The Impact of Climate Change on Indigenous Arabica Coffee (Coffea arabica): Predicting Future Trends and Identifying Priorities

Precise modelling of the influence of climate change on Arabica coffee is limited; there are no data available for indigenous populations of this species. In this study we model the present and future predicted distribution of indigenous Arabica, and identify priorities in order to facilitate appropriate decision making for conservation, monitoring and future research. Using distribution data we perform bioclimatic modelling and examine future distribution with the HadCM3 climate model for three emission scenarios (A1B, A2A, B2A) over three time intervals (2020, 2050, 2080). The models show a profoundly negative influence on indigenous Arabica. In a locality analysis the most favourable outcome is a c. 65% reduction in the number of pre-existing bioclimatically suitable localities, and at worst an almost 100% reduction, by 2080. In an area analysis the most favourable outcome is a 38% reduction in suitable bioclimatic space, and the least favourable a c. 90% reduction, by 2080. Based on known occurrences and ecological tolerances of Arabica, bioclimatic unsuitability would place populations in peril, leading to severe stress and a high risk of extinction. This study establishes a fundamental baseline for assessing the consequences of climate change on wild populations of Arabica coffee. Specifically, it: (1) identifies and categorizes localities and areas that are predicted to be under threat from climate change now and in the short- to medium-term (2020–2050), representing assessment priorities for ex situ conservation; (2) identifies ‘core localities’ that could have the potential to withstand climate change until at least 2080, and therefore serve as long-term in situ storehouses for coffee genetic resources; (3) provides the location and characterization of target locations (populations) for on-the-ground monitoring of climate change influence. Arabica coffee is confimed as a climate sensitivite species, supporting data and inference that existing plantations will be neagtively impacted by climate change.     

Cortical and Spinal Excitability during and after Lengthening Contractions of the Human Plantar Flexor Muscles Performed with Maximal Voluntary Effort

This study was designed to investigate the sites of potential specific modulations in the neural control of lengthening and subsequent isometric maximal voluntary contractions (MVCs) versus purely isometric MVCs of the plantar flexor muscles, when there is enhanced torque during and following stretch. Ankle joint torque during maximum voluntary plantar flexion was measured by a dynamometer when subjects (n = 10) lay prone on a bench with the right ankle tightly strapped to a foot-plate. Neural control was analysed by comparing soleus motor responses to electrical nerve stimulation (M-wave, V-wave), electrical stimulation of the cervicomedullary junction (CMEP) and transcranial magnetic stimulation of the motor cortex (MEP). Enhanced torque of 17±8% and 9±8% was found during and 2.5–3 s after lengthening MVCs, respectively. Cortical and spinal responsiveness was similar to that in isometric conditions during the lengthening MVCs, as shown by unchanged MEPs, CMEPs and V-waves, suggesting that the major voluntary motor pathways are not subject to substantial inhibition. Following the lengthening MVCs, enhanced torque was accompanied by larger MEPs (p≤0.05) and a trend to greater V-waves (p≤0.1). In combination with stable CMEPs, increased MEPs suggest an increase in cortical excitability, and enlarged V-waves indicate greater motoneuronal output or increased stretch reflex excitability. The new results illustrate that neuromotor pathways are altered after lengthening MVCs suggesting that the underlying mechanisms of the enhanced torque are not purely mechanical in nature.     

Effect of Aging and Dietary Salt and Potassium Intake on Endothelial PTEN (Phosphatase and Tensin Homolog on Chromosome 10) Function

Aging promotes endothelial dysfunction, defined as a reduction in bioavailable nitric oxide (NO) produced by the endothelial isoform of nitric oxide synthase (NOS3). This enzyme is critically regulated by phosphorylation by protein kinase B (Akt), which in turn is regulated by the lipid phosphatase, PTEN. The present series of studies demonstrated a reduction in bioavailable NO as the age of rats increased from 1 to 12 months. At 12 months of age, rats no longer demonstrated increases in phosphorylated NOS3 in response to high dietary salt intake. Endothelial cell levels of PTEN increased with age and became refractory to change with increased salt intake. In contrast to the reduction in NO production, endothelial cell production of transforming growth factor-ß (TGF-ß) relative to NO increased progressively with age. In macrovascular endothelial cells, PTEN was regulated in a dose-dependent fashion by TGF-ß, which was further regulated by extracellular [KCl]. When combined with prior studies, the present series of experiments suggested an integral role for PTEN in endothelial cell pathobiology of aging and an important mitigating function of TGF-ß in endothelial PTEN regulation. The findings further supported a role for diet in affecting vascular function through the production of TGF-ß and NO.     

Influence of common non-synonymous Toll-like receptor 4 polymorphisms on bronchopulmonary dysplasia and prematurity in human infants

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease and major risk factor for severe respiratory syncytial virus (RSV) infection among preterm infants. The Toll-like receptor 4 (TLR4) is involved in oxidative injury responses in the lungs. Two non-synonymous single nucleotide polymorphisms in the TLR4 gene have been associated with RSV infection in children. However, it is unclear to what extent this association is confounded by BPD or prematurity. In this study, we analyzed two population-based cohorts of preterm infants at risk for BPD as well as ethnicity-matched infants born at term, to test whether the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are independently associated with BPD or premature birth. In a Canadian cohort (n = 269) composed of a majority of Caucasian preterm infants (BPD incidence of 38%), the TLR4-299 heterozygous genotype was significantly under-represented in infants without BPD (1.6% of infants versus 12% in infants with severe BPD) after adjusting for twins, ethnicity, gestational age, birth weight and gender (p = 0.014). This association was not replicated in a Finnish cohort (n = 434) of premature singletons or first-born siblings of Caucasian descent, although the incidence of BPD was substantially lower in this latter population (15%). We did not detect a significant association (>2-fold) between TLR4 genotypes and prematurity (p>0.05). We conclude that these TLR4 genotypes may have, at best, a modest influence on BPD severity in some populations of high-risk preterm infants. Further studies are warranted to clarify how clinical heterogeneity may impact genetic susceptibility to BPD.     

A novel highly potent therapeutic antibody neutralizes multiple human chemokines and mimics viral immune modulation

Chemokines play a key role in leukocyte recruitment during inflammation and are implicated in the pathogenesis of a number of autoimmune diseases. As such, inhibiting chemokine signaling has been of keen interest for the development of therapeutic agents. This endeavor, however, has been hampered due to complexities in the chemokine system. Many chemokines have been shown to signal through multiple receptors and, conversely, most chemokine receptors bind to more than one chemokine. One approach to overcoming this complexity is to develop a single therapeutic agent that binds and inactivates multiple chemokines, similar to an immune evasion strategy utilized by a number of viruses. Here, we describe the development and characterization of a novel therapeutic antibody that targets a subset of human CC chemokines, specifically CCL3, CCL4, and CCL5, involved in chronic inflammatory diseases. Using a sequential immunization approach, followed by humanization and phage display affinity maturation, a therapeutic antibody was developed that displays high binding affinity towards the three targeted chemokines. In vitro, this antibody potently inhibits chemotaxis and chemokine-mediated signaling through CCR1 and CCR5, primary chemokine receptors for the targeted chemokines. Furthermore, we have demonstrated in vivo efficacy of the antibody in a SCID-hu mouse model of skin leukocyte migration, thus confirming its potential as a novel therapeutic chemokine antagonist. We anticipate that this antibody will have broad therapeutic utility in the treatment of a number of autoimmune diseases due to its ability to simultaneously neutralize multiple chemokines implicated in disease pathogenesis.     

Four loci explain 83% of size variation in the horse

Horse body size varies greatly due to intense selection within each breed. American Miniatures are less than one meter tall at the withers while Shires and Percherons can exceed two meters. The genetic basis for this variation is not known. We hypothesize that the breed population structure of the horse should simplify efforts to identify genes controlling size. In support of this, here we show with genome-wide association scans (GWAS) that genetic variation at just four loci can explain the great majority of horse size variation. Unlike humans, which are naturally reproducing and possess many genetic variants with weak effects on size, we show that horses, like other domestic mammals, carry just a small number of size loci with alleles of large effect. Furthermore, three of our horse size loci contain the LCORL, HMGA2 and ZFAT genes that have previously been found to control human height. The LCORL/NCAPG locus is also implicated in cattle growth and HMGA2 is associated with dog size. Extreme size diversification is a hallmark of domestication. Our results in the horse, complemented by the prior work in cattle and dog, serve to pinpoint those very few genes that have played major roles in the rapid evolution of size during domestication.     

Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort

Background

Intrahepatic cholestasis of pregnancy (ICP) has important fetal implications. There is increased risk for poor fetal outcomes, including preterm delivery, meconium staining of amniotic fluid, respiratory distress, fetal distress and demise.

Methods

One hundred and one women diagnosed with ICP between January 2005 and March 2009 at San Francisco General Hospital were included in this study. Single predictor logistic regression models were used to assess the associations of maternal clinical and biochemical predictors with fetal complications. Clinical predictors analyzed included age, race/ethnicity, gravidity, parity, history of liver or biliary disease, history of ICP in previous pregnancies, and induction. Biochemical predictors analyzed included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, and total bile acids (TBA).

Results

The prevalence of ICP was 1.9%. Most were Latina (90%). Labor was induced in the majority (87%) and most were delivered by normal spontaneous vaginal delivery (84%). Fetal complications occurred in 33% of the deliveries, with respiratory distress accounting for the majority of complications. There were no statistically significant clinical or biochemical predictors associated with an increased risk of fetal complications. Elevated TBA had little association with fetal complications until reaching greater than 100 µmoL/L, with 3 out of 5 having reported complications. ICP in previous pregnancies was associated with decreased risk of fetal complications (OR 0.21, p = 0.046). There were no cases of late term fetal demise.

Conclusions

Maternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.     

CRIM1 complexes with ß-catenin and cadherins, stabilizes cell-cell junctions and is critical for neural morphogenesis

In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1) is a single-pass (type 1) transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using CRIM1 antisense morpholino oligonucleotides resulted in a failure of neural development. The CRIM1 knockdown phenotype was, in some cases, mild and resulted in perturbed neural fold morphogenesis. In severely affected embryos there was a dramatic failure of cell adhesion in the neural plate and complete absence of neural structures subsequently. Investigation of the mechanism of CRIM1 function revealed that it can form complexes with ?-catenin and cadherins, albeit indirectly, via the cytosolic domain. Consistent with this, CRIM1 knockdown resulted in diminished levels of cadherins and ?-catenin in junctional complexes in the neural plate. We conclude that CRIM1 is critical for cell-cell adhesion during neural development because it is required for the function of cadherin-dependent junctions.