain lesions that define Alzheimer disease (AD) consist of senile plaques and neurofibrillary tangles. Undulated pathological filaments--curly fibers or neuropil threads--also occur in the neuropil. Beta-amyloid precursor proteins are synthesized by many cells outside the central nervous system and recently, deposition of beta-amyloid-protein was reported to occur in non-neuronal tissues. In addition, increasing data claim the importance of chronic inflammation in the pathogenesis of AD. These observations suggest that AD may be a widespread systemic disorder. Here we report that pathological argyrophilic filaments with histochemical properties of amyloid showing striking morphological similarity to curly fibers and/or tangles accumulate not only in ependymal layer and in epithelial cells of choroid plexus, but also in several other organs (e.g. liver, pancreas, ovary, testis, thyroid) in AD. The ependyma, choroid plexus, and various organs of 39 autopsy cases were analyzed. In search of curly fiber and tangle-like changes in organs other than brain, 395 blocks from 21 different tissues of 24 AD cases, 5 cases with discrete or moderate AD-type changes, and 10 control cases were investigated. We found in non-neuronal cells "curly fibers" or "tangles" immunoreactive with antibodies to P component, Tau-protein, ubiquitin, fibronectin, and Apolipoprotein-E, but lacking immunoreactivity with antibodies to neurofilament proteins. Ultrastructurally they consist of densely packed straight and paired helical filaments and closely resemble neurofibrillary tangles and neuropil threads. These observations indicate that the formation of "curly fibers" and "tangles" is not unique to the central nervous system. The results suggest that AD might be a systemic disorder or that similar fibrillary changes to tangles and curly fibers may also be associated with other amyloidosis than beta-amyloidosis. Further investigations are necessary to understand the pathogenetic interest of these fibrillary changes outside the CNS.

The transcription factor c-Maf controls touch receptor development and function.

The sense of touch relies on detection of mechanical stimuli by specialized mechanosensory neurons. The scarcity of molecular data has made it difficult to analyze development of mechanoreceptors and to define the basis of their diversity and function. We show that the transcription factor c-Maf/c-MAF is crucial for mechanosensory function in mice and humans. The development and function of several rapidly adapting mechanoreceptor types are disrupted in c-Maf mutant mice. In particular, Pacinian corpuscles, a type of mechanoreceptor specialized to detect high-frequency vibrations, are severely atrophied. In line with this, sensitivity to high-frequency vibration is reduced in humans carrying a dominant mutation in the c-MAF gene. Thus, our work identifies a key transcription factor specifying development and function of mechanoreceptors and their end organs.

Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses.

Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell-cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2-driven differentiation of marginal zone B cells and of Esam(+) dendritic cells. Moreover, conditional inactivation of DL4 in lymph node fibroblasts resulted in impaired follicular helper T cell differentiation and, consequently, in reduced numbers of germinal center B cells and absence of high-affinity antibodies. Our data demonstrate previously unknown roles for DL ligand-expressing fibroblasts in SLO niches as drivers of multiple Notch-mediated immune differentiation processes.

"A renewed sense of purpose": Mothers' and fathers' experience of having a child following a recent stillbirth.

Background Most research has focused on mothers¿ experiences of perinatal loss itself or on the subsequent pregnancy, whereas little attention has been paid to both parents¿ experiences of having a child following late perinatal loss and the experience of parenting this child. The current study therefore explored mothers¿ and fathers' experiences of becoming a parent to a child born after a recent stillbirth, covering the period of the second pregnancy and up to two years after the birth of the next baby.MethodIn depth interviews were conducted with 7 couples (14 participants). Couples were eligible if they previously had a stillbirth (after 24 weeks of gestation) and subsequently had another child (their first live baby) who was now under the age of 2 years. Couples who had more than one child after experiencing a stillbirth and those who were not fluent in English were excluded. Qualitative analysis of the interview data was conducted using Interpretive Phenomenological Analysis.ResultsFive superordinate themes emerged from the data: Living with uncertainty; Coping with uncertainty; Relationship with the next child; The continuing grief process; Identity as a parent. Overall, fathers' experiences were similar to those of mothers', including high levels of anxiety and guilt during the subsequent pregnancy and after the child was born. Coping strategies to address these were identified. Differences between mothers and fathers regarding the grief process during the subsequent pregnancy and after their second child was born were identified. Despite difficulties with bonding during pregnancy and at the time when the baby was born, parents' perceptions of their relationship with their subsequent child were positive.ConclusionsFindings highlight the importance of tailoring support systems not only according to mothers' but also to fathers' needs. Parents¿, and particularly fathers', reported lack of opportunities for grieving as well as the high level of anxiety of both parents about their baby's wellbeing during pregnancy and after birth implies a need for structured support. Difficulties experienced in bonding with the subsequent child during pregnancy and once the child is born need to be normalised.

Do seismic waves sense fracture connectivity?

A defining characteristic of fractured rocks is their very high level of seismic attenuation, which so far has been assumed to be mainly due to wave-induced fluid flow (WIFF) between the fractures and the pore space of the embedding matrix. Using oscillatory compressibility simulations based on the quasi-static poroelastic equations, we show that another important, and as of yet undocumented, manifestation of WIFF is at play in the presence of fracture connectivity. This additional energy loss is predominantly due to fluid flow within the connected fractures and is sensitive to their lengths, permeabilities, and intersection angles. Correspondingly, it contains key information on the governing hydraulic properties of fractured rock masses and hence should be accounted for whenever realistic seismic models of such media are needed.

Extrafollicular plasmablast B cells play a key role in carrying retroviral infection to peripheral organs.

B cells can either differentiate in germinal centers or in extrafollicular compartments of secondary lymphoid organs. Here we show the migration properties of B cells after differentiation in murine peripheral lymph node infected with mouse mammary tumor virus. Naive B cells become activated, infected, and carry integrated retroviral DNA sequences. After production of a retroviral superantigen, the infected B cells receive cognate T cell help and differentiate along the two main differentiation pathways analogous to classical Ag responses. The extrafollicular differentiation peaks on day 6 of mouse mammary tumor virus infection, and the follicular one becomes detectable after day 10. B cells participating in this immune response carry a retroviral DNA marker that can be detected by using semiquantitative PCR. We determined the migration patterns of B cells having taken part in the T cell-B cell interaction from the draining lymph node to different tissues. Waves of immigration and retention of infected cells in secondary lymphoid organs, mammary gland, salivary gland, skin, lung, and liver were observed correlating with the two peaks of B cell differentiation in the draining lymph node. Other organs revealed immigration of infected cells at later time points. The migration properties were correlated with a strong up-regulation of alpha(4)beta(1) integrin expression. These results show the migration properties of B cells during an immune response and demonstrate that a large proportion of extrafolliculary differentiating plasmablasts can escape local cell death and carry the retroviral infection to peripheral organs.

Sense of coherence and job characteristics in predicting burnout in a South African sample

Orientation: Research that considers the effects of individual characteristics and job characteristics jointly in burnout is necessary, especially when one considers the possibility of curvilinear relationships between job characteristics and burnout. Research purpose: This study examines the contribution of sense of coherence (SOC) and job characteristics to predicting burnout by considering direct and moderating effects. Motivation for this study: Understanding the relationships of individual and job characteristics with burnout is necessary for preventing burnout. It also informs the design of interventions. Research design, approach and method: The participants were 632 working adults (57% female) in South Africa. The measures included the Job Content Questionnaire, the Sense of Coherence Questionnaire and the Maslach Burnout Inventory. The authors analysed the data using hierarchical multiple regression with the enter method. Main findings: Job characteristics and SOC show the expected direct effects on burnout. SOC has a direct negative effect on burnout. Job demands and supervisor social support show nonlinear relationships with burnout. SOC moderates the effect of demands on burnout and has a protective function so that the demands-burnout relationship differs for those with high and low SOC. Practical/managerial implications: The types of effects, the shape of the stressor-strain relationship and the different contributions of individual and job characteristics have implications for designing interventions. Contribution/value add: SOC functions differently when combined with demands, control and support. These different effects suggest that it is not merely the presence or absence of a job characteristic that is important for well-being outcomes but how people respond to its presence or absence.

Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis

Cells, including endothelial cells, continuously sense their surrounding environment and rapidly adapt to changes in order to assure tissues and organs homeostasis. The extracellular matrix (ECM) provides a physical scaffold for cell positioning and represents an instructive interface allowing cells to communicate over short distances. Cell surface receptors of the integrin family emerged through evolution as essential mediators and integrators of ECM-dependent communication. In preclinical studies, pharmacological inhibition of vascular integrins suppressed angiogenesis and inhibited tumor progression. alpha(V)beta(3) and alpha(V)beta(5) were the first integrins targeted to suppress tumor angiogenesis. Subsequently, additional integrins, in particular alpha(1)beta(1), alpha(2)beta(1), alpha(5)beta(1), and alpha(6)beta(4), emerged as potential therapeutic targets. Integrin inhibitors are currently tested in clinical trials for their safety and antiangiogenic/antitumor activity. In this chapter, we review the role of integrins in angiogenesis and present recent advances in the use of integrin antagonists as potential therapeutics in cancer and discuss future perspectives.

Do Objective Measures of Blood Alcohol Concentrations Make More Sense than Self-reports in Emergency Department Studies?

Purpose: Concerns about self-reports have led to calls for objective measures of blood alcohol concentration (BAC). The present study compared objective measures with self-reports. Methods: BAC from breath or blood samples were obtained from 272 randomly sampled injured patients who were admitted to a Swiss emergency department (ED). Self-reports were compared a) between those providing and refusing a BAC test, and b) to estimated peak BAC (EPBAC) values based on BACs using the Widmark formula. Results: Those providing BACs were significantly (P < 0.05) younger, more often male, and less often reported alcohol consumption before injury, but consumed higher quantities when drinking. Eighty-eight percent of those with BAC measures gave consistent reports (positive or negative). Significantly more patients reported consumption with negative BAC measures (N = 29) than vice versa (N = 3). Duration of consumption and times between injury and BAC measurement predicted EPBAC better than did the objective BAC measure. Conclusions: There is little evidence that patients who provide objective BAC measures deliberately conceal consumption. ED studies must rely on self-reports, eg, take the time period between injury and ED admission into account. Clearly, objective measures are of clinical relevance, eg, to provide optimal treatment in the ED. However, they may be less relevant to establishing effects in an epidemiologic sense, such as estimating risk relationships. In this respect, efforts to increase the validity and reliability of self-reports should be preferred over the collection of additional objective measures.