Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding.

We recently reported on a linkage study within a Quarter Horse lineage segregating hyperkalaemic periodic paralysis (HYPP), an autosomal dominant condition showing potassium-induced attacks of skeletal muscle paralysis. HYPP co-segregated with the equine adult skeletal muscle sodium channel alpha subunit gene, the same gene that causes human HYPP. We now describe the Phe to Leu mutation in transmembrane domain IVS3 which courses the horse disease. This represents the first application of molecular genetics to an important horse disease, and the data will provide an opportunity for control or eradication of this condition.     

Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.     

Simulation of Weld Depth in A-TIG Welding with Unified Arc-electrode model

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The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.

We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes.     

Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.     

The failing heart.

Cardiomyopathies are disorders affecting heart muscle that usually result in inadequate pumping of the heart. They are the most common cause of heart failure and each year kill more than 10,000 people in the United States. In recent years, there have been breakthroughs in understanding the molecular mechanisms involved in this group of conditions, with knowledge of the genetic basis for cardiomyopathies perhaps seeing the largest advance, enabling clinicians to devise improved diagnostic strategies and preparing the stage for new therapies.     

Microbial degradation of bitumen

Summary A blown bitumen Mexphalte R 90/40 with a high content of saturated hydrocarbons was degraded by several microorganisms to the same extent. In batch cultures ofSaccharomycopsis lipolytica, maximal biodegradation was estimated to be about 9% w/w, 3.2·10^–3 g/cm² and 3.1·10^–3 cm of degraded bitumen. The Mexphalte R 90/40 degradation rate was closely coupled to biofilm formation. The microbial activity concerned predominantly the oxidation of saturated hydrocarbons. A direct distillation bitumen 80/100 with a low content of saturated hydrocarbons and a high content of aromatic hydrocarbons and resins was more resistant to biodegradation.     

Function of DnaJ and DnaK as chaperones in origin-specific DNA binding by RepA

Heat-shock proteins are normal constituents of cells whose synthesis is increased on exposure to various forms of stress. They are interesting because of their ubiquity and high conservation during evolution. Two families of heat-shock proteins, hsp60s and hsp70s, have been implicated in accelerating protein folding and oligomerization and also in maintaining proteins in an unfolded state, thus facilitating membrane transport. The Escherichia coli hsp70 analogue, DnaK, and two other heat-shock proteins, DnaJ and GrpE, are required for cell viability at high temperatures and are involved in DNA replication of phage lambda and plasmids P1 and F. These three proteins are involved in replication in vitro of P1 DNA along with many host replication proteins and the P1 RepA initiator protein. RepA exists in a stable protein complex with DnaJ containing a dimer each of RepA and DnaJ. We report here that DnaK and DnaJ mediate an alteration in the P1 initiator protein, rendering it much more active for oriP1 DNA binding.     

Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis.

The fragile-X syndrome is the most frequent inherited form of mental retardation, with an incidence of 1 in 1,500 males. It is characterized by the presence of a fragile site at Xq27.3 induced in vitro by folate deprivation or by inhibitors of deoxynucleotide synthesis. Its mode of inheritance is unusual for an X-linked trait, with incomplete penetrance in both males and females. Some phenotypically normal males transmit the mutation to all their daughters who rarely express any symptoms, but penetrance is high in sons and daughters of these carrier women. Genetic and physical mapping of the Xq27-q28 region has confirmed that the disease locus is located at or very near the fragile site. Hypotheses proposed to account for the abnormalities in the inheritance of the disease include sequence rearrangements by meiotic recombination or a mutation that affects reactivation of an inactive X chromosome during differentiation of female germ cells. To detect such rearrangements, or methylation changes that may reflect a locally inactive X chromosome, we used pulsed-field gel analysis of DNA from fragile-X patients with probes close to the fragile-X locus. The probe Do33 (DXS465) detected abnormal patterns in fragile-X patients, but not in normal controls or in non-expressing male transmitters.