Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13

Myoclonic epilepsies with onset in infancy and childhood are clinically and etiologically heterogeneous. Although genetic factors are thought to play an important role, to date very little is known about the etiology of these disorders. We ascertained a large Italian pedigree segregating a recessive idiopathic myoclonic epilepsy that starts in early infancy as myoclonic seizures, febrile convulsions, and tonic-clonic seizures. We typed 304 microsatellite markers spanning the 22 autosomes and mapped the locus on chromosome 16p13 by linkage analysis. A maximum LOD score of 4.48 was obtained for marker D16S3027 at recombination fraction 0. Haplotype analysis placed the critical region within a 3.4-cM interval between D16S3024 and D16S423. The present report constitutes the first example of an idiopathic epilepsy that is inherited as an autosomal recessive trait.     

Comparative analysis of the facilitating effects induced on muscular periphery by the microstimulation of various cerebellar nuclei

The facilitatory effects evoked on the motor periphery by the activation of neuronal pools in cerebellar nuclei were analized in 13 cats. The aim of the work was to compare the frequency and the characteristics of the motor facilitations induced on the ipsilateral forelimb by the microstimulation of cerebellar foci in the fastigial (CBM or in the interposital (NIA) nucleus. CBM or NIA sites, previously identified for the motor effects, were microstimulated, together with the contralateral motor cortex, to give evidence of the facilitations. It was observed that 51% of the NIA motor sites, 46% of the rostral and 33% of the caudal CBM ones, were able, when activated, to evoke facilitatory effects on at least one muscle. The most frequent motor pattern observed following NIA microstimulation was the contraction of a proximal muscle and simultaneously the facilitation of a distal one. Similar responses were detected upon activation of neuronal pools in both zones of CBM. A good number of CBM foci (39% in the rostral division and 33% in the caudal one), however, was unable to induce facilitation, eliciting, upon stimulation, only massive axial movements. Distal muscles were involved by facilitatory effects in a higher number of cases following NIA stimulation (61% of all the facilitatory responses) than CBM rostral (39%) or caudal (43%) one. Furthermore, a particular characteristic of a good percentage of CBM facilitating foci (36% in rostral and 28% in caudal CBM) was the capability to elicit motor activity in the contralateral side and simultaneously facilitation in the ipsilateral one.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular diagnostics and personalized medicine in oncology: Challenges and opportunities

Increasing evidence demonstrates that target‐based agents are active only in molecularly selected populations of patients. Therefore, the identification of predictive biomarkers has become mandatory to improve the clinical development of these novel drugs. Mutations of the epidermal growth factor receptor (EGFR) or rearrangements of the ALK gene in non‐small‐cell lung cancer, and BRAF mutations in melanoma are clear examples of driver mutations and predictive biomarkers of response to treatment with specific inhibitors. Predictive biomarkers might also identify subgroups of patients that are not likely to respond to specific drugs, as shown for KRAS mutations and anti‐EGFR monoclonal antibodies in colorectal carcinoma. The discovery of novel driver molecular alterations and the availability of drugs capable to selectively block such oncogenic mechanisms are leading to a rapid increase in the number of putative biomarkers that need to be assessed in each single patient. In this respect, two different approaches are being developed to introduce a comprehensive molecular characterization in clinical practice: high throughput genotyping platforms, which allow the detection of recognized genetic aberrations in clinical samples, and next generation sequencing that can provide information on all the different types of cancer‐causing alterations. The introduction of these techniques in clinical practice will increase the possibility to identify molecular targets in each individual patient, and will also allow to follow the molecular evolution of the disease during the treatment. By using these approaches, the development of personalized medicine for patients with cancer will finally become possible. J. Cell. Biochem. 114: 514–524, 2013. © 2012 Wiley Periodicals, Inc.     

Adaptation of Enterovirus 71 to Adult Interferon Deficient Mice

Non-polio enteroviruses, including enterovirus 71 (EV71), have caused severe and fatal cases of hand, foot and mouth disease (HFMD) in the Asia-Pacific region. The development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. In this study, a mouse adapted EV71 strain was produced by conducting serial passages through A129 (α/β interferon (IFN) receptor deficient) and AG129 (α/β, γ IFN receptor deficient) mice. A B2 sub genotype of EV71 was inoculated intraperitoneally (i.p.) into neonatal AG129 mice and brain-harvested virus was subsequently passaged through 12 and 15 day-old A129 mice. When tested in 10 week-old AG129 mice, this adapted strain produced 100% lethality with clinical signs including limb paralysis, eye irritation, loss of balance, and death. This virus caused only 17% mortality in same age A129 mice, confirming that in the absence of a functional IFN response, adult AG129 mice are susceptible to infection by adapted EV71 isolates. Subsequent studies in adult AG129 and young A129 mice with the adapted EV71 virus examined the efficacy of an inactivated EV71 candidate vaccine and determined the role of humoral immunity in protection. Passive transfer of rabbit immune sera raised against the EV71 vaccine provided protection in a dose dependent manner in 15 day-old A129 mice. Intramuscular injections (i.m.) in five week-old AG129 mice with the alum adjuvanted vaccine also provided protection against the mouse adapted homologous strain. No clinical signs of disease or mortality were observed in vaccinated animals, which received a prime-and-boost, whereas 71% of control animals were euthanized after exhibiting systemic clinical signs (P<0.05). The development of this animal model will facilitate studies on EV71 pathogenesis, antiviral testing, the evaluation of immunogenicity and efficacy of vaccine candidates, and has the potential to establish correlates of protection studies.     

Thermococcus kodakarensis encodes three MCM homologs but only one is essential

The minichromosome maintenance (MCM) complex is thought to function as the replicative helicase in archaea and eukaryotes. In eukaryotes, this complex is an assembly of six different but related polypeptides (MCM2-7) but, in most archaea, one MCM protein assembles to form a homohexameric complex. Atypically, the Thermococcus kodakarensis genome encodes three archaeal MCM homologs, here designated MCM1-3, although MCM1 and MCM2 are unusual in having long and unique N-terminal extensions. The results reported establish that MCM2 and MCM3 assemble into homohexamers and exhibit DNA binding, helicase and ATPase activities in vitro typical of archaeal MCMs. In contrast, MCM1 does not form homohexamers and although MCM1 binds DNA and has ATPase activity, it has only minimal helicase activity in vitro. Removal of the N-terminal extension had no detectable effects on MCM1 but increased the helicase activity of MCM2. A T. kodakarensis strain with the genes TK0096 (MCM1) and TK1361 (MCM2) deleted has been constructed that exhibits no detectable defects in growth or viability, but all attempts to delete TK1620 (MCM3) have been unsuccessful arguing that that MCM3 is essential and is likely the replicative helicase in T. kodakarensis. The origins and possible function(s) of the three MCM proteins are discussed.     

Population genetic structure in german cockroaches (blattella germanica): differentiated islands in an agricultural landscape

Although a number of species live syanthropically with humans, few rely entirely on humans for their survival and distribution. Unlike other cosmopolitan human commensals, the German cockroach (Blattella germanica), an insect of both public and livestock health concern, is considered incapable of dispersal outside human dwellings. Patterns of genetic association are therefore constrained and may not be associated with distance. Analogies with other human-commensal species are therefore impossible to draw with any degree of accuracy. In the past 2 decades, B. germanica has become a prominent pest within the US swine production system. Swine production is mainly carried out through contracted producers, each associated with a management company. It has been hypothesized that cockroach populations will be genetically structured based on association to a specific management company. Here, we tested this hypothesis using microsatellite genotypes (8 polymorphic loci) from 626 individual cockroaches collected from 22 farms in southeastern North Carolina representing 3 management companies. Significant genetic differentiation was detected (F(ST) = 0.171), most of which was partitioned among the 22 farms rather than the 3 management groups. All pair-wise population comparisons yielded F(ST) values significantly greater than zero. Our results reveal that structure does not correspond to management company of origin, but instead it may be regional and influenced strongly by the unintentional movement of cockroaches by farm workers.     

Population dynamics and conservation biology of the over-exploited Mediterranean red coral

The main goal of ecologists is nowadays to foster habitat and species conservation. Life-history tables and Leslie-Lewis transition matrices of population growth can be powerful tools suitable for the study of age-structured over harvested and/or endangered species dynamics. Red coral (Corallium rubrum L 1758) is a modular anthozoan endemic to the Mediterranean Sea. This slow growing, long lived species has been harvested since ancient times. In the last decades harvesting pressure increased and the overall Mediterranean yield reduced by 23. Moreover, mass mortality (putatively-linked to global warming) recently affected some coastal populations of this species. Red coral populations are discrete genetic units, gonochoric, composed by several overlapping generations and provided of a discrete (annual) reproduction. A population of this precious octocoral was studied in detail and its static life table was compiled. In order to simulate the trends overtime of the population under different environmental conditions and fishing pressures, a discrete, non-linear model, based on Leslie-Lewis transition matrix, was applied to the demographic data. In this model a bell-shaped curve, based on experimental data, representing the dependence of recruitment on adult colonies density was included. On these bases the stability of the population under different density, reproduction and mortality figures was analysed and simulations of the population trends overtime were set out. Some simulations were also carried out applying to the studied population the mortality values measured during the anomalous mass mortality event which really affected some red coral populations in 1999. The population under study showed high stability and a strong resilience capability, surviving to a 61% reduction of density, to a 27.7% reduction of reproduction rate and to an unselective harvesting affecting 95% of the reproductive colonies.