Abnormal expression of p27kip1 protein in levator ani muscle of aging women with pelvic floor disorders – a relationship to the cellular differentiation and degeneration

BACKGROUND: Pelvic floor disorders affect almost 50% of aging women. An important role in the pelvic floor support belongs to the levator ani muscle. The p27/kip1 (p27) protein, multifunctional cyclin-dependent kinase inhibitor, shows changing expression in differentiating skeletal muscle cells during development, and relatively high levels of p27 RNA were detected in the normal human skeletal muscles. METHODS: Biopsy samples of levator ani muscle were obtained from 22 symptomatic patients with stress urinary incontinence, pelvic organ prolapse, and overlaps (age range 38–74), and nine asymptomatic women (age 31–49). Cryostat sections were investigated for p27 protein expression and type I (slow twitch) and type II (fast twitch) fibers. RESULTS: All fibers exhibited strong plasma membrane (and nuclear) p27 protein expression. cytoplasmic p27 expression was virtually absent in asymptomatic women. In perimenopausal symptomatic patients (ages 38–55), muscle fibers showed hypertrophy and moderate cytoplasmic p27 staining accompanied by diminution of type II fibers. Older symptomatic patients (ages 57–74) showed cytoplasmic p27 overexpression accompanied by shrinking, cytoplasmic vacuolization and fragmentation of muscle cells. The plasma membrane and cytoplasmic p27 expression was not unique to the muscle cells. Under certain circumstances, it was also detected in other cell types (epithelium of ectocervix and luteal cells). CONCLUSIONS: This is the first report on the unusual (plasma membrane and cytoplasmic) expression of p27 protein in normal and abnormal human striated muscle cells in vivo. Our data indicate that pelvic floor disorders are in perimenopausal patients associated with an appearance of moderate cytoplasmic p27 expression, accompanying hypertrophy and transition of type II into type I fibers. The patients in advanced postmenopause show shrinking and fragmentation of muscle fibers associated with strong cytoplasmic p27 expression

Simulating North American Weather Types With Regional Climate Models

Regional climate models (RCMs) are able to simulate small-scale processes that are missing in their coarser resolution driving data and thereby provide valuable climate information for climate impact assessments. Less attention has been paid to the ability of RCMs to capture large-scale weather types (WTs). An inaccurate representation of WTs can result in biases and uncertainties in current and future climate simulations that cannot be easily detected by standard model evaluation metrics. Here we define 12 hydrologically important WTs in the contiguous United States (CONUS). We test if RCMs from the North American CORDEX (NA-CORDEX) and the Weather Research and Forecasting (WRF) model large physics ensembles (WRF36) can capture those WTs in the current climate and how they simulate changes in the future. Our results show that the NA-CORDEX RCMs are able to simulate WTs more accurately than members of the WRF36 ensemble. The much larger WRF36 domain in combination with not constraining large-scale conditions by spectral nudging results in lower WT skill. The selection of the driving global climate model (GCM) has a large effect on the skill of NA-CORDEX simulations but a smaller impact on the WRF36 runs. The formulation of the RCM is of minor importance except for capturing the variability within WTs. Changing the model physics or increasing the RCM horizontal grid spacing has little effect. These results highlight the importance of selecting GCMs with accurate synoptic-scale variability for downscaling and to find a balance between large domains that can result in biased WT representations and small domains that inhibit the realistic development of mesoscale processes. At the end of the century, monsoonal flow conditions increase systematically by up to 30% and a WT that is a significant source of moisture for the Northern Plains during the growing seasons decreases systematically up to –30%

Climate change projections of the North American Regional Climate Change Assessment Program (NARCCAP)

We investigate major results of the NARCCAP multiple regional climate model (RCM) experiments driven by multiple global climate models (GCMs) regarding climate change for seasonal temperature and precipitation over North America. We focus on two major questions: How do the RCM simulated climate changes differ from those of the parent GCMs and thus affect our perception of climate change over North America, and how important are the relative contributions of RCMs and GCMs to the uncertainty (variance explained) for different seasons and variables? The RCMs tend to produce stronger climate changes for precipitation: larger increases in the northern part of the domain in winter and greater decreases across a swath of the central part in summer, compared to the four GCMs driving the regional models as well as to the full set of CMIP3 GCM results. We pose some possible process-level mechanisms for the difference in intensity of change, particularly for summer. Detailed process-level studies will be necessary to establish mechanisms and credibility of these results. The GCMs explain more variance for winter temperature and the RCMs for summer temperature. The same is true for precipitation patterns. Thus, we recommend that future RCM-GCM experiments over this region include a balanced number of GCMs and RCMs

Seasonality, intensity, and duration of rainfall extremes change in a warmer climate

Precipitation extremes are expected to intensify under climate change with consequent impacts in flooding and ecosystem functioning. Here we use station data and high‐resolution simulations from the WRF convection permitting climate model (∼4 km, 1 h) over the US to assess future changes in hourly precipitation extremes. It is demonstrated that hourly precipitation extremes and storm depths are expected to intensify under climate change and what is now a 20‐year rainfall will become a 7‐year rainfall on average for ∼ 75% of gridpoints over the US. This intensification is mostly expressed as an increase in rainfall tail heaviness. Statistically significant changes in the seasonality and duration of rainfall extremes are also exhibited over ∼ 95% of the domain. Our results suggest more non‐linear future precipitation extremes with shorter spell duration that are distributed more uniformly throughout the year

Cyclophilin A interacts with diverse lentiviral capsids

BACKGROUND: The capsid (CA) protein of HIV-1 binds with high affinity to the host protein cyclophilin A (CypA). This binding positively affects some early stage of the viral life-cycle because prevention of binding either by drugs that occupy that active site of cyclophilin A, by mutation in HIV-1 CA, or RNAi that knocks down intracellular CypA level diminishes viral infectivity. The closely related lentivirus, SIVcpz also binds CypA, but it was thought that this interaction was limited to the HIV-1/SIVcpz lineage because other retroviruses failed to interact with CypA in a yeast two-hybrid assay. RESULTS: We find that diverse lentiviruses, FIV and SIVagmTAN also bind to CypA. Mutagenesis of FIV CA showed that an amino acid that is in a homologous position to the proline at amino acid 90 of HIV-1 CA is essential for FIV interactions with CypA. CONCLUSION: These results demonstrate that CypA binding to lentiviruses is more widespread than previously thought and suggest that this interaction is evolutionarily important for lentiviral infection

Host cell species-specific effect of cyclosporine A on simian immunodeficiency virus replication

<p>Abstract</p> <p>Background</p> <p>An understanding of host cell factors that affect viral replication contributes to elucidation of the mechanism for determination of viral tropism. Cyclophilin A (CypA), a peptidyl-prolyl <it>cis-trans </it>isomerase (PPIase), is a host factor essential for efficient replication of human immunodeficiency virus type 1 (HIV-1) in human cells. However, the role of cyclophilins in simian immunodeficiency virus (SIV) replication has not been determined. In the present study, we examined the effect of cyclosporine A (CsA), a PPIase inhibitor, on SIV replication.</p> <p>Results</p> <p>SIV replication in human CEM-SS T cells was not inhibited but rather enhanced by treatment with CsA, which inhibited HIV-1 replication. CsA treatment of target human cells enhanced an early step of SIV replication. CypA overexpression enhanced the early phase of HIV-1 but not SIV replication, while CypA knock-down resulted in suppression of HIV-1 but not SIV replication in CEM-SS cells, partially explaining different sensitivities of HIV-1 and SIV replication to CsA treatment. In contrast, CsA treatment inhibited SIV replication in macaque T cells; CsA treatment of either virus producer or target cells resulted in suppression of SIV replication. SIV infection was enhanced by CypA overexpression in macaque target cells.</p> <p>Conclusions</p> <p>CsA treatment enhanced SIV replication in human T cells but abrogated SIV replication in macaque T cells, implying a host cell species-specific effect of CsA on SIV replication. Further analyses indicated a positive effect of CypA on SIV infection into macaque but not into human T cells. These results suggest possible contribution of CypA to the determination of SIV tropism.</p

Literature survey on epidemiology and pathology of gangliocytic paraganglioma

<p>Abstract</p> <p>Background</p> <p>Although gangliocytic paraganglioma (GP) has generally been regarded as a neuroendocrine tumor, its origin remains unclear. We therefore aimed to investigate the details of this disease by carefully analyzing and extracting common features of the disease as presented in selected publications.</p> <p>Methods</p> <p>We searched for English and Japanese cases of GP using the PubMed and IgakuChuoZasshi databases on August 2010. We then extracted and sampled raw data from the selected publications and performed appropriate statistical analyses. Additionally, we evaluated the expression of hormone receptors based on our previously reported case.</p> <p>Results</p> <p>192 patients with GP were retrieved from the databases. Patient ages ranged from 15 y to 84 y (mean: 52.3 y). The gender ratio was 114:76 (male to female, 2 not reported). Maximum diameter of the tumors ranged from 5.5 mm to 100 mm (mean: 25.0 mm). The duodenum (90.1%, 173/192) was found to be the most common site of the disease. In 173 patients with duodenal GP, gastrointestinal bleeding (45.1%, 78/173) was found to be the most common symptom of the disease, followed by abdominal pain (42.8%, 74/173), and anemia (14.5%, 25/173). Rate of lymph node metastasis was 6.9% (12/173). Our statistical analysis indicated that significant differences were found for gender between GP within the submucosal layer and exceeding the submucosal layer. Furthermore, our immunohistochemical evaluation showed that both epithelioid and pancreatic islet cells showed positive reactivity for progesterone receptors.</p> <p>Conclusions</p> <p>Our literature survey revealed that there were many more cases of GP exceeding the submucosal layer than were expected. Meanwhile, our statistical analyses and immunohistochemical evaluation supported the following two hypotheses. First, vertical growth of GP might be affected by progesterone exposure. Second, the origin of GP might be pancreatic islet cells. However, it is strongly suspected that our data have been affected by publication bias and to confirm these hypotheses, further investigation is required.</p