Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency.

Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with female external genitalia. Such individuals are usually raised as females, but virilize at the time of expected puberty as the result of increases in serum testosterone. Here we describe mutations in 12 additional subjects/families with this disorder. The 14 mutations characterized to date include 10 missense mutations, 3 splice junction abnormalities, and 1 small deletion that results in a frame shift. Three of these mutations have occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations have been constructed and expressed in reporter cells; 8 of the 9 missense mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function, missense mutations testosterone levels in testicular venous blood were very low. Considered together, these findings strongly suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes

Ab Initio Molecular Dynamics on the Electronic Boltzmann Equilibrium Distribution

We prove that for a combined system of classical and quantum particles, it is possible to write a dynamics for the classical particles that incorporates in a natural way the Boltzmann equilibrium population for the quantum subsystem. In addition, these molecular dynamics do not need to assume that the electrons immediately follow the nuclear motion (in contrast to any adiabatic approach), and do not present problems in the presence of crossing points between different potential energy surfaces (conical intersections or spin-crossings). A practical application of this molecular dynamics to study the effect of temperature in molecular systems presenting (nearly) degenerate states - such as the avoided crossing in the ring-closure process of ozone - is presented.Comment: published in New J. Phy

Yes, but is it Linked Open Data?

Poster presented at Digital Frontiers. This poster presents preliminary results from an analysis of 407 success proposals to the National Endowment for the Humanities' Office of Digital Humanities grant program

Ensemble density-functional theory for ab-initio molecular dynamics of metals and finite-temperature insulators

A new method is presented for performing first-principles molecular-dynamics simulations of systems with variable occupancies. We adopt a matrix representation for the one-particle statistical operator Gamma, to introduce a ``projected'' free energy functional G that depends on the Kohn-Sham orbitals only and that is invariant under their unitary transformations. The Liouville equation [ Gamma , H ] = 0 is always satisfied, guaranteeing a very efficient and stable variational minimization algorithm that can be extended to non-conventional entropic formulations or fictitious thermal distributions.Comment: 5 pages, two-column style with 2 postscript figures embedded. Uses REVTEX and epsf macros. Also available at http://www.physics.rutgers.edu/~dhv/preprints/index.html#nm_meta

Comparative analysis of long DNA sequences by per element information content using different contexts

BACKGROUND: Features of a DNA sequence can be found by compressing the sequence under a suitable model; good compression implies low information content. Good DNA compression models consider repetition, differences between repeats, and base distributions. From a linear DNA sequence, a compression model can produce a linear information sequence. Linear space complexity is important when exploring long DNA sequences of the order of millions of bases. Compressing a sequence in isolation will include information on self-repetition. Whereas compressing a sequence Y in the context of another X can find what new information X gives about Y. This paper presents a methodology for performing comparative analysis to find features exposed by such models. RESULTS: We apply such a model to find features across chromosomes of Cyanidioschyzon merolae. We present a tool that provides useful linear transformations to investigate and save new sequences. Various examples illustrate the methodology, finding features for sequences alone and in different contexts. We also show how to highlight all sets of self-repetition features, in this case within Plasmodium falciparum chromosome 2. CONCLUSION: The methodology finds features that are significant and that biologists confirm. The exploration of long information sequences in linear time and space is fast and the saved results are self documenting.

Challenges in clinical and laboratory diagnosis of androgen insensitivity syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Androgen is a generic term usually applied to describe a group of sex steroid hormones. Androgens are responsible for male sex differentiation during embryogenesis at the sixth or seventh week of gestation, triggering the development of the testes and penis in male fetuses, and are directed by the testicular determining factor: the gene <it>SRY </it>(sex determining region on Y chromosome) located on the short arm of chromosome Y. The differentiation of male external genitalia (penis, scrotum and penile urethra) occurs between the 9th and 13th weeks of pregnancy and requires adequate concentration of testosterone and the conversion of this to another more potent androgen, dihydrotestosterone, through the action of 5α-reductase in target tissues.</p> <p>Case presentation</p> <p>This report describes the case of a teenage girl presenting with a male karyotype, and aims to determine the extension of the mutation that affected the AR gene. A Caucasian girl aged 15 was referred to our laboratory for genetic testing due to primary amenorrhea. Physical examination, karyotype testing and molecular analysis of the androgen receptor were critical in making the correct diagnosis of complete androgen insensitivity syndrome.</p> <p>Conclusions</p> <p>Sex determination and differentiation depend on a cascade of events that begins with the establishment of chromosomal sex at fertilization and ends with sexual maturation at puberty, subsequently leading to fertility. Mutations affecting the <it>AR </it>gene may cause either complete or partial androgen insensitivity syndrome. The case reported here is consistent with complete androgen insensitivity syndrome, misdiagnosed at birth, and consequently our patient was raised both socially and educationally as a female. It is critical that health care providers understand the importance of properly diagnosing a newborn manifesting ambiguous genitalia. Furthermore, a child with a pseudohermaphrodite phenotype should always undergo adequate endocrine and genetic testing to reach a conclusive diagnosis before gender is assigned and surgical interventions are carried out. Our results show that extreme care must be taken in selecting the genetic tools that are utilized for the diagnosis for androgen insensitivity syndrome.</p

Genes for hereditary sensory and autonomic neuropathies: a genotype–phenotype correlation

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype–phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis

Composition Dependence of the Structure and Electronic Properties of Liquid Ga-Se Alloys Studied by Ab Initio Molecular Dynamics Simulation

Ab initio molecular dynamics simulation is used to study the structure and electronic properties of the liquid Ga-Se system at the three compositions Ga$_2$Se, GaSe and Ga$_2$Se$_3$, and of the GaSe and Ga$_2$Se$_3$ crystals. The calculated equilibrium structure of GaSe crystal agrees well with available experimental data. The neutron-weighted liquid structure factors calculated from the simulations are in reasonable agreement with recent neutron diffraction measurements. Simulation results for the partial radial distribution functions show that the liquid structure is closely related to that of the crystals. A close similarity between solid and liquid is also found for the electronic density of states and charge density. The calculated electronic conductivity decreases strongly with increasing Se content, in accord with experimental measurements.Comment: REVTeX, 8 pages and 12 uuencoded PostScript figures, submitted to Phys. Rev. B. corresponding author: [email protected]

Do Physicians with Self-Reported Non-English Fluency Practice in Linguistically Disadvantaged Communities?

BackgroundLanguage concordance between physicians and patients may reduce barriers to care faced by patients with limited English proficiency (LEP). It is unclear whether physicians with fluency in non-English languages practice in areas with high concentrations of people with LEP.ObjectiveTo investigate whether physician non-English language fluency is associated with practicing in areas with high concentrations of people with LEP.DesignCross-sectional cohort study.ParticipantsA total of 61,138 practicing physicians no longer in training who participated in the California Medical Board Physician Licensure Survey from 2001-2007.MeasuresSelf-reported language fluency in Spanish and Asian languages. Physician practice ZIP code corresponding to: (1) high concentration of people with LEP and (2) high concentration of linguistically isolated households.MethodsPractice location ZIP code was geocoded with geographic medical service study designations. We examined the unadjusted relationships between physician self-reported fluency in Spanish and selected Asian languages and practice location, stratified by race-ethnicity. We used staged logistic multiple variable regression models to isolate the effect of self-reported language fluency on practice location controlling for age, gender, race-ethnicity, medical specialty, and international medical graduate status.ResultsPhysicians with self-reported fluency in Spanish or an Asian language were more likely to practice in linguistically designated areas in these respective languages compared to those without fluency. Physician fluency in an Asian language [adjusted odds ratio (AOR) = 1.77; 95% confidence intervals (CI): 1.63-1.92] was independently associated with practicing in areas with a high number of LEP Asian speakers. A similar pattern was found for Spanish language fluency (AOR = 1.77; 95% CI: 1.43-1.82) and areas with high numbers of LEP Spanish-speakers. Latino and Asian race-ethnicity had the strongest effect on corresponding practice location, and this association was attenuated by language fluency.ConclusionsPhysicians who are fluent in Spanish or an Asian language are more likely to practice in geographic areas where their potential patients speak the corresponding language

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin (PRX) gene. Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F