Experimentally Constrained Molecular Relaxation: The Case of Glassy GeSe2

An ideal atomistic model of a disordered material should contradict no experiments,and should also be consistent with accurate force fields (either {\it ab initio}or empirical). We make significant progress toward jointly satisfying {\it both} of these criteria using a hybrid reverse Monte Carlo approach in conjunction with approximate first principles molecular dynamics. We illustrate the method by studying the complex binary glassy material g-GeSe$_2$. By constraining the model to agree with partial structure factors and {\it ab initio} simulation, we obtain a 647-atom model in close agreement with experiment, including the first sharp diffraction peak in the static structure factor. We compute the electronic state densities and compare to photoelectron spectroscopies. The approach is general and flexible.Comment: 6 pages, 4 figure

Scope and limitations of iodothyronine deiodinases in hypothyroidism.

The coordinated expression and activity of the iodothyronine deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition

Fitting in a complex chi^2 landscape using an optimized hypersurface sampling

Fitting a data set with a parametrized model can be seen geometrically as finding the global minimum of the chi^2 hypersurface, depending on a set of parameters {P_i}. This is usually done using the Levenberg-Marquardt algorithm. The main drawback of this algorithm is that despite of its fast convergence, it can get stuck if the parameters are not initialized close to the final solution. We propose a modification of the Metropolis algorithm introducing a parameter step tuning that optimizes the sampling of parameter space. The ability of the parameter tuning algorithm together with simulated annealing to find the global chi^2 hypersurface minimum, jumping across chi^2{P_i} barriers when necessary, is demonstrated with synthetic functions and with real data

Strategies to improve global influenza surveillance: a decision tool for policymakers.

BACKGROUND: Global pandemic influenza preparedness relies heavily on public health surveillance, but it is unclear that current surveillance fully meets pandemic preparedness needs. METHODS: We first developed a conceptual framework to help systematically identify strategies to improve the detection of an early case or cluster of novel human influenza disease during the pre-pandemic period. We then developed a process model (flow diagram) depicting nine major pathways through which a case in the community could be detected and confirmed, and mapped the improvement strategies onto this model. Finally, we developed an interactive decision tool by building quantitative measures of probability and time into each step of the process model and programming it to calculate the net probability and time required for case detection through each detection pathway. Input values for each step can be varied by users to assess the effects of different improvement strategies, alone or in combination. We illustrate application of the tool using hypothetical input data reflecting baseline and 12-month follow-up scenarios, following concurrent implementation of multiple improvement strategies. RESULTS: We compared outputs from the tool across detection pathways and across time, at baseline and 12-month follow up. The process model and outputs from the tool suggest that traditional efforts to build epidemiology and laboratory capacity are efficient strategies, as are more focused strategies within these, such as targeted laboratory testing; expedited specimen transport; use of technologies to streamline data flow; and improved reporting compliance. Other promising strategies stem from community detection - better harnessing of electronic data mining and establishment of community-based monitoring. CONCLUSION: Our practical tool allows policymakers to use their own realistic baseline values and program projections to assess the relative impact of different interventions to improve the probability and timeliness of detecting early human cases or clusters caused by a novel influenza virus, a possible harbinger of a new pandemic. Policymakers can use results to target investments to improve their surveillance infrastructure. Multi-national planners can also use the tool to help guide directions in surveillance system improvements more globally. Finally, our systematic approach can also be tailored to help improve surveillance for other diseases

Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint that Underlies Associated Clinical Syndromes

Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of nineteen postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected, i.e. the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells but were normalized after 24h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers

Inclusion of Experimental Information in First Principles Modeling of Materials

We propose a novel approach to model amorphous materials using a first principles density functional method while simultaneously enforcing agreement with selected experimental data. We illustrate our method with applications to amorphous silicon and glassy GeSe$_2$. The structural, vibrational and electronic properties of the models are found to be in agreement with experimental results. The method is general and can be extended to other complex materials.Comment: 11 pages, 8 PostScript figures, submitted to J. Phys.: Condens. Matter in honor of Mike Thorpe's 60th birthda

Reverse Monte Carlo modeling of amorphous silicon

An implementation of the Reverse Monte Carlo algorithm is presented for the study of amorphous tetrahedral semiconductors. By taking into account a number of constraints that describe the tetrahedral bonding geometry along with the radial distribution function, we construct a model of amorphous silicon using the reverse monte carlo technique. Starting from a completely random configuration, we generate a model of amorphous silicon containing 500 atoms closely reproducing the experimental static structure factor and bond angle distribution and in improved agreement with electronic properties. Comparison is made to existing Reverse Monte Carlo models, and the importance of suitable constraints beside experimental data is stressed.Comment: 6 pages, 4 PostScript figure

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics.

There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3'-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3'-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism

Neuro Imaging Researc

A Novel Pathway Regulates Thyroid Hormone Availability in Rat and Human Hypothalamic Neurosecretory Neurons

Hypothalamic neurosecretory systems are fundamental regulatory circuits influenced by thyroid hormone. Monocarboxylate-transporter-8 (MCT8)-mediated uptake of thyroid hormone followed by type 3 deiodinase (D3)-catalyzed inactivation represent limiting regulatory factors of neuronal T3 availability. In the present study we addressed the localization and subcellular distribution of D3 and MCT8 in neurosecretory neurons and addressed D3 function in their axons. Intense D3-immunoreactivity was observed in axon varicosities in the external zone of the rat median eminence and the neurohaemal zone of the human infundibulum containing axon terminals of hypophysiotropic parvocellular neurons. Immuno-electronmicroscopy localized D3 to dense-core vesicles in hypophysiotropic axon varicosities. N-STORM-superresolution-microscopy detected the active center containing C-terminus of D3 at the outer surface of these organelles. Double-labeling immunofluorescent confocal microscopy revealed that D3 is present in the majority of GnRH, CRH and GHRH axons but only in a minority of TRH axons, while absent from somatostatin-containing neurons. Bimolecular-Fluorescence-Complementation identified D3 homodimers, a prerequisite for D3 activity, in processes of GT1-7 cells. Furthermore, T3-inducible D3 catalytic activity was detected in the rat median eminence. Triple-labeling immunofluorescence and immuno-electronmicroscopy revealed the presence of MCT8 on the surface of the vast majority of all types of hypophysiotropic terminals. The presence of MCT8 was also demonstrated on the axon terminals in the neurohaemal zone of the human infundibulum. The unexpected role of hypophysiotropic axons in fine-tuned regulation of T3 availability in these cells via MCT8-mediated transport and D3-catalyzed inactivation may represent a novel regulatory core mechanism for metabolism, growth, stress and reproduction in rodents and humans