Postnatal proteasome inhibition induces neurodegeneration and cognitive deficiencies in adult mice: a new model of neurodevelopment syndrome

Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation.     

Sterile Inflammation in Acetaminophen-induced Liver Injury Is Mediated by Cot/tpl2

Cot/tpl2 (MAP3K8) activates MKK1/2-Erk1/2 following stimulation of the Toll-like/IL-1 receptor superfamily. Here, we investigated the role of Cot/tpl2 in sterile inflammation and drug-induced liver toxicity. Cot/tpl2 KO mice exhibited reduced hepatic injury after acetaminophen challenge, as evidenced by decreased serum levels of both alanine and aspartate aminotransferases, decreased hepatic necrosis, and increased survival relative to Wt mice. Serum levels of both alanine and aspartate aminotransferases were also lower after intraperitoneal injection of acetaminophen in mice expressing an inactive form of Cot/tpl2 compared with Wt mice, suggesting that Cot/tpl2 activity contributes to acetaminophen-induced liver injury. Furthermore, Cot/tpl2 deficiency reduced neutrophil and macrophage infiltration in the liver of mice treated with acetaminophen, as well as their hepatic and systemic levels of IL-1α. Intraperitoneal injection of damage-associated molecular patterns from necrotic hepatocytes also impaired the recruitment of leukocytes and decreased the levels of several cytokines in the peritoneal cavity in Cot/tpl2 KO mice compared with Wt counterparts. Moreover, similar activation profiles of intracellular pathways were observed in Wt macrophages stimulated with Wt or Cot/tpl2 KO damage-associated molecular patterns. However, upon stimulation with damage-associated molecular patterns, the activation of Erk1/2 and JNK was deficient in Cot/tpl2 KO macrophages compared with their Wt counterparts; an effect accompanied by weaker release of several cytokines, including IL-1α, an important component in the development of sterile inflammation. Taken together, these findings indicate that Cot/tpl2 contributes to acetaminophen-induced liver injury, providing some insight into the underlying molecular mechanisms.     

Tuberculosis patients co-infected with Mycobacterium bovis and Mycobacterium tuberculosis in an urban area of Brazil

In this cross-sectional study, mycobacteria specimens from 189 tuberculosis (TB) patients living in an urban area in Brazil were characterised from 2008-2010 using phenotypic and molecular speciation methods (pncA gene and oxyR pseudogene analysis). Of these samples, 174 isolates simultaneously grew on Löwenstein-Jensen (LJ) and Stonebrink (SB)-containing media and presented phenotypic and molecular profiles of Mycobacterium tuberculosis, whereas 12 had molecular profiles of M. tuberculosis based on the DNA analysis of formalin-fixed paraffin wax-embedded tissue samples (paraffin blocks). One patient produced two sputum isolates, the first of which simultaneously grew on LJ and SB media and presented phenotypic and molecular profiles of M. tuberculosis, and the second of which only grew on SB media and presented phenotypic profiles of Mycobacterium bovis. One patient provided a bronchial lavage isolate, which simultaneously grew on LJ and SB media and presented phenotypic and molecular profiles of M. tuberculosis, but had molecular profiles of M. bovis from paraffin block DNA analysis, and one sample had molecular profiles of M. tuberculosis and M. bovis identified from two distinct paraffin blocks. Moreover, we found a low prevalence (1.6%) of M. bovis among these isolates, which suggests that local health service procedures likely underestimate its real frequency and that it deserves more attention from public health officials.     

Comparison of two populations of the pantropical predator Amblyseius largoensis (Acari: Phytoseiidae) for biological control of Raoiella indica (Acari: Tenuipalpidae)

The red palm mite, Raoiella indica Hirst (Acari: Tenuipalpidae), was recently introduced in the Americas. It spread quickly throughout coconut palm growing areas, expanding considerably its host range. The invasion of this species has caused high economic impact in several countries. In Brazil, extensive areas are expected to be affected. For logistical reasons and other concerns, chemical control does not seem desirable for the control of this pest in most Latin American countries. Biological control of R. indica by introducing exotic natural enemies seems to be an important control measure to be considered. Surveys in many countries have shown that Amblyseius largoensis (Muma) (Acari: Phytoseiidae) is a very common predator on coconut palms. This study compared the biology of a population of A. largoensis found for a long time in association with R. indica in La Reunion Island (Indian Ocean) with a population from Roraima State (northern Brazil), where R. indica was first found about two and a half years ago. No significant differences were observed between populations in relation to the duration of different immature stages or total survivorship. However, the oviposition period, prey consumption and net reproductive rate were significantly higher for the La Reunion population, warranting further investigation to determine whether that population should be released in Roraima to control the pest.     

A tight balance between natural selection and gene flow in a southern African arid-zone endemic bird

Gene flow is traditionally thought to be antagonistic to population differentiation and local adaptation. However, recent studies have demonstrated that local adaptation can proceed provided that selection is greater than the homogenizing effects of gene flow. We extend these initial studies by combining ecology (climate), phenotype (body size), physiological genetics (oxidative phosphorylation genes), and neutral loci (nuclear microsatellites and introns) to test whether selection can counter-balance gene flow and hence promote local adaptation in a bird whose distribution spans an aridity gradient. Our results show that the Karoo scrub-robin's climatic niche is spatially structured, providing the potential for local adaptation to develop. We found remarkably discordant patterns of divergence among mtDNA, morphology, and neutral loci. For the mitochondrial genes, two amino acid replacements, strong population structure and reduced gene flow were associated with the environmental gradient separating western coastal sites from the interior of southern Africa. In contrast, morphology and the neutral loci exhibited variation independent of environmental variables, and revealed extensive levels of gene flow across the aridity gradient, 50 times larger than the estimates for mitochondrial genes. Together, our results suggest that selective pressures on physiology, mediated by the mitochondrial genome, may well be a common mechanism for facilitating local adaptation to new climatic conditions.     

Risk Acceptance in Multiple Sclerosis Patients on Natalizumab Treatment

Objective

We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance.

Methods

From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits’ scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls.

Results

No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). In low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group.

Conclusions

Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.     

New variants in Spanish Niemann–Pick type c disease patients

Molecular Biology Reports - Niemann–Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by...     

Habitat disturbance modifies dominance,coexistence, and competitive interactions in tropical ant communities

1. Interspecific competition is a major structuring principle in ecological communities. Despite their prevalence, the outcome of competitive interactions is hard to predict, highly context-dependent, and multiple factors can modulate such interactions. 2. We tested predictions concerning how competitive interactions are modified by anthropogenic habitat disturbance in ground-foraging ant assemblages inhabiting fragmented Inter-Andean tropical dry forests in southwestern Colombia, and investigated ant assemblages recruiting to baits in 10 forest fragments exposed to varying level of human disturbance. 3. Specifically, we evaluated how different components of competitive interactions (patterns of species co-occurrence, resource partitioning, numerical dominance, and interspecific trade-offs between discovery and dominance competition) varied with level of habitat disturbance in a human-dominated ecosystem. 4. Multiple lines of evidence suggest that the role of competitive interactions in structuring ground-foraging ant communities at baits varied with respect to habitat disturbance. As disturbance increased, community structure was more likely to exhibit random co-occurrence patterns, higher levels of monopolization of food resources by dominant ants, and disproportionate dominance of a single species, the little fire ant (Wasmannia auropunctata). At a regional scale, we found evidence for a trade-off between dominance and discovery abilities of the 15 most common species at baits. 5. Together, these results suggest that human disturbance modifies the outcome of competitive interactions in ground-foraging ant assemblages and may promote dominant species that reduce diversity and coexistence in tropical ecosystems.     

Resolution,structures, and vibrational circular dichroism of helicoidal trinickel and tricobalt paddlewheel complexes

It has been recently shown that enantiomers of the helicoidal paddlewheel complex [Co₃(dpa)₄(CH₃CN)₂]²⁺ (dpa = the anion of 2,2′-dipyridylamine) can be resolved using the chiral [As₂(tartrate)₂]²⁻ anion (AsT) and that these complexes demonstrate a strong chiroptical response in the ultraviolet-visible and X-ray energy regions. Here we report that the nickel congener, [Ni₃(dpa)₄(CH₃CN)₂]²⁺, can likewise be resolved using AsT. Depending on the stereochemistry of the enantiopure AsT anion, one or the other of the trinickel enantiomers crystallize from CH₃CN and diethyl ether in space group P42₁2 as the (NBu₄)₂[Ni₃(dpa)₄(CH₃CN)₂](AsT)₂·[solvent] salt. After resolution, the AsT salts were converted into the PF₆⁻ salts by anion exchange, with retention of the chirality of the trinickel complex. The enantiopure [Ni₃(dpa)₄(CH₃CN)₂](PF₆)₂·2CH₃CN and [Co₃(dpa)₄(CH₃CN)₂](PF₆)₂·CH₃CN·C₄H₁₀O compounds crystallize in space groups C2 and P2₁, respectively. Both the Ni(II) and Co(II) complex cations are stable towards racemization in CH₃CN. Vibrational circular dichroism (VCD) data obtained in CD₃CN demonstrate the expected mirror image spectra for the enantiomers, the observed peaks arising from the dpa ligand. The VCD response is significant, with Δε values up to 6 Lmol⁻¹ cm⁻¹ and vibrational dissymmetry factors on the order of 10⁻³. Density functional theory calculations well reproduce the experimental spectra, showing little difference between the peak position, sign, and intensity in the VCD for the cobalt and nickel complexes. These results suggest that VCD enhancement of these peaks is unlikely, and their remarkable intensity may be due to their rigid helicoidal structure.