Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease

The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta-analysis by combining all available case–control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel–Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR = 1.212 for T allele, 95% CI = 1.097–1.340, p-value = 0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR = 1.187 for T allele, 95% CI = 1.058–1.332, p-value = 0.004) and Asian samples (allelic model, pooled OR = 1.293 for T allele, 95% CI = 1.058–1.580, p-value = 0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value = 0.0149) and CHB (Chinese, p-value = 0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD.     

Genus Bembidion Latreille (Coleoptera: Carabidae) in New Zealand: A revision

The cosmopolitan genus Bembidion is represented in New Zealand by 20 species, of which 19 are endemic; B. brullei appears to be a recent introduction. On phenetic characters the species fall into 7 subgenera, as follows: Zeplataphus n.subg.—maorinum Bates, dehiscens Broun, charile Bates, granuliferum n.sp., townsendi n.sp., tairuense Bates; Zeactedium Netolitzky—orbiferum Bates, musae Broun; Zeperyphodes n.subg.—callipeplum Bates; Zeperyphus n.subg.—actuarium Broun; Zemetal‐lina n.subg.—chalceipes Bates, solitarium n.sp., anchonoderum Bates, tekapoense Broun, wanakense n.sp., urewerense n.sp., hokitikense Bates, parviceps Bates; Ananotaphus Netolitzky—rotundicolle Bates; Notaphus Stephens—brullei Gemminger & Harold. The North Island population of maorinum is distinct from the typical South Island form in having reduced microscrulpture on the elytra, and is here separated as levatum n.ssp. An apparent geographic isolate of anchonoderum, represented by 2 females from Stewart Island, is provisionally recognised as stewartense n.ssp. The polymorphic complex within subg. Ananotaphus is here regarded as a single species, of which the North Island population is sufficiently distinct to warrant subspecific status as eustictum Bates; however, intergrades occur in the north‐west of the South Island. The following names fall into synonymy: latiusculum Broun (= maorinum); diaphanum Broun (= musae); nesophilum Broun (= callipeplum)’, tinctellum Broun (= chalceipes);antipodum Broun (= anchonoderum)’, tantillum Broun and probably attenuatum Broun (=hokitikense)’, clevedonense Broun and waikatoense Broun (= rotundicolle, ssp. eustictum)’, gameani Jeannel (= brullei). The relationships and aspects of the biology and ecology of the New Zealand Bembidion fauna are discussed.     

Mathematical modelling and computer simulation of Brownian motion and hybridisation of nanoparticle–bioprobe–polymer complexes in the low concentration limit

A wide variety of nano-biotechnological applications are being developed for nanoparticles based on in vitro diagnostic and imaging systems. Some of these systems allow highly sensitive detection of molecular biomarkers. Frequently, the very low concentration of the biomarkers makes very difficult the mathematical simulation of the motion of nanoparticles based on classical, partial differential equations. We address the issue of incubation times for low concentration systems using Monte Carlo simulations. We describe a mathematical model and computer simulation of Brownian motion of nanoparticle–bioprobe–polymer contrast agent complexes and their hybridisation to immobilised targets. We present results for the dependence of incubation times on the number of particles available for detection, and the geometric layout of the DNA-detection assay on the chip.     

SPERMATOGENESIS IN A TRICHUROID NEMATODE,TRICHURIS MURIS. II. FINE STRUCTURE OF PRIMARY SPERMATOCYTE AND FIRST MEIOTIC DIVISION

Ultrastructural observations indicate that the primary spermatocyte of Trichuris muris is larger than the spermatogonial stage with an increased cytoplasm to nucleus ratio. The cytoplasm contains an extensive reticular system, mitochondria, numerous free ribosomes and prominent Golgi complexes which may contribute to the formation of a sub-surface, vesicular complex. Although only two spermatocytes were seen to be linked by a cytoplasmic bridge it is suggested that the number of conjoined cells is probably greater. The rearrangement of mitochondria in a ring around the nucleus and the indentation and vesiculation of the nuclear envelope preceeded its disappearance and indicated the onset of meiosis. Centrioles were frequently resolved at this stage. They were composed of nine peripheral doublets surrounded by a dense pericentriolar sheath. Three dense chromatin areas indicative of haploid chromosomes were present in later meiotic stages. Each chromosome was surrounded by a number of mitochondria and there was a clear separation of the chromosome-mitochondrial clusters from the remainder of the cytoplasm. This was particularly evident at telophase when two daughter cells were partially separated by membrane infoldings. This reflects incomplete cytokinesis in the dividing spermatocyte of T. muris and is similar to that described in other trichuroid species. A close association with processes of the non-germinal, sustentacular cells was noted throughout the spermatocyte stage.     

Metabolic impact assessment for heterologous protein production in Streptomyces lividans based on genome-scale metabolic network modeling

The metabolic impact exerted on a microorganism due to heterologous protein production is still poorly understood in Streptomyces lividans. In this present paper, based on exometabolomic data, a proposed genome-scale metabolic network model is used to assess this metabolic impact in S. lividans. Constraint-based modeling results obtained in this work revealed that the metabolic impact due to heterologous protein production is widely distributed in the genome of S. lividans, causing both slow substrate assimilation and a shift in active pathways. Exchange fluxes that are critical for model performance have been identified for metabolites of mouse tumor necrosis factor, histidine, valine and lysine, as well as biomass. Our results unravel the interaction of heterologous protein production with intracellular metabolism of S. lividans, thus, a possible basis for further studies in relieving the metabolic burden via metabolic or bioprocess engineering.     

Cyclooxygenase‐1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease

Several epidemiological and preclinical studies suggest that non‐steroidal anti‐inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β‐amyloid (Aβ) production and inhibit neuroinflammation. However, follow‐up clinical trials, mostly using selective cyclooxygenase (COX)‐2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX‐1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro‐inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX‐1 inhibition, rather than COX‐2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20‐month‐old triple transgenic AD (3 × Tg‐AD) mice with the COX‐1 selective inhibitor SC‐560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC‐560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg‐AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX‐1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg‐AD mice. Thus, selective COX‐1 inhibition should be further investigated as a potential therapeutic approach for AD.     

Mus in Morocco: a Quaternary sequence of intraspecific evolution

North Africa is an intricate biogeographical region at the crossroads of immigration waves from tropical Africa and Asia. Species confined between various barriers (Atlas Mountains, arid environments such as the Sahara in the south, water masses such as the Mediterranean Sea in the north, and the Atlantic Ocean in the west) were generally forced to adapt locally to environmental changes instead of tracking their habitat by shifting their distribution area. The present study aims at providing first insight into the evolution of the genus Mus, and more specifically of the western Mediterranean species Mus spretus in this area. The study relies on the abundant Late Pleistocene and Middle Holocene fossil assemblage from the El Harhoura 2 cave (Rabat‐Témara, Morocco). This exceptional record was studied using geometric morphometrics applied to first upper and lower molars, constituting the most informative and best preserved fossil remains for such small rodents. Two main issues were addressed. (1) Geometric morphometrics was used to clarify taxonomic status and phylogenetic relationships among fossil and modern species in this area. Morphometric analysis revealed good discrimination of most modern and fossil species but failed to document intermediate forms tracing anagenetic evolution. Not mutually exclusive, the occurrence of complex processes of morphological evolution in this genus such as parallel evolution and the action of stabilizing selection may make it difficult to translate patterns of morphological evolution into phylogenetic conclusions. (2) The record was shown to document a sequence of intraspecific evolution of M. spretus. The morphology of the molars through the fossil record of El Harhoura 2 was surprisingly stable despite extensive modern variation. The limited temporal variation largely failed to correlate to palaeoenvironmental proxies. The mouse fossil record at El Harhoura 2 thus presents an intriguing case of morphological stasis despite extensive environmental changes. This long‐term stability may have been recently perturbed by anthropogenic factors including landscape changes and introduction of various competitors and predators, leading to a size reduction. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 109 , 599–621.     

A population-based study of first and second-line drug-resistant tuberculosis in a high-burden area of the Mexico/United States border

The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.     

Protective effects of EphB2 on Aβ1–42 oligomer-induced neurotoxicity and synaptic NMDA receptor signaling in hippocampal neurons

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized pathologically by the abnormal deposition of extracellular amyloid-β (Aβ) oligomers. However, the nature and precise mechanism of the toxicity of Aβ oligomers are not clearly understood. Aβ oligomers have been previously shown to cause a major loss of EphB2, a member of the EphB family of receptor tyrosine kinases. To determine the effect of EphB2 on Aβ oligomer-induced neurotoxicity and the underlying molecular mechanisms, we examined the EphB2 gene in cultured hippocampal neurons. Using a cellular model of AD, Aβ_1–42 oligomers were confirmed to induce neurotoxicity in a time-dependent manner and result in a major decrease of EphB2. EphB2 overexpression could prevent the neurotoxicity of hippocampal neurons from exposure to Aβ_1–42 oligomers for 1 h. Further analysis revealed that EphB2 overexpression increased synaptic NR1 and NR2B expression in Aβ_1–42 oligomer-treated neurons. Moreover, EphB2 overexpression prevented Aβ_1–42 oligomer-induced downregulation of dephosphorylated p38 MAPK and phosphorylated CREB. Together, these results suggest that EphB2 is a factor which protects hippocampal neurons against the toxicity of Aβ_1–42 oligomers, and we infer that the protection of EphB2 is achieved by increasing the synaptic NMDA receptor level and downstream p38 MAPK and CREB signaling in hippocampal neurons. This study provides new molecular insights into the neuroprotective effect of EphB2 and highlights its potential therapeutic role in the management of AD.     

Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain

Prior work has shown that iron interacts with hyperphosphorylated tau, which contributes to the formation of neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD), whereas iron chelator desferrioxamine (DFO) slows down the clinical progression of the cognitive decline associated with this disease. However, the effects of DFO on tau phosphorylation in the presence or absence of iron have yet to be determined. Using amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mouse brain as a model system, we investigated the effects and potential mechanisms of intranasal administration of DFO on iron induced abnormal tau phosphorylation. High-dose iron treatment markedly increased the levels of tau phosphorylation at the sites of Thr205, Thr231 and Ser396, whereas highly induced tau phosphorylation was abolished by intranasal administration of DFO in APP/PS1 transgenic mice. Moreover, DFO intranasal administration also decreases Fe-induced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β), which in turn suppressing tau phosphorylation. Cumulatively, our data show that intranasal DFO treatment exerts its suppressive effects on iron induced tau phosphorylation via CDK5 and GSK3β pathways. More importantly, elucidation of DFO mechanism in suppressing tau phosphorylation may provide insights for developing therapeutic strategies to combat AD.