Impaired alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and function by mutant huntingtin

Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5, which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and cognitive processes in HD conditions.     

Structure of ubiquitin-fold modifier 1-specific protease UfSP2

Ubiquitin-fold modifier 1 (Ufm1)-specific protease 2 (UfSP2) is a cysteine protease that is responsible for the release of Ufm1 from Ufm1-conjugated cellular proteins, as well as for the generation of mature Ufm1 from its precursor. The 2.6 Å resolution crystal structure of mouse UfSP2 reveals that it is composed of two domains. The C-terminal catalytic domain is similar to UfSP1 with Cys²⁹⁴, Asp⁴¹⁸, His⁴²⁰, Tyr²⁸², and a regulatory loop participating in catalysis. The novel N-terminal domain shows a unique structure and plays a role in the recognition of its cellular substrate C20orf116 and thus in the recruitment of UfSP2 to the endoplasmic reticulum, where C20orf116 predominantly localizes. Mutagenesis studies were carried out to provide the structural basis for understanding the loss of catalytic activity observed in a recently identified UfSP2 mutation that is associated with an autosomal dominant form of hip dysplasia.     

Number and mode of inheritance of QTL influencing backfat thickness on SSC2p in Sino-European pig pedigrees

Background

In the pig, multiple QTL associated with growth and fatness traits have been mapped to chromosome 2 (SSC2) and among these, at least one shows paternal expression due to the IGF2-intron3-G3072A substitution. Previously published results on the position and imprinting status of this QTL disagree between analyses from French and Dutch F2 crossbred pig populations obtained with the same breeds (Meishan crossed with Large White or Landrace).

Methods

To study the role of paternal and maternal alleles at the IGF2 locus and to test the hypothesis of a second QTL affecting backfat thickness on the short arm of SSC2 (SSC2p), a QTL mapping analysis was carried out on a combined pedigree including both the French and Dutch F2 populations, on the progeny of F1 males that were heterozygous (A/G) and homozygous (G/G) at the IGF2 locus. Simulations were performed to clarify the relations between the two QTL and to understand to what extent they can explain the discrepancies previously reported.

Results

The QTL analyses showed the segregation of at least two QTL on chromosome 2 in both pedigrees, i.e. the IGF2 locus and a second QTL segregating at least in the G/G F1 males and located between positions 30 and 51 cM. Statistical analyses highlighted that the maternally inherited allele at the IGF2 locus had a significant effect but simulation studies showed that this is probably a spurious effect due to the segregation of the second QTL.

Conclusions

Our results show that two QTL on SSC2p affect backfat thickness. Differences in the pedigree structures and in the number of heterozygous females at the IGF2 locus result in different imprinting statuses in the two pedigrees studied. The spurious effect observed when a maternally allele is present at the IGF2 locus, is in fact due to the presence of a second closely located QTL. This work confirms that pig chromosome 2 is a major region associated with fattening traits.     

Improving Maternal and Newborn Health: Effectiveness of a Community Health Worker Program in Rural Kenya

Background

Volunteer community health workers (CHWs) form an important element of many health systems, and in Kenya these volunteers are the foundation for promoting behavior change through health education, earlier case identification, and timely referral to trained health care providers. This study examines the effectiveness of a community health worker project conducted in rural Kenya that sought to promote improved knowledge of maternal newborn health and to increase deliveries under skilled attendance.

Methods

The study utilized a quasi-experimental nonequivalent design that examined relevant demographic items and knowledge about maternal and newborn health combined with a comprehensive retrospective birth history of women’s children using oral interviews of women who were exposed to health messages delivered by CHWs and those who were not exposed. The project trained CHWs in three geographically distinct areas.

Results

Mean knowledge scores were higher in those women who reported being exposed to the health messages from CHWs, Eburru 32.3 versus 29.2, Kinale 21.8 vs 20.7, Nyakio 26.6 vs 23.8. The number of women delivering under skilled attendance was higher for those mothers who reported exposure to one or more health messages, compared to those who did not. The percentage of facility deliveries for women exposed to health messages by CHWs versus non-exposed was: Eburru 46% versus 19%; Kinale 94% versus 73%: and Nyakio 80% versus 78%.

Conclusion

The delivery of health messages by CHWs increased knowledge of maternal and newborn care among women in the local community and encouraged deliveries under skilled attendance.     

Myofibrillar tightly bound calcium in skeletal muscle fibers: a possible role of this cation in titin strands aggregation

In muscle cells, part of the calcium is tightly bound to the N1- and N2-line of the sarcomere but its physiological significance was unknown. In the present work we reported the ability of a recombinant titin fragment spanning titin domains Z9 to I1 to tightly bind calcium ions with a K(d) of 0.049+/-0.004 nM. We further showed that calcium induced a spontaneous aggregation of the titin fragment and that the major aggregate is a tetramer. The implication of these findings on the organization of the six titin strands that emanate from the end of the thick filament within the I-band is discussed.     

Progeny-testing of full-sibs IBD in a SSC2 QTL region highlights epistatic interactions for fatness traits in pigs

Background

Tetraena mongolica (Zygophyllaceae), an endangered endemic species in western Inner Mongolia, China. For endemic species with a limited geographical range and declining populations, historical patterns of demography and hierarchical genetic structure are important for determining population structure, and also provide information for developing effective and sustainable management plans. In this study, we assess genetic variation, population structure, and phylogeography of T. mongolica from eight populations. Furthermore, we evaluate the conservation and management units to provide the information for conservation.

Results

Sequence variation and spatial apportionment of the atp B- rbc L noncoding spacer region of the chloroplast DNA were used to reconstruct the phylogeography of T. mongolica. A total of 880 bp was sequenced from eight extant populations throughout the whole range of its distribution. At the cpDNA locus, high levels of genetic differentiation among populations and low levels of genetic variation within populations were detected, indicating that most seed dispersal was restricted within populations.

Conclusions

Demographic fluctuations, which led to random losses of genetic polymorphisms from populations, due to frequent flooding of the Yellow River and human disturbance were indicated by the analysis of BEAST skyline plot. Nested clade analysis revealed that restricted gene flow with isolation by distance plus occasional long distance dispersal is the main evolutionary factor affecting the phylogeography and population structure of T. mongolica. For setting a conservation management plan, each population of T. mongolica should be recognized as a conservation unit.     

Age-matched comparison of children hospitalized for 2009 pandemic H1N1 influenza with those hospitalized for seasonal H1N1 and H3N2

BACKGROUND: A wide spectrum of clinical manifestation ranging from deaths to a mild course of disease has been reported in children infected with the 2009 pandemic H1N1 (pH1N1) influenza. METHODOLOGY/MAJOR FINDINGS: We conducted an age-matched control study comparing children hospitalized for pH1N1 with historic controls infected with seasonal H1N1 and H3N2 influenza to correct for the effect of age on disease susceptibility and clinical manifestations. We also compared children with pH1N1 to children concurrently admitted for seasonal influenza during the pandemic period to adjust for differences in health-seeking behavior during the pandemic or other potential bias associated with historic controls. There was no death or intensive care admission. Children with pH1N1 were more likely to have at least one risk condition for influenza, an underlying chronic pulmonary condition, more likely to have asthma exacerbation and to be treated with oseltamivir. There was no difference in other aspects of the clinical course or outcome. CONCLUSION: Disease manifestation of children hospitalized for pH1N1 infection was mild in our patient population.     

Vascular endothelial growth factor inhibition: Conflicting roles in tumor growth

Angiogenesis, the physiological process of sprouting of new blood vessels from pre-existing ones, is a key biological feature of almost all cancers. Among the multitude of factors driving tumor angiogenesis, vascular endothelial growth factor (VEGF) is the most potent, exerting myriad effects on vascular pruning and sprouting, permeability, network formation, proliferation, and cell death. Despite the initial unimpressive clinical performance of anti-VEGF antibody (bevacizumab) as cancer monotherapy, clear improvements in clinical outcomes following combination bevacizumab and chemotherapy regimens and multi-targeted VEGF receptor tyrosine kinase inhibitors (sorafenib and sunitinib) in select tumor types have established VEGF-targeted agents as an effective means of controlling cancer growth. Prolongation of overall survival and cure with these agents, however, remains elusive. Moreover, recent data has revealed key differences in the therapeutic and biological tumor response to antibody versus receptor kinase VEGF inhibitors and suggested, at least pre-clinically, that VEGF blockade in certain circumstances may actually promote more aggressive tumor growth. Given the diverse mechanisms and potentially opposing roles of VEGF neutralization in cancer biology, identification of novel biomarkers predictive of in vivo angiogenic responses may hold the key to optimizing therapeutic outcomes of anti-VEGF therapy in future cancer patients.     

A randomized,double-blind,placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide

Mitochondria are the most complex and the most important organelles of eukaryotic cells, which are involved in many cellular processes, including energy metabolism, apoptosis, and aging. And mitochondria have been identified as the "hot spot" by researchers for exploring relevant associated dysfunctions in many fields. The emergence of comparative proteomics enables us to have a close look at the mitochondrial proteome in a comprehensive and effective manner under various conditions and cellular circumstances. Two-dimensional electrophoresis combined with mass spectrometry is still the most popular techniques to study comparative mitochondrial proteomics. Furthermore, many new techniques, such as ICAT, MudPIT, and SILAC, equip researchers with more flexibilities inselecting proper methods. This article also reviews the recent development of comparative mitochondrial proteomics on diverse human diseases. And the results of mitochondrial proteomics enhance a better understanding of the pathogenesis associated with mitochondria and provide promising therapeutic targets.