1,552 research outputs found
Health and healthcare access among Zambia's female prisoners: a health systems analysis.
BackgroundResearch exploring the drivers of health outcomes of women who are in prison in low- and middle-income settings is largely absent. This study aimed to identify and examine the interaction between structural, organisational and relational factors influencing Zambian women prisoners' health and healthcare access.MethodsWe conducted in-depth interviews of 23 female prisoners across four prisons, as well as 21 prison officers and health care workers. The prisoners were selected in a multi-stage sampling design with a purposive selection of prisons followed by a random sampling of cells and of female inmates within cells. Largely inductive thematic analysis was guided by the concepts of dynamic interaction and emergent behaviour, drawn from the theory of complex adaptive systems.ResultsWe identified compounding and generally negative effects on health and access to healthcare from three factors: i) systemic health resource shortfalls, ii) an implicit prioritization of male prisoners' health needs, and iii) chronic and unchecked patterns of both officer- and inmate-led victimisation. Specifically, women's access to health services was shaped by the interactions between lack of in-house clinics, privileged male prisoner access to limited transport options, and weak responsiveness by female officers to prisoner requests for healthcare. Further intensifying these interactions were prisoners' differential wealth and access to family support, and appointments of senior 'special stage' prisoners which enabled chronic victimisation of less wealthy or less powerful individuals.ConclusionsThis systems-oriented analysis revealed how Zambian women's prisoners' health and access to healthcare is influenced by weak resourcing for prisoner health, administrative biases, and a prevailing organisational and inmate culture. Findings highlight the urgent need for investment in structural improvements in health service availability but also interventions to reform the organisational culture which shapes officers' understanding and responsiveness to women prisoners' health needs
Identification of the bHLH Factor Math6 as a Novel Component of the Embryonic Pancreas Transcriptional Network
Background: Basic helix-loop-helix (bHLH) transcription factors play important roles in differentiation processes during embryonic development of vertebrates. In the pancreas, the atonal -related bHLH gene Neurogenin3 (Neurog3) controls endocrine cell fate specification in uncommitted progenitor cells. Therefore, it is likely that Neurog3-regulated factors will have important functions during pancreatic endocrine cell differentiation. The gene for the atonal -related bHLH factor Math6 was recognized as a potential target of Neurog3 in a genomic scale profiling during endocrine differentiation. Herein we have explored the role of Math6 during endocrine pancreas development. Results: We demonstrate that the Math6 gene is a direct target of Neurog3 in vitro and that, during mouse development, Math6 is expressed in both endocrine and exocrine pancreatic precursor cells. We have investigated the role of Math6 in endocrine differentiation by over-expressing this factor in pancreatic duct cells. Math6 possesses intrinsic transcriptional repressor activity and, in contrast to Neurog3 it does not induce the endocrine differentiation program; however, it can modulate some of the pro-endocrine functions of Neurog3 in this system. In addition, we show that Math6 is broadly expressed in mouse embryonic tissues and its expression is induced by tissue-specific bHLH genes other than Neurog3. Furthermore, inactivation of the Math6 gene in the mouse results in early embryonic lethality demonstrating an essential role of this factor in organismal development. Conclusions: These data demonstrate that Math6 is a novel component of the pancreatic transcriptional network during embryonic development and suggest a potential role for Math6 as a modulator of the differentiation program initiated by the pro-endocrine factor Neurog3. Furthermore, our results demonstrate that Math6 is indispensable for early embryonic development and indicate a more widespread function for this factor in tissue-specific differentiation processes that are dependent on class II bHLH genes
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A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response.
Insulin production by the pancreatic Ī²-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused on Spry2-a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose homeostasis. We showed that Spry2 is a novel UPR target and its upregulation is dependent on PERK. Knockdown of Spry2 resulted in reduced expression of Serca2, reduced endoplasmic reticulum calcium levels, and induction of the UPR. Spry2 deletion in the adult mouse Ī²-cell caused hyperglycemia and hypoinsulinemia. Our study greatly expands the compendium of insulin promoter regulators and demonstrates a novel Ī²-cell link between Spry2 and human diabetes
Precise pattern of recombination in serotonergic and hypothalamic neurons in a Pdx1-cre transgenic mouse line
<p>Abstract</p> <p>Background</p> <p>Multicellular organisms are characterized by a remarkable diversity of morphologically distinct and functionally specialized cell types. Transgenic techniques for the manipulation of gene expression in specific cellular populations are highly useful for elucidating the development and function of these cellular populations. Given notable similarities in developmental gene expression between pancreatic Ī²-cells and serotonergic neurons, we examined the pattern of Cre-mediated recombination in the nervous system of a widely used mouse line, Pdx1-cre (formal designation, Tg(Ipf1-cre)89.1Dam), in which the expression of Cre recombinase is driven by regulatory elements upstream of the <it>pdx1 </it>(pancreatic-duodenal homeobox 1) gene.</p> <p>Methods</p> <p>Single (hemizygous) transgenic mice of the <it>pdx1-cre</it><sup>Cre/0 </sup>genotype were bred to single (hemizygous) transgenic reporter mice (Z/EG and rosa26R lines). Recombination pattern was examined in offspring using whole-mount and sectioned histological preparations at e9.5, e10.5, e11.5, e16.5 and adult developmental stages.</p> <p>Results</p> <p>In addition to the previously reported pancreatic recombination, recombination in the developing nervous system and inner ear formation was observed. In the central nervous system, we observed a highly specific pattern of recombination in neuronal progenitors in the ventral brainstem and diencephalon. In the rostral brainstem (r1-r2), recombination occurred in newborn serotonergic neurons. In the caudal brainstem, recombination occurred in non-serotonergic cells. In the adult, this resulted in reporter expression in the vast majority of forebrain-projecting serotonergic neurons (located in the dorsal and median raphe nuclei) but in none of the spinal cord-projecting serotonergic neurons of the caudal raphe nuclei. In the adult caudal brainstem, reporter expression was widespread in the inferior olive nucleus. In the adult hypothalamus, recombination was observed in the arcuate nucleus and dorsomedial hypothalamus. Recombination was not observed in any other region of the central nervous system. Neuronal expression of endogenous <it>pdx1 </it>was not observed.</p> <p>Conclusions</p> <p>The Pdx1-cre mouse line, and the regulatory elements contained in the corresponding transgene, could be a valuable tool for targeted genetic manipulation of developing forebrain-projecting serotonergic neurons and several other unique neuronal sub-populations. These results suggest that investigators employing this mouse line for studies of pancreatic function should consider the possible contributions of central nervous system effects towards resulting phenotypes.</p
Expression of neurogenin3 reveals an islet cell precursor population in the pancreas
Differentiation of early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events controlled by transcription factors including the basic helix-loop-helix (bHLH) proteins. To delineate this cascade, we began by establishing the position of neurogenin3, a bHLH factor found in the pancreas during fetal development. We detect neurogenin3 immunoreactivity transiently in scattered ductal cells in the fetal mouse pancreas, peaking at embryonic day 15.5. Although not detected in cells expressing islet hormones or the islet transcription factors Isl1, Brn4, Pax6 or PDX1, neurogenin3 is detected along with early islet differentiation factors Nkx6.1 and Nkx2.2, establishing that it is expressed in immature cells in the islet lineage. Analysis of transcription factor-deficient mice demonstrates that neurogenin3 expression is not dependent on neuroD1/BETA2, Mash1, Nkx2.2, Nkx6.1, or Pax6. Furthermore, early expression of neurogenin3 under control of the Pdx1 promoter is alone sufficient to drive early and ectopic differentiation of islet cells, a capability shared by the pancreatic bHLH factor, neuroD1/BETA2, but not by the muscle bHLH factor, MyoD. However, the islet cells produced in these transgenic experiments are overwhelmingly Ī± cells, suggesting that factors other than the bHLH factors are required to deviate from a default Ī± cell fate. These data support a model in which neurogenin3 acts upstream of other islet differentiation factors, initiating the differentiation of endocrine cells, but switching off prior to final differentiation. The ability to uniquely identify islet cell precursors by neurogenin3 expression allows us to determine the position of other islet transcription factors in the differentiation cascade and to propose a map for the islet cell differentiation pathway
Separation of suspended particles in microfluidic systems by directional-locking in periodic fields
We investigate the transport and separation of overdamped particles under the
action of a uniform external force in a two-dimensional periodic energy
landscape. Exact results are obtained for the deterministic transport in a
square lattice of parabolic, repulsive centers that correspond to a
piecewise-continuous linear-force model. The trajectories are periodic and
commensurate with the obstacle lattice and exhibit phase-locking behavior in
that the particle moves at the same average migration angle for a range of
orientation of the external force. The migration angle as a function of the
orientation of the external force has a Devil's staircase structure. The first
transition in the migration angle was analyzed in terms of a Poincare map,
showing that it corresponds to a tangent bifurcation. Numerical results show
that the limiting behavior for impenetrable obstacles is equivalent to the high
Peclet number limit in the case of transport of particles in a periodic pattern
of solid obstacles. Finally, we show how separation occurs in these systems
depending on the properties of the particles
Gene regulatory networks in lactation: identification of global principles using bioinformatics
<p>Abstract</p> <p>Background</p> <p>The molecular events underlying mammary development during pregnancy, lactation, and involution are incompletely understood.</p> <p>Results</p> <p>Mammary gland microarray data, cellular localization data, protein-protein interactions, and literature-mined genes were integrated and analyzed using statistics, principal component analysis, gene ontology analysis, pathway analysis, and network analysis to identify global biological principles that govern molecular events during pregnancy, lactation, and involution.</p> <p>Conclusion</p> <p>Several key principles were derived: (1) nearly a third of the transcriptome fluctuates to build, run, and disassemble the lactation apparatus; (2) genes encoding the secretory machinery are transcribed prior to lactation; (3) the diversity of the endogenous portion of the milk proteome is derived from fewer than 100 transcripts; (4) while some genes are differentially transcribed near the onset of lactation, the lactation switch is primarily post-transcriptionally mediated; (5) the secretion of materials during lactation occurs not by up-regulation of novel genomic functions, but by widespread transcriptional suppression of functions such as protein degradation and cell-environment communication; (6) the involution switch is primarily transcriptionally mediated; and (7) during early involution, the transcriptional state is partially reverted to the pre-lactation state. A new hypothesis for secretory diminution is suggested ā milk production gradually declines because the secretory machinery is not transcriptionally replenished. A comprehensive network of protein interactions during lactation is assembled and new regulatory gene targets are identified. Less than one fifth of the transcriptionally regulated nodes in this lactation network have been previously explored in the context of lactation. Implications for future research in mammary and cancer biology are discussed.</p
Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)
Atonal Homolog 8 (Atoh8) is a basic helix-loop-helix (bHLH) transcription factor that is highly conserved across species and expressed in multiple tissues during embryogenesis. In the developing pancreas, Atoh8 is expressed in endocrine progenitors but declines in hormone-positive cells, suggesting a role during early stages of the endocrine differentiation program. We previously generated a whole-body Atoh8 knockout but early lethality of null embryos precluded assessment of Atoh8 functions during organ development. Here we report the generation of a conditional Atoh8 knockout mouse strain by insertion of two loxP sites flanking exon 1 of the Atoh8 gene. Pancreas-specific Atoh8 knockout (Atoh8 Īpanc) mice were obtained by mating this strain with a Pdx1-Cre transgenic line. Atoh8 Īpanc mice were born at the expected mendelian ratio and showed normal appearance and fertility. Pancreas weight and gross pancreatic morphology were normal. All pancreatic cell lineages were present, although endocrine Ī“ (somatostatin) cells were modestly augmented in Atoh8 Īpanc as compared to control neonates. This increase did not affect whole-body glucose tolerance in adult knockout animals. Gene expression analysis in embryonic pancreases at the time of the major endocrine differentiation wave revealed modest alterations in several early endocrine differentiation markers. Together, these data argue that Atoh8 modulates activation of the endocrine program but it is not essential for pancreas formation or endocrine differentiation in the mouse. Given the ubiquitous expression pattern of Atoh8, the availability of a mouse strain carrying a conditional allele for this gene warrants further studies using temporally regulated Cre transgenic lines to elucidate time or cell-autonomous functions of Atoh8 during development and in the adult
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