Migration towards Bangladesh coastlines projected to increase with sea-level rise through 2100.

To date, projections of human migration induced by sea-level change (SLC) largely suggest large-scale displacement away from vulnerable coastlines. However, results from our model of Bangladesh suggest counterintuitively that people will continue to migrate toward the vulnerable coastline irrespective of the flooding amplified by future SLC under all emissions scenarios until the end of this century. We developed an empirically calibrated agent-based model of household migration decision-making that captures the multi-faceted push, pull and mooring influences on migration at a household scale. We then exposed ~4800 000 simulated migrants to 871 scenarios of projected 21st-century coastal flooding under future emissions pathways. Our model does not predict flooding impacts great enough to drive populations away from coastlines in any of the scenarios. One reason is that while flooding does accelerate a transition from agricultural to non-agricultural income opportunities, livelihood alternatives are most abundant in coastal cities. At the same time, some coastal populations are unable to migrate, as flood losses accumulate and reduce the set of livelihood alternatives (so-called 'trapped' populations). However, even when we increased access to credit, a commonly-proposed policy lever for incentivizing migration in the face of climate risk, we found that the number of immobile agents actually rose. These findings imply that instead of a straightforward relationship between displacement and migration, projections need to consider the multiple constraints on, and preferences for, mobility. Our model demonstrates that decision-makers seeking to affect migration outcomes around SLC would do well to consider individual-level adaptive behaviors and motivations that evolve through time, as well as the potential for unintended behavioral responses.

Climate change adaptation in conflict-affected countries: A systematic assessment of evidence.

People affected by conflict are particularly vulnerable to climate shocks and climate change, yet little is known about climate change adaptation in fragile contexts. While climate events are one of the many contributing drivers of conflict, feedback from conflict increases vulnerability, thereby creating conditions for a vicious cycle of conflict. In this study, we carry out a systematic review of peer-reviewed literature, taking from the Global Adaptation Mapping Initiative (GAMI) dataset to documenting climate change adaptation occurring in 15 conflict-affected countries and compare the findings with records of climate adaptation finance flows and climate-related disasters in each country. Academic literature is sparse for most conflict-affected countries, and available studies tend to have a narrow focus, particularly on agriculture-related adaptation in rural contexts and adaptation by low-income actors. In contrast, multilateral and bilateral funding for climate change adaptation addresses a greater diversity of adaptation needs, including water systems, humanitarian programming, and urban areas. Even among the conflict-affected countries selected, we find disparity, with several countries being the focus of substantial research and funding, and others seeing little to none. Results indicate that people in conflict-affected contexts are adapting to climate change, but there is a pressing need for diverse scholarship across various sectors that documents a broader range of adaptation types and their results.

Clinical potential of DAS181 for treatment of parainfluenza-3 infections in transplant recipients.

Parainfluenza virus (PIV) infections can cause serious respiratory infections and death in immunocompromised patients. No antiviral agents have proven efficacy against PIV, and therapy generally consists of supportive care. DAS181, a novel sialidase fusion protein that temporarily disables airway epithelial PIV receptors by enzymatic removal of sialic acid moieties, has been shown to inhibit infection with PIV strains in vitro and in an animal model. We describe here the clinical course of 2 immunocompromised patients with PIV-3 infection, one with a history of lung transplantation and the other neutropenic after autologous hematopoietic stem cell transplantation for multiple myeloma. Both patients had substantial clinical improvement in respiratory and systemic symptoms after a 5-day DAS181 treatment course, although the clinical improvement in the autologous stem cell transplantation patient also paralleled neutrophil engraftment.

Frequency of seeing characteristics of the short wavelength sensitive visual pathway in clinically normal subjects and diabetic patients with focal sensitivity loss.

AIMS: To define the frequency of seeing (FOS) characteristics of the short wavelength (SW) sensitive visual pathway in clinically normal subjects and in diabetic patients with focal SW sensitivity loss. METHODS: For clinically normal subjects, FOS was assessed at two retinal locations (4.24 degrees and 9.90 degrees eccentricity) for both white on white (WW) and SW stimulus parameters. Inter-examination variability was quantified for the clinically normal subjects only. For patients with diabetes, FOS was assessed inside an area of focal SW sensitivity loss, and at the same eccentricity in the quadrant diametrically opposite, using SW stimulus parameters only. RESULTS: For clinically normal subjects, the group mean SW FOS slope was significantly flatter (p<0.0001) than that of WW at both locations. The coefficient of repeatability for SW FOS slope was+/-41.55 dB(-1) (relative to a group mean sensitivity of 23.98 dB(-1)) and+/-19.98 dB(-1) (group mean sensitivity 16.15 dB(-1)) for 4.24 degrees and 9.90 degrees , respectively. For the patients with diabetes, the group mean SW FOS slope was significantly flatter (p=0.020), and group mean SW threshold significantly higher (p=0.007) in the area of focal SW sensitivity loss than in that of the non-focal sensitivity loss. CONCLUSIONS: The results of this study suggest that the clinical utility of SW automated perimetry will be limited by a greater magnitude of measurement variability, as indicated by a flatter FOS slope, compared to conventional automated perimetry.

Eccentricity and measurement variability and repeatability with the retinal thickness analyser.

AIMS: To define the variability and repeatability of retinal thickness measurements using the retinal thickness analyser (RTA) and to elucidate any interaction between eccentricity (that is, position relative to the fovea) and variability and repeatability. METHODS: The sample comprised 20 normal subjects of mean age 33 years. Each subject attended for two visits. Repeated RTA scans were acquired centred on the fovea and for any one of the four possible non-foveal scan areas. The mean retinal thickness (+SD) was calculated for a series of concentric circular bands centred on fixation. A repeated measures analysis of variance (ANOVA) was used to determine any significant interaction between the variability of RTA thickness values and eccentricity. RESULTS: The group mean coefficient of variation and coefficient of repeatability were highest at the fovea. The repeated measures ANOVA revealed that the within test variability of RTA measurements varied significantly with eccentricity (p<0.0001). Similarly, the between test repeatability varied significantly with eccentricity (p = 0.045). CONCLUSION: The significantly elevated within test variability and between test repeatability in the foveal area need to be considered when using the RTA to evaluate patients with macular disease.

Neocortical cell migration: GABAergic neurons and cells in layers I and VI move in a cyclin-dependent kinase 5-independent manner.

The adult mammalian cerebral cortex arises from a complex series of neuronal migrations. The primitive layer known as the preplate is split into an outer marginal zone and an inner subplate by invading cortical plate neurons in an "inside-out" pattern of layering with respect to time of neuronal origin. In cyclin-dependent kinase 5 (Cdk5)-deficient mice (cdk5(-/-)), the earliest born cortical neurons split the preplate, but later born neurons arrest below the subplate, resulting in an ectopic "outside-in" layer of neurons normally destined for layers II-V. We have pursued this analysis in cdk5(-/-) <--> wild-type chimeric mice coupled with experiments in cell culture. In vitro migration assays show no difference in migrational ability between embryonic cdk5(-/-) and wild-type neurons. In cdk5(-/-) chimeras, layers I and VI are made up of both mutant and wild-type genotype neurons, whereas layers II-V contain predominantly wild-type cells. In addition, a thin layer of neurons is found below layer VI, made up of cdk5(-/-) cells; bromodeoxyuridine labeling suggests that these neurons were destined for layers II-V. Scattered cdk5(-/-) cells are found throughout layers II-V, but these neurons are always found to be GABAergic. The findings suggest that Cdk5 is not required for migration of either the deepest cortical plate neurons or the GABAergic neurons from the ganglionic eminences. The migration of layer II-V pyramidal neurons, however, is intrinsically blocked by Cdk5 deficiency, thus suggesting that different neuronal cell types use distinct mechanisms of migration.

SRC family kinases mediate epithelial Na+ channel inhibition by endothelin.

The epithelial Na(+) channel (ENaC) is implicated in the pathogenesis of salt-sensitive hypertension. Recent evidence from animal models suggests that the vasoactive peptide, endothelin (ET-1), may be an important negative regulator of ENaC in vivo. We investigated the signaling pathway involved in endothelin-mediated ENaC inhibition. Experiments were performed in NIH 3T3 cells stably expressing genes for the three (alpha, beta, and gamma) ENaC subunits. In whole cell patch clamp experiments, we found that ET-1 treatment induced a dose-dependent decrease in amiloride-sensitive currents. Using receptor-specific antagonists, we determined that the effects of ET-1 were attributed to activation of the ET(B) receptor. Moreover, the inhibitory effect of ET-1 on ENaC could be completely blocked when cells were pretreated with the selective Src family kinase inhibitor, PP2. Further studies revealed that basal Src family kinase activity strongly regulates ENaC whole cell currents and single channel gating. These results suggest that Src family kinases lie in a signaling pathway activated by ET-1 and are components of a novel negative regulatory cascade resulting in ENaC inhibition.

The role of tangential migration in the establishment of mammalian cortex.

In the developing nervous system, neurons are generated at sites distant from their ultimate location. In the vertebrate CNS, neurons utilize distinct migration strategies to reach their ultimate residence. This review discusses the contribution of tangential migration to the architectural development of the cerebral cortex and cerebellum.

Cortical development: receiving reelin.

Recent genetic and biochemical studies indicate that lipoprotein receptors are components of the neuronal receptor for Reelin, mediating the glycoprotein's essential function in cortical development. At least eight cadherin-related neuronal receptors may also play a part in this signalling system.

Cell birth, cell death, cell diversity and DNA breaks: how do they all fit together?

Substantial death of migrating and differentiating neurons occurs within the developing CNS of mice that are deficient in genes required for repair of double-stranded DNA breaks. These findings suggest that large-scale, yet previously unrecognized, double-stranded DNA breaks occur normally in early postmitotic and differentiating neurons. Moreover, they imply that cell death occurs if the breaks are not repaired. The cause and natural function of such breaks remains a mystery; however, their occurrence has significant implications. They might be detected by histological methods that are sensitive to DNA fragmentation and mistakenly interpreted to indicate cell death when no relationship exists. In a broader context, there is now renewed speculation that DNA recombination might be occurring during neuronal development, similar to DNA recombination in developing lymphocytes. If this is true, the target gene(s) of recombination and their significance remain to be determined.

Migration defects of cdk5(-/-) neurons in the developing cerebellum is cell autonomous.

Cyclin-dependent kinase 5 (Cdk5) is a member of the family of cell cycle-related kinases. Previous neuropathological analysis of cdk5(-/-) mice showed significant changes in CNS development in regions from cerebral cortex to brainstem. Among the defects in these animals, a disruption of the normal pattern of cell migrations in cerebellum was particularly apparent, including a pronounced abnormality in the location of cerebellar Purkinje cells. Complete analysis of this brain region is hampered in the mutant because most of cerebellar morphogenesis occurs after birth and the cdk5(-/-) mice die in the perinatal period. To overcome this disadvantage, we have generated chimeric mice by injection of cdk5(-/-) embryonic stem cells into host blastocysts. Analysis of the cerebellum from the resulting cdk5(-/-) left arrow over right arrow cdk5(+/+) chimeric mice shows that the abnormal location of the mutant Purkinje cells is a cell-autonomous defect. In addition, significant numbers of granule cells remain located in the molecular layer, suggesting a failure to complete migration from the external to the internal granule cell layer. In contrast to the Purkinje and granule cell populations, all three of the deep cerebellar nuclear cell groupings form correctly and are composed of cells of both mutant and wild-type genotypes. Despite similarities of the cdk5(-/-) phenotype to that reported in reeler and mdab-1(-/-) (scrambler/yotari) mutant brains, reelin and disabled-1 mRNA were found to be normal in cdk5(-/-) brain. Together, the data further support the hypothesis that Cdk5 activity is required for specific components of neuronal migration that are differentially required by different neuronal cell types and by even a single neuronal cell type at different developmental stages.

Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex.

The cerebral cortex of mice with a targeted disruption in the gene for cyclin-dependent kinase 5 (cdk5) is abnormal in its structure. Bromodeoxyuridine labeling reveals that the normal inside-out neurogenic gradient is inverted in the mutants; earlier born neurons are most often found superficial to those born later. Despite this, the early preplate layer separates correctly and neurons with a normal, pyramidal morphology can be found between true marginal zone and subplate. Consistent with their identity as layer VI corticothalamic neurons, they can be labeled by DiI injections into thalamus. The DiI injections also reveal that the trajectories of the cdk5(-/-) thalamocortical axons are oblique and cut across the entire cortical plate, instead of being oriented tangentially in the subcortical white matter. We propose a model in which the cdk5(-/-) defect blocks cortical development at a heretofore undescribed intermediate stage, after the splitting of the preplate, but before the migration of the full complement of cortical neurons.

Cortical development: layers of complexity.

Studies of spontaneous mutant mice with neurological phenotypes, particularly the cloning and analysis of the genes responsible, are shedding light on the complex processes that lead to formation of the deceptively simple layered structure of the cerebral cortex.

Construction of a yeast artificial chromosome contig encompassing the human acidic fibroblast growth factor (FGF1) gene: toward the cloning of the ANLL/MDS tumor-suppressor gene.

The region surrounding the human acidic fibroblast growth factor (FGF1) locus on chromosome 5q31 is of particular interest since it represents a critical region consistently lost in acute nonlymphocytic leukemia (ANLL) or myelodysplastic syndrome (MDS) patients who have a demonstrable deletion of the distal portion of the long arm of chromosome 5. It is proposed that an ANLL/MDS leukemia suppressor gene resides on 5q31. We have previously shown that the gene is most likely localized between FGF1 and PDGFRB/CSF1R loci. The region has also been linked to at least four other genetic diseases, Treacher Collins syndrome, diastrophic dysplasia, limb-girdle muscular dystrophy, and an autosomal dominant deafness, by linkage analysis. Here, we describe yeast artificial chromosomes (YAC) spanning 450 kb around the FGF1 gene. Six YAC clones were isolated from a human YAC library and their restriction enzyme maps were determined. The overlap of the clones with each other and with FGF1 cosmid and phage clones was characterized. Three of the YAC clones were found to contain the entire FGF1 gene, which spans more than 100 kb. Proximal and distal ends of several of these YAC clones were isolated for further overlap cloning. The proximal ends of both Y2 and Y4 were localized to previously isolated FGF1 DNA by sequence analysis. The distal ends of these two clones also hybridized to a human-hamster hybrid containing chromosome 5 as the only human genetic material. These results suggest that these YAC clones represent colinear DNA around the FGF1 locus.(ABSTRACT TRUNCATED AT 250 WORDS)

A multiyear study of blood cholinesterase activity in urban pesticide applicators.

This article is a review of blood cholinesterase activity in a cohort of urban pesticide applicators ranging from 1680 to over 3800 workers. During the period 1981-1991, 208, 788 blood samples were taken for measurement of cholinesterase activity with an average of 6 samples per year from each worker. A total of 150 workers or 0.44% of the cohort was removed from exposure to cholinesterase-inhibiting insecticides because of decreased cholinesterase activity. No worker required treatment for signs of cholinesterase inhibition.

Detection of the PTC/retTPC oncogene in human thyroid cancers.

We have investigated the PTC/retTPC oncogene, an activated form of ret proto-oncogene with a specific rearrangement, in thyroid malignancies. Southern analysis was used to screen 36 thyroid papillary carcinomas (PC), 22 normal thyroid tissues from glands with PC elsewhere, three follicular carcinomas, eight follicular adenomas and 30 other non-malignant thyroids. Rearrangements were detected in four PCs (11%) using probes derived from the ret proto-oncogene. Genomic breakpoints from a PC and a PC cell line (TPC-1) were cloned and sequenced. The rearrangement points of ret proto-oncogene were found in the intron between the exon for the transmembrane domain and the first exon for the tyrosine kinase domain. Furthermore, the PTC/retTPC chimeric transcripts were detected in two PCs with the rearrangement by reverse transcription polymerase chain reaction. Distant metastases were present in 50% (2/4) of PCs with the rearrangement, but in only two out of 32 PCs without a detectable rearrangement (P = 0.05, Fisher exact test). Our study suggests that the rearrangement of the ret proto-oncogene may be involved in the development of distant metastases in patients with papillary thyroid carcinomas. However, a larger clinical study will be required to verify this observation.