The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway

Mutation of the inositol polyphosphate 5-phosphatase OCRL1 results in two disorders in humans, namely Lowe syndrome (characterized by ocular, nervous system, and renal defects) and type 2 Dent disease (in which only the renal symptoms are evident). The disease mechanisms of these syndromes are poorly understood. Here we identify two novel OCRL1-binding proteins, termed inositol polyphosphate phosphatase interacting protein of 27 kDa (IPIP27)A and B (also known as Ses1 and 2), that also bind the related 5-phosphatase Inpp5b. The IPIPs bind to the C-terminal region of these phosphatases via a conserved motif similar to that found in the signaling protein APPL1. IPIP27A and B, which form homo- and heterodimers, localize to early and recycling endosomes and the trans-Golgi network (TGN). The IPIPs are required for receptor recycling from endosomes, both to the TGN and to the plasma membrane. Our results identify IPIP27A and B as key players in endocytic trafficking and strongly suggest that defects in this process are responsible for the pathology of Lowe syndrome and Dent disease.     

A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development

Epigenetic regulation of gene expression by histone-modifying corepressor complexes is central to normal animal development. The NAD(+)-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 corepressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1-associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans.     

Flowering phenology change and climate warming in southwestern Ohio

Global surface temperature has increased markedly over the last 100 years. This increase has a variety of implications for human societies, and for ecological systems. One of the most obvious ways ecosystems are affected by global climate change is through alteration of organisms’ developmental timing (phenology). We used annual botanical surveys that documented the first flowering for an array of species from 1976 to 2003 to examine the potential implications of climate change for plant development. The overall trend for these species was a progressively earlier flowering time. The two earliest flowering taxa (Galanthus and Crocus) also exhibited the strongest shift in first flowering. We detected a significant trend in climate suggesting higher temperatures in winter and spring over the sampling interval and found a significant relationship between warming temperatures and first flowering time for some species. Although 60% of the species in our study flowered earlier over the sampling interval, the remaining species exhibited no statistically detectable change. This variation in response is ostensibly associated with among-species variation in the role of climate cues in plant development. Future work is needed to isolate specific climate cues, and to link plant phenology to the physiological processes that trigger plant development.     

Dispelling dog dogma: an investigation of heterochrony in dogs using 3D geometric morphometric analysis of skull shape

Heterochrony is an evolutionary mechanism that generates diversity via perturbations of the rate or timing of development that requires very little genetic innovation. As such, heterochrony is thought to be a common evolutionary mechanism in the generation of diversity. Previous research has suggested that dogs evolved via heterochrony and are paedomorphic wolves. This study uses three-dimensional landmark-based coordinate data to investigate heterochronic patterns within the skull morphology of the domestic dog. A total of 677 adult dogs representing 106 different breeds were measured and compared with an ontogenetic series of 401 wolves. Geometric morphometric analysis reveals that the cranial shape of none of the modern breeds of dogs resembles the cranial shapes of adult or juvenile wolves. In addition, investigations of regional heterochrony in the face and neurocranium also reject the hypothesis of heterochrony. Throughout wolf cranial development the position of the face and the neurocranium remain in the same plane. Dogs, however, have a de novo cranial flexion in which the palate is tilted dorsally in brachycephalic and mesaticephalic breeds or tilted ventrally in dolichocephalic and down-face breeds. Dogs have evolved very rapidly into an incredibly morphologically diverse species with very little genetic variation. However, the genetic alterations to dog cranial development that have produced this vast range of phylogenetically novel skull shapes do not coincide with the expectations of the heterochronic model. Dogs are not paedomorphic wolves.     

Effectiveness of the standard WHO recommended retreatment regimen (category II) for tuberculosis in Kampala, Uganda: a prospective cohort study

Background

Each year, 10%–20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated.

Methods and Findings

From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12–33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10–5.22), HIV infection (2.16; 1.01–4.61), age (aOR for 10-year increase 1.59; 1.13–2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04–1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p<0.0001). Multidrug-resistant TB at enrolment was the only common risk factor for death during follow-up for both HIV-infected (adjusted hazard ratio [aHR] 17.9; 6.0–53.4) and HIV-uninfected (14.7; 4.1–52.2) individuals. Other risk factors for death during follow-up among HIV-infected patients were CD4<50 cells/ml and no antiretroviral treatment (aHR 7.4, compared to patients with CD4≥200; 3.0–18.8) and Karnofsky score <70 (2.1; 1.1–4.1); and among HIV-uninfected patients were poor adherence (missing half or more of doses) (3.5; 1.1–10.6) and duration of TB symptoms (aHR for a 1-month increase 1.9; 1.0–3.5).

Conclusions

The recommended regimen for retreatment TB in Uganda yields an unacceptable proportion of unsuccessful outcomes. There is a need to evaluate new treatment strategies in these patients. Please see later in the article for the Editors'' Summary     

Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice

Anti‐angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain–hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion‐associated domain in MUC4 and other proteins (AMOP) domain at the C‐terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C‐terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)‐basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF‐stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase‐dependent pathway. ISM binds to αvβ5 integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmen‐tal vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis.     

Observing copepods through a genomic lens

Background

Copepods outnumber every other multicellular animal group. They are critical components of the world's freshwater and marine ecosystems, sensitive indicators of local and global climate change, key ecosystem service providers, parasites and predators of economically important aquatic animals and potential vectors of waterborne disease. Copepods sustain the world fisheries that nourish and support human populations. Although genomic tools have transformed many areas of biological and biomedical research, their power to elucidate aspects of the biology, behavior and ecology of copepods has only recently begun to be exploited.

Discussion

The extraordinary biological and ecological diversity of the subclass Copepoda provides both unique advantages for addressing key problems in aquatic systems and formidable challenges for developing a focused genomics strategy. This article provides an overview of genomic studies of copepods and discusses strategies for using genomics tools to address key questions at levels extending from individuals to ecosystems. Genomics can, for instance, help to decipher patterns of genome evolution such as those that occur during transitions from free living to symbiotic and parasitic lifestyles and can assist in the identification of genetic mechanisms and accompanying physiological changes associated with adaptation to new or physiologically challenging environments. The adaptive significance of the diversity in genome size and unique mechanisms of genome reorganization during development could similarly be explored. Genome-wide and EST studies of parasitic copepods of salmon and large EST studies of selected free-living copepods have demonstrated the potential utility of modern genomics approaches for the study of copepods and have generated resources such as EST libraries, shotgun genome sequences, BAC libraries, genome maps and inbred lines that will be invaluable in assisting further efforts to provide genomics tools for copepods.

Summary

Genomics research on copepods is needed to extend our exploration and characterization of their fundamental biological traits, so that we can better understand how copepods function and interact in diverse environments. Availability of large scale genomics resources will also open doors to a wide range of systems biology type studies that view the organism as the fundamental system in which to address key questions in ecology and evolution.     

A comparison of the metabolic response to abdominal obesity in two Canadian Inuit and First Nations population

Inuit and Cree populations are known for high obesity rates despite markedly different rates of type 2 diabetes (T2DM). To document this apparent discrepancy we evaluated the impact of body size parameters and fasting insulin (FI) on several T2DM risk factors among Inuit and Cree populations (Québec, Canada). A total of 1,104 adults (≥18 years) Inuit and Cree individuals participated in a cross-sectional investigation. Interestingly, across both genders, across all levels of waist circumference (WC), Inuit showed lower levels of FI (age-adjusted, P < 0.0001) and fasting glucose (P < 0.0001) than Cree individuals. In both groups, a comparison of multi-sample structural equation models confirmed the predominant influence of WC on other traditional risk factors, compared to BMI. A preponderant direct impact of WC was observed on blood pressure (BP) parameters (P < 0.0001), high-density lipoprotein cholesterol (HDL-C) (P < 0.0001), and FI (P < 0.0001). Fasting glucose level appear to be influenced by WC via FI in both ethnic groups (P < 0.0001), while triacylglycerol (TAG) level was predominantly impacted by WC via FI, but only in Cree individuals (P < 0.0001). The main ethnic difference found was the strength of the impact of WC on FI, which was considerably higher among the Cree (λ = 2.4, P < 0.0001) than the Inuit (λ = 1.8, P < 0.0001). These results confirm the predominant role of abdominal adiposity in the complex and tenuous links of different traditional T2DM determinants. However, the ethnic difference in the impact of abdominal obesity on insulin levels across all WCs needs to be explored further.     

Use of saliva for early dengue diagnosis

Background

The necessity of a venous blood collection in all dengue diagnostic assays and the high cost of tests that are available for testing during the viraemic period hinder early detection of dengue cases and thus could delay cluster management. This study reports the utility of saliva in an assay that detects dengue virus (DENV)–specific immunoglobulin A (Ig A) early in the phase of a dengue infection.

Methods and Findings

Using an antigen capture anti-DENV IgA (ACA) ELISA technique, we tested saliva samples collected from dengue-confirmed patients. The sensitivity within 3 days from fever onset was over 36% in primary dengue infections. The performance is markedly better in secondary infections, with 100% sensitivity reported in saliva samples from day 1 after fever onset. Serum and salivary IgA levels showed good correlation (Pearson''s r = 0.69, p<0.001). Specificity was found to be 97%.

Conclusion

Our findings suggest that this technique would be very useful in dengue endemic regions, where the majority of dengue cases are secondary. The ACA-ELISA is easy to perform, cost effective, and especially useful in laboratories without sophisticated equipment. Our findings established the usefulness and reliability of saliva for early dengue diagnosis.